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and Linscheid classified scaphoid fractures according to their displacement. Undisplaced: Stable, no displacement evident on any of the views Displaced: Unstable – More than 1 mm displacement on AP and oblique views, or – More than 15◦ lunocapitate angulation on lateral view, or – More than 45◦ scapholunate angulation Diagnosis The patient usually presents with pain in the wrist. The commonest find- ing, on examination, is tenderness in the anatomical snuff box (scaphoid). Movements of the wrist and thumb are often painful, especially in the pres- ence of an associated injury to the intercarpal ligaments. ‘Watson’s Test’ is often used to detect scapholunate instability. As the wrist is moved towards the radial side from its starting position of ulnar deviation, the patient often experiences significant pain due to an abnormal dorsal displacement of the scaphoid. Capillary refilling and peripheral neurological function should also be assessed. 109 Wrist and hand 2.3 Neck fracture (Type I) Proximal fracture pole Waist fracture (Type II) (Type IV) Distal body fracture (Type III) Tuberostial fracture Distal articular osteochondral fracture Fig. 21(b). Anatomical classification of scaphoid fractures. (Reproduced with permission from Bucholz, R. W. & Heckman, J. D. Rockwood and Green’s Fractures in Adults, vol. 1. Philadelphia: Lippincott Williams and Wilkins, 1991.) Special radiographs called ‘scaphoid views’ (AP, lateral and oblique pro- jections in ulnar and radial deviation) are necessary. If the initial X-rays fail to reveal a fracture, they should be repeated within two weeks. It is also vital to assess the orientation of the carpal bones in order to detect any obvious carpal instability. The scapholunate angle (normal 30◦– 60◦) is formed by the intersection of the long axes of the lunate and scaphoid bones. Similarly, the long axes of the lunate and capitate join to form the lunocapitate angle (normal <20◦). These angles can be easily drawn on a lateral radiograph of the wrist and deviation from normal suggests a dorsal or ventral intercalated segmental instability (DISI or VISI). An increased scapholunate gap (normal <2 mm), on an AP view, indicates disruption of intercarpal ligaments. An associated fracture of the radial styloid is not uncommon, especially in severe injuries. If symptoms persist and there are no radiological findings, a bone scan may be considered. Treatment It must be remembered that failure to identify and treat scaphoid fractures early may result in permanent impairment of wrist function. Cast immo- bilization is recommended in patients with clinical suspicion of a scaphoid fracture, even if the radiological signs of a fracture are absent. Treat the 110 symptoms and signs not the X-ray! Classification and diagnosis in orthopaedic trauma Undisplaced fractures are generally treated in a ‘scaphoid cast’ (slight dorsiflexion of the wrist with immobilization of the thumb interphalangeal 2.3 joint). Displaced fractures are generally best treated by internal fixation with a single screw (Herbert’s, Acutrek, etc.). Percutaneous fixation is usually successful. However, significant fracture displacement or angulation may warrant an open reduction and internal fixation. Complications
Non-union and avascular necrosis The fracture may fail to unite even after appropriate treatment. This usually occurs due to disruption of the intraosseous blood vessels. Fractures close to the proximal pole are particularly at risk. The proximal pole may show signs of ischaemia (increased radiopacity) on X-rays. Open reduction and internal fixation should be supplemented with bone grafting (Russe, vascularized bone graft, etc.), if non-union occurs.
Recurrent carpal instability and scapholunate advanced collapse (SLAC) Disruption of the radioscapholunate and intercarpal ligaments, if left untreated, may result in chronic ‘scapholunate dissociation’. Degenerative osteoarthritis gradually develops affecting the radial styloid process ini- tially, followed by the involvement of the articulating surfaces of capitate and lunate. The wrist function is significantly impaired due to severe mechanical derangement of the carpal bones. 2.3.C Fractures of other carpal bones (lunate, capitate, etc.) In comparison with the scaphoid, fractures in the other carpal bones are much less frequent. Pain is the most common presenting complaint. The affected carpal bone is tender and signs of instability may be present although they are often subtle. There have been reports of involvement of the ulnar nerves and vessels following fractures of the hook of hamate. Therefore, a thorough assessment of the peripheral neurovascular system is necessary. Fractures involving small carpal bones are often quite difficult to diagnose. X-rays (AP, lateral and oblique) should be performed. Further imaging (e.g. CT Scan) may be necessary, if symptoms persist. Immobilization in a plaster cast is the most commonly recommended treatment. However, very occasionally, internal fixation may be necessary. Complications such as avascular necrosis (e.g. Keinbock’s disease of Lunate), post-traumatic 111 Wrist and hand 2.3 Fig. 22. A perilunate disruption. Note that the normal relationship of the lunate and capitate is lost and the lunate is ‘empty’. arthritis, recurrent instability and median or ulnar nerve palsy have been reported. 2.3.D Carpal instability Fractures involving the scaphoid and other carpal bones are often associated with significant disruption of the scapholunate, lunotriquetral, scaphotri- quetral and radiotriquetral ligaments (Fig. 22). This may result in an uncoordinated movement of the proximal row of the carpus, which causes significant functional impairment of the wrist. Mechanism of injury and classification A fall on the outstretched hand causes loading of the wrist in extension. The destabilizing force usually passes through the body of the scaphoid (Tran- 112 scaphoid) or via the scapholunate joint. The same force may progress distally Classification and diagnosis in orthopaedic trauma and ulnarwards involving other carpal bones and ligaments. This results in ‘dorsal intercalary segmental instability’ (DISI), which causes volar transla- 2.3 tion of the lunate. There is loss of the normal ‘rhythm’ between the lunate and scaphoid and therefore, the former ‘extends’ when the latter ‘flexes’. Volar intercalated segmental injury (VISI) is a much less common injury pattern. It results from the radial spread of an ulnar force that causes failure of the lunotriquetral ligament and collapse of the triquetral bone. Diagnosis The patient usually presents with a painful and swollen wrist. On examina- tion, there is tenderness over the anatomical snuff box and other carpal bones. Gross disruptions of the carpus may be associated with consid- erable wrist swelling and deformity. DISI can be assessed by ‘Watson’s test’. The wrist is moved radialwards from a position of complete ulnar deviation while pressure is applied over the scaphoid tuberosity with the examiner’s thumb on volar aspect. Pain and a sense of instability may be noticed due to the subluxation of the proximal pole of scaphoid during movement. Scaphoid views (AP, lateral and oblique views in ulnar and radial devia- tions of the wrist) are essential. A clear gap of >3 mm may be visible between the scaphoid and lunate on the AP view of the wrist. The scaphoid, which is palmar flexed, may also appear abnormal (‘double cortical ring’) due to the overlap of the cortices. These radiological signs, if present, are strongly suggestive of a scapholunate dissociation. If clinical suspicion is high and X-rays appear normal, further imaging (arthrography or bone scan) may be considered. In DISI, the angle formed by the long axes of scaphoid and lunate (scapho- lunate angle) is usually >70o (normal 30–60o). The lunocapitate angle also increases (normal <20o). Treatment Many patients with carpal instability require operative treatment. The prin- ciples of treatment are satisfactory reduction of subluxation/dislocation of carpal bones, repair of the intercarpal ligaments and stabilization of the frac- tures. Fixation is achieved by using K-wires and the wrist is immobilized in a plaster cast for 4–6 weeks. Carpal fusion may be considered in patients with chronic instability. Complications
Post-traumatic arthritis
Recurrent instability 113 Wrist and hand 2.3 Fig. 23. Fractures of the base of I first metacarpal. I, Bennett’s fracture. II, Rolando’s fracture. III A, Transverse extra-articular fracture. III B, oblique extra-articular fracture. IV, SH II epiphyseal fracture (paediatric). (Reproduced with permission from Green, D. P. & O’Brien, E. T. Fractures of the thumb metacarpal. South. Med. J., 65, 807, 1972.) 2.3.E Fractures of the first metacarpal Fractures of the thumb metacarpal (Fig. 23), in the absence of proper treatment, can significantly impair thumb function. Intra-articular involve- ment is often associated with subluxation or dislocation of the thumb car- pometacarpal joint (Bennett’s fracture). Mechanism of injury Extra-articular fractures are usually oblique or transverse in pattern. The displacement of the fragments depends upon the pull exerted by the abduc- tor policis longus (AbPL) and adductor pollicis (AP) tendons and actions 114 of the thenar muscles. Classification and diagnosis in orthopaedic trauma The pattern of intra-articular fractures depends upon the severity of the force applied and also on the position of the thumb at the time of injury. In 2.3 general, an axial force applied to a slightly flexed thumb may cause an intra- articular fracture at the base (Bennett’s type) in such a way that the whole metacarpal subluxes or dislocates dorsally leaving a small triangular frac- tured fragment behind. This occurs due to the intact volar oblique ligament, which remains attached to the small fragment while the main metacarpal fragment moves dorsally because of the pull exerted by the abductor pollicis longus tendon on the metacarpal. Comminution at the base (Rolando’s fracture) is common if forces involved are large and these fractures often show typical ‘T’ or ‘Y’ patterns. The metacarpal, in such injuries, often appears shortened and adducted due to the combined action of the adductor, flexor and extensor tendons of the thumb. Classifications Green & O’Brien have classified first metacarpal fractures into four types (Fig. 23): Type I: Bennett’s fracture. Type II: Rolando’s fracture. Type IIIA: Transverse extra-articular. Type IIIB: Oblique extra-articular. Type IV: Type II Salter Harris epiphyseal fracture (paediatric). Diagnosis Pain and swelling are common complaints. The thumb appears flexed, adducted and shortened. The base of the first metacarpal is prominent, espe- cially if subluxation or dislocation is present. Joint movements are painful. X-rays of the hand (AP and lateral in hyperpronation) confirm the diag- nosis. Involvement of the thumb carpometacarpal joint should be noted. Treatment Most extra-articular and undisplaced intra-articular fractures are success- fully treated by immobilization in a ‘thumb spica’. The length of the metacarpal and reduction of any subluxation or dislocation can often be achieved with closed manipulation and cast immobilization. However, if reduction is difficult to maintain with plaster immobilization alone, a K- wire may be introduced across the metacarpal base into the carpus. Any major surgical intervention, especially in the presence of severe com- minution, gives very poor results and hence is best avoided. Moreover, complications such as infection and superficial radial nerve injury are also not uncommon with surgical treatment. 115 Wrist and hand 2.3 Fig. 24. Spiral fractures involving the fourth and fifth metacarpals. Complications
Post-traumatic arthritis
Malunion 2.3.F Fractures of other metacarpals (second to fifth) Although fractures involving the metacarpals may occur at any level (Fig. 24), those at the neck are more common. In general, a fracture of the fifth metacarpal neck (‘Boxer’s fracture’) is the commonest metacarpal injury and fractures of other metacarpals are relatively rare. Mechanism of injury Metacarpal fractures, are usually caused by direct trauma. ‘Boxer’s fracture’ for example, occurs due to a direct impact to the fifth metacarpal head caused by punching a wall or any other hard surface. The distal fragment, in such fractures, typically angulates forwards and the knuckle loses its prominence. Diagnosis Pain and local swelling are the usual presenting complaints. This is associated 116 with local tenderness and bruising. Close examination of the finger may Classification and diagnosis in orthopaedic trauma reveal a significant deformity due to malrotation of the distal fragment. Normally, the tip of each finger should point towards the scaphoid when the 2.3 fingers are completely flexed. Any deviation from this suggests malrotation of the affected ray. Similarly, the nail of the affected finger may lie in a different plane when all the fingers are semiflexed and viewed end on; comparison should be made with the opposite side. A peripheral neurovascular examination is also necessary. AP, lateral and oblique views of the hand are taken to confirm the diag- nosis. The carpometacarpal joints should be examined carefully, especially when fractures involve the bases of the metacarpals, as subluxations or dis- locations of these joints can be easily missed. Treatment Most fractures of the metacarpals can be successfully treated conservatively. Because of relatively greater mobility at

the carpometacarpal joints of the fourth and fifth metacarpal, up to 40◦ of angulation can be easily accepted at the fracture site. However, the second and third metacarpals only tolerate about 15◦ of residual angulation as they are less mobile. ‘Neighbour strapping’ of the fingers avoids stiffness in the metacarpopha- langeal joints while the fracture is healing. The patient should be warned about the development of a cosmetic deformity, extensor lag and stiffness in finger joints. These fractures can also be immobilized in a volar hand splint with flexion at the MCP (70◦) and interphalangeal (10–15◦) joints. This allows sufficient stretching of the collateral ligaments to prevent stiffness. Fractures involving multiple metacarpals and those associated with sig- nificant angulation or rotation at the fracture site may require manipulation with or without internal fixation (K-wires, mini plates, etc.). However, the risks of infection and stiffness in the hand are exceptionally high with opera- tive treatment, and it is rare for malunion of a metacarpal fracture to impair hand function significantly. Complications
Stiffness
Malunion Note: It is essential to remember that optimum function, after any hand injury, is obtained by mobilization of the injured part as early as possi- ble. Early mobilization prevents stiffness in the metacarpophalangeal and interphalangeal joints. 117 Wrist and hand 2.3 2.3.G Ulnar collateral ligament injury of the thumb (gamekeeper’s or skier’s thumb) This injury was initially described in British gamekeepers who injured their ulnar collateral ligaments due to forceful stretching of the thumb while killing wounded rabbits. Nowadays, it is usually seen following falls during sporting activities (e.g. skiing). Mechanism of injury A sudden abduction stress at the metacarpophalangeal joint may cause a complete or partial rupture of the ulnar collateral ligament of the thumb resulting in significant instability at this joint. Healing is often significantly affected as the aponeurosis of the adductor pollicis muscle comes to lie between the torn ends of the ligament (Stener’s lesion). Diagnosis Pain and swelling are common complaints. Stress testing of the thumb should be ideally performed after local anaesthetic (1% lignocaine) infil- tration around the metacarpophalangeal joint. Stability of this joint should be assessed, both in flexion and extension, and comparison with the opposite side is essential. X-rays (AP and oblique) may demonstrate an avulsion fracture of the base of the proximal phalanx. Sometimes, stress views may be necessary, especially if the diagnosis is not certain on initial clinical examination. Treatment Partial ruptures can be treated successfully with a spica cast with the thumb immobilized in slight flexion for about 4 to 6 weeks. However, complete ruptures associated with significant instability often require direct suturing with a non-absorbable suture. If there is an avulsion fracture affecting more than 25% of the articular surface of the proximal phalanx, it may also require fixation with a K-wire. Complications
Instability and weakness of the thumb
Stiffness 118 Classification and diagnosis in orthopaedic trauma 2.3 Fig. 25. Transverse fractures involving the shafts of the proximal phalanges of the ring and middle fingers. 2.3.H Phalangeal fractures Phalangeal fractures (Fig. 25) are common injuries that can result in signif- icant limitation of hand function. Factors such as joint involvement, finger rotation and soft tissue damage can significantly influence the outcome of treatment. More than any other fracture, early mobilization of a fractured finger maximizes final function. Mechanism of injury Fractures involving the phalanges may occur both, by direct or indirect mechanisms. Indirect injuries are often seen after falls or during sporting activities. Axial compression associated with excessive flexion, extension or lateral bending, can result in different fracture patterns. Such injuries may also be 119 Wrist and hand 2.3 associated with subluxation or dislocation of the adjacent interphalangeal joint. Crush injuries occur due to a direct force applied perpendicular to the finger. A common example is a laceration sustained due to entrapment of the fingertip in a closing door or window. There is significant damage to the underlying soft tissues. Subungual haematoma and nail bed injuries are common. Often there is an open and comminuted fracture of the underlying phalanx. Classification Phalangeal fractures are usually classified as:
Intra-articular
Extra-articular Diagnosis Pain, swelling and deformity are common features. Close examination of the finger may reveal a significant deformity due to malrotation of the distal fragment. Normally, the tip of each finger should point towards the scaphoid when the fingers are completely flexed. Any deviation from this suggests malrotation of the affected ray. Similarly, the nail of the affected finger may lie in a different plane when all the fingers are semiflexed and viewed end on; comparison should be made with the opposite side. A peripheral neurovascular examination is also necessary. X-rays (AP, lateral and oblique views) of the hand should be requested. Treatment Most fractures of the proximal phalanges heal satisfactorily with conservative treatment without any significant functional impairment. Undisplaced or minimally displaced fractures can be treated satisfactorily by ‘neighbour strapping’ of the affected finger for 3–4 weeks. However, injuries involving the metacarpophalangeal and interphalangeal joints or those associated with significant rotation of the distal fragment, often require closed or open reduction and sometimes, internal fixation (K-wires). Stiffness and chronic pain are common post-operative problems associated with these fractures. Uncomplicated injuries affecting distal phalanges require only symp- tomatic treatment. Immobilization is usually not indicated unless there is involvement of the long extensor tendon (‘mallet finger’). Open fractures of the distal phalanx (e.g. crush injuries), however, 120 require debridement and proper soft tissue management. Associated nail Classification and diagnosis in orthopaedic trauma bed injuries should be sutured and the nail plate reimplanted, if possible. Occasionally, fracture stabilization with a K-wire may also be necessary. 2.3 Complications
Malunion
Stiffness
Non-union Note: ‘Mallet finger’ is a flexion deformity of the DIP joint caused by the rupture of the long finger extensor due to forced flexion. Such injuries are common during sporting activities (‘baseball finger’). Active extension at the DIP joint is impossible and significant disability may result, especially if proper treatment is not instituted early. An avulsion fracture of the articular surface may also be present. Most injuries heal with prolonged immobiliza- tion (6–8 weeks) in a mallet splint which keeps the DIP joint extended while the extensor tendon is healing. Very rarely, internal fixation (mini screws, K- wire) is indicated, especially if the avulsed fragment of bone is large. Finger stiffness is a common complication. 2.3.I Dislocations of the interphalangeal joints (PIP/DIP) The interphalangeal joint is a hinge, which is supported by collateral liga- ments on the sides and the volar plate in the front. Abnormal flexion and extension of the interphalangeal joints may cause failure of these structures resulting in ‘subluxation’ or ‘dislocation’ (Fig. 26). Associated intra-articular fractures are not uncommon. Mechanism of injury Forced hyperextension coupled with axial compression, as seen in sports injuries (football, basketball, etc.), is the commonest mechanism in a dorsal dislocation of the interphalangeal joint. A ‘volar dislocation’ is commonly seen after hyperflexion injuries to the interphalangeal joint. Diagnosis The patient presents with a painful, swollen and deformed finger. The diag- nosis is quite obvious on examination. A thorough neurological examina- tion of the fingers is essential to rule out any injury to the digital nerves. Stability of the interphalangeal joint can be assessed after instillation of local anaesthetic (ring block). AP and lateral views of the affected hand 121 Wrist and hand 2.3 Fig. 26. Subluxation of the distal interphalangeal joint of the little finger. may also demonstrate an associated fracture of the dislocated phalanx. The more quickly the dislocation is reduced, the more rapid and complete is the recovery of function. Treatment Prompt reduction is essential to minimize damage to the joint and sur- rounding soft tissues. Application of longitudinal traction with pressure on the base of the dislocated phalanx (under ring block with 1% lignocaine), is generally enough to reduce the interphalangeal joint. The affected fin- ger is ‘neighbour strapped’ for 2–3 weeks. Early joint motion should be encouraged to avoid finger stiffness. If the articular surface is fractured and the fragment is large, an extension block aluminium splint may be advised to prevent recurrent dorsal subluxation. Occasionally, open reduction and internal fixation (K-wires, mini-screws, etc.) may be required. The results of operative intervention for such injuries are not very encouraging. Persistent 122 symptoms may warrant a fusion of the joint in the long term. Classification and diagnosis in orthopaedic trauma Complications 2.3
Post-traumatic arthritis
Stiffness Points to remember in children
The principles of classification and diagnosis for metacarpal and pha- langeal fractures in children are the same as in adults.
Most fractures are epiphyseal injuries (Salter–Harris type I or II).
Closed manipulation is often necessary, especially if the epiphyseal injury is associated with displacement or rotational deformity. Internal fixation should be avoided as the risk of complications is high.
Prognosis is generally good if early mobilization is encouraged. 123 Wrist and hand PART I I I Lower limb 3.1 Pelvis 3.1.A Fractures of the pelvis Pelvic fractures are associated with high rates of mortality and morbidity. Severe ligamentous disruption may cause diastasis of the pubic symphy- sis and disruption of the sacroiliac joints. Fractures usually involve the pelvic ring, iliac wings and sacrum (Fig. 27). Low energy injuries, such as pubic rami fractures in elderly patients, are often uncomplicated and usually require only symptomatic treatment. Mechanism of injury
Road traffic accidents and high energy falls account for the vast majority of pelvic injuries. Various mechanisms that may be responsible for pelvic disruption are discussed below: – Anteroposterior compression (open book): The pelvis opens anteriorly, hinging on the intact sacroiliac ligaments (stable). – Lateral compression: A direct force to the iliac crests from the lateral side may cause disruption of the posterior pelvic arch resulting in varying degrees of instability. – Vertical shear forces are directed perpendicularly through the sacrum or ilium. Severe disruptions of the sacroiliac joint, ilium and sacrum may occur, leading to significant pelvic instability. For example, bilateral fractures of the superior and inferior pubic rami associated with a sacral fracture or sacroiliac disruption (Malgaigne fracture) are often caused due to vertical shear.
Avulsion fractures seen in young athletes occur following a sudden con- traction of a large muscle (e.g. rectus femoris).
Pubic rami fractures in osteoporotic bones of elderly patients often result from trivial domestic falls. Classification Tile (1988) classified pelvic fractures into various types based on the mech- anism of injury and fracture stability. 127 3.1 Fig. 27. Fracture of the right inferior pubic ramus associated with disruption of the left sacroiliac joint and symphysis pubis. Type A: Stable fracture
A1: Fractures of the pelvis not involving the pelvic ring
A2: minimally displaced fractures of the pelvic ring Type B: Rotationally unstable, vertically stable fractures
B1: Anteroposterior compression fractures (open book)
B2: Lateral compression injuries (ipsilateral)
B3: Lateral compression injuries (contralateral) Type C: Rotationally and vertically unstable fractures
C1: Rotationally and vertically unstable
C2: Bilateral
C3: Associated with an acetabular fracture Diagnosis Initial assessment and treatment should be performed on the basis of the Advanced Trauma Life Support (ATLS) guidelines. Haemodynamic insta- bility should be corrected and patient optimally resuscitated. The exact mechanism and severity of the injury should be ascertained. Local examination should focus on detecting any pelvic deformity or instability, leg length discrepancy, soft tissue disruption and urogenital injuries. An assessment of pelvic instability by pelvic compression and distraction may precipitate a profuse and uncontrollable haemorrhage from a pelvic haematoma. 128 Classification and diagnosis in orthopaedic trauma A discrepancy in leg-length usually results from axial displacement of the fracture. The affected limb can appear shortened and externally rotated. 3.1 Important signs of an associated urethral injury are perineal bruising, blood at the external urinary meatus, scrotal haematoma and a high riding prostate. Insertion of a urethral urinary catheter is contra-indicated if a urethral injury is present. A rectal examination should be performed to detect rectal bleeding and injury to the pelvic nerves. Associated trauma to the abdominal and pelvic viscera, chest, spine and musculoskeletal system should be excluded by systematic examination of the whole body. An AP view of the pelvis is necessary for radiographic confirmation of the diagnosis. However, special ‘Judet’ views (outlet, inlet and

oblique) may be required for complete assessment. A CT scan will help define the anatomy of fractures involving the acetabulum and posterior half of the pelvic ring. Treatment All patients presenting with a pelvic disruption after major trauma should be assessed according to the advanced trauma life support (ATLS) guide- lines. Optimal resuscitation is essential before any definitive treatment is instituted. Initial haemodynamic stabilization may be achieved with intra- venous fluid replacement (crystalloids, colloids and blood). Urgent appli- cation of an external fixator often helps to ‘close the book’ and con- tributes in controlling pelvic bleeding. This can be continued until the fracture heals, providing satisfactory reduction and stability have been achieved. It must be remembered that pelvic fractures are associated with high mortality rates (30–50% for open fractures; 10–30% for closed injuries). Stabilization of a pelvic fracture can be achieved successfully with early external or internal fixation. A pelvic suspension sling may be used for initial stabilization whilst preparations are made for operative treatment. Some examples of injuries requiring open reduction and internal fixa- tion (plates and screws) are sacroiliac disruptions, diastasis of the pubic symphysis, significantly displaced pelvic ring fractures, etc. Similarly, avul- sion fractures occurring in teenagers and young adults may require internal fixation if the fracture displacement is significant. Minor injuries, such as pubic rami fractures sustained after trivial falls, usually heal satisfactorily with conservative management. Symptomatic treatment followed by early mobilization is recommended for most undis- placed or minimally displaced fractures. 129 Pelvis 3.1 Fractures of the ilium not involving the sacroiliac or hip joint can be treated similarly. Complications
Associated injuries – Haemorrhage – Genitourinary trauma (bladder, urethra, uterus, etc.) – Rectal and anal injuries – Large lacerations (open fractures)
Infection (e.g. open injuries)
Thromboembolism
Malunion Points to remember in children
Fortunately, pelvic fractures are rare in children.
Some of these injuries are avulsion fractures that occur as a result of excessive muscle pull during sporting activities. Most avulsion fractures are treated conservatively with bed rest and early mobilization.
Pelvic fractures associated with major trauma are often associated with other serious injuries involving the head, neck, chest and abdomen. Ini- tial treatment should be aimed at optimal resuscitation of the patient. It should also be remembered that a child will maintain a normal blood pressure until about 20–30% of blood volume is lost. Hypotension is therefore, a late manifestation. Persistent tachycardia is often a reliable indicator in this situation.
Most pelvic fractures can be satisfactorily treated conservatively with bed rest and protected ambulation. Unstable fractures may require external or internal fixation. 3.1.B Fractures of the acetabulum Acetabular fractures (Fig. 28) are important injuries that can result in sig- nificant disability, especially in the absence of appropriate treatment. These fractures have variable patterns and are often complex. It is important to have a clear understanding of ‘walls’ and ‘columns’ of the acetabulum to appreci- ate the pathoanatomy of these fractures. The anterior column (iliopectineal) extends from the iliac crest to the symphysis pubis and includes the anterior wall of the acetabulum, whereas the posterior column (ilioischial) is formed 130 Classification and diagnosis in orthopaedic trauma 3.1 Fig. 28. A fracture of the acetabular floor. by the superior gluteal notch, posterior wall of the acetabulum, obturator foramen, ischial tuberosity and the inferior pubic ramus. The acetabular roof or dome is the actual weight-bearing area and is shared by the anterior and posterior columns. Mechanism of injury Most acetabular fractures occur following high velocity trauma from road traffic accidents and falls. Direct impact of the femoral head disintegrates the acetabular surface and the displacement and pattern of the fracture depends upon the position of the leg at the time of impact. Classifications Based on their patterns, acetabular fractures have been divided into ‘ele- mentary’ and ‘asssociated’ patterns (Judet & Letournel). Elementary patterns include:
Anterior wall fractures
Posterior wall fractures
Anterior column fractures
Posterior column fractures
Transverse fractures 131 Pelvis 3.1 Associated patterns include:
Both anterior and posterior column fractures
Posterior column with posterior wall fractures
Transverse with posterior wall fractures
T-shaped fractures
Anterior column with posterior hemitransverse fractures Diagnosis Because most acetabular fractures occur as a result of high energy trauma, associated injuries to the soft tissues, hip and knee are not uncommon. Movements of the hip are painful and should be avoided. A posteriorly displaced fragment may involve the sciatic nerve and therefore a thorough neurological assessment is essential. The peripheral circulation should also be assessed. Initial radiological evaluation should be performed with standard AP and oblique views taken in 45o of internal and external rotation of the pelvis. A CT scan may be required for further assessment of the fracture, especially if internal fixation is indicated. Treatment The patient should be optimally resuscitated. All serious life and limb threatening injuries should be identified and treated according to the ATLS guidelines. Acetabular fractures are important injuries that can result in considerable long term disability. The goals of treatment are to restore function, promote early mobility and prevent posttraumatic osteoarthritis. Important factors such as the age of the patient and pattern and displacement of the frac- ture should always be considered while planning treatment for acetabular fractures. In general, all undisplaced or minimally displaced fractures can be treated with skeletal traction for 4–6 weeks. This promotes adequate soft tissue and fracture healing and reduces the incidence of complications. Internal fixation using reconstruction plates and screws is reserved for fractures with incongruent joint surface or those associated with >5 mm of displacement. Surgical treatment of most acetabular fractures can be delayed for 48– 72 hours. Urgent operative treatment is indicated if an associated anterior or posterior hip dislocation fails to reduce with closed methods. 132 Classification and diagnosis in orthopaedic trauma Complications 3.1
Injury to the nerves (a) Sciatic nerve: 16–33% cases may be associated with a sciatic nerve palsy. This may be directly related to the initial injury or can occur as a result of surgery. (b) Femoral nerve (c) Superior gluteal nerve
Injury to superior gluteal artery
Heterotopic ossification
Avascular necrosis of the femoral head
Post-traumatic osteoarthritis 133 Pelvis 3.2 Hip and thigh 3.2.A Dislocations of the hip Dislocations of the hip usually occur following significant trauma and there- fore, associated injuries (e.g. acetabular fractures, ligamentous disruptions of the knee, etc.) are not uncommon. Early reduction of the dislocated hip joint is essential to reduce the risk of development of ‘avascular necrosis’ of the femoral head is high. Hip dislocations following joint replacements may result from minor trauma and are often related to malpositioning of the prosthetic components and soft tissue imbalance. Mechanism and classifications High energy trauma (e.g. road traffic accidents) accounts for the majority of hip dislocations.
Dislocations of the hip are grouped into three broad categories: 1. Anterior dislocations 2. Posterior dislocations (90%) 3. Central dislocations In an anterior dislocation, the femoral head is levered out of the joint by an axial force when the hip is in an attitude of flexion, abduction and external rotation, whereas a posterior dislocation (Fig. 29) results from an axial force exerted to a flexed, adducted and internally rotated hip. Central dislocations of the hip usually occur due to a direct impact over the lateral aspect of the greater trochanter. An axial force through the femoral neck fractures the acetabular floor and pushes the femoral head into the pelvis.
Posterior hip dislocations are classified further into five types (Thompson & Epstein, 1951): Type I: With or without a minor fracture. 134 Type II: With a large single fracture of the posterior acetabular rim. 3.2 Fig. 29. A posterior dislocation of the hip associated with a fracture of the femoral head (pipkin Type II). Type III: With comminution of the acetabular rim with or without a major fragment. Type IV: With fracture of the acetabular floor. Type V: With fracture of the femoral head. Diagnosis Because hip dislocations generally occur following a high energy impact, the possibility of other limb and life-threatening conditions should always be considered. A detailed assessment, based on the ATLS protocol, should be performed for systematic identification and treatment of associated injuries. The dislocation should be addressed once the patient has been optimally resuscitated and stabilized. The patient complains of severe hip pain and is unable to bear weight. The hip is flexed, adducted and internally rotated in a posterior dislocation; whereas in an anterior dislocation it is flexed, abducted and externally rotated. The severity of deformity in a central hip dislocation depends upon the degree of central migration of the femoral head. Assessment of the peripheral neurovascular status is of vital importance. Sciatic nerve palsy is seen in 10–14% patients with posterior dislocations. Injuries to the femoral vessels and nerve have also been reported after some anterior dislocations. A plain X-ray (AP view) of the pelvis confirms the diagnosis. If possi- ble, a lateral view of the hip should also be taken. A CT scan of the hip may be necessary for further assessment, especially if internal fixation is indicated. 135 Hip and thigh 3.2 Treatment The patient should be resuscitated immediately and all life-threatening injuries identified and treated according to the ATLS guidelines. The dis- location should be promptly reduced under anaesthetic. This is achieved by applying axial traction to the femur with the knee and hip flexed to 90o. Slight internal (in anterior dislocation) or external (in posterior dislocation) rotation with hip flexed usually relocates the head into its normal position. Reassessment of the peripheral neurovascular status is vital after reduction. Check X-rays of the hip should also be performed routinely. Skeletal traction applied through a Steinman’s pin in the proximal tibia for a few weeks promotes soft tissue healing. Occasionally, a dislocation may fail to reduce due to insufficient muscle relaxation, acetabular or femoral head fractures or soft tissue interposition. Open reduction is indicated in such a situation. Asscociated acetabular fractures, if present, can be fixed at the same time to avoid recurrent hip instability. Complications
Sciatic nerve palsy: 10–14% patients with posterior dislocations may have sciatic nerve involvement.
Myositis ossificans
Avascular neurosis of the femoral head
Post-traumatic arthritis 3.2.B Fractures of the femoral head Fractures of the femoral head are high impact injuries that usually occur in association with dislocations of the hip (Fig. 29). Mechanism of injury The location of a femoral head fracture depends upon the position of the hip at the time of impact. However, in general, posterior dislocations are associated with fractures of the inferior part of the femoral head, whereas anterior fracture–dislocations usually involve the superior aspect. For fur- ther details of the mechanism of this injury, please refer to ‘dislocations of the hip’ (page 134). Classifications
Pipkin (1957) classified femoral head fractures, mainly on the basis of 136 their level and location in the hip (Fig. 30) Classification and diagnosis in orthopaedic trauma 3.2 Fig. 30. Pipkin’s classification of femoral head fractures. (Reproduced with permission from Pynsent, P. B., Fairbank, J. C. T. & Carr, A. J. Classification of Musculoskeletal Trauma. Butterworth-Heinemann (Hodder Arnold, 1999.) Type I: Fracture inferior to fovea centralis. Type II: Fracture superior to fovea centralis. Type III: Type 1 or 2 + femoral neck fracture. Type IV: Type 1, 2 or 3 + acetabular fracture. AO classification Alphanumeric code: 31C, where Bone = femur = 3 Segment = proximal = 1 Type = head fracture = C Type C is classified into three groups: C1, C2 and C3, where C1: Head fracture, split C2: Head fracture, with depression C3: Head fracture, with neck fracture Note: Further details (e.g. subgroups A1.1, A1.2, etc.) are beyond the scope of this book. Diagnosis The patient presents with hip pain and inability to bear weight. On exam- ination, the leg is shortened and rotated (internally or externally depend- ing upon the type of dislocation). A peripheral neurovascular examination should be performed in order to rule out injury to the sciatic nerve and femoral vessels. 137 Hip and thigh 3.2 Plain X-rays (AP, lateral and oblique) of the hip are performed to confirm the diagnosis. A CT scan may also be necessary for further assessment. Treatment The patient should be resuscitated and

stabilized according to the ATLS guidelines. The treatment of femoral head fractures depends upon the pattern of the nature of injuries and expertise of the surgeon. In general, the following guidelines may be followed. Type I: Excision or fixation. Type II: Open reduction and internal fixation with screws. Type III: Same as Type II in young patients, and joint replacement, if the patient is elderly. Type IV: Same as in Type III + Acetabular fracture fixation. Complications
Avascular necrosis
Post-traumatic arthritis 3.2.C Fractures of the neck of femur: general aspects Proximal femoral fractures are the most commonly encountered orthopaedic injuries and usually occur in elderly patients. All intracapsular, intertrochanteric and subtrochanteric (within 5 cm of the lesser trochanter) fractures have traditionally been referred to as ‘fractures of the neck of femur’. The capsule of the hip joint attaches along the intertrochanteric line anteriorly but it extends for only half this distance on the posterior aspect of the femoral neck. Basicervical fractures are, therefore, always partly extra- capsular. Most femoral neck fractures require operative treatment. The treatment depends upon the age of the patient, displacement and location of the frac- ture. In general, extracapsular fractures have a rich blood supply and heal satisfactorily with internal fixation, whereas intracapsular fractures do not unite easily and often require a hemiarthroplasty. Subcapital fractures Most intracapsular injuries are commonly referred to as ‘subcapital frac- tures’. Some authors, in the past, have tried to separate subcapital fractures 138 from transcervical ones. However, this differentiation is of little practical Classification and diagnosis in orthopaedic trauma significance as there is often considerable overlap and many subcapital frac- tures frequently extend into the transcervical region. 3.2 Basicervical fractures These fractures are located close to the intertrochanteric line and are there- fore, at least partly, extracapsular. Such fractures often require internal fix- ation with a sliding screw (e.g. dynamic hip screw). Intertrochanteric fractures The ‘intertrochanteric line’ is an imaginary line joining the greater and lesser trochanters, anteriorly. Fractures occurring along this line are clas- sified as intertrochanteric fractures and are mostly extracapsular. The intertrochanteric region is richly supplied with blood vessels (extracapsular ring) and therefore, fracture healing is rapid after internal fixation with a dynamic hip screw. Pertrochanteric fractures Fractures occurring along the intertrochanteric line, but involving one or both trochanters, are referred to as ‘pertrochanteric fractures’. Often, these fractures are comminuted and unstable. They are very similar to intertrochanteric fractures. Subtrochanteric fractures The fracture line extends distal to the lesser trochanter up to a distance of about 5 cm. These fractures are often unstable and difficult to treat. They are often treated with a dynamic hip screw or an intramedullary device. Blood supply of the proximal (head and neck) femur The complex vascular arrangement of the proximal femur (Fig. 31) needs to be understood clearly in order to institute appropriate treatment for frac- tures in this region. There are three major groups of vessels that supply the femoral neck. The first is an ‘extracapsular ring’ at the base which is formed by the anastomosis of an anterior branch, from the lateral femoral cir- cumflex artery and a posterior branch, from the medial circumflex femoral artery. Intracapsular vessels arising from this ring form the ascending cervi- cal arteries, which lie in close relation to the bone and synovial reflections. They terminate by forming another ring at the base of the articular cartilage (femoral head–neck junction). ‘Epiphyseal vessels’ emerge from this intra- capsular ring. Of these, the lateral epiphyseal vessel is the most important branch as it supplies the superolateral weight bearing part of the head and 139 Hip and thigh 3.2 Capsule Subsynovial intracapsular arterial ring Obturator artery Foveal artery Retinacular arteries Ligamentum teres Ascending cervical arteries Extracapsular arterial ring Femoral artery Lateral femoral circumflex artery (a) Profunda femoris artery Retinacular arteries Ascending cervical arteries Extracapsular arterial ring Medial femoral circumflex artery (b) Fig. 31. Blood supply of the head and neck of the femur; anterior and posterior views. (Reproduced with permission from Evarts, C. M. Vascular supply of the femoral head and neck. In Surgery of the Musculoskeletal System. Churchill Livingstone, 1990.) is very likely to rupture following a femoral neck fracture. These epiphyseal vessels anastomose with the arteries of the ligamentum teres and supply the articular surface of the femoral head. 3.2.D Femoral neck fractures (subcapital) Subcapital femoral neck fractures (Fig. 32(a)) are associated with high rates of morbidity and mortality. Although these fractures are more common in elderly people with osteoporotic bones, they may also occur in young adults 140 and children. Classification and diagnosis in orthopaedic trauma 3.2 Fig. 32(a). A displaced subcapital fracture (Garden IV) of the neck of femur. Mechanism of injury Fractures of the femoral neck can occur following both direct and indirect mechanisms. Indirect: The femoral head remains fixed by the capsule and iliofemoral ligaments when the leg rotates externally during a fall. The osteoporotic femoral neck buckles and fractures due to this abnormal stress. Direct: In younger patients, these fractures occur as a result of a direct blow to the greater trochanter, which transmits an axial force to the femoral neck. Classification Most classification systems are based on the displacement of the fracture and on its location in the femoral neck. Garden’s classification Garden, in 1961, proposed a classification in which he divided subcapital fractures into four major types on the basis of the alignment of the trabeculae in the femoral neck (Fig. 32(b)). 141 Hip and thigh 3.2 Fig. 32(b). Garden’s classification of femoral neck fractures. (Reproduced with permission from Weissman, B. N. & Sledge C. B. Orthopaedic Radiology. W. B. Saunders, 1986.) Garden I This is an incomplete (unicortical) subcapital fracture in which the trabec- ulae are angulated and the femoral neck assumes a valgus position due to impaction at the fracture site. Garden II The fracture line is complete and therefore involves both cortices of the femoral neck. The trabecular pattern is interrupted but the fracture is still undisplaced. Garden III There is a complete fracture of the femoral neck with partial displacement of the fragments. The alignment of the trabeculae in the femoral head does not match with that of the acetabulum. Garden IV There is complete displacement of the fracture with no cortical contact. The femoral head assumes its normal position and therefore, trabecular pattern between the femoral head and acetabulum appears normal. This fracture 142 has a poor prognosis. Classification and diagnosis in orthopaedic trauma 3.2 Fig. 32(c). Pauwels’ classification of femoral neck fractures. (Reproduced with permission from Evarts, C. M. Surgery of the Musculoskeletal System. Churchill Livingstone, 1990.) In general, the differentiation between undisplaced (Garden I and II) and displaced (Garden III and IV) fractures is important for planning treatment and predicting prognosis. Pauwels’ classification Pauwels observed that the obliquity of the fracture line with the horizontal plane significantly affected the prognosis of the fracture. The angle formed by extending the fracture line upwards to meet an imaginary horizontal line drawn through the transtubercular (iliac crest) plane on AP film is described as ‘Pauwels’ angle’. The higher the value of this angle, the greater is the instability of the fracture (Fig. 32(c)). Type Pauwels’ angle I Less than 30 degrees II Between 30 and 70 degrees III More than 70 degrees AO classification Proximal femoral neck fractures have been classified as follows (Fig. 32(d)). Bone = femur = 3 Segment = proximal = 1 Type = A, B, C (A = trochanteric region, B = femoral neck, C = femoral head) Type B fractures are subdivided further into three groups: B1: Subcapital fractures with slight displacement B2: Transcervical fractures B3: Subcapital fractures with significant displacement Example: A Garden grade III fracture has an alphanumeric value of 31B1. 143 Hip and thigh A A1 A2 A3 B B1 B2 B3 C C1 C2 C3 Fig. 32(d). AO classification of proximal femoral fractures. (Reproduced with permission from Muller, M. E., Nazarian, S., Koch, P. & Schatzker, J. The Comprehensive Classification of Fractures of Long Bones. Heidelberg: Springer-Verlag, 1990.) Diagnosis 3.2 The diagnosis may be clear in most displaced femoral neck fractures. The leg is shortened and externally rotated and the hip is tender. However, in undisplaced impacted fractures this may not be the case. In such patients, although active elevation and weight-bearing may be possible, hip discom- fort is usual. An AP view of the pelvis, along with a lateral film of the injured hip, is usually sufficient for diagnosis. It is useful to position the affected limb in internal rotation when an AP view is taken in order to clear visualize the femoral neck. A high clinical suspicion combined with further investigations (bone scan, CT/MRI, etc.) may aid in diagnosis in doubtful cases. Treatment It is important to remember that a fracture of the femoral neck in young patients is an orthopaedic emergency. Early anatomic reduction, followed by internal fixation, is essential to prevent long-term complications. Because the treatment essentially depends on the degree of displacement of the fracture and the age of the patient, the following treatment plan is suitable for most cases. Garden I and II: Percutaneous or open multiple pins (cannulated screws) Garden III and IV: Hemiarthroplasty in the elderly. Children and young adults, closed/open reduction. A hemiarthroplasty involves excision of the femoral head followed by its replacement with a metallic prosthesis (‘Austin Moore, ‘cemented Thomp- son,’ bipolar, etc.). This procedure permits early and relatively pain-free mobilization, which significantly reduces the frequency of important com- plications such as hypostatic pneumonia, deep vein thrombosis (DVT), etc. in elderly patients. Treatment recommendations for special situations Young patients Immediate fixation is indicated for all femoral neck fractures occurring in young patients. Although sometimes open reduction may be necessary, the fracture should preferably be reduced closed and then fixed with multiple pins (cannulated screws). Patient choice in developing countries Excision of the femoral head (Girdlestone’s arthroplasty), although used infrequently in the west, remains a useful alternative to hemiarthroplasty in areas where prostheses are not available, or where social reasons such 145 Hip and thigh 3.2 as squatting for toilet purposes might make it the preferred option for treatment. Associated diseases Proper planning and appreciation of the patient’s pre-existing problems are important considerations for successful treatment of femoral neck fractures. Primary total hip replacement may be considered in patients with pre-existing hip conditions such as osteoarthritis, rheumatoid-arthritis, metabolic bone diseases, etc. Neurological impairment secondary to Parkinson’s disease, stroke, etc. may require additional soft tissue correction (e.g. tenotomy) to prevent dislocation of the hip prosthesis. Complications
Non-union The incidence of non-union following fixation of the femoral neck fractures ranges from 10–30%.
Avascular necrosis 15–33% patients may develop avascular necrosis of the femoral head.
Infection
Deep vein thrombosis and pulmonary embolism.
Up to 40% of patients may develop clots in their leg veins post-operatively. However, less than 10% of these are symptomatic. Adequate precautions such as: compression stockings, pneumatic pumps, chemical prophylaxis, etc. should be tried to prevent DVT. However, early mobilization remains the most important factor in preventing DVT.
Mortality: High (up to 30% in the first year) Points to remember in children
Most hip fractures in children occur as a result of high velocity trauma following road traffic accidents, heavy falls, etc.
Hip fractures are classified into four broad groups on the basis of the level of fracture (Delbet): Type I: Transepiphyseal with or without dislocation. 146 Type II: Transcervical. Classification and diagnosis in orthopaedic trauma Type III: Cervicotrochanteric. 3.2 Type IV: Intertrochanteric.
It should be remembered that a hip fracture in a child is a surgical emergency. Most fractures require operative treatment. The fracture is reduced (closed or open) and internally fixed with smooth pins or cannulated screws.
Important complications include avascular necrosis (40%), coxa vara, growth arrest and non-union. 3.2.E Intertrochanteric fractures Fractures occurring in the trochanteric region are extracapsular and usually heal satisfactorily as this area is richly supplied with blood vessels (extracap- sular ring). The demographic patterns of intertrochanteric and subcapital fractures are similar. Mechanism of injury Both direct and indirect mechanisms may be responsible. Intertrochanteric fractures (Fig. 33(a)) usually result from a direct impact or blow to the trochanter. Osteoporosis enhances the risk of these fractures and therefore, they are more commonly seen in elderly females. Indirect injuries

occur due to external rotation of the leg combined with the muscle action of the iliopsoas and hip abductors. Classification Evans’ classification Intertrochanteric fractures are generally described in terms of the number of fragments visualized on X-ray (two, three or four parts). However, it is useful to understand the principles of Evans’ classification (Fig. 33(b)) as it helps in assessing fracture stability. Type I: Fracture line extends upwards and outwards from the lesser trochanter (stable). Type II: Fracture line extends downwards and outwards from the lesser trochanter (reversed obliquity/unstable). These fractures are unstable and have a tendency to drift medially. Type I fractures can be further subdivided as: Ia: Undisplaced two-fragment fracture. Ib: Displaced two-fragment fracture. 147 Hip and thigh 3.2 Fig. 33(a). A displaced and comminuted Intertrochanteric fracture. Ic: Three-fragment fracture without posterolateral support, owing to dis- placement of greater trochanter fragment. Id: Three-fragment fracture without medial support, owing to displaced lesser trochanter or femoral arch fragment. Ie: Four-fragment fracture without postero-lateral and medial support (combination of Type III and Type IV). AO classification: 31A (Fig. 32(d)) Bone = femur = 3 Segment = proximal = 1 Type = A1, A2, A3 A1: Trochanteric area fracture, pertrochanteric simple A2: Trochanteric area fracture, pertrochanteric multi-fragmentary A3: Trochanteric area fracture, intertrochanteric Note: Further details (e.g. Subgroups of A1.1, A2.2, etc.) are beyond the 148 scope of this book. Classification and diagnosis in orthopaedic trauma 3.2 Fig. 33(b). Evans’ classification of intertrochanteric fractures. (Reproduced with permission from Bucholz, R. W. & Heckman, J. D. Rockwood and Green’s Fractures in Adults, vol. 2. Philadelphia: Lippincott Williams and Wilkins, 1991.) Diagnosis Pain and inability to weight-bear are common presenting features. On exam- ination, the leg appears shortened and externally rotated if the fracture is displaced. These abnormalities are, characteristically, more pronounced in 149 Hip and thigh 3.2 extracapsular fractures. Local bruising, tenderness and pain on movement are also common. X-rays (AP pelvis and lateral hip) are used for confirmation of the diag- nosis. Important factors to consider are the neck-shaft angle, fracture com- minution and osteoporosis. Treatment Unless the patient is terminally ill, the treatment of intertrochanteric frac- tures should almost always be operative. The fracture is usually closed on a fracture table and internal fixation is performed with a dynamic hip screw. This device causes a controlled collapse of the fracture leading to compres- sion and ultimately, union of the fracture. Sometimes, a cannulated screw is also used along with the dynamic hip screw in order to prevent rotation at the fracture site. Immediate weight bearing can be recommended if a satisfactory fixation has been achieved. Internal fixation is preferred to conservative treatment with traction because prolonged bed rest is associated with high morbidity and mortality rates. Complications
Varus collapse: This is directly related to the instability at the fracture site and is usually due to a failure of fixation.
Wound infection
Non-union: Rare (less than 2%)
Avascular neurosis: Rare (less than 1%)
Mortality: High (up to 30% in the first year) 3.2.F Subtrochanteric fractures Subtrochanteric fractures occur within 5 cm of the lesser trochanter (Fig. 34(a)). These fractures are often comminuted and may extend into the inter-trochanteric region. Sometimes, there is significant soft tissue inter- position, which makes closed reduction difficult. Mechanism Direct trauma resulting from falls (elderly patients) or road traffic accidents (young patients) is the commonest cause of these fractures. Pathological fractures resulting from metastatic deposits frequently occur 150 in the subtrochanteric region. Classification and diagnosis in orthopaedic trauma 3.2 Fig. 34(a). A comminuted subtrochanteric fracture. Classifications The involvement of the medial cortex is an important criterion for assessing the stability of subtrochanteric fractures. Several classifications have been proposed. Seinsheimer’s classification This classification is based on the number of fragments and location and pattern of the fracture (Fig. 34(b)). Type I Undisplaced fractures with less than 2 mm displacement of the fractured fragments. Type II Two-part fractures IIA: Two-part transverse fractures IIB: Two-part spiral fractures with lesser trochanter attached to the proxi- mal fragment IIC: Two-part spiral fractures with lesser trochanter attached to the distal fragment 151 Hip and thigh 3.2 Fig. 34(b). Seinsheimer’s classification of subtrochanteric fractures. (Reproduced with permission from Seinsheimer, F. Subtrochanteric fractures of the femur. J. Bone Joint Surg. Am., 60A, 300–306, 1978.) Type III Three-part fractures IIIA: Three-part spiral fractures in which the lesser trochanter is part of the third fragment, which has an inferior spike of varying length IIIB: Three-part spiral fractures of the proximal third of the femur, in which the third part is a butterfly fragment Type IV Comminuted fractures with four or more fragments Type V Subtrochanteric-intertrochanteric fractures; including any subtrochanteric fracture with extension through the greater trochanter. Fielding’s classification (Fig. 34(c)) Type I: Fracture at the level of the lesser trochanter Type II: Fracture within 2.5 cm of the lesser trochanter 152 Type III: Fracture between 2–2.5 cm of the lesser trochanter Classification and diagnosis in orthopaedic trauma 3.2 Fig. 34(c). Fielding’s classification of subtrochanteric fractures. (Reproduced with permission from Fielding, J. W. & Mangaliato H. J. Subtrochanteric fractures. Surg. Gynecol. Obstet. (JAMA), 122, 555–560, 1966.) In general, Type III fractures are considered more difficult to treat than the other types. AO classification According to the AO group, fractures lying below a transverse line drawn through the inferior limit of the lesser trochanter should be classified as subtrochanteric fractures. Please refer to the section on AO classification of femoral shaft fractures for further details (page 156). Diagnosis The patient presents with a painful and externally rotated lower limb. Local tenderness and pain on movement are common findings on examination. Blood loss can be severe and a thorough general examination is recom- mended to rule out any signs of shock. Associated injuries may also be present. The distal neurovascular status should also be ascertained. X-rays (AP and lateral) are used to confirm the diagnosis. Treatment Like intertrochanteric fractures, most of these fractures can be treated sat- isfactorily by closed reduction and internal fixation with a dynamic hip screw. However, unstable fracture patterns may sometimes require more 153 Hip and thigh 3.2 Fig. 35(a). A comminuted fracture of the femoral shaft immobilized in a Thomas’ splint. complex fixation with intramedullary devices such as intramedullary hip screws (IMHS), proximal femoral nail (PFN), etc. Complications
Non-union
Malunion
General complications such as shock, deep vein thrombosis (DVT), pul- monary embolism (PE), etc. 3.2.G Femoral shaft fractures It should be remembered that most femoral shaft fractures (Fig. 35(a)) will unite in time if the leg is placed in traction. Because these fractures usually occur following high velocity trauma, they are often associated with signifi- cant haemorrhage, pulmonary insufficiency, intra-abdominal, intrathoracic and other serious injuries. Optimum resuscitation is of vital importance 154 before any definitive treatment is considered. Classification and diagnosis in orthopaedic trauma 3.2 Fig. 35(b). Winquist’s classification of femoral shaft fractures. (Reproduced with permission from Poss, R. Orthopaedic Knowledge Update 3, American Academy of Orthopaedic Surgeons, 1990.) Mechanism of injury Most fractures result from major trauma, including road traffic accidents, falls from height and gunshot wounds. Underlying diseases such as osteomyelitis, osteoporosis and tumours may cause significant weakness of the bone and therefore, which may fracture easily even in the absence of any significant trauma. Such pathological frac- tures are very common in the proximal femur. Classification Femoral shaft fractures are often described in terms of the level at which they occur (proximal, middle, distal third) and configuration (spiral, transverse, oblique, segmental, comminuted). In 1980, Winquist proposed a classification based on fracture comminu- tion (Fig. 35(b)). Type I Minimal or no comminution If comminution is present, there is involvement of 25% or less of the bony circumference. 155 Hip and thigh 3.2 Type II Comminuted fragments involve up to 50% of the width of the bone. Type III Comminuted fragment involves more than 50% of the width of the bone that leaves only a small area of contact between the proximal and distal fragments. Type IV Comminution involves the entire bony circumference and there is no cortical contact. AO classification: (Fig. 35(c)) Alphanumeric code: 32A/B/C Bone = femur = 3 Segment = diaphysis = 2 Type = A, B, C 32 Femur diaphysis 32-A Femur diaphysis, simple fracture 32-B Femur diaphysis, wedge fracture 32-C Femur diaphysis, complex fracture Groups A1: Simple fracture, spiral A2: Simple fracture, oblique (≥30o) A3: Simple fracture, transverse (<30o) B1: Wedge fracture, spiral wedge B2: Wedge fracture, bending wedge B3: Wedge fracture, fragmented wedge C1: Complex fracture, spiral C2: Complex fracture, segmental C3: Complex fracture, irregular Note: Further details (e.g. subgroups A1.1, A1.2, etc.) are beyond the scope of this book. Diagnosis Airway, Breathing and Circulation should be assessed and managed accord- ing to the ATLS guidelines. A systematic ‘head to toe’ examination, should be performed in order to detect other associated injuries. The diagnosis is often 156 obvious at presentation. The thigh is painful, swollen and deformed and the Classification and diagnosis in orthopaedic trauma Fig. 35(c). AO (ASIF) classification of femoral shaft fractures. (Reproduced with permission from Muller, M. E., Nazarian, S., Koch, P. & Schatzker, J. The Comprehensive Classification of Fractures of Long Bones. Heidelberg: Springer-Verlag, 1990.) 3.2 leg appears shortened. Great emphasis should be placed on the examination of the pelvis and ipsilateral hip and knee. A thorough assessment of the peripheral neurovascular status of the limb is mandatory. Any attempt to move the affected limb may cause severe pain and additional soft tissue damage. Hence, the limb should be handled very carefully and splinted as soon as possible. AP and lateral views of the thigh are requested and ipsilateral hip and knee joints should be included in the films. If this is not possible, separate films of these joints should be obtained. X-rays of the neck, chest and pelvis (trauma series) should be performed as soon as possible in all patients attending the emergency department fol- lowing high-energy trauma. Treatment As mentioned earlier, the patient should be resuscitated optimally before any definitive management is planned. All life-threatening injuries (e.g. chest trauma) should be identified and treated according to the Advanced Trauma Life Support (ATLS) guidelines. Intravenous administration of crystalloids, colloids and blood are fre- quently required. Open wounds may be photographed, assessed and covered with a sterile dressing. Antibiotics and tetanus prophylaxis may be indicated for open wounds, especially if they are contaminated. Immobilizing the limb controls pain, bleeding and further soft tissue injuries. If possible, early intramedullary nailing is the treatment of choice for femoral shaft fractures in adults. Proximal and distal locking of the nail pro- vides axial and rotational stability to the fractured bone and union occurs in >95% cases. In general, unreamed intramedullary nails cause little disrup- tion to the endosteas blood supply, are less time consuming and have fewer pulmonary effects (e.g. ARDS) than reamed nails. Closed nailing requires image intensification. External fixation may be used in certain special situations (e.g. multiple injuries or contaminated open fracture). However, complications such as pin tract infection, knee stiffness, malunion, etc. have made it a less popular option nowadays. Complications
Infection: Incidence of infection after closed femoral nailing is about 1%.
Vascular injuries: Femoral vessels may be involved in 2% of cases.
Non-union: Usually due to a failure of fixation. 158
Malunion: May be axial or rotational Classification and diagnosis in orthopaedic trauma
Neurological involvement: Injuries to the sciatic and pudendal nerves have been reported following traction on the fracture table. 3.2
Associated injuries: Ipsilateral femoral neck fractures, ligamentous injuries of the knee, etc.
Heterotopic ossification Special situations Open fractures Surgical débridement, antibiotics and tetanus prophylaxis should be con- sidered. The choice of treatment depends upon the level of wound contam- ination, comminution and general condition of the patient. Intramedullary nailing is the most popular option, especially if the wound appears clean. Ipsilateral femoral neck and shaft fractures Early identification of this injury may reduce the risk of serious complica- tions such as osteonecrosis (4%) or non-union of the femoral neck fractures (5%). An intramedullary nail with proximal locking screws into the femoral neck (reconstruction nail) is desirable for such fractures. Although fixation of the femoral neck can be performed by placing screws anterior to the intramedullary nail, it is often, technically, quite demanding. Points to remember

for paediatric femoral shaft fractures
Although most of these fractures occur as a result of direct trauma, the possibility of pathologic fractures (e.g. cystic lesions, osteogenesis imperfecta, etc.) and non-accidental injury (NAI) should be ruled out.
Because children have a great remodelling potential, spontaneous cor- rection of minor deformities is common. The acceptable limits of anteroposterior and varus/valgus angulations are 30◦ and 10◦, respect- ively. The rotational malalignment is not well tolerated and should be less than 10◦. Up to 2 cm of shortening or lengthening can be accepted. The older the child, the lesser is the remodelling potential.
The vast majority of these fractures unite satisfactorily with non- surgical treatment, which consists of hip spica in children less than 2 years of age and simple skin traction in older children. Younger chil- dren may show a lengthening of about 2 cm up to 2 years from the injury. The leg lengths equalize as the child grows.
Operative treatment is rarely necessary. 159 Hip and thigh 3.3 Knee and leg 3.3.A Supracondylar fractures of the femur The supracondylar region is a zone in the distal femur lying approximately 9 cm proximal to the distal articular surface. Fractures involving this area (Fig. 36(a)) are difficult to treat because they are severely comminuted and the bone is often osteoporotic. There may be associated soft tissue injuries and intra-articular involvement. Mechanism of injury The vast majority of fractures occur in elderly patients with osteoporotic bones after simple falls. However, in young adults the cause of injury is usually a high velocity impact, e.g. road traffic accident. Most supracondylar fractures are caused by axial loading, combined with a varus or valgus stress. Classification AO classification (Fig. 36(b)) Alphanumeric code: 33 A/ B/ C Bone = femur = 3 Segment = distal = 3 Types = A/B/C A: Femur distal, extra-articular fracture B: Femur distal, partial articular fracture C: Femur distal, complete articular fracture Groups A1: Extra-articular fracture, simple A2: Extra-articular fracture, metaphyseal wedge A3: Extra-articular fracture, metaphyseal complex B1: Partial articular fracture, lateral condyle, sagittal B2: Partial articular fracture, medial condyle, sagittal 160 B3: Partial articular fracture, frontal 3.3 Fig. 36(a). An angulated supracondylar fracture of the femur. C1: Complete articular fracture, articular simple, metaphyseal simple C2: Complete articular fracture, articular simple, metaphyseal multifragmentary C3: Complete articular fracture, multifragmentary Note: Further details (e.g. subgroups A1.1, A1.2, etc.) are beyond the scope of this book. Diagnosis Local pain, swelling and bruising are common. Displaced fractures are often associated with significant limb shortening and deformity at the fracture site. The displacement is usually posteromedial (due to the pull of the adductors and gastrocnemius). A careful assessment of the distal neurovascular status is essential. The radiographic examination should include AP and lateral views of the knee and thigh. It is important to note the status of the proximal femur and the knee joint when planning treatment. 161 Knee and leg Fig. 36(b). AO classification of distal femoral fractures. (Reproduced with permission from Muller, M. E., Nazarian, S., Koch, P. & Schatzker, J. The Comprehensive Classification of Fractures of Long Bones. Heidelberg: Springer-Verlag, 1990.) 3.3 Fig. 37. A displaced fracture of the lateral condyle of the femur. Treatment Most fractures require operative treatment. The choice of implant depends upon the comminution of the fracture, displacement of the fragments, involvement of the joint and also on the preference of the surgeon. A ret- rograde intramedullary nail, with proximal and distal locking screws, is the preferred method of fixation. However, other implants such as a dynamic condylar screw or condylar blade plate can also be used. An external fixator may be used for temporary initial mobilization of open fractures. In certain situations, conservative treatment with cast brace or skeletal traction may be advised. This is especially considered if the fracture is undis- placed/impacted or if the patient is too unwell to withstand major surgery. Complications
Malunion
Non-union
Knee stiffness 3.3.B Condylar and intercondylar fractures of the femur Fractures involving the femoral condyles (Fig. 37) may occur in association with supracondylar fractures or as isolated injuries. The primary aim of 163 Knee and leg 3.3 Fig. 38(a). A displaced tibial plateau fracture involving the lateral condyle. treatment is to restore joint congruity. This is usually achieved by open reduction and internal fixation using transcondylar lag screws. 3.3.C Fractures of the tibial plateau Fractures of the tibial plateau (Fig. 38(a)) occur in the proximal 10 cm of the tibia. These injuries can lead to significant impairment of knee function due to damage of the articular surface and involvement of the collateral ligaments. Mechanism of injury Tibial plateau fractures usually occur following a strong varus or valgus stresses, combined with axial loading. More than half of these fractures, are seen following road traffic accidents. Falls from a height, sporting activities etc. are other common mechanisms. In elderly patients with osteoporotic 164 bones, these fractures often occur following relatively minor trauma. Classification and diagnosis in orthopaedic trauma 3.3 Type I Type II Type III Type IV Type V Type VI Fig. 38(b). Schatzker classification of tibial plateau fractures. (Reproduced with permission from Schatzker, J., McBromm, R. & Bruce, D. The tibial plateau fracture: the Toronto experience. Clin. Orthop. Relat. Res., 138, 94–104, 1979.) Classification Schatzker’s classification In 1987, Schatzker described a classification system in which he divided all tibial plateau fractures into six types (Fig. 38(b)). Type I: Pure cleavage fracture of the lateral tibial plateau. Type II: Cleavage fracture + depression of the lateral tibial plateau. Type III: Pure depression fracture of the lateral tibial plateau. Type IV: Medial tibial plateau fracture. Type V: Bicondylar fracture. Type VI: Extension of the fracture line to the diaphysis. AO classification Alphanumeric value for tibial plateau fractures: 41C In general, proximal tibial/fibular fractures are classified as follows (Fig. 38(c)):
Bone = tibia = 4
Segment = proximal = 1
Type = A/B/C A: Extra-articular B: Partially articular C: Completely articular Groups A1: Extra-articular fracture, avulsion A2: Extra-articular fracture, metaphyseal simple A3: Extra-articular fracture, metaphyseal multifragmentary B1: Partial articular fracture, pure split B2: Partial articular fracture, pure depression B3: Partial articular fracture, split-depression C1: Complete articular fracture, articular simple, metaphyseal simple 165 Knee and leg Fig. 38(c). AO classification of proximal tibial fractures. (Reproduced with permission from Muller, M. E., Nazarian, S., Koch, P. & Schatzker, J. The Comprehensive Classification of Fractures of Long Bones. Heidelberg: Springer-Verlag, 1990.) C2: Complete articular fracture, articular simple, metaphyseal multifrag- mentary 3.3 C3: Complete articular fracture, multifragmentary Note: Further details (e.g. subgroups A1.1, A1.2, etc.) are beyond the scope of this book. Diagnosis Pain and swelling around the knee are common presenting features. Oedema, contusion, fracture blisters and compartment syndrome signify a severe injury to the soft tissues. Associated injuries to the collateral liga- ments and menisci are not uncommon. A careful assessment of the periph- eral nerves and vessels is necessary. The entire limb should be thoroughly examined to rule out other injuries (e.g. distal tibial fractures, compartment syndrome, etc.). Standard radiographic views (AP and lateral) of the knee are required. Further evaluation with a CT scan is often useful in planning treatment. Treatment Non-operative treatment is advocated for most undisplaced or mini- mally displaced fractures of the tibial plateau. Simple immobilization in a plaster cast or knee brace is often sufficient. Early knee mobilization is encouraged to avoid knee stiffness. However, weight bearing should be delayed (approximately 6 weeks) until radiological signs of healing are present. Operative treatment is recommended for most fractures with significant depression of the articular surface (>3 mm). A simple split associated with a small depression in the articular surface may be fixed with percutaneous lag screws across the condyles after reduction of the fracture but a but- tress plate may also be required. If the fracture involves both condyles, fixation is achieved by using two buttress plates and cancellous screws following anatomical reduction. Sometimes, a cortical window is required to elevate the joint surface and to fill the subarticular bone defect with autogenous cancellous bone graft from the iliac crest. If the fracture is severely comminuted, it may be stabilized using a circular frame (Illizarov’s fixator). Complications
Associated soft tissue injuries – Rupture of collateral ligaments 167 Knee and leg 3.3 – Meniscal tears – Open wounds
Vascular involvment – Compartment syndrome – Popliteal artery injury
Peroneal nerve palsy
Impaired fracture healing – Malunion – Non-union
Post-traumatic arthritis
Knee stiffness 3.3.D Fractures of the tibial spine (intercondylar eminence) Tibial spine fractures frequently occur following high velocity injuries (e.g. road traffic accidents). They are often associated with significant knee insta- bility due to the involvement of the cruciate and collateral ligaments. More than 50% of these injuries occur in children and adolescents. Mechanism of injury Tibial spine fractures usually result from a twisting movement of the knee. Abnormal valgus/varus or hyperflexion/hyperextension forces can cause avulsion of the tibial eminence. Such injuries are common after road traffic accidents or sporting activities. Classification In 1959, based on the degree of displacement, Meyers and McKeever classi- fied these fractures into three broad groups (Fig. 39). Type I Undisplaced: only the anterior edge of the eminence is elevated Type II Partially displaced: anterior elevation of the eminence Type III Entire eminence is involved 168 Classification and diagnosis in orthopaedic trauma 3.3 Fig. 39. Classification of fractures of the tibial spine (intercondylar eminence). (Reproduced with permission from Meyers, M. H. & McKeever, I. M. Fracture of the intercondylar eminence of the tibia. J. Bone Joint Surg. Am., 52, 1677–1684, 1970.) IlIA: Entire eminence lies above its bed, out of contact with tibia IlIB: Eminence is rotated as well as out of contact. Diagnosis Pain and swelling of the knee are common presenting features. Often, there is a block to extension and signs of instability may be present. AP and lateral views of the knee are required for confirmation of the diagnosis. Sometimes, a CT scan is necessary for further evaluation. Treatment Most tibial spine fractures can be treated conservatively by a long leg plaster cast with the knee in full extension. Operative treatment is reserved for grossly displaced fractures (III A and III B). The fragment is reduced and fixed with a suture or lag screw. This may be performed arthroscopically. Complications
Non-union of the fragment: This may cause an extension block
Knee stiffness 169 Knee and leg 3.3 Fig. 40. A displaced transverse fracture of the patella. 3.3.E Fractures of the patella The patella is the largest sesamoid bone of the body. Avulsion fractures of the patella are common as it is a site of attachment of two strong structures, the quadriceps tendon superiorly and the patellar ligament inferiorly. Patellar fractures (Fig. 40) result in significant impairment of knee function due to disruption of the extensor mechanism. Mechanism of injury Patellar fractures can occur due to direct and indirect mechanisms. Fractures caused by direct forces are often associated with severe com- minution and intra-articular involvement. Such injuries usually occur after high-energy trauma (road traffic accidents, heavy falls, etc.). The retinacular expansions are often preserved and therefore, the patient may still demon- 170 strate active knee extension. Classification and diagnosis in orthopaedic trauma Indirect injuries, on the other hand, result from violent contraction of the quadriceps muscles during a fall leading to disruption of the retinacular 3.3 fibres and extensor mechanism. Such fractures usually show a transverse pattern. Classification Patellar fractures are mainly classified according to their pattern and displacement – Transverse, comminuted, vertical, etc. – Displaced/undisplaced Diagnosis The patient usually presents with pain and swelling around the knee. Local abrasions and contusions are also common. Occasionally, there may be an associated femoral shaft fracture or a hip dislocation. Haemarthrosis and tenderness are common findings on examination. In displaced transverse fractures, a gap is palpable over the patella. Active knee extension should be tested in every patient in order to assess the integrity of the extensor mechanism. AP and lateral radiographs are required for confirmation of the diagnosis. Treatment The treatment of patellar fractures depends mainly on the integrity of the retinacular expansion (extensor mechanism) and displacement of the fracture. Fractures with ≤3 mm displacement and an intact extensor mechanism can be satisfactory managed conservatively with a cylinder cast and

quadri- ceps strengthening exercises. Sometimes displaced fractures may be treated conservatively, if the patient is medically unfit for surgery and has low func- tional demands. The extensor mechanism should be carefully repaired when operative treatment is undertaken. Most fractures with ≥3 mm displacement require internal fixation. This is usually performed by ‘tension band wiring’. In this method, two straight K-wires are introduced across the fracture and compression is achieved by tightening a looped (‘figure-of-eight’) wire. Fol- lowing this type of fixation, when the knee extends, distraction’ forces of the quadriceps are converted into compression forces. Early knee movement and weight-bearing should be encouraged. 171 Knee and leg 3.3 Other methods of treatment are: (a) Cerclage wiring: The cerclage wire is placed anteriorly to the patella and passed through the quadriceps and patellar tendons. (b) Partial patellectomy: This method is particularly useful for comminuted lower pole fractures and involves excision of the comminuted fragments. (c) Total patellectomy: Very severely comminuted fractures may rarely require total excision of the patella. However, it causes significant impairment of knee function may occur. Complications
Post-traumatic arthritis
Extensor lag 3.3.F Fractures of the proximal fibula Fractures of the proximal fibula usually occur following knee or ankle trauma. Associated injuries to the knee ligaments (e.g. fibular collateral ligaments), biceps tendon and peroneal nerve are not uncommon. Uncom- plicated injuries do not require any specific treatment. Mechanism of injury Avulsion fractures of the fibular head usually occur following a varus stress to the knee. Some fractures may occur as a result of a supination–external rotation injury of the ankle. In such cases, abnormal external rotation of the supinated foot causes disruption of the inferior tibiofibular diastasis, interosseus mem- brane and proximal fibula (‘Maisonneuve injury’). Classification Refer to AO classification for tibial plateau fractures (page 165). Diagnosis Pain and swelling around the knee are common complaints. Local tenderness over the head of the fibula, and lateral collateral ligament laxity are not uncommon. A careful assessment of the peripheral neurovascular status of the leg is 172 mandatory. Foot drop and loss of sensation over the dorsum of the foot Classification and diagnosis in orthopaedic trauma 3.3 Fig. 41. An anteriorly dislocated knee. represent common peroneal nerve involvement. Examination of the ankle joint should also be performed in all cases. The radiological examination should include imaging (AP and lateral views) of the knee, leg and ankle. Treatment Most fibular fractures heal satisfactorily without any treatment. However, avulsion injuries of the fibular head often require open reduction and inter- nal fixation of the fracture and repair of the fibular collateral ligament. Early exploration is advised if the peroneal nerve is involved. 3.3.G Dislocations of the knee Knee dislocations (Fig. 41) are, fortunately, very rare injuries. However, the diagnosis can be difficult as they often reduce spontaneously. Associated injuries to popliteal vessels and common peroneal nerve are common. 173 Knee and leg 3.3 Mechanism of injury Knee dislocations usually occur due to road traffic accidents or sports injuries. Abnormal hyperextension, valgus or varus stresses cause failure of the major knee stabilizers, the cruciate and collateral ligaments. Classification Depending upon the displacement of the tibia in relation to the femur, five types of knee dislocations have been described:
Anterior
Posterior
Medial
Lateral
Rotatory (postero-lateral) Diagnosis A dislocated knee is swollen, painful and deformed. Palpation of the pos- terior tibial and dorsalis paedis probes are essential in order to rule out an injury to the popliteal artery. Foot drop associated with loss of sensation over the dorsum of the foot suggests common peroneal nerve involvement. The knee is clearly unstable. Plain films (AP and lateral) of the knee should be taken as soon as possible. An angiogram is helpful if injury to the popliteal artery is suspected. An MRI scan may be required for further assessment of the soft tissues. Treatment The patient should be resuscitated according to the ATLS (Airway, Breathing, Circulation) guidelines. If feasible the dislocation should be reduced before a radiological exam- ination is performed. Knee stability should be assessed after reduction. In cases associated with vascular compromise, urgent arterial repair is indi- cated. Vein graft is commonly used for this purpose. Fasciotomy of the leg may also be required. Simultaneous repair of the ligaments is advisable if there are no vascular contraindications. Complications
Popliteal artery rupture: 35–45%
Peroneal nerve injury: 25–35% 174
Knee stiffness Classification and diagnosis in orthopaedic trauma 3.3.H Anterior cruciate ligament injuries 3.3 The anterior cruciate ligament originates at the postero medial aspect of the lateral femoral condyle and attaches to the interspinous region of the tibia. It prevents the posterior displacement of the tibia on the femur and plays an important role in proprioception. Mechanism of injury ACL injuries are common following sporting activities: football, basketball, skiing, etc. Any valgus load on the knee when the tibia is in external rotation, may cause failure of the anterior cruciate ligament. Associated injuries to the medial collateral ligament and medial meniscus (O’ Donoghue’s triad) may occur. Other mechanisms that have been suggested are a varus load on a flexed knee or a direct force applied to a flexed or hyperextended knee. Classification Anterior cruciate ligament injuries may be classified as: Grade I: Stretching Grade II: Partial rupture Grade III: Complete rupture Diagnosis About 30–50% of patients describe an audible ‘pop’ when the knee twists in the typical deceleration type of injury. A large haemarthrosis is typically noted within a few hours. Instability is difficult to assess in the acute phase due to pain and swelling. Tests of stability should be preferably performed when the acute phase of the injury has settled down. Best results are achieved when the examination is performed under a general anaesthetic, which permits adequate relaxation. And any abnormal movement of the injured knee is easily detected. (a) Lachman test The knee of the supine patient is flexed to 30◦ and one hand of the examiner grasps the femur while the other holds the tibia. An anter- iorly directed force is applied with the hand grasping the proximal tibia (Fig. 42(a)). Any abnormal forward displacement of the tibia suggests an anterior cruciate ligament injury. Comparison with the normal side is essential and abnormal forward movement is recorded as +1 (0–5 mm), +2 (5–10 mm), +3 (10–15 mm). 175 Knee and leg 3.3 Fig. 42(a). Lachman’s test detects abnormal anterior translation of proximal tibia in 30 degrees of knee flexion. Fig. 42(b). Anterior drawer test detects abnormal anterior translation of proximal tibia in 90 degrees of knee flexion. (b) Anterior drawer test The knee of the supine patient is flexed to 90◦ and the examiner stabi- lizes the leg by sitting on the forward pointing foot. The proximal tibia is grasped with both hands such that the thumbs are on the anterior aspect and the fingers are curled backwards to feel the relaxed ham- string tendons (Fig. 42(b)). An anteriorly directed force from the hands pushes the tibia forwards if anterior instability is present. Comparison with the opposite side is essential. It must also be remembered that a ruptured posterior cruciate ligament may erroneously give rise to a positive anterior drawer test if ‘posterior sag’ is not detected initially. Hence, it is important to assess the position of both tibial tuberosities 176 with the knees flexed before the anterior drawer test is performed. Classification and diagnosis in orthopaedic trauma 3.3 Fig. 42(c). Pivot shift test detects abnormal anterolateral laxity of the knee joint due to a deficient anterior cruciate ligament. (Reproduced with permission from Scott, N. W. Ligament and Extensor Mechanism Injuries of the Knee: Diagnosis and Treatment. Mosby-Yearbook, 1991.). (c) Pivot shift test The leg is rotated internally with the knee in full extension. The thumb of one hand of the examiner applies pressure over the fibular head while the other hand holding the foot exerts a valgus stress to the internally rotated leg (Fig. 42(c)). The knee is slowly flexed from its initial position of full extension. Reduction of the lateral tibial plateau on the lateral femoral condyle is felt as a ‘clunk’ in 20–30o of flexion. This occurs due to the pull of the iliotibial band on the subluxing lateral tibial plateau. The examination of an ACL deficient knee is not complete without a thorough assessment of the collateral and posterior cruciate ligaments. Plain radiographs (AP and lateral views) should be taken to rule out a fracture. Avulsion fracture (‘Segond fracture’) of the rim of the lateral tibial plateau is pathognomic of an ACL rupture. An MRI scan is useful in confirming the clinical diagnosis and in identifying associated injuries to the ligaments, menisci and bones. Treatment About two-thirds of patients exhibit symptomatic instability following an anterior cruciate ligament rupture. Subsequent development of osteoarthri- tis is not uncommon. Treatment depends upon the age, functional demands and the presence of other injuries. 177 Knee and leg 3.3 Most surgeons recommend conservative treatment initially. This is focused, on the rehabilitation of the quadriceps and hamstrings muscles. A temporary removable brace may be used in the beginning for comfort. Direct repair of the ruptured ACL is associated with poor results. Most surgeons prefer to perform late reconstruction of the ligament using a bone patellar tendon bone or a hamstrings tendon graft (arthroscopic or open), if continuing instability is present. The tendon graft is passed through predrilled tunnels in the tibia and femur and is fixed with screws at either end. However, the majority of patients with ACL rupture can be rehabilitated and managed conservatively. Complications
Post-traumatic arthritis
Persistent instability
Knee stiffness 3.3.I Posterior cruciate ligament injuries The posterior cruciate ligament originates from the lateral aspect of the medial femoral condyle and inserts posteriorly on the posterior tibia close to the rim of the tibial plateau. It prevents the posterior displacement of the tibia on the femur. Complete ruptures of the posterior cruciate ligament are uncommon and they usually occur in association with injuries to the structures of the postero-lateral ligament complex. Mechanism of injury A blow to the anterior aspect of tibia (e.g. dashboard injury in a vehicle collision) or a hyperflexion injury to the knee usually leads to the failure of the posterior cruciate ligament. Diagnosis A complete evaluation of the knee is required. Important tests that may help in identifying injuries to the posterior cruciate ligament are mentioned below. Posterior sag sign With both knees flexed to 90o, the tibial condyles are seen to sag posteriorly on the affected side, thus indicating a rupture of the posterior cruciate 178 ligament. Classification and diagnosis in orthopaedic trauma Posterior drawer test With knee flexed to 90◦, the examiner grasps the proximal tibia and with 3.3 the knee flexed to 90o applies a posteriorly directed force with his hands. Excessive (abnormal) movement is suggestive of a PCL tear. The tests should be repeated on the normal side for comparison. The degree of posterior instability can be graded as follows: Gr I: 5 mm posterior displacement Gr II: 5–10 mm posterior displacement Gr III: >10 mm of posterior displacement X-rays of the knee should be routinely performed. MRI scan is a highly sensitive and specific investigation for diagnosis complete ruptures of the PCL. Treatment Most PCL injuries can be managed successfully non-operatively. This mainly involves quadriceps rehabilitation with closed kinetic chain extension exercises. Early hamstring rehabilitation should be avoided. Very few symptomatic PCL ruptures, for example, some Grade II injuries, require surgical stabi- lization with tendon grafts (e.g. quadriceps, hamstrings, patellar tendons, etc.). 3.3.J Medial collateral ligament injuries The medial collateral ligament (MCL) is made up of two layers: superficial and deep. The superficial medial collateral ligament (also known as tib- ial collateral ligament) originates from the medial femoral epicondyle and inserts about 5–7 cm below the medial joint line on the tibia underneath the medial hamstrings (‘pes anserinus’). The deep part of the MCL is divided into meniscofemoral and meniscotibial fibres. It is firmly attached to the edge of the medial tibial plateau and also to the meniscus. The main role of the MCL is to resist valgus and external rotation forces. Mechanism of injury Injury to the MCL is seen when the knee is subjected to a valgus stress. This can occur following a direct blow from the side (e.g. football and

rugby injuries) or by indirect mechanisms (e.g. skiing accidents). The severity of the injury depends upon the degree of trauma and also on the position of the leg at the time of injury. 179 Knee and leg 3.3 Classification Various classifications systems have been proposed. The underlying basis of most of the classification systems is the degree of laxity (medial joint opening) in response to a valgus stress. Clinically, the medial instability can be graded as follows: Injury Laxity Grade I Mild 1–5 mm Grade II Moderate 5–10 mm Grade III Severe >10 mm (Some authors prefer to include Grade O and IV as well, where Grade O is normal and Grade IV is medial laxity greater than 15 mm.) It must be remembered that the chances of damage to other ligaments (mainly, anterior cruciate and ligament) are high with severe medial liga- ment disruptions and this may have a bearing on treatment. Diagnosis Patients are usually able to clearly describe the mechanism of injury – valgus stress with or without external rotation. Ambulation may or may not be possible. Some patients may experience a ‘pop’ or a ‘snap’ and this almost always suggests a concomitant anterior cruciate ligament rupture. Tenderness is common and may be elicited along the whole course of the ligament. The site of maximum tenderness corresponds to the level of rupture. The knee is swollen, often due to the rupture of blood vessels or a synovial reaction. It is extremely important to assess medial laxity of the knee, both in full extension and 30o of flexion. The MCL is the primary medial stabilizer in 30o of knee flexion. The anterior cruciate ligament takes over this role in full knee extension and therefore, the MCL only acts as a secondary medial stabilizer in this position. The valgus stress test (Fig. 43) is a reliable method of assessing medial laxity. One hand of the examiner supports the posterior aspect of the knee which is held in 30o of flexion. A valgus stress is applied over the medial malleolus with the examiner’s other hand. Laxity and/or pain on the medial aspect of the knee indicates a sprain in the MCL. Comparison with the opposite side is necessary. As outlined earlier, the assessment of the integrity of the other ligaments (mainly, ACL) is of vital importance if there is a suspicion of an MCL sprain. Therefore, Lachmann and anterior drawer tests should be performed 180 routinely. Classification and diagnosis in orthopaedic trauma 3.3 Fig. 43. Laxity of the collateral ligaments can be assessed by applying a varus or valgus stress with knee flexed to about 30 degrees. Although plain radiographs are of little benefit in acute ruptures, they are often helpful in detecting calcification along the femoral attachment of the MCL due to a long-standing tear (Pelligrini–Steida lesion). An MRI scan is helpful in identifying the level and type of the MCL rup- ture. It also provides useful information regarding other structures (Menis- cus, ACL, etc.). Treatment Almost all isolated MCL injuries are satisfactorily treated conservatively. Application of ice packs and use of a knee brace is advised in the initial stages. A gradual quadriceps rehabilitation programme should be started. Most patients show good recovery in 3–6 weeks. Operative treatment is only indicated for Grade III tears associated with an anterior cruciate ligament injury. 3.3.K Lateral collateral ligament injuries Isolated injuries to the lateral collateral ligament (LCL) are relatively rare. Lateral laxity on varus stress to the knee may be present. The principles for diagnosis and treatment are similar to that of the MCL injuries. 3.3.L Meniscal injuries The peripheral articular surface of the tibial plateau is covered with two semilunar fibrocartilages: the medial and lateral menisci. 181 Knee and leg 3.3 Fig. 44. Classification of meniscal tears. (Reproduced with permission from Fu, F. H., Harner, C. D. & Vince, K. G. Knee Surgery, vol. 1. Baltimore: William & Wilkins, 1994.) The menisci play an important role in the normal function of the knee. They aid in load transmission and ‘shock absorption’. Besides providing stability to the knee joint, they have a role in the distribution of synovial fluid. The vascularity of a meniscus varies from the periphery to the centre and three vascular zones have been described. (a) Red on red ≥3 mm from peripheral attachment of meniscus to the bone (b) Red on white 3–5 mm from peripheral attachment of meniscus to the bone (c) White on white ≥5 mm from peripheral attachment of meniscus to the bone Both menisci are subjected to large amounts of stresses, especially during twisting movements of the knee. Due to its relatively immobile nature, the medial meniscus is more prone to develop tears after trauma. Mechanism of injury Excessive load applied to the knee, especially during a twisting injury with the knee in flexion, may cause a tear in the substance of the meniscus. Such injuries are common in footballers, rugby players, etc. Associated ligamen- tous disruptions are not uncommon. Classification Meniscal tears can be classified as (Fig. 44)
Bucket handle: a vertical longitudinal tear
Radial: a tear involving the free margin of the meniscal tissue 182
Horizontal cleavage: a horizontal tear in the meniscal tissue Classification and diagnosis in orthopaedic trauma
Flap: a tear with oblique vertical cleavage (parrot beak)
Degenerate: tears with complex patterns; that is often combination of the 3.3 other types Diagnosis Pain is the most prominent symptom. This is often associated with swelling of the knee. Some patients with a displaced bucket handle tear may present with a locked knee, in which full extension is impossible even under anaes- thetic. On examination, there is tenderness along the joint line. Synovial reaction gives rise to an effusion, which is slow to develop. Quadriceps wasting may be evident in long-standing cases. The following provocative tests are useful in the diagnosis of meniscal tears. McMurray’s test The leg is rotated externally while a valgus force is applied to the flexed knee with the opposite hand. The knee is extended slowly and a painful click or pop is heard or felt, if medial meniscus is torn. For lateral meniscal tears, the leg is rotated internally while the same manoeuvre is repeated. This may well be an inadvisable test in an acutely injured knee because of pain. Apley’s grinding test The patient lies prone with the knee flexed to about 90o. The examiner compresses and simultaneously rotates the joint by holding the foot. Pain is usually felt along the joint lines with this manoeuvre. This may well be an inadvisable test in an acutely injured knee. Plain films are advised to rule out any other bony injury. Most menis- cal tears (>90%) can be identified by clinical examination or MRI scans. Arthroscopic examination is both diagnostic and curative. Treatment Incomplete meniscal tears may be satisfactorily treated conservatively. Arthroscopic assessment will help with appropriate therapeutic surgery. 3.3.M Posterolateral corner injuries of the knee The main structures forming the postero-lateral corner of the knee are the popliteus and biceps tendon, iliotibial tract, popliteo-fibular and lateral collateral ligaments. 183 Knee and leg 3.3 Mechanism of injury A posterolaterally directed blow to the medial part of the tibia in an extended knee is the most common mechanism of injury to the postero-lateral cor- ner. These abnormal stresses force the knee into hyperextension, external rotation and varus. Diagnosis Pain over the posterolateral aspect of the knee is the commonest complaint. Up to 30% of patients may also have paraesthesia and motor weaknesses due to associated injury to the peroneal nerve. Instability with knee extension may produce changes in the gait pattern. The following tests are useful in the assessment of posterolateral inst- ability. External rotation recurvatum test The great toe is grasped and the foot is raised from the table. The knee tends to move into hyperextension, external rotation and varus if posterolateral instability is present. Prone external rotations test at 30o This test is performed at 30o and 90o of knee flexion with the patient lying prone on the examination table. Both feet are externally rotated simultane- ously. The test is positive if external rotation is 10o greater than the normal side. If performed properly, this test gives a fairly reliable assessment of postero-lateral instability. Associated ligament injuries (e.g. posterior cruciate, collateral ligament disruptions) should be ruled out. There is marked varus laxity, posterior translation and external rotation of the tibia if a combined posterior cruciate and postero-lateral instability is present. A careful assessment of the distal neurovascular status is also necessary. Plain radiographs are helpful in the identification of associated bony injuries, if any. An MRI scan can give useful information about the postero- lateral corner. Arthroscopic examination of the knee under general anaes- thetic may also be helpful. Treatment It must be emphasized that injuries involving the posterolateral corner are sometimes complex. Primary repair of the posterolateral structures is possible. Local augmentation is performed using soft tissues such as biceps tendon, iliotibial tract, etc. Injuries to other structures (e.g. cruciate 184 Classification and diagnosis in orthopaedic trauma ligaments), should be addressed at the same time. Bony procedures (e.g. valgus osteotomies) have also been performed for chronic injuries to the 3.3 posterolateral complex. Many of these injuries are best treated by rest and observation. 3.3.N Osteochondral fractures of the knee Osteochondral injuries are relatively rare. They usually occur in response to a shearing force or due to direct compression while the knee moves abnormally during injury. The resulting lesion may appear as a simple linear crack or it may adopt a more complex pattern. The knee is generally painful and swollen. Crepitus and episodes of locking may be present. Plain radiographs may reveal a loose fragment, especially if the subchon- dral bone is involved. Arthroscopic examination confirms an osteochondral lesion which often requires excision or fixation. If the size of the loose osteochondral fragment is less than 5 mm, conservative treatment with analgesia, restriction of weight- bearing, ice compression and range of motion exercises achieves satisfactory results. Recent techniques such as osteochondral grafting and autologus condro- cyte implantation, are still in the experimental stage. 3.3.O Extensor mechanism injuries The extensor mechanism plays a critical role in the overall function of the knee. The major constituents of the extensor apparatus are the quadriceps muscles and tendon, the lateral retinacula, the patellar tendon, tibial tuber- cle, and the patellar ligament. Ruptures of the extensor mechanism mainly involve the quadriceps or patellar tendon. Mechanism of injury Injuries to the extensor apparatus occur after excessive tension created by strong contraction of the quadriceps. However, they can also result from direct trauma to the anterior aspect of the knee. The tendons (quadri- ceps or patellar) usually rupture close to their insertion in the patella. Isolated transverse fractures of patella without any direct involvement of these tendons are also common. Irrespective of the level of injury, loss of 185 Knee and leg 3.3 Fig. 45. A high-riding patella (patella alta) following rupture of the patellar tendon. continuity of the extensor mechanism results in severe impairment of knee function. Diagnosis Severe pain over the ruptured tendon (quadriceps or patellar) is the common presenting complaint. Mobilization is difficult and the patient often requires assistance. On examination, subcutaneous bruising, a palpable defect, local tender- ness and swelling are common findings. Assessment of the patient’s ability to perform active knee extension is vital for diagnosis. It also enables the examiner to differentiate between a complete or an incomplete tear. Active knee extension (straight leg raise) is significantly impaired if the tendon rupture is complete. Plain radiographs may reveal avulsed bony fragments from the patella. The position of the patella may be altered (patella ‘baja’ or ‘alta’) (Fig. 45). Although rupture of the quadriceps or patellar tendon is primarily a clinical diagnosis, an ultrasound or MRI scan is indicated in doubtful cases. 186 Classification and diagnosis in orthopaedic trauma Treatment 3.3 Partial or incomplete tears can be satisfactorily managed conservatively with a plaster cast for 4–6 weeks. The cast is discontinued once the patient is able to perform active knee extension without any discomfort. An early end-to-end surgical repair is advisable for complete ruptures of the extensor mechanism. The repair is usually performed with a non-absorbable suture and the knee is immobilized in a plaster cast for 4–6 weeks.

Sometimes, a circular wire is also used to augment the repair. An intense rehabilitation programme is essential to regain good knee function. Complications
Knee stiffness
Extensor lag
Re-rupture 3.3.P Tibial shaft fractures Fractures of the tibial shaft (Fig. 46(a)) are often associated with significant soft tissue injuries. Such injuries require close attention and regular moni- toring. The treatment of such injuries pose a great challenge to every trauma surgeon. Mechanism of injury A direct impact on the subcutaneous surface of the tibia is the most common cause of a tibial shaft fractures. It is frequently seen after motor vehicle accidents. Indirect violence usually occurs as a result of a sports injury (e.g. football) or after a fall; the tibia is subjected to a large amount of stress caused by a twist to the leg when the foot is still anchored to the ground. A low energy twisting force causes a spiral fracture, whereas a high-energy force may lead to a comminuted fracture with varying patterns. Classification
Based on fracture configuration, most tibial fractures are commonly referred to as transverse, oblique, spiral or comminuted.
These fractures have been classified by the AO group as follows (Fig. 46(b)): Bone = tibia = 4 Segment = middle = 2 187 Knee and leg 3.3 Fig. 46(a). A displaced fracture of the shaft of the tibia. Types = A/B/C = simple/wedge/complex Groups A1: Simple fracture, spiral A2: Simple fracture, oblique ≥30o A3: Simple fracture, transverse, <30o B1: Wedge fracture, spiral wedge B2: Wedge fracture, bending wedge B3: Wedge fracture, fragmented wedge C1: Complex fracture, spiral C2: Complex fracture, segmental C3: Complex fracture, irregular Note: Further details (e.g. subgroups A1.1, A1.2, etc.) are beyond the scope 188 of this book Classification and diagnosis in orthopaedic trauma > 30° < 30° A A1 A2 A3 42- B B1 B2 B3 C 42-A 42-B 42-C C1 C2 C3 Fig. 46(b). AO classification of the mid-diaphyseal fractures of the tibia. (Reproduced with permission from Muller, M. E., Nazarian, S., Koch, P. & Schatzker, J. The Comprehensive Classification of Fractures of Long Bones. Heidelberg: Springer-Verlag, 1990.) 3.3 Gustilo classified open fractures into three broad categories, mainly depend- ing upon the degree of soft tissue damage. Type I Clean wound smaller than 1 cm in diameter, simple fracture pattern, no skin crushing. Type II A laceration larger than 1 cm but without significant soft tissue crushing, including no flaps, degloving or contusion. Fracture pattern may be more complex. Type III An open segmental fracture or a single fracture with extensive soft tissue injury. Also included are injuries older than 8 hours. Type III injuries are subdivided as: Type III A: Adequate soft tissue coverage of the fracture, despite high energy trauma or extensive laceration or skin flaps. Type III B: Inadequate soft tissue coverage with periosteal stripping. Soft tissue reconstruction is necessary. Type III C: Any open fracture that is associated with an arterial injury that requires repair. Although universally applicable to all open fractures, this classification is particularly important in relation to tibial fractures. It has gained wide acceptance throughout the orthopaedic community. Diagnosis Pain is the most prominent symptom. Soft tissue swelling and bruising are also common. On examination, there is marked tenderness at the fracture site. The leg may appear deformed, especially if the fracture is significantly displaced. The size and location of the wound should be recorded carefully. It is very important to assess and document the neurovascular status of the limb. Periodic evaluation is needed, especially in cases with considerable swelling. Features that should arouse suspicion of a compartment syndrome include excessive pain in the leg excacerbated by passive stretching of the toes, swelling, blisters, neurovascular impairment, etc. Radiographic examination of the leg should include AP and lateral views of the leg including knee and ankle joints. Intra-articular extension is not 190 uncommon, especially in the more proximal or distal fractures. Classification and diagnosis in orthopaedic trauma Although associated injuries of the fibula are usually considered to be clinically insignificant, a comminuted proximal fibular fracture may often 3.3 suggest high-energy trauma. Soft tissue damage may be massive in such cases. Fibular neck fractures may also be associated with a foot drop due to involvement of the common peroneal nerve. Treatment All tibial fractures resulting from high energy trauma (e.g. motor vehicle accidents) should be treated initially according to the Advanced Trauma Life Support (ATLS) guidelines. Airway, Breathing and Circulation should be assessed and abnormalities corrected at the same time. Adequate resusci- tation of the patient is essential before any definitive treatment of the fracture is considered. In general, most undisplaced or displaced but reducible fractures can be satisfactorily treated in a long leg cast. The progress of union should be closely monitored. If there are good signs of fracture healing, a patellar tendon- bearing cast may be considered at 6–8 weeks. This allows early mobilization of the knee and promotes healing. Fractures with significant displacement or those that have failed to unite with conservative treatment, may require operative stabilization. Although plating still has a role in certain special situations (e.g. fractures of the distal third, non-union, etc.), most unstable tibial shaft fractures are fixed with a reamed or an unreamed intramedullary nail. In general, reaming increases the diameter of the medullary canal, thereby permitting the application of a large sized (well fitting) nail. However, this occurs at the expense of disruption to the endosteal blood supply, thermal damage and other systemic complications. Unreamed nails are thinner, easier to insert and are associated with less complications. However, stability provided to the fracture may not be as much as that with a reamed nail. Ideally, if an image intensifier is available, all intramedullary nails should be locked proximally and distally. Tetanus immunization (if not already covered), antibiotic therapy, intra- venous fluids and temporary immobilization in a splint form the basic prin- ciples of the initial treatment of all open tibial fractures. Wound debridement is necessary to clear any unhealthy and contaminated tissues. If bone and soft tissue loss is extensive, an external fixator may be used to immobilize the fracture. Primary internal fixation (plating or intramedullary nailing) can be considered in Grade I and II injuries. Soft tissue injuries should be treated with respect, as their survival often determines the subsequent outcome of these complex fractures. In summary, tibial fractures can be treated conservatively if the displace- ment is minimal or if a satisfactory reduction is achieved with gentle mani- pulation. Adequate stabilization is necessary for most unstable and displaced 191 Knee and leg 3.3 fractures. Careful treatment of the soft tissues is of primary importance in open fractures. Complications
Non-union Infection, vascular insufficiency combined with soft tissue damage may cause fracture non-union. Open reduction and internal fixation (plating or nailing) with bone grafting may be considered. Sometimes, special devices such as ring fixators, combined with bone transport procedures, are neces- sary to achieve union.
Compartment syndrome The incidence of compartment syndrome ranges from 1–9%. It occurs due to a rise in the compartment pressure (>30 mm Hg) following a massive soft tissue injury or vascular insult. Excessive pain exacerbated by the passive stretching of the muscles is the most prominent feature. Close monitor- ing and repeated evaluation are essential. Fasciotomy should be performed promptly, otherwise irreversible damage to the soft tissues is inevitable.
Anterior knee pain
About 10–60% of patients complain of pain over the patellar tendon at the site of nail insertion. 3.3.Q Fractures of the fibular shaft Most fibular shaft fractures occur as a result of direct trauma. Associated tib- ial fractures and soft tissue injuries are also common. The patient presents with pain, swelling and bruising over the fracture site. Immobilization is rarely necessary for isolated fractures as the fibula participates only mini- mally in weight bearing. Symptomatic treatment is usually sufficient. Points to remember in children
Fractures of the tibia and fibula are very common in children. Almost half of these fractures involve the distal tibia.
A spiral fracture of the distal tibia in a young child (9 m–3 yrs) due to low energy trauma is known to as a toddler’s fracture. The child crawls and is reluctant to bear weight.
Road traffic accidents and falls are common causes of these fractures. 192 Classification and diagnosis in orthopaedic trauma
Most fractures can be satisfactorily treated with a long leg plaster 3.3 cast. Some displaced fractures may require manipulation before plas- ter application. However, if displacement is severe or the fracture is open, operative treatment should be considered. This consists of open reduction and internal fixation.
Compartment syndrome and malunion are important complications. 3.3.R Stress fractures of the tibia or fibula Young athletic individuals, dancers or military recruits may develop a stress fracture in the shaft of the tibia or fibula. X-rays may show a hair-line crack with periosteal reaction. The fracture is usually located in the proximal and middle third of the bone. Pain is the most common presenting feature. Treatment is mainly symptomatic. Crutches and general reduction in activity are advised. Rarely, cast immobilization may be necessary. 193 Knee and leg 3.4 Ankle and foot 3.4.A Ankle fractures The ankle joint is formed by the distal articular surfaces of the tibia, fibula and the talus with their supporting ligaments. It is estimated that 1mm of talar shift reduces the joint contact area by more than 40%. This causes a concentration of forces over a small area of the articular surface, which may lead to the development of early arthritis. Hence, it is essential that all ankle fractures (Fig. 47(a)) should be reduced anatomically so that the congruity of the ankle mortise is restored. Any talar shift greater than 3 mm should not be accepted. Mechanism of injury and classification Most ankle injuries result from a twist to the ankle during weight-bearing. In some cases, heavy falls may cause axial loading in dorsiflexion leading to severe ankle disruptions. Lauge–Hansen first described the pattern of ankle fractures. This description was essentially based on the position of the foot at the time of injury and the direction of the deforming force influencing the eventual pattern of the ankle fractures. Type ↓ ↓ ↓ Position of foot Deforming force All ankle injuries, were therefore classified originally into four major types and a fifth group was added later on. Under this classification scheme, the first factor is the position of the foot and the second, the deforming force. Accordingly, the various subgroups are: 1. Supination adduction 2. Supination external rotation 3. Pronation abduction 4. Pronation external rotation 194 5. Pronation dorsiflexion. 3.4 Fig. 47(a). A displaced trimalleolar fracture of the ankle. Various injury patterns may result due to these deforming forces. Frequently, there is a combined injury to the malleoli (medial, lateral and posterior) and surrounding ligaments (mainly deltoid and lateral). These injuries are discussed in the next section. Lauge–Hansen classification Type Position of foot Deforming force 1. Supination–adduction Supination Adduction 2. Supination–external rotation Supination External rotation 3. Pronation–abduction Pronation Abduction 4. Pronation–external rotation Pronation External rotation 5. Pronation–dorsiflexion Pronation Dorsiflexion Danis–Weber classification Danis–Weber classified ankle fractures according to the level of the fibular fracture (Fig. 47(b)). In general, the higher the fracture of the fibula, the greater the likelihood of ankle instability. This is particularly due to disrup- tion of the inferior tibifibular syndesmosis and interosseus membrane in these injuries. 195 Ankle and foot 3.4 A B C1 C2 Fig. 47(b). Danis–Weber classification of ankle fractures. (Reproduced with permission from Weber, B. G. Die verletzungen des oberen sprunggelenkes. In Aktuelle Problème in der Chirurgie: Bern, Verlag Hans Huber, 1966 & Campbell’s Operative Orthopaedics, vol. III, Mosby, 2003.) Injury to Equivalent Lauge–hansen Type Level of fibular # syndesmosis type A Below the syndesmosis Absent Supination adduction B At the level of Present Supination external syndesmosis rotation C Above syndesmosis Present Pronation external rotation or Pronation abduction AO classification Danis–Weber’s types have been subclassified by the AO group as follows (Fig. 47(c)): Bone = tibia/fibula = 4 Segment = malleolar = 4 Types A = infradesmotic B = transsyndesmotic 196 C = supradesmotic Classification and diagnosis in orthopaedic trauma A A1 A2 A3 4 44- B B1 B2 B3 C 44-A 44-B 44-C C1 C2 C3 Fig. 47(c). AO classification of

ankle fractures. (Reproduced with permission from Muller, M. E., Nazarian, S., Koch, P. & Schatzker, J. The Comprehensive Classification of Fractures of Long Bones. Heidelberg: Springer-Verlag, 1990.) 3.4 Groups A1: Infrasyndesmotic lesion, isolated A2: Infrasyndesmotic lesion, with a fracture of the medial malleolus A3: Infrasyndesmotic lesion, with a posteromedial fracture B1: Transsyndesmotic fibula fracture, isolated B2: Transsyndesmotic fibula fracture, with a medial lesion B3: Transsyndesmotic fibula fracture, with a medial lesion and Volkmann (fracture of the posterolateral rim) C1: Suprasyndesmotic lesion, diaphyseal fracture of the fibula, simple C2: Suprasyndesmotic lesion, diaphyseal fracture of the fibula, multifragmentary C3: Suprasyndesmotic lesion, proximal fibula Subgroups A1: Infrasyndesmotic lesion, isolated A2: Infrasyndesmotic lesion, with fracture of the medial malleolus A3: Infrasyndesmotic lesion, wltb posteromedial fracture B1: Transsyndesmotic fibular fracture, isolated B2: Transsyndesmotic fibular fracture, with medial lesion B3: Transsyndesmotic fibular fracture, with medial lesion and a Volkmann (fracture of the posterolateral rim) C1: Suprasyndesmotic lesion, diaphyseal fracture of the fibula, simple C2: Suprasyndesmotic lesion, diaphyseal fracture of the fibula, multlfragmentary C3: Suprasyndesmotic lesion, proximal fibular lesion Diagnosis The ankle is painful and swollen on presentation. Local bony tenderness, deformity and ecchymosis are important findings on examination. Severe swelling may cause stretching and blistering of the skin. Medial soft tissue tenderness indicates an injury to the deltoid ligament. Ankle stability should be assessed once the patient is suitably anaesthetized or sedated. The fibula should be palpated along its whole length and any discontinuity or tenderness should be noted. Assessment of the peripheral neurovascular status is also of vital importance. An associated fracture of the fibular neck (Maisonneuve injury) may cause a foot drop with altered sensation on the dorsum of the foot. Radiological evaluation is performed with AP, lateral and mortise views of the ankle. A mortise view is an anteroposterior projection with leg internally rotated to about 20o. This helps to focus the X-ray beam perpendicular to 198 the intermalleolar line so that the articular surface is clearly visualized. Classification and diagnosis in orthopaedic trauma It is important to note ‘talar shift’, ‘talar tilt’ and ‘talocrural angle’ on the mortise view. The spaces between the articular surface of the talus and 3.4 malleoli are known as clear spaces (medial and lateral). Any difference in the width of clear space between the medial and lateral side indicates talar ◦ shift, whereas talar tilt (normal 0 ± 1.5 ) indicates angular displacement of the talus in relation to tibia. Horizontal lines drawn along the apposing articular surfaces of the tibia and talus can give a fair assessment of the talar tilt. In a normal ankle, these lines are parallel. The talocrural angle (normal range is 8o–15o) is formed by the lines joining the tips of medial and lateral malleoli and articular surface of the distal tibia. Any abnormality in the position of the talus is an indication for reduction and/or internal fixation. An assessment of the fibular length, fracture comminution and status of the inferior tibio-fibular joint is necessary. Stress views, aimed at determin- ing joint instability, should be performed only under anaesthetic. Treatment Any subluxation or dislocation of the ankle joint should be reduced imme- diately, under intravenous sedation or anaesthetic, even before X-rays are performed. This reduces the risk of further soft tissue and articular surface damage. It is important to realize that the ankle mortise should be restored as closely as possible to its normal anatomic position, in order to avoid any further damage to the articular surface. Weight-bearing on an incongruous ankle joint may result in early arthritis. Most undisplaced fractures involving one or both malleoli can be treated satisfactorily in a below knee cast for about 6 weeks. However, displaced fractures often require open reduction and internal fixation. If the patient is elderly or unfit for surgery, closed reduction may be performed under intravenous sedation or anaesthetic. A below knee cast should be applied, if manipulation is successful. Check radiographs are necessary after manipu- lation and in the first few weeks. Most unstable fractures, especially those associated with gross disruption of the ankle mortise require open reduction and internal fixation. This is usually achieved by applying a lateral 1/3 tubular plate that neutralizes the deforming axial and rotational forces over the lateral malleolus. The medial malleolar fragment is reduced and often fixed with a couple of cancellous screws (4 mm). It should be remembered that these fragments can also be fixed by ‘tension-band wiring’. The fixation of the posterior malleolus is only necessary if the involvement of the articular surface is more than 25%. 199 Ankle and foot 3.4 The results of delayed surgery are inferior to those of immediate open reduction and internal fixation. Early surgery should not be delayed, hoping that swelling will reduce by rest, ice, compression and elevation. Acute ligament repair is not usually necessary, as most injuries heal after a few weeks of immobilization. Most authors recommend immobilization of the ankle for about 6 weeks, irrespective of the method of treatment of these fractures. Complications
Malunion
Post-traumatic arthritis
Non-union
Infection
Chronic regional pain syndrome (Sudek’s dystrophy)
Compartment syndrome
Osteochondral fractures of the talus Points to remember in children
Most fractures involve the epiphysis (Salter–Harris I–V; commonest is Type II). These injuries usually result from inversion or inversion combined with abnormal rotation of the leg. Some of them may be caused by axial compression.
‘Tillaux fracture’ is an epiphyseal injury (Salter–Harris Type III) of the distal tibia, following abnormal external rotation of the ankle. It involves avulsion of the unfused antero lateral tibial epiphysis due to stretching of the strong anterior tibofibular ligament. The medial two- thirds of the epiphysis is unaffected as it has already fused. Most of these injuries are satisfactorily managed conservatively with closed reduction and immobilization in a plaster cast. Open reduction and internal fixation may be indicated in special situations such as a Salter–Harris Type III injury, open fractures, etc.
Premature closure of the epiphysis may cause deformity and growth disturbance. 3.4.B Pilon (tibial plafond) fractures Distal metaphyseal fractures of the tibia involving the ankle joint (Fig. 48(a)) 200 are often associated with severe comminution and extensive soft tissue Classification and diagnosis in orthopaedic trauma 3.4 Fig. 48(a). A displaced pilon (tibial plafond) fracture. damage, which makes reconstruction very difficult. Therefore, they often have a have a poor outcome even with aggressive initial management. Mechanism of injury Tibial plafond injuries are common in elderly patients with osteoporotic bones. Axial compression, following a heavy fall or a road traffic accidents, causes a burst type fracture of the tibial plafond. Rotational injuries to the distal tibia producing spiral or oblique frac- ture configurations are much less common. They result from low energy accidents such as skiing. Classification In 1979, Ruedi and Allgower proposed the following classification on the basis of involvement of the articular surface and comminution of the fracture (Fig. 48(b)). 201 Ankle and foot 3.4 Type I Type II Type III Fig. 48(b). Ruedi & Allgower classification of pilon (tibial plafond) fractures. (Reproduced with permission from Ruedi, T. P. & Allgower, M. The operative treatment of intra-articular fractures of the lower end of the tibia. Clin. Orthop. Relat. Res., 138, 105–110, 1979.) Type I: Intra-articular fracture of the distal tibia without significant dis- placement. Type II: Intra-articular fracture of the distal tibia with significant displace- ment but minimal comminution. Type III: Fracture of distal tibia with severe comminution and significant intra-articular displacement. AO classification There is no separate AO classification for pilon fractures. These injuries may be described using the AO classification scheme of the distal tibia/fibula (Fig. 48(c)) Bone = 4 = tibia/fibula Segment = 3 = distal Type = A/B/C A: Extra-articular fracture B: Partial articular fracture C: Complete articular fracture Groups A1: Extra-articular fracture, metaphyseal simple 202 A2: Extra-articular fracture, metaphyseal wedge Classification and diagnosis in orthopaedic trauma A A1 A2 A3 4 43- B B1 B2 B3 C 43-A 43-B 43-C C1 C2 C3 Fig. 48(c). AO classification of pilon (tibial plafond) fractures. (Reproduced with permission from Muller, M. E., Nazarian, S., Koch, P. & Schatzker, J. The Comprehensive Classification of Fractures of Long Bones. Heidelberg: Springer-Verlag, 1990.) 3.4 A3: Extra-articular fracture, metaphyseal complex B1: Partial articular fracture, pure split B2: Partial articular fracture, split-depression B3: Partial articular fracture, multifragmentary depression C1: Complete articular fracture, articular simple, metaphyseal simple C2: Complete articular fracture, articular simple, metaphyseal multifragmentary C3: Complete articular fracture, multifragmentary Note: Further details (e.g. subgroups A1.1, A1.2, etc.) are beyond the scope of this book. Diagnosis Pain, bruising and swelling around the ankle are common. The deformity is obvious and local tenderness over the distal fibula may indicate an associated fibular fracture. The dorsalis pedis and posterior tibial pulses should be examined care- fully. The degree of soft tissue damage should be estimated and noted. A systematic ‘head to toe’examination of the entire body is necessary in order to rule out other major injuries. Radiographic assessment consists of AP, lateral and oblique views of the ankle and a CT scan may help further eval- uation. Treatment The treatment of Pilon fractures is a considerable challenge to the orthopaedic surgeon. In general, Type I injuries can be treated non-surgically with a long leg cast for 6–12 weeks. However, Type II and III injuries often require surgical intervention, which is dictated by the fracture pattern and experience of the surgeon. A careful monitoring of the soft tissues is essential. Open injuries require debridement and meticulous treatment due to a high risk of infection. External fixation supplemented with limited internal fixation (e.g. lag screws) often achieves a satisfactory result. Most authors recommend fixa- tion of the fibular fracture, if present, prior to reconstruction of the tibial articular surface. Remember, bad surgery may be worse than no surgery! Complications
Post-traumatic arthritis
Malunion 204
Infection Classification and diagnosis in orthopaedic trauma 3.4 Fig. 49. A displaced fracture of the neck of the talus. 3.4.C Fractures of the neck of talus Almost 60% of the surface of the talus consists of articular cartilage. As there are no muscles or tendons attached to it, the vascular supply to the talus is mainly through the synovial linings, ligamentous and capsular attach- ments. Any disruption to these structures can seriously impair the osseous circulation leading to ‘avascular necrosis’ (AVN) of the proximal half of the bone. The talus acts as the most important link between the foot and rest of the body. It supports the body weight and plays a pivotal role in walking through its complex articulations with the tibia above and the calcaneum below. Therefore, any disturbance in the normal anatomy can cause significant disruption of the foot biomechanics. Although fractures usually involve the neck (Fig. 49), other parts, the head or body of the talus, may also be affected. Mechanism of injury Anderson described this injury as ‘aviators’ astragalus as they were very com- mon in pilots during the First World War. Talar neck fractures usually occur following a sudden hyperdorsiflexion force to the talus as seen following motor vehicle accidents and falls from heights. 205 Ankle and foot 3.4 After fracturing the talus, the force if it continues to act, may also cause disruption of the medial malleolus, deltoid ligament and ankle or subtalar joints. Classification Hawkins classified talar neck fractures into three types, on the basis of the displacement of the fracture and involvement of the associated joints. Type I: Undisplaced. Risk of avascular necrosis (AVN) is <10%. Type II: Displaced fracture with subtalar subluxation or dislocation. Risk of AVN is >40%. Type III: Displaced fracture with subtalar and ankle dislocation. Risk of avascular necrosis (AVN) is >90%. Type IV: Type III + variants (e.g. dislocation of talonavicular joint). Risk of AVN is 100%. Diagnosis There is almost always a suggestion of a hyperdorsiflexion injury. The patient presents with pain and swelling in the ankle and foot. The dorsum of the foot may appear markedly deformed, especially if the fracture is significantly displaced. The skin may appear stretched and bruised. Local tenderness and a palpable deformity are frequent findings on examination. Neurovascular involvement is not uncommon. Associated fractures of the medial malleolus and tarsal bones may also be present. The status of the surrounding soft tissue envelope should be assessed carefully. The diagnosis is confirmed

with radiographs (AP, lateral and oblique) of the foot and ankle. Treatment All displaced talar neck fractures, especially those posing a threat to the skin and its blood supply, should be promptly reduced; either open or closed. Open injuries require early debridement. In general, the following scheme may be followed to treat talar neck fractures. Type I: Cast immobilization for 8–12 weeks. Type II: Prompt closed or open reductions followed by internal fixation with cancellous screws or K-wires. Type III and IV: Prompt open reduction and internal fixation with cancel- 206 lous screws or K-wires. Classification and diagnosis in orthopaedic trauma Complications 3.4
Infection: This is common after open fractures or following significant soft tissue damage leading to ischaemia of the skin.
Delayed union
Non union: Most common complication (21–58%)
Malunion: Varus deformity is common
Avascular necrosis of the body of talus
Osteoarthritis of the ankle and subtalar joints 3.4.D Fractures of the body, head and process of the talus Fractures of other parts of the talus are relatively rare compared with those of the neck. The presentation and treatment of these fractures depend upon the severity of injury, degree of displacement and clinical abnormalities. In general, treatment is similar to that of a talar neck fracture. Most frac- tures involving the lateral or posterior processes are treated conservatively unless the fragments are large or cause chronic pain. 3.4.E Dislocation of the talus The whole talus may displace as a result of severe trauma. This causes disrup- tion of the subtalar and ankle joints. The clinical picture closely resembles that of a talar fracture. Dislocation of the talus is an important cause of ‘acquired flat foot’. Neu- rovascular involvement is not uncommon in these injuries. Urgent reduc- tion, closed or open, is essential. 3.4.F Fractures of the calcaneum The calcaneum is the most commonly fractured tarsal bone. About 75% of calcaneal fractures have intra-articular involvement (Fig. 50(a)). Mechanism of injury Fractures of the calcaneum result from axial compression of the heel, usually following a fall from a height or after road traffic accidents. The lateral pro- cess of the talus acts as a splitting wedge and disrupts the articular (subtalar) surface of the calcaneum. 207 Ankle and foot 3.4 Fig. 50(a). A comminuted fracture of the calcaneum. Classification Although various classifications have been proposed, none is universally accepted due to a variability and lack of understanding of the fracture pat- tern. Essex–Lopresti classification Essex–Lopresti broadly divided calcaneal fractures into two groups: 1. Extra-articular Anterior process Tuberosity (beak or avulsion) Medial process Sustentaculum tali Body 2. Intra-articular 70–75% fractures are associated with joint involvement –Undisplaced –Joint depression type –Comminuted Based on their appearance on the coronal CT images, intra-articular fractures have been classified into four major types (Sanders). This classification (Fig. 50(b)) is particularly useful in predicting the overall 208 outcome of treatment. Classification and diagnosis in orthopaedic trauma 3.4 Sustentaculum medial central lateral A B C Type IIA Type IIB Type IIC A B A C B C III AB III AC III BC Type IV Fig. 50(b). Sanders’ classification of calcaneal fractures. (Reproduced with permission from Sanders, R., Fortin, P., DiPasquale, T. & Walling, A. Operative treatment in 120 displaced intra-articular calcaneal fractures: results using a prognostic computed tomography scan classification. Clin. Orthop. Relat. Res., 290, 87–95, 1993.) A coronal CT image showing the posterior facet in widest profile should be selected. The posterior facet is divided into three equal zones: A (lateral), B (central) and C (medial) by drawing imaginary vertical lines. In general, fractures involving the medial zone have a poor outcome. Type I: Undisplaced fractures. Type II: Two-part or split fractures. Type III: Three-part or split depression fractures. Type IV: Four-part or highly comminuted articular fractures. Diagnosis Severe pain, swelling and ecchymosis of the soft tissues, classically over the sole of the foot (Mondor sign) are important presenting features. Blisters are common, especially if soft tissue damage is severe. The shape and size of the heel may appear distorted. A careful assessment of the distal neurovascular status is mandatory. 209 Ankle and foot 3.4 Fig. 50(c). Bohler’s angle. (See text for details.) About 10% of calcaneal injuries are associated with spinal fractures and up to 70% of patients may have other limb injuries. Bilateral calcaneal involvement is not uncommon. Axial, AP and lateral radiographs should be requested in all cases with a suspected calcaneal fracture. Widening of the calcaneum and extent of intra-articular involvement should be noted carefully. The severity of the intra-articular calcaneal fractures is commonly deter- mined by drawing the Bohler’s and Gissane’s angles on a lateral radiograph. Bohler’s angle (Normal 25–40o) This is the angle formed by the intersection of a line drawn by joining the highest point of the anterior process and the highest point of the pos- terior facet with a second line drawn from the highest point on the cal- caneal tuberosity extended forwards to meet the posterior facet (Fig. 50(c)). Bohler’s angle is reduced markedly if the posterior facet is disrupted. Gissane angle (Normal 125–140o) This is an angle formed by the intersection of a line drawn along the posterior facet with a second line drawn along the middle and anterior facets 210 (Fig. 50(d)). Classification and diagnosis in orthopaedic trauma 3.4 Fig. 50(d). Gissane’s angle. (See text for details.) Further assessment with a CT scan is recommended if there is significant intra-articular involvement. Treatment Most extra-articular fractures, especially those involving the calcaneal tuberosity and the medial anterior process, respond well to conservative treatment. Non-surgical treatment consists of ice packs, elevation and subsequent early range of motion exercises. The patient should remain non-weight- bearing for 6–8 weeks. Surgery is indicated only if there is significant displacement leading to cal- caneal widening, peroneal tendon impingement and impairment of plantar flexion. Intra-articular fractures are complex injuries and often require opera- tive treatment. Restoration of the articular congruity, especially that of the posterior facet is desirable but may be difficult to achieve. Essex–Lopresti recommended closed reduction and pinning to reduce the displaced fragments. However, recent studies have shown that satisfactory 211 Ankle and foot 3.4 Fig. 51. A comminuted fracture of the navicular with disruption of the talonavicular joint. results may be achieved following fixation with reconstruction plates through a lateral approach. Complications
Malunion
Subtalar and calcaneocuboid joint arthritis
Peroneal tendonitis 3.4.G Fractures of the midtarsal bones (navicular cuboid, cuneiforms) Injuries involving the navicular (Fig. 51), cuboid and cuneiforms bones are 212 relatively rare. They usually occur in response to moderate or severe trauma Classification and diagnosis in orthopaedic trauma 3.4 Fig. 52(a). A tarso-metatarsal joint (Lisfranc’s) injury. (Reproduced with permission from Bucholz, R. W., Heckman, J. D. Rockwood and Green’s Fractures in Adults, vol. 2. Philadelphia: Lippincott, Williams and Wilkins, 1991.) to the foot and are often overlooked. The diagnosis is confirmed with AP, lateral and oblique views of the foot. Most injuries can be successfully treated conservatively by immobilization in a plaster cast for 4–6 weeks. However, displaced fractures involving adjacent joints (e.g. talonavicular or navicu- locuneiform) often require anatomical reduction and internal fixation with K-wires or screws. 3.4.H Tarsometatarsal joint injuries Injuries affecting the tarsometatarsal joints of the foot are popularly referred to as ‘Lisfranc’s injuries’ (Fig. 52(a)). It must be remembered that all tarso- metatarsal disruptions are caused by a relatively large force. A strong index of suspicion is necessary because these injuries are serious and are often easily missed. Improper treatment can result in significant disabilities. 213 Ankle and foot 3.4 Type I Type II Type III Fig. 52(b). Classification of tarso-metatarsal joint (Lisfranc’s) injuries. Mechanism of injury The tarsometatarsal joints are intrinsically rigid due to complex articulations and supporting ligaments. Axial loading appears to be the most common mechanism of injury to these joints. This usually occurs when the foot is fixed to the ground in an equinus position and a strong force is applied to the midfoot by the body weight. The tarsometatarsal ligaments, especially the second, rupture in response to abnormal loading. These injuries are often associated with fractures of the adjacent metatarsals and cuneiforms. Twisting movements cause disruption of the tarsometatarsal joints, usually due to an abduction force at these joints. Such injuries may be seen following high energy motor vehicle or indus- trial accidents. Classification In 1909, Quenn & Kuss proposed a classification system (Fig. 52(b)), based on the the extent and pattern of injuries to the tarsometatarsal joints. Type I: Homolateral: All five metatarsals are displaced in the same direc- tion. Type II: Isolated: One or two metatarsals are displaced from the others. Type III: Divergent: Displacement of the metatarsals in both sagittal and 214 coronal planes. Classification and diagnosis in orthopaedic trauma Diagnosis 3.4 The clinical picture depends upon the severity of the injury, which can range from a simple sprain of the tarsometatarsal ligament to a frank disloca- tion. There may be very few clinical findings if a dislocation or subluxation reduces spontaneously after injury. The tarsometatarsal articulations are almost always tender. Gentle passive abduction and pronation of the fore- foot produces pain. Swelling over the dorsum of the foot is common and, if severe, may mask an underlying deformity. The forefoot appears shortened and widened and the base of the first metatarsal may be seen and felt over the dorsum of the midfoot. Significant soft tissue damage and subsequent compartment syndromes of the foot have been reported in association with these injuries. The dorsalis pedis artery is especially susceptible to injury, as it dips between the first and second metatarsal just distal to their articulation at the bases. In addition, significant swelling in the foot increases the likelihood of the development of a compartment syndrome. A peripheral neurovascular examination is therefore necessary. Antero-posterior, lateral and oblique radiographs are required for con- firmation of the diagnosis. In a few cases, a CT scan may be required for further evaluation. Normally, the base of the second metatarsal and the middle cuneiform form a straight line on an AP film of the foot. Similarly, the medial surface of the cuboid forms an unbroken straight line with the medial side of the base of the fourth metatarsal. Disruption of these lines suggest a tarsometatarsal injury. Treatment In general, all injuries including minor sprains of the tarsometatarsal liga- ments, should be cautiously treated in order to avoid serious complications. In general, the following scheme may be adopted for treatment. (a) Sprain – plaster immobilization for 6 weeks. (b) Subluxation or dislocation – closed or open reduction followed by per- cutaneous K-wire fixation – If displacement is greater than Open reduction and internal with 2 mm and tarsometatarsal angle – screws or wires followed by plaster more than 15◦ immobilization for 6–8 weeks – Complications
Post-traumatic arthritis
Persistent instability 215 Ankle and foot 3.4 Fig. 53. Jones fracture of the base of the fifth metatarsal. 3.4.I Fractures of the fifth metatarsal The fifth metatarsal is the most commonly fractured metatarsal. Although fractures can occur at any level, those involving the base are more common. It must be remembered that a true ‘Jones’ fracture involves the diaphyseo- metaphysial junction and, therefore, lies approximately 2–2.5 cm distal to the proximal articular surface of the fifth metatarsal (Fig. 53). Robert Jones, the famous British Orthopaedic Surgeon who first described this fracture, sustained it himself whilst dancing in a party. Healing in the diaphyseal region of the fifth metatarsal is slow due to reduced vascularity and hence, these fractures may fail to heal even after prolonged immobilization. Avulsion fractures occur slightly more proximal to Jones fractures and usually unite satisfactorily with conservative treatment. Severely displaced fractures may require open reduction and internal fixation with a screw. 216 Classification and diagnosis in orthopaedic trauma Stress fractures, although being more common in the second and third, may also involve the fifth metatarsals. They occur in young persons 3.4 (sportsmen or soldiers) due to overuse. Internal fixation is rarely necessary. Mechanism of injury Most fractures of the base of the fifth metatarsal occur as a result of an indirect injury. Jones fracture is caused by a strain applied to an inverted foot with the heel in equinus posotion. ‘Avulsion injuries’, on the other hand, result from sudden inversion causing contraction of the peroneus brevis muscle, and avulsion of

its attachment to the tubersoity. The lateral ligament may also be involved in such cases. Classification These injuries are usually described on the basis of their anatomical level and joint involvement.
Head/neck/shaft/base
Intra-articular/extra-articular Diagnosis The patient may be able to clearly describe the mechanism of injury. Pain, especially on weight-bearing, is common. Ecchymosis and tender- ness over the fracture site are regular findings. The ankle and foot should be assessed to rule out other injuries. The diagnosis is confirmed with X-rays (AP, lateral and oblique) of the foot. Sometimes, sesamoids in the peroneal tendons can be mistaken for a fracture. Treatment Most metatarsal base fractures can be managed satisfactorily with symp- tomatic treatment and physiotherapy. Some surgeons prefer to immobilize the foot in a plaster to control pain and achieve union. More distal injuries (e.g. Jones’ or stress fractures) may require internal fixation with bone graft- ing, if prolonged immobilization leads to non-union. Complications
Delayed union
Non-union 217 Ankle and foot 3.4 Fig. 54. A displaced fracture of the second metatarsal. 3.4.J Fractures of other metatarsals (I–IV) Direct blows such as those caused by a fall of a heavy object, may pro- duce single or multiple metatarsal fractures (Fig. 54). Severe soft tissue injuries may give rise to a significant swelling over the foot. Careful evalua- tion of the peripheral pulses is mandatory in such cases, in order to rule out ischaemia. Indirect injuries, mainly caused by an awkward twist or inversion of the foot, may produce a spiral fracture of the shaft of a metatarsal. Pain, especially on weight-bearing, is the commonest complaint. Ecchy- mosis and local bony tenderness are frequent findings on examination. X- rays (AP, lateral and oblique) are required for confirmation of diagnosis. Irrespective of the fracture level, most metatarsal injuries are managed non-operatively. Active range of motion exercises are commenced after a 218 short period of plaster immobilization. Classification and diagnosis in orthopaedic trauma 3.4 Fig. 55. Subluxation of the fifth metatarsophalangeal joint. Severely displaced fractures of the first metatarsal, open injuries involving metatarsals or tarsometatarsal joints and ununited metaphyseal or diaphy- seal fractures, however, often require operative treatment. Open fractures should be debrided. Significantly displaced fractures, especially those involving multiple metatarsals, may require K-wiring after reduction. 3.4.K Dislocations of the metatarsophalangeal joints Because the metatarsophalangeal joints are quite stable, dislocations are rare. Injuries to these joints (Fig. 55). usually occur in response to a significant high velocity force (e.g. road traffic accidents). Most dislocations are dorsal. Physical examination reveals a deformity at the level of the affected metatarsophalangeal joint(s). The toe appears shortened and the overlying skin may be significantly tented, causing circu- latory compromise. Capillary filling should therefore, be carefully assessed. Radiographs (AP and lateral) are taken to confirm the diagnosis. 219 Ankle and foot 3.4 Fig. 56. A comminuted fracture of the proximal phalanx of the little toe. Closed manipulation usually reduces the dislocation. This should be fol- lowed by strapping the affected toe to the adjacent toe (‘neighbour strap- ping’) for 3–4 weeks. Only very rarely, a close manipulation fails and open reduction is required. 3.4.L Phalangeal fractures Phalangeal fractures are caused by either a direct blow (e.g. fall of a heavy object) or by the toe striking a hard object. Patients complain of severe pain in the toe. Swelling and bruising are common. AP and oblique radiographs (Fig. 56) show the fracture clearly. Most minimally displaced or undisplaced fractures involving the proxi- mal and distal phalanges can be treated satisfactorily with neighbour strap- ping of the toes. However, displaced intra-articular fractures involving the metacarpal phalangeal (MCP), proximal interphalangeal (PIP) or distal interphalangeal (DIP) joints may require closed or open reduction followed 220 by K-wire or screw fixation. Classification and diagnosis in orthopaedic trauma 3.4 Fig. 57. Positive Simmond’s test indicates rupture of the Achilles’ tendon. Fusion may be indicated for long-standing cases with severe disruption of the interphalangeal joints. 3.4.M Dislocations of the interphalangeal joints Excessive hyperflexion or hyperextension at the interphalangeal joints may cause subluxations or dislocations. The patient has a painful and deformed toe. The distal neurovascular status should be assessed carefully. AP and oblique views of the foot are required for radiographic confirmation of the diagnosis. Closed manipulation of the toe usually reduces the dislocation. This should be followed by strapping the affected toe to the adjacent toes (‘neigh- bour strapping’) for 3–4 weeks. Only very rarely, a close manipulation fails and open reduction is required. 3.4.N Rupture of the Achilles tendon Tears of the Achilles tendon are common in middle-aged individuals, espe- cially in those involved in inadvisable athletic activities. There may be a pre-existing history of Achilles tendonitis in these patients. 221 Ankle and foot 3.4 Mechanism of injury A sudden forceful contraction of the gastrocnemius during push-off move- ment may cause a rupture, which usually occurs 2–5 cm proximal to the calcaneal insertion of the Achilles tendon. This area is considered to be relatively hypovascular. Diagnosis Most patients describe hearing a ‘snap’ on the back of the heel while playing. ‘Feeling of being kicked in the calf’ is another description of this injury. The patient presents with pain and is unable to weight-bear on the affected side. Local tenderness, swelling and ecchymosis are common. Often, if the swelling is not massive, a gap is palpable at the site of rupture. Absence of plantar flexion on squeezing the calf (positive Simmond’s test), with the patient lying prone, is an important sign of tendon discontinuity (Fig. 57). This test should be repeated on the normal side for comparison. Diagnosis of this injury is mainly clinical; rarely, confirmation with an ultrasound may be necessary. Treatment Ruptures of the Achilles tendon may often be managed conservatively. The ankle is immobilized in a plaster cast with the foot in the equinus position; initially for approximately 4 weeks and in neutral for a further 4 weeks. Immobilization should be followed by an intense rehabilitation programme. Alternatively, ‘end to end’ surgical repair (Kessler’s or modified Kessler’s procedure) is performed. However, prolonged immobilization with plasters is still necessary. Although re-rupture rates following operative treatment are low, the risk of infection is present. Complications
Rerupture
Infection
Sural nerve injury
Ankle stiffness 222 Classification and diagnosis in orthopaedic trauma PART IV Spinal injuries 4.1 Spinal injuries 4.1.A Spinal injuries: general aspects Road traffic accidents and falls from a height are the common causes of most spinal injuries. Standard precautions should be observed in all cases with a suspected spinal injury. The use of a ‘hard cervical collar’ and principles of ‘in-line immobilization’ and ‘log roll’ are mandatory in order to avoid any further injury. Pain is the most common symptom in a conscious patient. Local bruis- ing, tenderness and a palpable step suggest a significant spinal injury. A complete neurological assessment (Fig. 58(a)(i)(ii)) should be carried out at initial presentation; and repeated at regular intervals. This should include the assessment of the cranial nerves, motor and sensory functions and testing of reflexes (anal, bulbocavernosus, deep tendon reflexes, etc.). Rectal examination is mandatory in order to detect the loss of anal tone, diminution in perianal sensation and presence of blood in the anal canal. About 10% of patients with a spinal injury at one level may have spinal involvement at a different level. Therefore, a complete clinical and radiolo- gical assessment of the entire spine is necessary in all cases. Standard AP and lateral radiographs should be requested for all spinal injuries irrespective of the level of involvement. However, an open mouth (peg view) is also required to rule out injury to the odontoid process or body of the second cervical vertebrae (axis). Oblique and flexion–extension views are reserved for stable injuries and should be performed only under the supervision of an experienced clinician. Advanced imaging techniques such as CT and MRI scans are often indicated for further assessment of a spinal injury. The CT scan provides better description of the fracture pat- tern, whereas magnetic resonance imaging gives a relatively accurate assess- ment of the status of neural elements, canal encroachment and soft tissue involvement. Denis and colleagues studied spinal fractures in detail and proposed a ‘three-column concept’ for these fractures (Fig. 58(b)). Anterior column – made up of the anterior longitudinal ligament and the anterior half of the vertebral body, disc, and annulus. 225 ANDARD NEUROLOGICAL SUBCLASSIFICATION OF SPINALCORD INJURY MOTOR LIGHT PIN TOUCH PRICK SENSORY ASIA impairment scale R L KEY MUSCLES R L R L KEY SENSORY POINTS C2 C2 A = Complete: No motor or sensory C3 C3 0 = absent function is preserved in the sacral C4 C4 1 = impaired segments S4–S5. 2 = normal C5 Elbow flexors C5 NT = not testable C2 B = Incomplete: Sensory but not C6 Wrist extensors C6 C3 motor function is preserved below C7 Elbow extensors C7 C4 the neurological level and includes C8 Finger flexors (distal phalanx of middle finger) C8 T2 T2 T3 the sacral segments S4–S5. C5 C5 T1 Finger abductors (little finger) T1 T4 T5 C = Incomplete: Motor function is T2 T2 T6 T7 preserved below the neurological T3 0 = total paralysis T3 T8 level, and more than half of key T1 T4 1 = palpable or visible contraction T4 T9 T1 C6 T10 C6 muscles below the neurological T5 2 = active movement, T5 T11 level have a muscle grade less T6 gravity eliminated T6 T12 than 3. 3 = active movement, L1 L1 T7 T7 Palm Palm T8 against gravity D = Incomplete: Motor function is 4 = active movement, T8 preserved below the neurological T9 T9 L2 L2 level, and at least half of key against some resistance T10 5 = active movement, T10 muscles below the neurological T11 level have a muscle grade of 3 against full resistance T11 L3 L3 T12 NT = not testable T12 or more. Dorsum Dorsum L1 L1 E = Normal: motor and sensory L2 Hip flexors L2 function are normal L4 L4 L3 Knee extensors L3 L5 L5 L4 Ankle dorsiflexors L4 L5 Long toe extensors L5 Clinical syndromes S1 Ankle plantar flexors S1 Key Sensory Points S2 S2 S1 S1 Central cord S3 S3 S1 Brown–Sequard S4-5 Voluntary anal contraction (Yes/No) S4-5 Any anal sensation (Yes/No) Anterior cord TOTALS { + = PIN PRICK SCORE (max: 112) Conus medullaris TOTALS + = MOTOR SCORE + = Cauda equina LIGHT TOUCH SCORE (max: 112)(MAXIMUM) (50) (50) (100) (MAXIMUM) (56) (56) (56) (56) (a)(i) NEUROLOGICAL R L COMPLETE OR INCOMPLETE? ZONE OF PARTIAL R L LEVEL SENSORY Incomplete = Any sensory or motor function in S4-S5 PRESERVATION SENSORY The most caudal segment MOTOR Caudal extent of partially with normal function ASIA IMPAIRMENT SCALE MOTOR innervated segments (a)(ii) 2000 Rev. Fig. 58(a)(i) and (ii). Motor and sensory assessment chart (American Spinal Injury Association) for Spinal injuries. C C 7 8 C6 C7 C8 Middle column – made up of the posterior half of the vertebral body, disc, and annulus, and the posterior longitudinal ligament. 4.1 Posterior column – made up of the facet joints, ligamentum flavum, the posterior elements and the interconnecting ligaments. Injuries involving only the anterior column (e.g. wedge fractures) are generally stable, while those affecting two or more columns are unstable. Fractures with involvement of all three columns are likely to be highly unsta- ble, and these often require surgical stabilization. Complete and incomplete spinal injuries Spinal injuries are described as being ‘complete’ or ‘incomplete’. There is a total loss of motor and sensory function below the level of injury if the injury is ‘complete’. However, in an ‘incomplete injury’ there is partial involvement of the cord with some sparing (of motor cord sensory functions) depending upon the site of cord involvement. Examples of incomplete cord injuries are:
Brown Séquard syndrome
Central cord syndrome
Anterior cord syndrome
Posterior cord syndrome Neurogenic and spinal shock Generalized ‘neurogenic shock’ may occur after a serious cord injury. Widespread peripheral vasodilatation and loss of autonomous excitation of the heart may produce severe hypotension with bradycardia. This type of shock fails to respond to fluid replenishment and therefore, administration of vasopressors (e.g. dopamine, noradrenaline, etc.) should be considered early. ‘Spinal shock’ refers to the initial complete loss of motor and sensory functions after a spinal

injury. This is sometimes confused with neurogenic shock. The return of sacral reflexes (e.g. ‘bulbocavernosus’ and ‘anal’) indi- cates recovery from a spinal shock. Most spinal injuries occur as a result of significant trauma. It is extremely important to recognize and treat all life-threatening injuries first and therefore, a thorough assessment based on the Advanced Trauma Life Support (ATLS) guidelines should be performed. The patient should be optimally resuscitated while the whole spine is kept immobilized with a cervical collar, sand bags and a hard spinal board (‘in-line immobilization’). The support for use of high doses of steroids in spinal injuries is slowly growing. Most trials have recommended methylprednisolone in a dose of 227 Spinal injuries 4.1 Middle ligamentous complex Posterior ligamentous complex Posterior longitudinal ligament Facet capsules Annulus fibrosus Interspinous ligments Anterior ligamentous complex Anterior longitudinal ligament Annulus fibrosus Anterior column Middle column Posterior column Fig. 58(b). Denis’ three-column concept of spinal injuries. (Reproduced with permission from Bucholz, R. W. & Heckman, J. D. Rockwood and Green’s Fractures in Adults, vol. 2. Philadelphia: Lippincott, Williams and Wilkins, 1991.) 30 mg/kg of body weight as a bolus initially and then 5.4 mg/kg of body weight/h for the next 23 hours. Specific treatment of spinal injuries depends upon the level, displacement of the fracture, neurological involvement and also on the facilities available. In general, undisplaced or minimally displaced fractures not compromis- ing the cord can be managed conservatively. However, injuries associated with neurological complications or those that are potentially unstable, may require operative stabilization. Stable injuries of the cervical spine can be managed with a cervical col- lar. Subluxations or dislocations may require controlled traction or closed reduction followed by immobilization in a ‘halo’ jacket or cast. Operative stabilization, if necessary, is performed using screws, wires and plates. If unstable, segments require fusion of the vertebrae with autogenous grafts or allografts. Most stable thoracolumbar fractures are treated symptomatically and early mobilization is recommended. However, if there are any concerns regarding stability, a thoracolumbar brace should be advised before com- mencing mobilization. Unstable fractures require internal fixation (e.g. transpedicular screw fixation) or a plaster jacket. Rehabilitation Early rehabilitation of spinal injuries is essential. This should be aimed at optimal restoration of function, prevention of complications and re- integration of the patient into the community. A multidisciplinary team consisting of the physiotherapists, occupational therapists, nurses and 228 Classification and diagnosis in orthopaedic trauma doctors should actively participate in the patient’s rehabilitation pro- gramme. The family of the patient may be of great assistance. 4.1 Spinal exercises involve stretching and strengthening spinal muscles in order to accelerate the recovery process. Regular passive movements of the limbs prevent the development of joint contractures. Psychological support is essential to allow the patient to re-adjust in his family and social life satisfactorily. Complications Special precautions are necessary in patients with spinal injuries, as they are associated with high rates of complications.
Pneumonia and atelectasis
Pressure sores on sacrum, heel, etc.
GI ulceration
Urinary tract infections
Joint contractures
Osteoporosis
Muscle atrophy
Associated injuries
Psychiatric disturbance 4.1.B Incomplete spinal injuries Important incomplete spinal lesions are:
Brown Séquard syndrome
Anterior cord syndrome
Central cord syndrome
Posterior cord syndrome In these injuries, motor and sensory impairment, primarily depends upon the site of involvement. The spinal lesions can therefore, be predominantly motor or sensory. However, most injuries show a mixed pattern. Brown Séquard syndrome An injury pattern comprising ipsilateral muscular paralysis and contralateral hyper-anaesthesia to pain and temperature is referred to as ‘Brown Séquard 229 Spinal injuries 4.1 syndrome’. In general, patients show some recovery of sensory and motor functions. Anterior cord syndrome This incomplete spinal injury pattern consists of complete motor paralysis and loss of pain and temperature modalities below the level of the lesion. However, posterior column sensation, i.e. proprioception, deep pressure and vibration are spared. The prognosis is poor and only 10–15% of patients show significant recovery. Central cord syndrome Central cord syndrome is the most commonly encountered incomplete spinal injury. There is differential involvement of the upper and lower limbs. A lesion of the central corticospinal and spinothalmic tracts in the white mat- ter of the spinal cord causes upper motor neuron paralysis of the trunk and lower extremities. However, in the upper limbs, especially in hand muscles, a flaccid lower motor neuron weakness is present. This is due to direct damage to the central grey matter. Central cord syndromes are commonly seen in osteoarthritic spines where osteophytes cause disruption of the nervous tissue. Sacral segments, due to their peripheral location in the cord, are often spared. Hence, the anal sensation and reflex may return early. Fifty to sixty per cent of patients show a satisfactory recovery, but hand function often remains permanently impaired. Posterior cord syndrome Posterior cord syndrome typically affects deep pressure and proprioception. Other sensory modalities and motor functions usually remain unaffected. 4.1.C Fractures of the cervical spine with eponyms The first two cervical vertebrae (C1 and C2) are structurally different from the others (C3–C7). The first cervical vertebra (atlas), is a ring-shaped bone with lateral masses for articulation with the skull and has no central body. The second cervical vertebra (axis), on the other hand, has a large body and a superior projection called odontoid process. This articulates with the atlas and is stabilized by the transverse and alar ligaments. Disruption of these ligaments plays a significant role in atlantoaxial instability. Because of its flexibility and lack of firm structural support, the cervical 230 spine is very prone to serious injury, such as a fracture or dislocation, which Classification and diagnosis in orthopaedic trauma may be associated with neurological involvement. Injuries to the cervical spine usually occur due to axial loading and compression-distraction forces. 4.1 Some of these injuries have acquired classical eponyms which are discussed in greater detail later in the text. Jefferson fracture (burst fracture of C1) (Fig. 59(a)) The injury pattern consists of three or four fractures in the anterior and posterior rings of the atlas. The transverse ligament stabilizing the odontoid process to the atlas may also rupture giving rise to gross instability at this level. There is a high risk of neurological impairment due to the failure of the middle column. Tear drop fracture (Fig. 59(b)) In certain flexion injuries the anterior column fails but the posterior liga- ment, forming the middle column, remains intact. This results in an avulsion fracture (‘tear drop’) of the anterior part of the vertebrae body. Neurological involvement is uncommon. Hangman’s fracture (see page 237) Sentinel fracture A sentinel fracture is a bilateral laminar fracture causing impingement of the cord. It is, therefore, a potentially unstable posterior element injury. Clay Shoveler’s fractures Sudden flexion may lead to an avulsion injury usually involving the spinous process of C6 vertebra (sometimes, T1). 4.1.D Atlanto-occipital injuries Fractures of the occipital condyles and disruptions of the atlanto-occipital joints are associated with high rates of mortality due to severe cord or nerve root damage. Cranial nerve palsies may be present. Stable condylar fractures may be treated with a hard cervical collar or a halo jacket. However, unstable injuries may require operative stabilization by occipito-cervical fusion. Atlanto-occipital dislocation can be treated with gentle traction and halo immobilization followed by a posterior occipito-cervical fusion. 231 Spinal injuries 4.1 Fig. 59(a). Jefferson fracture is an unstable injury. There is also involvement of the second cervical vertebra (axis). 232 Fig. 59(b). Tear drop fracture (arrow) of the seventh cervical vertebra (C7). Classification and diagnosis in orthopaedic trauma 4.1.E Fractures of the atlas 4.1 The spinal canal of the atlas, can be divided into three parts – one third being occupied by the odontoid, another third by the cord and the rest is a free space (Steel’s rule). Injuries involving the ring of the atlas may present as an isolated fracture or as multiple disruptions at three or more places (Jefferson fracture). Mechanism of injury Axial compression combined with hyper-flexion, hyper-extension or lateral tilt plays an important role in these injuries. Diagnosis Suboccipital pain is common but neurological involvement is rare. About 50% of these injuries are associated with other cervical fractures. Unstable injuries are often associated with disruption of the transverse atlantal liga- ment, which may cause instability. Radiographs (AP, lateral and open mouth views) are necessary for initial evaluation. However, a CT scan is frequently required for further assessment. If the distance between the dens and anterior arch of the atlas exceeds 3.5 mm on a lateral radiograph, an injury to the transverse atlas ligament should be suspected and an MRI scan should be performed for further analysis. Treatment Single fractures are usually stable and can be treated satisfactorily with a hard cervical collar. Halo fixation provides better and rigid fixation of the cervical spine but its use is limited to only those fractures that are potentially unstable. Instability arising due to rupture of the transverse atlantal ligament can be treated with a posterior transarticular atlantoaxial screw fixation or by arthrodesing C1 and C2. 4.1.F Atlantoaxial rotatory subluxation Atlantoaxial subluxations are characterized by abnormal movement between the atlas and axis, usually as a result of bony or ligamentous abnor- mality following trauma. 233 Spinal injuries 4.1 Mechanism of injury The exact mechanism of this injury is unknown. It is believed to occur from a combination of flexion, extension and rotational forces following a severe neck trauma. Classification Rotatory subluxation is classified into four types depending upon the degree of separation of the dens from the anterior arch of atlas: Type I: Atlanto-dens distance <3 mm. Transverse ligament intact. Type II: Atlanto-dens distance 3–5 mm. Transverse ligament ruptured. Type III: Atlanto-dens distance >5 mm. Alar ligaments ruptured. Type IV: Posterior subluxations of C1 on C2 (usually signifies an odontoid fracture or hypoplasia). Diagnosis The patient complains of occipital pain and limitation of neck movements. The head may be tilted in one direction (Cock robin position). An open mouth radiographic view shows rotation of the lateral mass towards midline and the relationship of the odontoid and lateral mass appears altered. Often, a CT scan is necessary for further assessment. Treatment The following treatment plan may be considered: Type I: Reduction by skeletal traction followed by halo immobiliza- tion. Type II– IV: Fusion. 4.1.G Fractures of the dens (odontoid) The axis consists of the dens (odontoid process) and a large spinous pro- cess. The dens is stabilized to the ring of the atlas with transverse and alar ligaments. Mechanism of injury Fractures involving the odontoid process are usually caused by high velocity road traffic accidents. Sudden flexion or extension of the neck causes abnormal stresses on the dens, which fractures and often displaces 234 Classification and diagnosis in orthopaedic trauma 4.1 I II III Fig. 60. Open mouth view showing location of Type I, II and III fractures of the dens (odontoid). forwards. In general, the displacement is anterior if the injury is due to flex- ion or axial loading. In hyperextension injuries, the displacement is usually posterior. Classification Anderson and D’Alonzo classified odontoid fractures into three types (Fig. 60): Type I: Oblique avulsion fractures of the upper part of the dens. Type II: Fractures at the junctions of the dens with the body of the axis (most common). Type III: Fractures extend into the body of the axis. Diagnosis Neck pain is common and may be associated with neurological features. Radiographic examination should include AP, lateral and open mouth odontoid views. Further imaging with a CT scan is often necessary. Treatment The treatment of odontoid fractures depends upon the age of the patient and displacement of the fragment. In general, halo immobilization is suitable for most Type I, and some Type II injuries. Anterior screw fixation with a 235 Spinal injuries 4.1 Fig. 61. An unstable fracture of the second cervical vertebrae (Hangman’s fracture). screw and fusion of C1–C2 vertebrae are recommended only for significantly severe and unstable injuries. 4.1.H Traumatic spondylolisthesis of the axis (Hangman’s fracture) Traumatic spondylolisthesis of the axis (Fig. 61) occurs due to bilateral fractures of the pars interarticularis or following facet dislocations. The axis either angulates or completely displaces forwards. Death in judicial hangings is believed to occur due to this mechanism. It may also be seen following high velocity road traffic accidents, especially

when the head strikes the windshield. This injury has been classified by Levine into three types: Type I: Upto 3 mm of displacement (stable with no angulation). Type II: More than 10◦ of angulation and displacement greater than 3 mm. Type IIa: II + posterior disc space widening. Type III: Severe displacement and angulation because of dislocation of 236 one or both facets. Classification and diagnosis in orthopaedic trauma The following treatment plan may be considered for these serious injuries: 4.1 Type I: Hard collar immobilization. Type II: Traction for reduction followed by halo immobilization. Type IIa: No traction. Halo immobilization after gentle manipulation. Type III: Open reduction and C2–C3 fusion. 4.1.I Injuries of the subaxial cervical spine Injuries of the lower cervical spine have been classified into six types, depend- ing upon the position of the neck (flexion, extension, lateral ending, etc.) and direction of force at the time of insult. This classification involves a clear understanding of the mechanism of injury and appreciation of the exact injury pattern on X-ray, CT and MRI scans. Depending upon the severity, these injuries may present as vertebral fractures, subluxations or dislocations: 1. Compression flexion injuries 2. Vertical compression injuries 3. Distraction flexion injuries 4. Compression extension injuries 5. Distraction extension injuries 6. Lateral flexion The cervicothoracic region (C7 T1) is a common site of injury to the neck because it marks the junction of the mobile cervical spine and the relatively immobile thoracic spine. However, these injuries can be easily missed, espe- cially if proper imaging (swimmers’ view, CT scan, etc.) is not performed. In general, subaxial injuries, especially subluxations and dislocations, can be satisfactorily treated with skeletal traction (e.g. Crutchfield tongs). Most stable injuries can be immobilized in a halo cast. However, if vertebral dis- ruption is severe with an established or impending danger of neurological damage, surgical stabilization and fusion is usually indicated. If there is trau- matic herniation of the disc (e.g. in distraction flexion injuries), a discectomy may also be required. 4.1.J Injuries of the thoracolumbar spine: general aspects Fractures involving the upper thoracic spine (upto T10) are generally stable because the sternum and rib cage provide inherent stability to this segment of the spine. However, fractures below this level (dorsolumbar spine) may show unstable patterns with neurological involvement. 237 Spinal injuries 4.1 Mechanism More than 60% of injuries involving the vertebral column are caused by motor vehicle accidents or heavy falls. The amount of energy imparted to the vertebrae determines the degree of bony and ligamentous disruption. Compression and distraction forces are the key elements responsible for various injury patterns and this is discussed later in this chapter. Classification It is important to understand the ‘three-column concept’ (see page 225–227) of vertebral injuries in order to assess the degree of damage. In general, the failure of the middle column indicates a potentially serious injury both, in terms of stability and neurological involvement. This can occur in four different ways: compression, distraction, rotation and shear. Common injury patterns resulting from these forces are: (a) Compression fractures (b) Burst fractures (c) Flexion distraction injuries (seat belt types) (d) Fracture dislocations. Compression fractures Such injuries are usually stable and only involve the anterior column. The anterior half of the vertebra appears wedged and neurological involvement is rare (Fig. 62). Burst fractures Burst fractures, are caused by axial loading of the vertebral column following a fall from a height. Both anterior and middle columns are involved and therefore, stability of the fracture is a serious concern. Although the posterior column may appear intact, an injury to the posterior ligament should always be suspected. Radiographs show an increased interpedicular distance and the posterior vertebral height is often reduced. Flexion distraction injuries These injuries usually result from a failure of all the three columns. They are common after road traffic accidents, especially following a head-on collision of a seat-belted driver or passenger. The anterior column acts as a hinge and the middle and posterior column fail due to distraction. The posterior longitudinal ligament and intervertebral discs are frequently affected and involvement of the bone (Chance fractures) is also not uncommon. On X-ray, the interspinous distance is widened and the posterior vertebral height appears reduced. Although stability is a major concern, neurological 238 involvement is uncommon. Classification and diagnosis in orthopaedic trauma 4.1 Fig. 62. A compression fracture of the second lumbar vertebra. Most of these injuries can be treated satisfactorily with conservative mea- sures. In severe cases with significant posterior disruption, fusion and segmental fixation may be considered. Fracture dislocation All three columns fail due to a combination of compression, tension, rota- tion and shear forces. Varying degrees of bony and ligamentous disruptions are present. Neurological involvement is common as the injury is highly unstable. An associated intra-abdominal injury (e.g. bowel disruption, liver or spleen lacerations, etc.) may also be present. Reduction and stability is achieved by operative treatment using internal fixation. Sacral fractures More than 50% of sacral injuries may be missed on plain X-ray. Displaced fractures involving the sacrum are serious injuries and may be associated with neurological deficit, dural tears and perforation of the pelvic viscera. A CT scan is usually necessary for recognition and complete evaluation of these fractures. The fracture line is often vertical and may involve the whole length of sacrum. 239 Spinal injuries 4.1 Denis classified these fractures into three types, according to their relation to the sacral foramina: Zone 1: Fracture line lies lateral to the neural foramina Zone 2: Fracture line passes through the sacral foramina Zone 3: Fractures involving the central sacral canal (neurological injuries are common) Most undisplaced sacral fractures can be managed satisfactorily. However, fractures associated with significant displacement often require reduction and stabilization with screws and plates. Points to remember in children
Road traffic accidents account for more than 50% of the injuries.
Most neck injuries in young children occur in the upper cervical region, above C3.
In children less than 8 yrs of age, there is hypermobility of C2 on C3 in flexion. Therefore, a normal ‘step’ between C2 and C3 may be misdiagnosed as a subluxation.
Atlantoaxial rotatory displacement of C1 over C2 is predominantly seen during childhood. Pain and torticollis are common presenting features.
Flexion–distraction injuries (Chance’s Fracture) involve the lumbar and thoracolumbar regions and are often associated with a high risk of spinal cord involvement.
Spinal cord injury without radiographic abnormality (SCIWORA) is present in 10–30% cases. It usually occurs due to a subluxation or dislocation of the vertebra that has reduced spontaneously. The child may present with delayed paraplegia and paraesthesia.
There should be a high index of suspicion for non-accidental injury, especially if multiple fractures are present.
All spinal injuries should be managed according to Advanced Trauma Life Support (ATLS) Guidelines (Airway, Breathing, Circulation and Disability). 240 Classification and diagnosis in orthopaedic trauma Index abbreviated injury score (AIS), 19 airway, breathing, circulation, disability, ABC approach see airway, breathing, exposure and environment (ABCDE) circulation, disability, exposure and approach, 8, 13–14, 25 environment (ABCDE) approach basic elements, 16–19 ABCDE approach see airway, breathing, in primary surveys, 16–18 circulation, disability, exposure and airways, with cervical spine immobilization, 17 environment (ABCDE) approach AIS (abbreviated injury score), 19 abductor pollicis brevis, loss of function, allergies, medication, past illnesses, last meal 32 and events (AMPLE) approach, 18 abductor pollicis longus (AbPL), 114–115 AMBRI (atraumatic, multidirectional, AbPL (abductor pollicis longus), 114–115 bilateral, rehabilitation, inferior acetabular fractures, 130–133 capsular shift), 49 classification, 131–132 American College of Surgeons, 15 complications, 133 AMPLE (allergies, medication, past illnesses, diagnosis, 132 last meal and events) approach, 18 mechanisms, 131 angulation, definition, 3–4 overview, 130–131 ankle treatment, 132 orthopaedic trauma, 194–222 Achilles tendon ruptures, 221–222 see also talus complications, 222 ankle fractures, 194–200 diagnosis, 222 children, 200 mechanisms, 222 classification, 194–198 overview, 221 AO, 196–198 Simmond’s test, 221, 222 Danis–Weber, 195–196 treatment, 222 Lauge–Hansen, 195 ACL injuries see anterior cruciate ligament complications, 200 (ACL) injuries diagnosis, 198–199 acromioclavicular joint injuries, 50–52 mechanisms, 194–198 classification, 50–51 overview, 194 diagnosis, 52 treatment, 199–200 mechanisms, 50 see also pilon fractures; talar neck fractures overview, 50 anterior cord syndrome, 230 treatment, 52 anterior cruciate ligament (ACL) adductor pollicis (AP) tendons, 114–115 injuries, 175–178 Advanced Trauma Life Support (ATLS), anterior drawer test, 176 25 classification, 175 basic elements, 16–19 complications, 178 guidelines, 8, 13–14, 128 diagnoses, 175–177 historical background, 15 Lachman test, 175, 176 and multiple trauma, 15–20 mechanisms, 175 training, 15 overview, 175 241 anterior cruciate ligament (cont.) and proximal humeral fractures, 45 pivot shift test, 177 and scaphoid fractures, 111 treatment, 177–178 AVN see avascular necrosis (AVN) anterior drawer test, 176 axilla, radial nerve injuries, 30 AO see Arbeitsgemeinschaft für axillary nerve, injuries, 32–33 Osteosynthesefragen (AO) axonotmesis, 28–29 AP (adductor pollicis) tendons, 114–115 Apley’s grinding test, 183 back injuries see spinal injuries Arbeitsgemeinschaft für Osteosynthesefragen Bankart’s lesion, 46 (AO), 6–7 Barton’s fracture, 99, 100 ankle fractures, 196–198 basicervical femoral neck fractures, 139 distal radial fractures, 104–105 Bauman’s angle, 65, 66 femoral shaft fractures, 156, 157 Bennett’s fracture, 114, 115 humeral shaft fractures, 58, 59 Bohler’s angle, 210 intertrochanteric fractures, 148 bone formation olecranon fractures, 82 mechanisms, 22 pilon fractures, 202–204 osteoinductive factors, 21–22 proximal humeral fractures, 41–43 bones radial diaphyseal fractures, 89–91 healing, 21–22 subcapital femoral neck fractures, 143, see also paediatric bones 144 boxer’s fracture, 116 subtrochanteric fractures, 153 brachial artery injuries, and humeral shaft supracondylar femoral fractures, 160–161 fractures, 60–61 supracondylar humeral fractures, 62–63, 64 brachial plexus, injuries, 33 tibial plateau fractures, 165–167 breathing, in primary surveys, 17 tibial shaft fractures, 187–188 Brown Séquard syndrome, 229–230 arm buckle fractures, 3, 107 orthopaedic trauma, 37–61 burst fractures, thoracolumbar spine, radial nerve injuries, 30 238 see also forearm; humeral shaft fractures; proximal humeral fractures calcaneal fractures, 207–212 ASIF (Association for the Study of Internal classification, 208–209 Fixation), 6–7, 41–43 Essex Lopresti, 208–209 Association for the Study of Internal Fixation complications, 212 (ASIF), 6–7, 41–43 diagnosis, 209–211 atlantoaxial rotatory subluxations, 233–234 mechanisms, 207 classification, 234 treatment, 211–212 diagnosis, 234 callus formation mechanisms, 234 and fracture healing, 21–22 overview, 233 impairment, 22 treatment, 234 capitellar fractures, 72–74 atlanto-occipital injuries, 231 classification, 73, 74 atlas fractures, 233 complications, 74 diagnosis, 233 diagnosis, 73 mechanisms, 233 mechanisms, 73 overview, 233 overview, 72 treatment, 233 treatment, 74 atraumatic, multidirectional, bilateral, card test, 31 rehabilitation, inferior capsular shift carpal bone fractures, 111–112 (AMBRI), 49 carpal instability, 112–113 avascular necrosis (AVN), 205 classification, 112–113 242 and fractures, 12 complications, 113 Index diagnosis, 113 Colles’ fracture, 3, 8, 12, 98, 99 mechanisms, 112–113 reverse, 98 overview, 112 comminuted fractures, definition, 4 treatment, 113 common peroneal nerve, injuries, 34 cast immobilization, distal radial fractures, compartment syndrome, 11–12, 24, 65 105 and supracondylar humeral fractures, 67 central cord syndrome, 230 and tibial shaft fractures, 192 cervical spine fractures, 230–231, 236 compound fractures see open fractures overview, 230–231 compression fractures, thoracolumbar cervical spine immobilization, 17 spine, 238, 239 chauffeur’s fracture, 99–101 compression plates, locking, 45 children computerized tomography (CT), fracture ankle fractures, 200 diagnosis, 8 clavicular fractures, 40 condylar fractures, 163–164 distal radial fractures, 107 Cooney–Dobyns–Linscheid classification, 109 elbow dislocations, 79 coronoid fractures, 79–81 femoral shaft fractures, 159 classification, 79–80 fibular shaft fractures, 192–193 complications, 81 Galeazzi fractures, 96–97 diagnosis, 81 interphalangeal joint dislocations, mechanisms, 79 123 treatment, 81 non-accidental injuries, 14 CRPS (chronic regional pain syndrome), 12 olecranon fractures, 84–85 CT (computerized tomography), 8 pelvic fractures, 130 cubitus valgus, and supracondylar humeral proximal humeral fractures, 46 fractures, 67 pulled elbow, 88 cubitus varus, and supracondylar humeral radial head fractures, 88 fractures, 67 radial neck injuries, 88 cuboid bone fractures, 212–213 subcapital femoral neck fractures, 146–147 cuneiform bone fractures, 212–213 thoracolumbar spine injuries, 240 tibial shaft Danis–Weber classification, 195–196 fractures, 192–193 debridement, definition, 4 see also paediatric bones; paediatric fractures deep vein thrombosis (DVT), and fractures, 11 chronic regional pain syndrome (CRPS), and delayed unions, fractures, 12 fractures, 12 dens fractures see odontoid fractures circulation, with haemorrhage control, 17 developing countries, subcapital femoral neck classification see fracture classification fracture treatment, 145–146 clavicular fractures, 37–40 DHSs see dynamic hip screws (DHSs) children, 40 DIP (distal interphalangeal) joint, classification, 37–38, 39 dislocations, 121–123 complications, 40 direct injuries, fractures, 5–6 diagnosis, 38–39 disabilities, neurologic assessment, 17 mechanisms, 37 discontinuities overview, 37 complete, 3 treatment, 39 incomplete, 3 claw hand, 31, 33 DISI see

dorsal intercalary segmental instability clay shoveller’s fractures, 231 (DISI) closed fractures, definition, 4 dislocations closed manipulation definition, 3 proximal humeral fractures, 44 incomplete, 3 supracondylar humeral fractures, 66 partial, 3 closed reduction, 8 talus, 207 243 Index dislocations (cont.) encirclage wiring, 172 see also elbow dislocations; glenohumeral environmental control, 18 joint dislocations; hip dislocations; Erb’s palsy, 33 interphalangeal joint dislocations; knee Essex Lopresti classification, 208–209 dislocations; metatarsophalangeal joint Evans’ classification, 147–148, 149 dislocations; shoulder dislocations examinations displacements general, 7 definition, 3 local, 7–8 types of, 3 look, feel and move scheme, 7–8 see also angulation exposure control, 18 distal interphalangeal (DIP) joint, extensor mechanism injuries, 185–187 dislocations, 121–123 complications, 187 distal radial fractures, 98–107 diagnosis, 186 cast immobilization, 105 mechanisms, 185–186 children, 107 overview, 185 classification, 101–105 treatment, 187 AO, 104–105 external fixation, 10–11 Frykman’s classification, 101, 102 complications, 11 Malone’s, 101–102, 103 distal radial fractures, 106 complications, 107 humeral shaft fractures, 60 diagnosis, 105 indications, 10 external fixation, 106 external rotation recurvatum test, 184 internal fixation, 106 manipulation, 105–106 falls, open fractures, 23 open reduction, 106 farming accidents, open fractures, 23 overview, 98 fat embolism, and fractures, 11 treatment, 105–106 femoral head fractures, 135, 136–138 dorsal intercalary segmental instability classification, 136–137 (DISI), 113 complications, 138 diagnosis, 113 diagnosis, 137–138 DVT (deep vein thrombosis), and fractures, 11 mechanisms, 136 dynamic hip screws (DHSs), 10 treatment, 138 complications, 10 femoral neck fractures, 138–140 basicervical, 139 elbow ipsilateral, 159 orthopaedic trauma, 62–97 overview, 138 radial nerve injuries, 30 pertrochanteric, 139 ulnar nerve injuries, 31 treatment, 138 see also capitellar fractures; coronoid see also intertrochanteric fractures; fractures; humeral intercondylar subcapital femoral neck fractures; fractures; lateral condylar fractures; subtrochanteric fractures medial epicondylar fractures; olecranon femoral shaft fractures, 154–159 fractures; radial head fractures; children, 159 supracondylar humeral fractures classification, 155–156 elbow dislocations, 76–79 AO, 156, 157 children, 79 Winquist, 155–156 classification, 77, 78 complications, 158–159 complications, 79 diagnosis, 156–158 diagnosis, 78 ipsilateral, 159 mechanisms, 77 mechanisms, 155 overview, 76 open, 159 244 treatment, 78–79 overview, 154 Index special situations, 159 Garden’s, 6, 141–143 treatment, 158 Gustilo’s, 190 fibula, stress fractures, 193 Ideberg’s, 55 fibular shaft fractures, 192–193 Lauge–Hansen, 195 children, 192–193 Malone’s, 101–102, 103 mechanisms, 192 Mason’s, 86 Fielding’s classification, 153 Milch, 70 fifth metatarsal fractures, 216–217 Pauwels’, 143 classification, 217 Russe, 109 complications, 217 Salter Harris, 13 diagnosis, 217 Schatzker’s, 165 mechanisms, 217 Seddon, 28–30 overview, 216–217 Seinsheimer’s, 151–152 treatment, 217 Winquist, 155–156 finger Zdrakovic-Damholt, 55 median nerve injuries, 32 fracture dislocations, thoracolumbar neighbour strapping, 117 spine, 239 see also interphalangeal joint dislocations; fracture healing, 21–22 phalangeal fractures and callus formation, 21–22 first metacarpal fractures, 114–116 and haematoma formation, 21 classification, 115 and inflammation, 21 complications, 116 remodelling, 22 diagnosis, 115 fractures mechanisms, 114–115 buckle, 3, 107 overview, 114 closed, 4 treatment, 115 comminuted, 4 flexion distraction injuries, thoracolumbar complications, 11–14 spine, 238–239 general, 11 flexor carpi radialis, loss of function, 32 local, 11–13 flexor pollicis longus, loss of function, 32 CT scans, 8 foot definition, 3, 5 midtarsal bone fractures, 212–213 delayed unions, 12 orthopaedic trauma, 194–222 diagnosis, 7 see also Achilles tendon ruptures; calcaneal radiographic confirmation, 8 fractures; interphalangeal joint direct injuries, 5–6 dislocations; metatarsal fractures; examinations metatarsophalangeal joint dislocations; general, 7 phalangeal fractures; tarsometatarsal local, 7–8 joint injuries general aspects, 5–14 foot drop, 34 greenstick, 3 forearm history, 7 orthopaedic trauma, 62–97 immobilization, 8–9 see also Galeazzi fractures; Monteggia impacted, 4 fractures; radial diaphyseal fractures; incomplete, 3 ulnar diaphyseal fractures internal fixation, 10 fracture classification, 6–7 intracapsular, 5 Cooney–Dobyns–Linscheid, 109 malunions, 12 Danis–Weber, 195–196 mechanisms, 5–6 Essex Lopresti, 208–209 indirect, 5 Evans’, 147–148, 149 non-union, 12, 61 Fielding’s, 153 olecranon, 5 Frykman’s, 6, 101, 102 open, 23–25 245 Index fractures (cont.) hand pathological, 5–6 median nerve injuries, 32 periprosthetic, 26–27 orthopaedic trauma, 98–123 reduction, 8–9 see also finger; interphalangeal joint rehabilitation, 8–9, 11 dislocations; metacarpal fractures; traction, 9 phalangeal fractures; ulnar collateral undisplaced, 4 ligament injuries see also displacements; open fractures; hanging casts, 59–60 paediatric fractures; stress fractures hangman’s fracture see traumatic fracture treatment, 8–9 spondylolisthesis of the axis conservative, 8–9 Hill–Sach’s lesion, 46 operative, 9–11 hip indications, 9–10 orthopaedic trauma, 134–159 see also external fixation; internal fixation see also femoral head fractures; femoral neck Froment’s sign, 31 fractures; intertrochanteric fractures Frykman’s classification, 6, 101, 102 hip dislocations, 134–136 classification, 134–135 Galeazzi fractures, 95–97 complications, 136 children, 96–97 diagnosis, 135 complications, 96 mechanisms, 134–135 diagnosis, 96 overview, 134 mechanisms, 95 treatment, 136 overview, 95 Hippocrates manoeuvre, 49 treatment, 96 Horner’s syndrome, 33 gamekeeper’s thumb see ulnar collateral humeral braces, 59–60 ligament injuries humeral head, prosthetic replacement, Garden’s classification, 6, 141–143 45 GCS (Glasgow Coma Score), 19–20 humeral intercondylar fractures, 67–70 Gissane angle, 210, 211 classification, 67–68, 69 Glasgow Coma Score (GCS), 19–20 complications, 70 glenohumeral joint dislocations, diagnosis, 69 46–49 mechanisms, 67 anterior, 47 overview, 67 Bankart’s lesion, 46 treatment, 69–70 classification, 47–48 humeral shaft fractures, 56–61 complications, 49 classification, 57–59 diagnosis, 48 AO, 58, 59 Hill Sach’s lesion, 46 morphological, 57 inferior, 48 complications, 60–61 mechanisms, 46–47 diagnosis, 59 and neurovascular injuries, 49 external fixation, 60 posterior, 48 internal fixation, 60 treatment, 48–49 intramedullary pinning, 60 golden hour, 15 and joint stiffness, 61 greenstick fractures, 3, 107 mechanisms, 57 gun shot wounds, open fractures, and nerve injuries, 60 23 non-union, 61 Gustilo’s classification, 190 open reduction, 60 overview, 56 haematoma formation, and fracture treatment, 59–60 healing, 21 and vascular injuries, 60–61 246 haemorrhage control, 17 hypotension, post-trauma, 17 Index Ideberg’s classification, 55 Jefferson fracture, 231, 232 immobilization joint stiffness cervical spine, 17 and fractures, 12 fractures, 8–9 and humeral shaft fractures, 61 types of, 9 Jones fractures see fifth metatarsal fractures in-line, spine, 18 methods, 9 Klumpke’s paralysis, 33 impacted fractures, definition, 4 knee impaction, definition, 4 lateral collateral ligament injuries, 181 incomplete dislocations, 3 orthopaedic trauma, 160–193 incomplete fractures, 3 see also anterior cruciate ligament (ACL) incomplete spinal injuries, 227, 229–230 injuries; extensor mechanism injuries; index finger, median nerve injuries, medial collateral ligament (MCL) 32 injuries; meniscal injuries; infections, and fractures, 11 osteochondral fractures of the knee; inflammation, and fracture healing, patellar fractures; posterior cruciate 21 ligament (PCL) injuries; posterolateral injury severity score (ISS), 19 corner of the knee injuries; proximal intercondylar fractures, 163–164 fibular fractures; supracondylar internal fixation femoral fractures; tibial plateau devices, 10 fractures; tibial spine fractures distal radial fractures, 106 knee dislocations, 173–174 fractures, 10 classification, 174 humeral shaft fractures, 60 complications, 174 proximal humeral fractures, 45 diagnosis, 174 interphalangeal joint dislocations, 121–123, mechanisms, 174 221 overview, 173 children, 123 treatment, 174 complications, 123 Kocher’s fracture see capitellar fractures diagnosis, 121–122 Kocher’s method, 48–49 mechanisms, 121 overview, 121 Lachman test, 175, 176 treatment, 122 lateral collateral ligament (LCL) injuries, 181 intertrochanteric fractures, 139, 147–150 lateral condylar fractures, 70–72 classification, 147–148 classification, 70–71, 72 AO, 148 complications, 72 Evans’, 147–148, 149 diagnosis, 71 complications, 150 mechanisms, 70 diagnosis, 149–150 overview, 70 mechanisms, 147 treatment, 71–72 overview, 147 Lauge–Hansen classification, 195 treatment, 150 LCL (lateral collateral ligament) injuries, 181 intracapsular fractures, 5 leg intramedullary nails, 10 orthopaedic trauma, 160–193 complications, 10 see also Achilles tendon ruptures; fibular humeral shaft fractures, 60 shaft fractures; stress fractures; tibial locking, 45 shaft fractures proximal humeral fractures, 45 leg muscles, wasting, 34 ipsilateral femoral neck fractures, 159 Lisfranc’s injuries see tarsometatarsal joint ipsilateral femoral shaft fractures, 159 injuries ischaemia, and fractures, 11–12 locking compression plates, 45 ISS (injury severity score), 19 locking intramedullary nails, 45 247 Index look, feel and move scheme, 7–8 treatment, 218–219 lower limb see also fifth metatarsal fractures orthopaedic trauma, 125 metatarsophalangeal joint peripheral nerve injuries, 33–34 dislocations, 219–220 see also ankle; foot; hip; knee; leg; pelvis; diagnosis, 219 thigh treatment, 219–220 midtarsal bone fractures, 212–213 McMurray’s test, 183 Milch classification, 70 mallet finger, 121 Monteggia fractures, 92–94 Malone’s classification, 101–102, 103 classification, 93 malunions, fractures, 12 complications, 94 Mangled Extremity Severity Score (MESS), 20 diagnosis, 94 manipulation, distal radial fractures, 105–106 mechanism, 92 Mason’s classification, 86 overview, 92 MCL injuries see medial collateral ligament treatment, 94 (MCL) injuries multiple trauma, and Advanced Trauma Life medial collateral ligament (MCL) Support, 15–20 injuries, 179–181 myositis ossificans, and fractures, 12 classification, 180–181 diagnosis, 180–181 NAIs (non-accidental injuries), children, 14 mechanisms, 179 navicular bone fractures, 212–213 overview, 179 neighbour strapping, fingers, 117 treatment, 181 nerve concussion see neuropraxia medial condylar fractures, 72 nerve damage, and fractures, 11 medial epicondylar fractures, 74–76 nerve injuries classification, 75 classification, 28–30 complications, 76 complete, 28 diagnosis, 76 and humeral shaft fractures, 60 mechanisms, 75 incomplete, 28 treatment, 76 and supracondylar fractures, 66 median nerve neurogenic shock, 227 injuries, 32 neurologic assessment, disabilities, 17 sensory involvement, 32 neuropraxia, 28, 29 meniscal injuries, 181–183 neurotmesis, 29 Apley’s grinding test, 183 neurovascular injuries, and glenohumeral joint classification, 182–183 dislocations, 49 diagnosis, 183 night stick fractures, 94 McMurray’s test, 183 non-accidental injuries (NAIs), children, 14 mechanisms, 182 overview, 181–182 odontoid fractures, 234–236 treatment, 183 classification, 235 MESS (Mangled Extremity Severity Score), 20 diagnosis, 235 metacarpal fractures, 116–117 mechanisms, 234–235 complications, 117 overview, 234 diagnosis, 116–117 treatment, 235–236 mechanisms, 116 olecranon fractures, 5, 81–85 overview, 116 children, 84–85 treatment, 117 classification, 81–82, 83 see also first metacarpal fractures AO, 82 metatarsal fractures, 218–219 complications, 84 diagnosis, 218 diagnosis, 84 248 mechanisms, 218 mechanisms, 81 Index overview, 81 pelvic fractures, 127–130 treatment, 84 children, 130 and ulnar nerve palsy, 84 classification, 127–128 open fractures, 23–25 complications, 130 classification, 24 diagnosis, 128–129 complications, 25 mechanisms, 127 definition, 4, 23 mortality rates, 129 diagnosis, 24 overview, 127 mechanisms, 23 treatment, 19, 129 treatment, 18–19, 25 pelvis open reduction, 10 orthopaedic trauma, 127–133 distal radial fractures, 106 see also acetabular fractures humeral shaft fractures, 60 percutaneous K-wires, 11, 106 proximal humeral fractures, 45 peripheral nerve injuries, 28–34 opponens pollicis, loss of function, 32 classification, 28–30 orthopaedic trauma pathological, 28–30 fracture healing, 21–22 diagnosis, 29 lower limbs, 125 lower limbs, 33–34 principles, 1 mechanisms, 28 spinal injuries, 223 treatment, 29 terminology, 3–4 conservative, 29 upper limbs, 35, 123 operative, 30 see also Advanced Trauma Life Support upper limbs, 30–33 (ATLS); dislocations; fractures periprosthetic fractures, 26–27 osteochondral fractures of the knee, 185 classification, 26 diagnosis, 185 complications, 27 mechanisms, 185 diagnosis, 27 treatment, 185 mechanisms, 26 osteoinductive factors, 21–22 treatment, 27 osteomyelitis, and fractures, 11 use of term, 26 pertrochanteric fractures, 139 paediatric bones phalangeal fractures, 119–121, 220–221 remodelling, 13 classification, 120 structure, 13 complications, 121 paediatric fractures, 13–14 diagnosis, 120 treatment, 13–14 mechanisms, 119–120 partial dislocations, 3 overview, 119 partial patellectomy, 172 treatment, 120–121, 220–221 patellar fractures, 170–172 physeal fractures, 13 classification, 171 classification, 13 complications, 172 pilon fractures, 200–204 diagnosis, 171 classification, 201–204 mechanisms, 170–171 AO, 202–204 overview, 170 complications, 204 treatment, 171–172 diagnosis, 204 patellectomy mechanisms, 201 partial, 172 overview, 200–201 total, 172 treatment, 204 pathological fractures, mechanisms, 5–6 pins, 10 Pauwels’ classification, 143 see also intramedullary nails PCL injuries see posterior cruciate ligament PIP (proximal interphalangeal) joint, (PCL) injuries dislocations, 121–123 249 Index pivot shift test, 177 radial diaphyseal fractures, 88–91 plastic deformation, 107 classification, 88–91 plates, 10 AO, 89–91 posterior cord syndrome, 230 complications, 91 posterior cruciate ligament (PCL) diagnosis, 91 injuries, 178–179 mechanisms, 88 diagnosis, 178–179 overview, 88 mechanisms, 178 treatment, 91 overview, 178 radial head fractures, 85–88 posterior drawer test, 179 children, 88 posterior sag sign, 178 classification, 86 treatment, 179 complications, 87 posterior drawer test, 179 diagnosis, 86–87 posterior sag sign, 178 mechanisms, 85 posterolateral corner of the knee overview, 85 injuries, 183–185 treatment, 87 diagnosis, 184 radial neck injuries, children, 88 external rotation recurvatum test, 184 radial nerve, injuries, 30 mechanisms, 184 radial nerve palsy, 60 prone external rotations test, 184 radiography treatment, 184–185 fracture diagnosis, 8 post-traumatic arthritis, and fractures, 13 trauma series radiographs, 16 primary surveys, 16–18 recurrent carpal instability, and scaphoid prone external rotations test, 184 fractures, 111 prosthetic replacement, humeral head, 45 reduction proximal femoral fractures, 138 closed, 8 proximal femur, blood supply, 139–140 definition, 4 proximal fibular fractures, 172–173 fractures, 8–9 classification, 172 open, 10 diagnosis, 172–173 rehabilitation mechanisms, 172 fractures, 8–9, 11 overview, 172 spinal injuries, 228–229 treatment, 173 remodelling, fracture healing, 22 proximal humeral fractures, 40–46 resuscitation, 16 and avascular necrosis, 45 revised trauma score (RTS), 19–20 children, 46 road traffic accidents, open fractures, 23 classification, 41–43 Rolando’s fracture, 114, 115 AO/ASIF, 41–43 rotator cuff tears, and shoulder dislocations, 49 closed manipulation, 44 RTS (revised trauma score), 19–20 complications, 45 Rush pins see intramedullary nails diagnosis, 44 Russe

classification, 109 internal fixation, 45 intramedullary pinning, 45 sacral fractures, thoracolumbar spine, 239–240 mechanisms, 40 Salter–Harris classification, 13 open reduction, 45 Salter–Harris injuries, 107 overview, 40 scaphoid fractures, 107–111 prosthetic replacement, 45 and avascular necrosis, 111 treatment, 44–45 classification, 109, 110 proximal interphalangeal (PIP) joint, complications, 111 dislocations, 121–123 diagnosis, 109–110 pulled elbow, children, 88 mechanisms, 108–109 250 pulmonary embolism, and fractures, 11 non-union, 111 Index overview, 107–108 Smith’s fracture, 98 and recurrent carpal instability, 111 soft tissue injuries, and fractures, 12 and scapholunate advanced collapse, spinal cord injury without radiographic 111 abnormality (SCIWORA), 240 treatment, 110–111 spinal injuries, 223 scaphoid views, 110 classification, 225–227, 228 scapholunate advanced collapse (SLAC), and complete, 227 scaphoid fractures, 111 complications, 229 scapular fractures, 54–56 diagnosis, 225 associated injuries, 56 incomplete, 227, 229–230 classification, 55 overview, 225 complications, 56 rehabilitation, 228–229 diagnosis, 55–56 sensory assessment charts, 226 mechanisms, 55 treatment, 227–228 overview, 54 see also atlantoaxial rotatory subluxations; treatment, 56 atlas fractures; cervical spine fractures; Schatzker’s classification, 165 odontoid fractures; subaxial cervical sciatic nerve, injuries, 33–34 spine injuries; thoracolumbar spine SCIWORA (spinal cord injury without injuries; traumatic spondylolisthesis of radiographic abnormality), 240 the axis screws, 10 spinal shock, 227 see also dynamic hip screws (DHSs) spine, in-line immobilization, 18 secondary surveys, 16, 18–19 sprains, definition, 3 Seddon classification, 28–30 sternoclavicular joint injuries, 52–54 Seinsheimer’s classification, 151–152 classification, 53 sentinel fracture, 231 complications, 54 septicaemia, and fractures, 11 diagnosis, 53 shock, and fractures, 11 mechanisms, 53 shoulder overview, 52 instability, 49 treatment, 53 orthopaedic trauma, 37–61 strains, definition, 3 see also acromioclavicular joint injuries; stress fractures clavicular fractures; scapular fractures; fibula, 193 sternoclavicular joint injuries mechanisms, 6 shoulder dislocations, 46–49 tibia, 193 associated fractures, 49 subaxial cervical spine injuries, 237 classification, 47–48 classification, 237 complications, 49 treatment, 237 diagnosis, 48 subcapital femoral neck fractures, 138–139, mechanisms, 46–47 140–147 recurrent, 49 associated diseases, 146 and rotator cuff tears, 49 children, 146–147 treatment, 48–49 classification, 141–143 see also glenohumeral joint dislocations AO, 143, 144 Simmond’s test, 221, 222 Garden’s, 141–143 simple fractures see closed fractures Pauwels,’ , 143 skeletal traction, 9 complications, 146 skier’s thumb see ulnar collateral ligament diagnosis, 145 injuries mechanisms, 141 skin traction, 9 direct, 141 SLAC (scapholunate advanced collapse), and indirect, 141 scaphoid fractures, 111 overview, 140 251 Index subcapital femoral (cont.) complications, 215 treatment, 145–146 diagnosis, 215 developing countries, 145–146 mechanisms, 214 young patients, 145 overview, 213 subluxation, definition, 3 treatment, 215 subtrochanteric fractures, 139, 150–154 tear drop fracture, 231, 232 classification, 151–153 terminology, 3–4 AO, 153 thenar muscles, wasting, 32 Fielding’s, 153 thigh Seinsheimer’s, 151–152 orthopaedic trauma, 134–159 complications, 154 see also femoral shaft fractures; diagnosis, 153 subtrochanteric fractures mechanisms, 150 thoracolumbar spine injuries, 237–240 overview, 150 burst fractures, 238 treatment, 153–154 children, 240 Sudek’s dystrophy (chronic regional pain classification, 238–240 syndrome), 12 compression fractures, 238, 239 Sunderland system, 29–30 flexion distraction, 238–239 supracondylar femoral fractures, 157, fracture dislocations, 239 160–163 mechanisms, 238 classification, 160–161, 162 overview, 237 complications, 163 sacral fractures, 239–240 diagnosis, 161 THR (total hip replacement), 146 mechanisms, 160 tibia, stress fractures, 193 overview, 160 tibial nerve, injuries, 34 treatment, 163 tibial plafond fractures see pilon fractures supracondylar humeral fractures, 62–67 tibial plateau fractures, 164–168 classification, 62–63 classification, 165–167 AO, 62–63, 64 AO, 165–167 closed manipulation, 66 Schatzker’s, 165 and compartment syndrome, complications, 167–168 67 diagnosis, 167 complications, 66–67 mechanisms, 164 and cubitus valgus, 67 overview, 164 and cubitus varus, 67 treatment, 167 diagnosis, 63–65 tibial shaft fractures, 187–192 mechanisms, 62 children, 192–193 and nerve injuries, 66 classification, 187–190 treatment, 65–66 AO, 187–188 Gustilo’s, 190 talar neck fractures, 205–207 and compartment syndrome, 192 classification, 206 complications, 192 complications, 207 diagnosis, 190–191 diagnosis, 206 mechanisms, 187 mechanisms, 205–206 non-union, 192 overview, 205 overview, 187 treatment, 206 treatment, 191 talus tibial spine fractures, 168–169 dislocations, 207 classification, 168–169 fractures, 207 complications, 169 tarsometatarsal joint injuries, 213–215 diagnosis, 169 252 classification, 214 mechanisms, 168 Index overview, 168 complications, 91 treatment, 169 diagnosis, 91 torus fractures see buckle fractures mechanisms, 88 total hip replacement (THR), 146 night stick fractures, 94 total patellectomy, 172 overview, 88 traction treatment, 91 fractures, 9 ulnar nerve, injuries, 31 skeletal, 9 ulnar nerve palsy, and olecranon fractures, 84 skin, 9 undisplaced fractures, definition, 4 trauma, multiple, 15–20 upper limb trauma calls, 16 orthopaedic trauma, 35, 123 trauma scoring systems, 19–20 peripheral nerve injuries, 30–33 trauma series radiographs, 16 see also arm; elbow; forearm; hand; trauma teams, 16 shoulder; wrist traumatic spondylolisthesis of the axis, 231, 236–237 vascular injuries classification, 236 and fractures, 11–12 mechanisms, 236 and humeral shaft fractures, 60–61 treatment, 237 VISI (volar intercalated segmental injury), traumatic, unilateral, Bankart lesion surgery 113 (TUBS), 49 volar intercalated segmental injury (VISI), trimodal death pattern, 15–16 113 first peak, 15 Volkmann’s ischaemic contractures, 12 second peak, 15 third peak, 15 Wallerian degeneration, 28–29 TUBS (traumatic, unilateral, Bankart lesion Watson’s test, 113 surgery), 49 Winquist classification, 155–156 wrist ulnar collateral ligament injuries, 118 orthopaedic trauma, 98–123 complications, 118 radial nerve injuries, 30 diagnosis, 118 ulnar nerve injuries, 31 mechanisms, 118 see also carpal instability; Colles’ fracture; overview, 118 distal radial fractures; scaphoid treatment, 118 fractures ulnar diaphyseal fractures, 88–91 wrist drop, 60 classification, 88–91 AO, 89–91 Zdrakovic–Damholt classification, 55 253 Index

Until recently, the standardization of diagnosis and assessment of per- sonality disorders has lagged considerably behind that for most other mental disorders. The IPDE is a new instrument which can produce through its two modules diagnoses in accordance with both ICD-10 and DSM-IV criteria. The IPDE is a semistructured clinical interview that provides a means of arriving at the diagnosis of major categories of per- sonality disorders and of assessing personality traits in a standardized and reliable way. It is unique in that it secures reliable information in dif- ferent cultural settings. Written by leading international authorities, this volume forms an invaluable reference manual to the IPDE instrument. Its first section includes an overview of the results of the worldwide field trials of the interview and discussion of the current status of diagnosis and assessment research. The second section detailing the full interview schedule and scoring system for the instrument will further facilitate its use by both clinician and researcher. Assessment and diagnosis of personality disorders Assessment and diagnosis of personality disorders The ICD-10 international personality disorder examination (IPDE) Edited by Armand W. Loranger, Cornell University Medical College, Aleksandar Janca, World Health Organization, and Norman Sartorius, University of Geneva CAMBRIDGE UNIVERSITY PRESS CAMBRIDGE UNIVERSITY PRESS Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, Sao Paulo Cambridge University Press The Edinburgh Building, Cambridge CB2 8RU, UK Published in the United States of America by Cambridge University Press, New York www.cambridge.org Information on this title: www.cambridge.org/9780521580434 © World Health Organization 1997 This publication is in copyright. Subject to statutory exception and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published 1997 This digitally printed version 2007 A catalogue record for this publication is available from the British Library Library of Congress Cataloguing in Publication data Assessment and diagnosis of personality disorders: the International Personality Disorder Examination (IPDE)/edited by Armand W. Loranger, Aleksandar Janca, and Norman Sartorius. p. cm. Includes index. ISBN 0-521-58043-9 (hardback) 1. International Personality Disorder Examination. 2. Personality disorders-Diagnosis. I. Loranger, Armand W. (Armand Walter), 1930- . II. Janca, A. III. Sartorius, N. [DNLM: 1. Personality Disorders — diagnosis. 2. Psychiatric Status Rating Scales. 3. Personality Assessment. WM 190 A846 1997] RC544.A87 1997 616.85'8-dc21 96-45992 CIP DNLM/DLC for Library of Congress ISBN 978-0-521-58043-4 hardback ISBN 978-0-521-04166-9 paperback VII Contents Contributors ix Preface Armand W. Loranger, Aleksandar Janca and Norman Sartorius xi Acknowledgements xiii I Background and Field Trial Background Problems in the field of personality disorders 3 Alv A. Dahl and Antonio Andreoli Review of diagnostic instruments for the assessment of personality disorders Armand W. Loranger 10 Epidemiology of DSM-III personality disorders in the community and in clinical populations James H. Reich and Giovanni de Girolamo 18 International personality disorder examination (IPDE) Armand W. Loranger 43 Experiences with the IPDE Alv A. Dahl and Antonio Andreoli 52 Field Trial Sampling, interviewers, interview procedures Werner Mombour 58 viii Contents Description of centres participating in the IPDE field trial Aleksandar Janca and Charles Pull 61 Results Armand W. Loranger 70 Discussion and conclusions Armand W. Loranger 79 Appendix II International personality disorder examination (IPDE) ICD-10 module Acknowledgements 113 Manual 114 History of the IPDE 114 ICD-10 and DSM-IV 115 Translations of the IPDE 115 Structure of the IPDE 116 Scope of the IPDE 117 Appropriate subjects 118 Limitations of the IPDE 118 Examiner qualifications and training 120 Administration of the IPDE 121 Scoring conventions 122 Recording the scores 124 Computer scoring 124 Handscoring 125 Frequently asked questions about the administration of the IPDE 125 Abbreviating the IPDE 127 Reliability and validity of the IPDE 128 References 129 ICD-10 criteria and corresponding IPDE items 130 IPDE ICD-10 module screening questionnaire 134 IPDE ICD-10 module screening questionnaire scoring summary 137 IPDE ICD-10 module interview schedule 138 IPDE ICD-10 module answer sheet 205 IPDE ICD-10 module handscoring algorithms and summary scoresheet 206 Index 223 IX Contributors Dr Antonio Andreoli Hopital cantonal Unite d'urgences psychiatriques Rue Micheli-du-crest 24 1211 Geneva 14 Switzerland Tel: 00 41 22 372 3866; Fax: 00 41 22 372 8599 DrAlvA.Dahl Department of Psychiatry University of Oslo P.O. Box 85 Vinderen 0319 Oslo 3 Norway Tel: 00 47 22 92 35 30; Fax: 00 47 22 49 58 61 Dr Giovanni de Girolamo Servizio Salute Mentale Viale Popoli 5 50123 Bologna Italy Tel: 00 39 51 649 1166; Fax: 00 39 51 649 2322 Dr Aleksandar Janca Division of Mental Health and Prevention of Substance Abuse World Health Organization 20 Avenue Appia 1211 Geneva 27 Switzerland Tel: 00 41 22 791 3856; Fax 00 41 22 791 4160 Contributors Dr Armand W. Loranger New York Hospital Cornell Medical Center Westchester Division 21 Bloomingdale Road White Plains, New York 10605 USA Tel: 00 1 914 997 5922; Fax: 00 1 914 946 5859 Dr Werner Mombour Leiter der Psychiatr. Poliklinik Max-Planck Institut fur Psychiatrie Kraepelinstrasse 10 80804 Munich Germany Tel: 00 49 89 30 62 2230; Fax: 00 49 89 30 62 2200 Dr Charles Pull Centre hospitalier de Luxembourg Service de Neuropsychiatrie 4 rue Barbie 1210 Luxembourg Tel: 00 352 4411 2256;4411 1706; Fax: 00 352 458 762 Dr James H. Reich 2255 North Point St. San Francisco C A 94123 USA Fax: 001 415 673 2950 Dr Norman Sartorius Department of Psychiatry University of Geneva 1205 Geneva Switzerland Tel: 00 41 22 328 0078; Fax: 00 41 22 328 0079 XI Preface One of the major goals of the World Health Organization's (WHO) Mental Health Programme has been the development of a common lan- guage for worldwide use by psychiatrists and other mental health profes- sionals. The WHO/NIH Joint Project on Diagnosis and Classification of Mental Disorders, Alcohol- and Drug-related Problems is the most recent endeavour in this programme. It has developed a number of diag- nostic instruments for the assessment of mental disorders in different cultures and tested them for their cross-cultural applicability, reliability and validity.12 One of these instruments, the Composite International Diagnostic Interview (CIDI),3 is highly structured and intended for use by lay inter- viewers in epidemiological studies. Another, the Schedules for Clinical Assessment in Neuropsychiatry (SCAN),4 is a semi-structured interview for use by clinicians, i.e., those capable of making independent psychi- atric diagnoses. Since neither interview covers personality disorders, it was necessary to develop an instrument to assess them according to cri- teria in the latest classification systems. The new instrument, the International Personality Disorder Examination (IPDE), has been developed from the Personality Disorder Examination (PDE),5 which was modified for international use and com- patibility with the International Classification of Diseases, 10th revision (ICD-10), and the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). The current version of the IPDE has been produced in two modules, one for ICD-10 and one for DSM-IV criteria for personality disorders. The IPDE was tested in a major international field trial at 14 centres in 11 countries in North America, Europe, Africa and Asia. The primary objectives were to determine its cultural acceptability, user-friendliness, interrater reliability and temporal stability. In the course of the field trial a large body of data on personality disorders in different cultures was collected. This book describes the trial, and it also addresses several xii Preface related issues, including problems in the assessment of personality disor- ders and their rates, distribution and characteristics around the world. The book also contains the ICD-10 module of IPDE; the DSM-IV mod- ule of IPDE, without accompanying text describing its background and field trial, can be obtained from the American Psychiatric Press, Inc. Dr Armand W. Loranger Dr Aleksandar Janca Dr Norman Sartorius References Sartorius, N. & Janca, A. Psychiatric assessment instruments developed by the World Health Organization. Social Psychiatry and Psychiatric Epidemiology, 1996; 31: 55-69. Janca, A., Ustun, T.B. & Sartorius, N. New versions of World Health Organization instruments for the assessment of mental disorders. Acta Psychiatrica Scandinavica, 1994; 90: 73-83. World Health Organization. The Composite International Diagnostic Interview (CIDI), core version 1.1. Washington, DC: American Psychiatric Press, Inc., 1993. World Health Organization. Schedules for Clinical Assessment in Neuropsychiatry (SCAN), version 2.0. Washington, DC: American Psychiatric Press, Inc., 1994. Loranger, A.W. Personality Disorder Examination (PDE) Manual. Yonkers, NY: D.V. Communications, 1988. XIII Acknowledgements The IPDE was developed for the World Health Organization (WHO) by Dr. Armand W. Loranger in collaboration with the following colleagues from the international psychiatric community: Drs. Antonio Andreoli (Geneva), Peter Berger (Vienna), Peter Buchheim (Munich), S. M. Channabasavanna (Bangalore), Bina Coid (London), Alv A. Dahl (Oslo), Rene F. W. Diekstra (Leiden), Brian Ferguson (Nottingham), Lawrence B. Jacobsberg (New York), Aleksandar Janca (WHO), Werner Mombour (Munich), Yutaka Ono (Tokyo), Charles Pull (Luxembourg), Norman Sartorius (Geneva), and R. Onyango Sumba (Nairobi). The IPDE was developed in the framework of the Joint Project on Diagnosis and Classification of Mental Disorders, Alcohol- and Drug- related Problems carried out by the WHO and US National Institutes of Health (formerly Alcohol, Drug and Mental Health Adminstration). I Background and Field Trial Background Problems in the field of personality disorders Alv A. Dahl and Antonio Andreoli When the World Health Organization/US Alcohol, Drug Abuse and Mental Health Administration (WHO/ADAMHA) decided to conduct the International Pilot Study of Personality Disorders (IPSPD), they entered one of the most controversial fields of mental disorders. Many psychiatrists have doubted the validity of personality disorders (PDs) and their diagnostic reliability has been found to be very low. Theories of their etiology have implicated constitution, genes, brain abnormali- ties, bad morals, poor environment, and disturbed psychological devel- opment. There are no generally accepted treatments for PDs, and their long-term outcome is often unknown. Since the introduction of DSM-III in 1980, however, empirical studies of PDs have flourished. The research has brought into focus many of the problems related to PDs. This chapter will describe some of them, and try to place the IPSPD and IPDE (International Personality Disorder Examination) within that context. Basic descriptions of personality Throughout history attempts have been made to identify the basic dimen- sions or categories that best define the essential similarities and differences among people. Hippocrates identified four basic temperaments based on the balance of the body fluids. The phrenologists stated that they were able to identify personality characteristics through the contour variations of the skull. Kretschmer and Sheldon described personality features based on physique, and believed that these personality types predisposed to the major mental disorders. In 1908 Heyman and Wiersma statistically ana- lyzed the personality traits of a great number of ordinary people, and they found that personality could be described by three orthogonal factors. The study of basic personality dimensions was later promoted by Eysenck who identified three dimensions called neuroticism, extraversion, and psychoti- cism. Personality psychologists later expanded these to five dimensions ('the big five'), adding conscientiousness and agreeableness.1 A. A. Dahl and A. Andreoli Psychoanalysis introduced a general theory of personality develop- ment based on the solution of phase-specific drive conflicts during child- hood. From this emerged the oral, anal, and phallic-genital personality types. As psychoanalysis progressed from a focus on drive conflicts to the study of ego functions, object relations, and self-development, a more interpersonal view was taken to describe conflicts and defects in personality functioning. For example, various interpersonal wishes and fears characterize the personality types described by Smith Benjamin.2 Recently, a basic separation of temperament and character was proposed by Cloninger et al? who stated that descriptive data about individual behaviour were insufficient to permit strong preferences among alterna- tive ways of summarizing personality traits. They proposed a general psychobiological model of personality based on three temperamental and four character dimensions. Deviant personalities, psychopathies, and personality disorders The problems in describing normal personality raise the fundamental question of what the difference is between normal and abnormal person- ality. Disorders of personality were described in the nineteenth century, along with such concepts as character, constitution, temperament, and self.4 Pinel, in 1801, described personalities that were deviant in their emotions. Pilchard, in 1835, identified patients who violated social norms as having 'moral insanity'. He raised the fundamental question, still very important in forensic psychiatry, of whether deviant personalities are mad or bad. In 1873, Koch described personality deviance in several domains as 'psychopathic inferiorities', thereby embracing the view of Morel that those with

deviant personalities are inferior to normal people. The moral- istic attitude towards deviant personalities was based on this assumption, and a derogatory view of patients with PD is still quite common. From the very beginning PD was debated as a nosological entity, because of moral judgements about unacceptable personality traits, problems of their delimitation with normality, and the lack of guilt and remorse in many such patients. Because individuals with PD often did not consider themselves mentally ill, their diagnosis was less reliable than it was for many other mental disorders. Schneider5 proposed the view that personality traits are continuously distributed, the extreme deviations of a trait being pathological, if the indi- vidual or society suffered because of them. His 10 types of PD illustrate the fundamental arbitrariness of categorical classification of abnormal Problems in the field of PD personalities. However, Schneider's classification of personality disorders influenced the International Classification of Diseases (ICD) of the WHO6 and The Diagnostic and Statistical Manual (DSM) of the American Psychiatric Association7 (Table 1). However, the fact that new disorders were added and deleted with each edition, confirms the validity of Lewis'8 observation. 'It is plain that Kraepelin found the classification of PD defeating, as he frankly admits. Successive editions of his textbook show him struggling with little success, to cope with the task of shaping cate- gories out of the rich variety of human character and conduct. His efforts and his failure are characteristic examples of the frustration which besets students of personality when they aim at precision.' Table 1. Classification of personality disorders Schneider (1923) ICD-10Q993) DSM-III-R(1987) Depressive Hyperthymic Cyclothymia* Fanatical Paranoid Paranoid Emotionally unstable: Explosive Impulsive type Explosive* Labile Borderline type Borderline Affectionless Dissocial Antisocial Insecure: sensitive Anxious (avoidant) Avoidant anancastic Anankastic Obsessive-compulsive Asthenic Hypochondriasis* Hypochondriasis* Attention-seeking Histrionic Histrionic Schizoid Schizoid Dependent Dependent Schizotypal Narcissistic Passive aggressive *Located elsewhere in the classification The relation to normal personality Abnormal personality traits exist in milder forms in normal individuals. If the traits manifest themselves as inflexible responses to a broad range A. A. Dahl and A. Andreoli of personal and social situations and result in considerable personal dis- tress or social disruption, they are called PD. They represent extreme or significant deviations from the way in which the average individual in a given culture perceives, thinks, feels, and relates to others. They are thus only quantitatively and not qualitatively different from normal personal- ity. However, the border between normal and abnormal personalities is difficult to draw. The relation to culture and sex Cultural diversity is a characteristic of human nature. Behavioural pat- terns considered normal in one culture are seen as deviant in another. To identify behavioural patterns that are deviant in all cultures is very diffi- cult. The PDs primarily reflect the views of Western European and North American psychiatry and they may not be equally applicable in other cultures. Role expectations and behaviour, also differ considerably between the sexes. Problems may arise if psychiatry defines personality deviance without considering social role expectations. Unknown personality traits and the use of informants Many individuals may be unaware of some of their personality traits and behavioural patterns. Therefore, an individual often can only provide limited information about him or herself. He/she may also consciously try to deny certain socially undesirable personality traits. These prob- lems can partially be solved by interviewing an informant who knows the individual well, but this is still not a standard procedure in the evalua- tion of PD. Sometimes informants describe PD-pathology that patients deny.9 When the accounts of the subject and the informant deviate, which source of information is more valid? A method of integrating information from such discrepant reports is needed. Separate axis and diagnostic criteria The DSM of Mental Disorders, Third Edition (DSM-III)7 published by the American Psychiatric Association in 1980 made two innovations of major importance for the study of PDs. They were placed on a separate axis (Axis II), and explicit criteria provided guidelines for the diagnosis of each of the 11 PDs. The introduction of diagnostic criteria stimulated empirical research on the reliability of PDs and the optimal diagnostic criteria. Problems in the field of PD In DSM-III, PDs were defined by both monothetic and polythetic sets of criteria. Monothetic requires that all criteria be fulfilled, while poly- thetic requires patients to meet a certain number of the total criteria set, thus allowing some variation in the symptoms of patients with the same disorder. In DSM-III-R7 all PDs were defined by sets of polythetic crite- ria. The number of criteria found in a patient can also be used as a dimen- sional rating of that PD. For each disorder a cut-off level for a positive diagnosis has been arbitrarily set. It has been shown9 that the interrater reliability of PD diagnoses is higher in samples of patients with more prototypical forms of a disorder. Following the publication of DSM-III there was considerable debate about the reliability and validity of certain criteria,10 and revisions were made in DSM-III-R and DSM-IV. 'State-Trait' problems When DSM-III separated the mental disorders into two axes, Axis II was reserved for disorders that, 'all share the features of generally having an onset in childhood or adolescence and usually persisting in a stable form (without periods of remission or exacerbation) into adult life. With only a few exceptions, these features are not present for Axis I disorders'.7 However, sometimes certain Axis I disorders may begin early in life and produce changes in personality. Some PDs may also predispose to Axis I disorders. Some Axis I disorders change behaviour temporarily, and in a cross-sectional evaluation it is often difficult to determine if the patient's behaviour represents longstanding personality traits or symptoms of a current Axis I disorder, that will disappear with improvement in the dis- order (state). Confounding trait and state seems to be one of the main reasons clinicians sometimes over-diagnose PDs. They often do not ade- quately explore the duration of a behavioural pattern. Self-report instru- ments for diagnosing PDs are especially sensitive to this artifact, which may explain the high proportion of false positive PD diagnoses with such instruments. The IPDE requires a duration of at least five years, and onset before the age of 25 for abnormal personality traits. Loranger et al.n demon- strated that the state-trait problem was negligible when the Personality Disorder Examination (PDE) was used by experienced clinicians. But Zimmerman, in his review of PD studies9 found that PD examinations during acute psychiatric states gave higher rates than after normalization of the Axis I disorder. If possible, a diagnosis of PD should be postponed if the patient is psychotic or severely depressed or anxious. Since PDs A. A. Dahl and A. Andreoli concern a patient's long-term functioning, the PD diagnosis should be stable over time. Test-retest reliability studies of PDs show a falloff in reliability from initial to short-term and long-term examination.9 Categories and dimensions In practice many patients receive a diagnosis of several PDs at the same examination. This diagnostic overlap creates problems in defining homogeneous groups in psychiatric research. Although DSM-III-R out- lined three clusters of PDs, the eccentric, dramatic, and anxious, diag- nostic overlap is often found both within and across these clusters. One cause of diagnostic overlap is that similar diagnostic criteria are used to define several PDs. Multiple PD diagnoses are also caused by the use of arbitrary categories, which may not correspond to latent constructs or personality dimensions. In DSM-IV12 the overlap in criteria has been reduced to some extent. DSM and ICD have adopted a categorical classification system. They provide simplified abstractions which are easy to communicate, but important information about the patient is subsequently lost. A dimen- sional approach to PD classification, which locates patients along a set of dimensions, has obvious advantages, but none have been used yet in any nosology. Although a dimensional approach provides more information, it is more difficult to communicate. There also seems to be a lack of agreement regarding which dimensions to include, but this problem now seems closer to a solution.13 Progress in the field of psychiatric diagnoses Although validation of psychiatric diagnoses is generally lacking, con- siderable progress has been made since the late 1980s.14 Diagnostic cri- teria for mental disorders have made diagnoses more reliable. This is particularly so, when used in combination with structured psychiatric interviews. Although several PD instruments have been developed recently, their transcultural validity is virtually unknown.15 Statistics have been developed which give a meaningful description of interrater reliability,16 and with the use of videotaped interviews patients can be diagnosed by trained clinicians all around the world. Because of this methodological progress, a study such as the ISPSD was indicated. Its objectives were to: determine the feasibilty of using a standardized semi- structured interview (IPDE) to identify and diagnose PDs in different Problems in the field of PD cultures; determine the interrater reliability of the IPDE in its various language versions; and investigate selected aspects of assessment, such as temporal stability. All of these objectives are essential to progress in the field of PD. References 1 McCrae, R.R. & Costa, Jr., P.T. Personality in Adulthood. New York: Guilford, 1990. 2 Smith Benjamin, L. Interpersonal Diagnosis and Treatment of Personality Disorders. New York: Guilford, 1993. 3 Cloninger, C.R., Svrakic, D.M. & Przybeck, T.R. A psychobiological model of temperament and character. Archives of General Psychiatry, 1993; 50: 975-90. 4 Berrios, G.E. European views on personality disorders: a conceptual history. Comprehensive Psychiatry, 1993; 34: 14-30. 5 Schneider, K. Psychopathic Personalities. London: Cassell, 1950. 6 World Health Organization. International Statistical Classification of Diseases and Related Health Problems, 10th revision. Geneva: World Health Organisation, 1992. 7 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 3rd revised edn. Washington, DC, American Psychiatric Press 1987. 8 Lewis, A. Psychopathic personality: a most elusive category. Psychological Medicine, 1974; 4: 133^0. 9 Zimmerman, M. Diagnosing personality disorders. A review of issues and research methods. Archives of General Psychiatry, 1994; 51: 225-45. 10 Livesley, W.J. & Jackson, D.N. Guidelines for developing, evaluating, and revis- ing the classification of personality disorders. Journal of Nervous and Mental Disease, 1992; 180: 609-18. 11 Loranger, A.W., Lenzenweger, M.F., Gartner, A.F., Susman, V.L. et al. Trait- state artifacts and the diagnosis of personality disorders. Archives of General Psychiatry, 1991; 48: 720-8. 12 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, revised 4th edn. Washington, DC, American Psychiatric Press 1994. 13 Widiger, T.A. Personality disorder dimensional models proposed for DSM-IV. Journal of Personality Disorders, 1991; 5: 386-98. 14 Kendell, R.E. Clinical validity. Psychological Medicine, 1989; 19: 45-55. 15 Reich, J.H. Instruments measuring DSM-III and DSM-III-R personality disor- ders. Journal Personality Disorders, 1987; 1: 220-40. 16 Bartko, J.J. & Carpenter, W. On the methods and theory of reliability. Journal Nervous and Mental Diseases, 1976; 163: 307-17. 10 Review of diagnostic instruments for the assessment of personality disorders Armand W. Loranger This chapter is intended to acquaint the reader with most of the instru- ments specifically designed to diagnose the personality disorders (PDs). The review makes no pretense at completeness. Preference is given to interviews and inventories that have also been used by investigators other than the developers themselves. The International Personality Disorder Examination (IPDE) is not included, since most of this volume (see Part II) is devoted to it. The account is mainly descriptive rather than analytical. For more of the latter, the interested reader will find Zimmerman's recent review especially informative.1 There is an axiom in psychometrics that the more closely a test sam- ples the criterion it attempts to predict, the more valid it is likely to be. Historically, the identification and delineation of PDs has emerged pri- marily from clinical observation. Therefore, it should not be surprising if diagnoses based on semistructured clinical interviews approximate clini- cal diagnoses more than those based on self-administered inventories. The obvious limitation of the latter is their inability to provide the obser- vations, cross-examination, and judgement of the experienced clinician. Except for the dementias and mental retardation, there is nothing in the history of clinical psychological tests to warrant their being viewed as a close approximation to a psychiatric diagnosis. Self-administered tests, however, may be valuable as economical screening devices. The literature suggests that personality disorder inven- tories are especially prone to false-positive diagnoses.2 Of course

this is precisely what one expects from a screening instrument, where the main concern is to guard against an intolerable number of false-negatives. Because dimensional information is often used to supplement categorical PD diagnoses, inventories may also prove useful in estimating the extent to which an individual shares certain maladaptive traits with those who fulfill the categorical requirements for a particular type of PD. The esti- mates, however, are likely to be no more than moderately correlated with dimensional assessments based on semistructured clinical interviews. 11 Review of diagnostic instruments Personality Disorder Interviews Diagnostic Interview for Borderlines (DIB) In the years immediately preceding the appearance of DSM-III, Gunderson and his colleagues developed an interview for the diagnosis of borderline personality disorder.3 The DIB was based on criteria quite similar to those ultimately adopted by the DSM-III. In its revised form (DIB-R)4 it consists of 186 questions divided into four sections: affect, cognition, impulse action patterns, and interpersonal relationships. The information obtained from the questions is used to rate 22 statements that describe important features of borderline personality disorder. The scores are then algorithmically scaled to yield a total score of 0 to 10, with a recommended cutoff score of 8 required for the diagnosis. Typically, the interview takes between 45 minutes and 1 hour to com- plete. In the 1980s the original DIB was used in a large number of research investigations of borderline disorder. There is now a consider- able literature and, not surprisingly, it shows varying agreement with clinical and other methods of diagnosing borderline disorder. Structured Interview for DSM-III-R Personality Disorders (SIDP-R) The revised form of the SIDP-R, developed by Pfohl and colleagues at the University of Iowa, is organized into 17 topically oriented sections, each containing about 10 questions.5 At the end of every section there is a list of those DSM-III-R criteria that are to be rated as: not present (0), moderately present (1), or severely present (2), on the basis of the sub- ject's responses to the questions in the section. Brief descriptors serve as anchors in rating, and a score of either 1 or 2 is considered evidence that the criterion has been met. At the end of the interview there is a summary rating form with the criteria listed by PD. The interview usually takes between one and a half and two hours. When feasible the interviewer is expected to use information from other sources, including an informant interview based on some of the same questions. The authors have reported poor agreement between patient and informant regarding whether or not a PD is present (kappa=.13).6 Other than the judgement of the interviewer, there are no specific guidelines for dealing with such conflicting information. Published data on interrater agreement in scoring the original version of the SIDP indicate that, in general, the reliability is quite satisfactory and comparable to that obtained with similar interviews.7 12 A. W. Loranger Structured Clinical Interview for DSM-III-R (SCID-II) The SCID-II is a personality disorder module of the popular SCID,8 a diagnostic interview developed by Spitzer and colleagues that is intended to help the clinician make most DSM-III-R diagnoses. It differs from the main Axis I SCID interview, as well as from other PD inter- views, in that it is preceded by a 113-item personality questionnaire con- cerning the Axis II criteria. The purpose of this is to save interview time. Ordinarily the patient is interviewed only about those criteria that are acknowledged on the questionnaire. The interview itself is organized on a disorder by disorder basis, rather than around certain topics or domains of behaviour. The examiner is expected to use follow-up questions as needed and is encouraged to use other sources of information as well. As one proceeds through the interview, the individual criteria are scored as: absent (1), subthreshold (2), or threshold (3). The SCID-II, along with the parent SCID, has been the subject of a multicentre study of interrater reliability. Detailed results have yet to be published, but they are reported to be similar to those with the SIDP and the IPDE.1 It will be particularly important to determine the extent to which false-negative diagnoses may be expected as a consequence of the questionnaire-inter- view format that is unique to the SCID-II. Personality Assessment Schedule (PAS) The PAS which is in its fifth revision, was developed in England by Tyrer and his colleagues911 and has received limited use elsewhere. The interview inquires about 24 personality characteristics that are rated on a 9-point scale at the conclusion. Preference is given to interviewing infor- mants rather than patients because they are thought to be in a better posi- tion to assess the social disruption caused by abnormal traits and to be free of the distortion produced by the current mental state. The interview is said to take about one hour to complete if both patient and informant are interviewed. The 24 personality attributes assessed by the schedule are pessimism, worthlessness, optimism, lability, anxiousness, suspiciousness, introspec- tion, shyness, aloofness, sensitivity, vulnerability, irritability, impulsive- ness, aggression, callousness, irresponsibility, childishness, resourcelessness, dependence, submissiveness, conscientiousness, rigidity, eccentricity, and hypochondriasis. The authors used a cluster analysis of their data to identify four major types of abnormal personality: sociopathic, passive-dependent, anankastic, and schizoid. Nine subsidiary categories 13 Review of diagnostic instruments also emerged: explosive (impulsive), sensitive aggressive, histrionic, asthenic, anxious, paranoid, hypochondriacal, dysthymic, and avoidant. Interrater agreement in rating the 24 attributes on a dimensional scale is reported to be generally good, as has that for the diagnosis of a PD per se. Poor agreement, however, has been found between patients and infor- mants, and some studies have used an arbitrary and complicated set of guidelines to determine which information to use. The 24 personality dimensions on the PAS are neither described in detail nor defined by specific criteria. They are rated according to the degree of social impairment they produce. This is a departure from DSM-III-R and ICD-10, which include subjective distress as well as social impairment in the definition of a personality disorder, although both are not required for a diagnosis. The PAS mandates social impair- ment and is not directly concerned with subjective distress. The assump- tion is that if subjective distress is high enough to be indicative of a personality disorder, then marked social impairment will be present. The PAS also follows a hierarchical system of diagnosis that identifies the disorder with the greatest social impairment as the primary one. Although the PAS was not developed to assess the PDs in DSM-III-R or ICD-10, it does provide algorithms for making diagnoses in those sys- tems. It is not known, however, whether the algorithms will identify the same cases as those interviews based on the criteria themselves. Standardized Assessment of Personality (SAP) The SAP12 is a short semistructured interview developed by Pilgrim and Mann, and designed for use with a relative or close friend of a patient. It takes 10-15 minutes to administer. The informant is asked to describe the patient's personality prior to illness, and a series of probes explores specific areas of personality. Although it claims to assess PDs in the ICD-10 and DSM-III-R classification systems, it does not systematically survey the more than 100 criteria on which those two systems are based. It has had limited use so far, other than by its developers. Personality Disorder Inventories Millon Clinical Multiaxial Inventory (MCMI) The MCMI is unique in that it is based on the author's own theory of per- sonality and psychopathology and also claims to be congruent with the 14 A. W. Loranger DSM-III-R nosology. It is not considered suitable for use with normals. The latest version (MCMI-II)13 consists of 175 true-false items aggre- gated in 20 clinical scales. These in turn are organized into three broad categories: persistent personality features, current symptom states, and levels of pathology. Norms for the test are based on several groups of normal subjects and numerous clinical samples. They include base rate scores calculated from prevalence data. The claim that it maps the domain of DSM-III Axis II has been challenged and remains to be demonstrated.1418 Although more research on this subject needs to be done, efforts so far to establish a correspondence between the MCMI and the clinical diagnosis of PDs have been disappointing.1922 Personality Diagnostic Questionnaire (PDQ-R) In its revised form the PDQ-R is a 189-item true-false questionnaire developed by Hyler and associates.23 The content is keyed to the DSM- III-R personality disorders. One or more items are devoted to each Axis II criterion, and the wording is close to the criteria. For example, the bor- derline criterion, 'Inappropriate, intense anger or lack of control of anger,' is assessed by these two statements: 'I rarely get so angry that I lose control' (false) and 'I've often gotten into more real physical fights than most people' (true). A borderline diagnosis is given when the respondent answers at least one of the items that sample each of the five or more criteria required for the diagnosis in the DSM-III-R. As with the MCMI, studies have generally found a poor correspon- dence between the PDQ and personality diagnoses made by clinicians with and without semistructured interviews.24"27 Tridimensional Personality Questionnaire (TPQ) The TPQ,28 developed by Cloninger is a 100-item self-report inventory that measures three major personality dimensions: novelty seeking, harm avoidance, and reward dependence. The inventory is based on a theoreti- cal biosocial model that integrates neuroanatomical and neurophysiolog- ical constructs with learning styles and three personality dimensions. Normative data are based on a US sample of 1019 adults. The TPQ is available in a number of languages. Novelty seeking has four subscales: exploratory excitability vs stoic rigidity (9 items), impulsiveness vs reflection (8 items), extravagance vs reserve (7 items), and disorderliness vs regimentation (10 items). Harm 15 Review of diagnostic instruments avoidance has four subscales: anticipatory worry vs uninhibited opti- mism (10 items), fear of uncertainty vs confidence (7 items), shyness with strangers vs gregariousness (7 items), and fatigability and asthenia vs vigor (10 items). Reward dependence has four subscales: sentimental- ity vs insensitiveness (5 items), persistence vs irresoluteness (9 items), attachment vs detachment (11 items) and dependence vs independence (5 items). Temperament and Character Inventory (TCI) As might have been anticipated, Cloninger discovered that certain tem- perament types occurred more frequently with some PDs. However, con- trary to his original expectation, individuals with extreme temperament profiles on the TPQ did not necessarily have PDs; indeed some were well adapted normals. Consequently, Cloninger subsequently invoked the additional role of 'character' traits. According to his revised theory29 temperament, which now includes a fourth dimension, persistence, determines the type of PD, but character determines whether there will be a PD. The 226-item true-false TCI, enlarges the scope of the TPQ to measure the acquired self-concept character traits of self-directedness, cooperatives, and self-transcendence. Preliminary data30 suggest that each type of PD in DSM-III-R is associated with a unique profile of scores on the TCI. Although the test has been promoted as an efficient guide to diagnosis and treatment, information is not yet available regard- ing the sensitivity and specificity of the TCI in identifying the individual DSM-III-R personality disorders, when they are diagnosed by clinicians using semistuctured interviews. References 1 Zimmerman, M. Diagnosing personality disorders: a review of issues and meth- ods. Archives of General Psychiatry, 1994; 51: 225^45. 2 Loranger, A.W. Are current self-report and interview measures adequate for epi- demiological studies of personality disorders? Journal of Personality Disorders, 1992; 6: 313-25. 3 Gunderson, J.G. & Kolb, J.E. The Diagnostic Interview for Borderlines. American Journal of Psychiatry, 1981; 138: 896. 4 Zanarini, M.C., Gunderson, J.G., Frankenburg, F.R. & Chauncey, D.L. The revised Diagnostic Interview for Borderlines: Discriminating BPD from other Axis II disorders. Journal of Personality Disorders, 1989; 3: 10. 5 Pfohl, B., Blum, N., Zimmerman, M. & Stangl, D. Structured Interview for 16 A. W. Loranger DSM-III-R Personality SIDP-R, draft edition. Iowa City, Department of Psychiatry, University of Iowa, April 27,1989. 6 Zimmerman, M., Pfohl, B., Coryell, W. et al. Diagnosing personality disorder in depressed patients. A comparison of patient and informant interviews. Archives of General Psychiatry, 1988; 45: 733. 7 Stangl, D., Pfohl, B., Zimmerman, M. et al. A structured interview for the DSM- III personality disorders: A preliminary report. Archives of General Psychiatry, 1985; 42: 591. 8 Spitzer,

R.L., Williams, J.B.W., Gibbon, M. & First, M. User's Guide for the Structured Clinical Interview for DSM-III-R. Washington, DC: American Psychiatric Association Press, 1990. 9 Tyrer, P. Personality Disorders: Diagnosis, Management and Course. Boston: Wright, 1988. 10 Tyrer, P., Strauss, J. & Cicchetti, D. Temporal reliability of personality in psy- chiatric patients. Psychological Medicine, 1983; 13: 393. 11 Tyrer, P., Cicchetti, D.V., Casey, P.R. et al. Cross-national reliability study of a schedule for assessing personality disorders. Journal of Nervous and Mental Disease, 1984; 172: 718. 12 Pilgrim, J. & Mann, A. Use of the ICD-10 version of the Standardized Assessment of Personality to determine the prevalence of personality disorder in psychiatric patients. Psychological Medicine, 1990; 20: 985-91. 13 Millon T. Manual for the MCMI-II, 2nd edn. Minneapolis: National Computer Systems, 1987. 14 Widiger, T.A., Williams, J.B.W., Spitzer, R.L. & Frances, A. The MCMI as a measure of DSM-III. Journal of Personality Assessment, 1985; 49: 366. 15 Widiger, T.A., Williams, J.B.W., Spitzer, R.L. & Frances, A. The MCMI and DSM-III: A brief rejoinder to Millon. Journal of Personality Assessment, 1986; 50: 198. 16 Widiger, T.A. & Sanderson, C. The convergent and discriminant validity of the MCMI as a measure of the DSM-III personality disorders. Journal of Personality Assessment, 1987; 51: 228. 17 Millon, T. The MCMI provides a good assessment of DSM-III disorders: The MCMI-II will prove even better. Journal of Personality Assessment, 1985; 49: 379. 18 Millon, T. The MCMI and DSM-III: Further commentaries. Journal of Personality Assessment, 1986; 50: 205. 19 Reich, J.H., Noyes, R. & Troughton, E. Comparison of three DSM-III personal- ity disorder instruments. In Conference on the Millon Clinical Inventories (MCMI, MBHI, MAPI). Minneapolis: National Computer Systems, 1987. 20 Wetzler, S. & Dubro, A. Diagnosis of personality disorders by the Millon Clinical Multiaxial Inventory. Journal of Nervous and Mental Disease, 1990; 178:261. 21 Piersma, H.L. The MCMI as a measure of DSM-III Axis II diagnoses: An empir- ical comparison. Journal of Clinical Psychology, 1987; 43: 479. 17 Review of diagnostic instruments 22 Repko, G.R. & Cooper, R. The diagnosis of personality disorder: A comparison of MMPI profile, Millon Inventory, and clinical judgment. Journal of Clinical Psychology, 1985; 41: 867. 23 Hyler, S.E. & Rieder, R.O. PDQ-R Personality Questionnaire. New York: New York State Psychiatric Institute, July 15,1986. 24 Hurt. S.W., Hyler, S.E., Frances, A. et al. Assessing borderline personality disor- der with self-report, clinical interview or semistructured interview. American Journal of Psychiatry, 1984; 141: 1228. 25 Hyler, S.E., Rieder, R.O., Williams, J.B.W. et al. A comparison of clinical and self-report diagnoses of DSM-III personality disorders in 552 patients. Comprehensive Psychiatry, 1989; 30: 170. 26 Pfohl, B., Barrash, J., True, B. & Alexander, B. Failure of two Axis I measures to predict medication noncompliance among hypertensive patients. Journal of Personality Disorders, 1989; 3: 45. 27 Dubro, A., Wetzler, S. & Kahn, M.W. A comparison of three self-report ques- tionnaires for the diagnosis of DSM-III personality disorders. Journal of Personality Disorders, 1988; 2: 256. 28 Cloninger, C.R. A systematic method for clinical description and classification of personality variants. A rchives of General Psychiatry, 1987; 44: 573-88. 29 Cloninger, C.R., Svrakic, D.M. & Przybeck, T.R. A psychobiological model of temperament and character. Archives of General Psychiatry, 1993; 50: 975-90. 30 Svrakic, D.M., Whitehead, C, Przybeck, T.R. & Cloninger, C.R. Differential diagnosis of personality disorders by the seven-factor model of temperament and character. A rchives of General Psychiatry, 1993; 50: 991-99. 18 Epidemiology of DSM-III personality disorders in the community and in clinical populations James H. Reich and Giovanni de Girolamo Although the early Greek philosophers wondered about the influence of personality on health, it is only recently that the epidemiology of person- ality disorders (PDs) has begun to be scientifically investigated. This is because we have now developed a number of standardized instruments to assess personality and PD in an empirical fashion. The first com- prehensive epidemiologic reviews in the English language have only been published since the mid-1980s.^ The need for the epidemiological investigation of PD seems justified for several reasons: firstly, as seen in the most recent epidemiological surveys, PDs are frequent and have been found in different countries and sociocultural settings; secondly, PDs can seriously impair the life of the affected individual and can be highly disruptive to societies, communities, and families; thirdly, personality status is often a major predictive variable in determining the outcome of psychiatric disorders and the response to treatment.56 In this chapter we review the main epidemiological literature on PDs up to the end of 1993, focusing mainly on studies employing DSM-III or DSM-III-related measures of personality. Firstly community prevalence studies of PD will be reviewed. We then look at the prevalence of indi- vidual PDs in the community. Finally, we consider PDs in psychiatric populations. Many of the DSM-III categories of PD have counterparts in the ICD-10 classification; however, when this chapter was being written, there were no studies yet which directly employed ICD-10 criteria. For those interested in the literature prior to DSM-III and ICD-10, Neugebauer et aV reviewed 20 epidemiological psychiatric studies car- ried out in Europe and North America since 1950. They found an aver- age prevalence rate for PD of 7%. However, their estimate included alcoholism and drug abuse among the PDs. A few years later Perry and Vaillant8 suggested that between 5 and 15% of the adult population can be expected to manifest PDs. Four recently published studies ascertained the prevalence rate of PD 19 Epidemiology of DSM-III PDs in community samples, and used assessment instruments specific for PD.9~~12 They will be briefly reviewed separately. In a random sample of 200 people selected from urban and rural com- munities and assessed with the Personality Assessment Schedule (PAS), a PD was found in 26 subjects (13%).9 Explosive PD was the most com- mon type. There were no differences between urban and rural samples, or between men and women among the 16 (8%) identified as psychiatric cases on the Present State Examination (PSE), more than half of whom also had a PD. Social functioning was worse in those with PD than in those with a normal personality, with no significant differences among the different categories of PD. Maier et al.10 surveyed an unscreened sample of 109 families for life- time diagnoses of both Axis I disorders and PD. Among 447 subjects who were personally interviewed with the Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-L) and the Structured Clinical Interview for DSM-III-R (SCID-II), they found rates of PD comparable to the other studies. The rate among males was 9.9% and among females 10.5%, and it was higher in younger than in older subjects. Significant associations between current Axis I disorders and PD were observed, in particular anxiety disorders with avoidant PD, and affective disorders with borderline PD. In a community sample of 235 adults surveyed with a self-adminis- tered instrument, the Personality Diagnostic Questionnaire (PDQ), 26 were diagnosed as having a PD, yielding an age-adjusted prevalence of 11.1%.U A history of alcohol abuse, poor employment, and marital problems was more common in the group with PDs. The age and sex dis- tribution of the DSM-III personality cluster traits was also assessed.13 Traits in the schizoid cluster were not associated with age, while those in the dramatic and the anxious clusters were. Women aged 31 to 40 and men aged 18 to 30 had the highest rate of PDs. Women aged 31 to 40 had a higher mean number of traits than their male counterparts, and also a corresponding increase in impairment. In a study by Zimmerman and Coryell, 697 relatives of psychiatric patients and healthy controls who were interviewed with the Structured Interview for Personality Disorders (SIPD) also took the PDQ.12 More had a PD according to the interview than the questionnaire (13.5% vs 10.33%). Schizotypal, histrionic, antisocial and passive-aggressive were the most frequent diagnoses from the SIDP, while dependent PD and multiple diagnoses were more frequent using the PDQ. One conclusion from this study that is especially relevant to the present review, is that 20 J. H. Reich and G. de Girolamo questionnaire and interview assessments of PD generally show a poor concordance. Therefore, the type of assessment can strongly affect the rate of a disorder. To summarize, although different investigators have used different instruments and populations, the prevalence of PD ranged from 10.3% to 13.5%, a highly consistent prevalence rate of PD in the community. The rate seems to vary with age, with a slight decrease in older age-groups. Urban populations and lower socioeconomic groups showed higher rates. Although the sex ratio is different for specific types of PD, the overall rates of PD are about equal for the two sexes. Community epidemiological studies of specified personality disorders Table 1 lists the prevalence rates for specific PDs. The majority of the estimates come from three studies.101213 In addition, data on the preva- lence of some specified PDs have been reported by Baron et al.,14 who assessed 750 first-degree relatives of chronic schizophrenics (n = 376) and normal control probands (n = 374). They administered the subjects the SADS, the Schedule for Interviewing Borderlines (SIB) and addi- tional items to diagnose other specific PDs, for which the two interview schedules did not provide adequate coverage. Paranoid Reich et al.15 and Zimmerman and Coryell12 have found comparable rates, ranging from 0.4% to 0.8%, while Maier et al.10 found slightly higher rates, 1.8%. Baron et al.14 found a significantly higher rate of paranoid PD among relatives of schizophrenic probands (7.3%) than among relatives of control probands (2.7%). This disorder seems to be more frequent among the members of the lower social classes. Schizoid Maier et al.,10 Reich et al.,15 and Zimmerman and Coryell12 reported rates ranging from 0.4% to 0.9%. Baron et al.14 reported a rate of 1.6% among relatives of schizophrenic probands and to no cases among rela- tives of control probands. Schizotypal Reich et al.15 and Zimmerman and Coryell12 reported rates of 3.0% and 5.6% respectively, while Maier et al.10 found a substantially lower rate Table 1. Prevalence rates of specified personality disorders (PDs) in epidemiologic surveys or in relatives Type of PD Author and Country Sample Assessment PD prevalence year of publication size method rate (%) (Ref. no.) Paranoid Barons aL, 1985(14) USA 376* SIB, SADS 7.3* 374** 2.7** Mdier etaL, 1992(10) Germany 447 SCID 1.8 Reich etaL, 1989b (15) USA 235 PDQ 0.8 Zimmerman & Coryell, 1990 (12) USA 697 PDQ 0.4 SIPD 0.4 Schizoid Baron etaL, 1985(14) USA 376* SIB, SADS 1.6* 374** 0** Maierer al., 1992(10) Germany 447 SCID 0.4 Reich etaL, 1989b (15) USA 235 PDQ 0.8 Zimmerman & Coryell, 1990 (12) USA 697 PDQ 0.9 SIPD 0.7 Schizotypal Baron etaL, 1985(14) USA 376* SIB, SADS 14.6* 374** 2.1** Maier^ a/., 1992(10) Germany 447 SCID 0.6 Reich etaL, 1989b (15) USA 235 PDQ 5.1 Zimmerman & Coryell, 1990 (12) USA 697 PDQ 5.6 SIPD3 3.0 Histrionic Maier etaL, 1992(10) Germany 447 SCID 1.3 Nestadt etaL, 1990(16) USA 810 SPE 2.1 Reich etaL, 1989b (15) USA 235 PDQ 2.1 Table \.{contd.) Type of PD Author and Country Sample Assessment PD prevalence year of publication size method rate (%) (Ref. no.) Zimmerman & Coryell, 1990 (12) USA 697 PDQ 2.7 SIPD 3.0 Narcissistic Maierefa/., 1992(10) Germany 447 SCID 0 Reich etaU 1989b (15) USA 235 PDQ 0.4 Zimmerman & Coryell, 1990 (12) USA 697 PDQ 0.4 SIPD 0 Borderline Barons aL, 1985(14) USA 376* SIB, SADS 1.9* 374** 1.6** Maieret aL, 1992(10) Germany 447 SCID 1.1 Reich etai, 1989b (15) USA 235 PDQ 1.3 Swartz etal., 1990(18) USA 1,541 DIB/DIS 1.8 Zimmerman & Coryell, 1990 (12) USA 697 PDQ 4.6 SIPD 1.7 Weissman & Myers, 1980 (17) USA 511 SADS-L 0.2 Avoidant Baron ef a/., 1985(14) USA 376* SIB, SADS 1.6* 374** Maieref a/., 1992(10) Germany 447 SCID 1.1 Reich etaU 1989b (15) USA 235 PDQ 0 Zimmerman & Coryell, 1990 (12) USA 697 PDQ 0.4 SIPD 1.3 Dependent Baron etal., 1985(14) USA 376* SIB, SADS 0.3* 374** o** Maierefa/., 1992(10) Germany 447 SCID 1.6 Reich etal., 1989b (15) USA 235 PDQ 5.1 Zimmerman & Coryell, 1990 (12) USA 697 PDQ 6.7 SIPD 1.7 Compulsive Mzier etal., 1992(10) Germany 447 SCID 2.2 Nestadter al., 1991(16) USA 759 SPE 1.7 Reich efaZ., 1989b (15) USA 235 PDQ 6.4 Zimmerman & Coryell, 1990 (12)

USA 697 PDQ 4.0 SIPD 1.7 Passive-Aggressive Maier^ al., 1992(10) Germany 447 SCID 1.8 Reich etal., 1989b (15) USA 235 PDQ 0 Zimmerman & Coryell, 1990 (12) USA 697 PDQ 0.4 SIPD 3.0 Adapted in part from Weissman, 1991 * First-degree relatives of chronic schizophrenics.** Normal control probands. Abbreviations: SIB, Schedule for Interviewing Borderlines; SADS, Schedule for Affective Disorders and Schizophrenia; SCID, Structured Clinical Interview for DSM-III-R; PDQ, Personality Diagnostic Questionnaire; SIPD, Structured Interview for Personality Disorders; SPE, Standardized Psychiatric Examination; SADS-L, Schedule for Affective Disorders and Schizophrenia - Lifetime Version; DIB, Diagnostic Interview for Borderlines; DIS, Diagnostic Interview Schedule. 24 J. H. Reich and G. de Girolamo (0.6%). The rates obtained with similar instruments such as the PDQ are strikingly similar despite differences in sample size, characteristics, and response rates. In the study by Baron et al.,14 schizotypal PD was remarkably more common among relatives of schizophrenic probands (14.6%) than among relatives of control probands (2.1%). This result provides additional support for the specific relationship between schizo- phrenia and schizotypal PD. Histrionic A study by Nestadt et al.,16 carried out at the Baltimore (USA) site of the Epidemiological Catchment Area Program (ECA), ascertained the prevalence of histrionic PD in the community. The authors found a prevalence of 2.1% in the general population, with virtually identical rates in men and women. No significant differences were found in terms of race and education, but the prevalence was significantly higher among separated and divorced persons. Moreover, 17% of the women with histrionic PD also had a depressive disorder, an increased rate of suicide attempts, and a fourfold increase in utilization of medical services. It should be noted that the study derived the diagnosis from instruments not originally intended to diagnose personality disorders. Narcissistic Reich et al.15 and Zimmerman and Cory ell,12 using the PDQ, found iden- tical rates (0.4%) of narcissistic disorder. No cases were found by Maier et al.10 with the SCID, or Zimmerman and Coryell12 with the SIPD. Borderline Borderline and antisocial, have been the most studied PDs. In 1975 Weissman and Myers,17 in a survey carried out in New Haven (USA) among a sample of 511 subjects using the SADS-L and RDC, reported a rate of only 0.2%. However, this rate was derived from an instrument not designed to measure DSM-III borderline PD. Reich et al.15 reported a rate of 1.3% of borderline PD with the PDQ. Zimmerman and Coryell12 obtained rates of 1.7% with the SIPD and 4.6% with the PDQ. The rate of 1.7% was similar to that (1.1%) reported by Maier et al.10 Borderlines, compared to those with other PDs, exhib- ited higher rates of alcohol, tobacco use, phobic disorders, suicide 25 Epidemiology of DSM-III PDs attempts, and schizophrenia. The borderlines were also younger and less likely to be married. Those who did marry were likely to be divorced or separated. Swartz et al.ls carried out a study among 1541 community subjects (19-55 years of age) at the North Carolina site of the EC A, using a diagnostic algorithm derived from the Diagnostic Interview Schedule (DIS). They found a rate of 1.8%, and the disorder was significantly more common among females, the widowed, and the unmarried. There was a trend towards an increase in the diagnosis in younger, non- white, urban, and poorer respondents. The highest rates were found in the 19 to 34 age range, with the rates declining with age. All border- line respondents had also a DIS DSM-III, Axis I lifetime diagnosis. The borderline group included high users of such services, with 50% having had contact with out-patient mental health services in the pre- vious six months. However, the borderlines did not use general medical services more than the total population, and they had similar rates of utilization of out-patient general health services. Borderline PD was significantly related to a poor marital relationship, a higher rate of physical disability, job difficulties, alcohol abuse, and psychosexual problems. Although some believe there is a preponderance of females with bor- derline personality disorder, they do not always take into account preva- lence of females in the populations studied.1920 Two studies did not find a higher female prevalence.2122 Antisocial (Dissocial) Antisocial is the most studied PD. Its prevalence has been assessed in large scale epidemiologic surveys, which employed standardized diag- nostic criteria (Table 2). In the ECA study, antisocial PD was investigated, and one month, six month, and lifetime prevalence rates of 0.5%, 1.2%, and 2.6% were found. There was a variation in the lifetime prevalence at three sites, ranging from 2.1% to 3.4%.23 The lifetime prevalence rate for males was significantly higher (4.5%) than for females (0.8%), and the disorder was found predominantly in those under the age of 45, urban residents, and those who did not complete high school. The male excess occurred in every age and ethnic group. Among those with no disorder in the past year, the average duration of the disorder was 19 years. Typically it appeared at the age of eight, with a variety of problems at home and in Ch Table 2. Lifetime rates (%) of antisocial personality disorders (DSM-III) based on community surveys or relatives Author and year Country Sample size Assessment Prevalence of publication method rate (%) Barons aL, 1985(14) USA 376* SIB, SADS 0.5* 374** 0** Bland etal., 1988a (26,27) Canada 3258 DIS 3.7 HwuetaL, 1989(28) Taiwan 11,004 DIS 0.08 KinzieetaL, 1992(29) USA (Indian village) 131 SADS-L 0.4 Koegelef aU 1988(32) USA 328 DIS 20.8 Lee etaU 1990(30) Korea 3134 (urban) DIS 2.1 1966 (rural) 0.9 Maier^ a/., 1992(10) Germany 447 SCID 0.2 Reich etal., 1989b (15) USA 235 PDQ 0.4 Robins ef aU 1991(23) USA (ECA Program) 18,571 DIS 2.1-3.4*** Weissman & Myers, 1980 (17) USA 511 SADS-U 0.2 Wells et aU 1989(25) New Zealand 1498 DIS 3.1 Zimmerman & Coryell, 1990 (12) USA 697 PDQ 0.9 SIPD 3.0 t Current, not lifetime rates.* First-degree relatives of chronic schizophrenics,** Normal control probands,*** Depending on the study site. Abbreviations: see Table 1. 27 Epidemiology of DSM-III PDs school. Less than half of the diagnosed subjects had a significant record of arrest. Occupational problems were found in 94% of the sample, vio- lence in 85%, and severe marital difficulties in 67%. Some form of sub- stance abuse occurred in 84% of individuals with antisocial PD.24 Associations with schizophrenia and mania were also found. In the Christchurch Psychiatric Epidemiologic Study, carried out in New Zealand with a methodology similar to the ECA, six month and lifetime antisocial PD prevalence rates of 0.9% and 3.1% were found among a sample of 1498 adults, aged 18 to 64 years.25 Males showed antisocial PD more frequently than females for both the six month (1.3% vs 0.5%) and lifetime (4.2% vs 0.5%) prevalence, but the differences did not achieve statistical significance. The authors also studied the one-year recovery rate, defined as the percentage of persons who had ever met cri- teria for a DIS DSM-III disorder but who had not experienced an episode or key symptoms of the disorder in the 12-months prior to the interview. The recovery rate for antisocial PD was 51.6%. However, it is possible that many recovered subjects were substance abusers, who no longer appeared personality disordered when abstinent. In the Edmonton (Canada) study 3258 randomly selected adult house- hold residents were interviewed with the DIS,2627 and 33.8% of the pop- ulation met criteria for one or more disorders at some time in their life. A prevalence rate of 3.7% (6.5% for males and 0.8% for females) was found for antisocial PD. The disorder showed the highest rate in the age group 18-34, and among widowed, separated, and divorced subjects. The mean age of onset was 8 years for males and 9 years for females. All cases of antisocial personality had their onset before 20 years of age. In Taiwan the rates of antisocial personality were considerably lower, ranging from 0.03% in rural villages to 1.4% in metropolitan Taipei.28 This was consistent with the lower rates of most DSM-III disorders at the Taiwan site. In a survey of 131 subjects living in an Indian village in the western US, who were administered the SADS-L, only one male and no female cases were found.29 Lee et al.30 performed a replication of the ECA study in the city of Seoul, Korea. They found a prevalence rate of antisocial personality dis- order of 2.08% in a community sample of 3134. As in other studies there was a higher prevalence in males than females (3.54% vs 0.78%). Another replication of the ECA study31 in Hong Kong, gave a prevalence of antisocial personality disorder of 2.78% in males and 0.53% in females in a sample of 7229 subjects. Antisocial personality disorder was one of the four most prevalent mental disorders found in males. 28 J. H. Reich and G. de Girolamo Both Reich et al.15 and Zimmerman and Coryell,12 using the PDQ, found considerably lower rates, 0.4% and 0.9% respectively. However, the rates increased to 3.0% when interviews were used, suggesting that self- reports may underestimate antisocial personality. Maier et al.,10 however, using a structured interview, also found a low rate of 0.2% in Germany. Interesting results were obtained by Koegel et al?2 in a survey carried out among 328 homeless individuals living in the inner city of Los Angeles, who were administered the DIS, modified for use with a home- less population. An overall lifetime rate of 20.8% of antisocial PD was found compared to a rate of 4.7% in the Los Angeles sample in the ECA study (N = 3055). The risk ratio of having antisocial PD in the homeless as compared to the ECA sample was 4.4. The difference in rates was even more striking when the six month prevalence rate was considered. The rate among the homeless was 17.4% compared to 0.8% in the ECA sample, for a risk ratio of 21.8. To summarize, antisocial PD seems to have a prevalence of around 3% in the general population, and to be more frequent among males than females, with sex ratios ranging from 2:1 to 7:1. It is also more common among younger adults, those living in urban areas, and the lower socioe- conomic classes. People with a diagnosis of antisocial PD are also high users of medical services. Avoidant Reich et al.15 and Baron et al.,14 in their sample of relatives of normal probands, found no cases of avoidant personality (Table 1). Zimmerman and Coryell12 reported rates ranging from 0.4% (PDQ) to 1.3% (SIPD). The rate reported by Maier et al.10 (1.1%) was comparable to that obtained by Zimmerman and Coryell12 and by Baron et al.14 (1.6%) among relatives of schizophrenic probands. Dependent Reich et al.15 and Zimmerman and Coryell,12 using the PDQ, reported rates of 5.1% and 6.7% respectively (Table 1). However, the rates were lower when a structured interview was used (SIPD: 1.7%; SCID: 1.6%).1210 Compulsive The rates of compulsive disorder were comparable in two studies1215 in which the PDQ was used (6.4%15 and 4.0%12). However, lower rates 29 Epidemiology of DSM-III PDs were reported with structured interviews, 1.7% with the SIPD12 and 2.2% with the SCID.10 Another study33 carried out at the EC A Baltimore site, ascertained the prevalence of compulsive PD in the community, and found a prevalence of 1.7%. Males had a rate about five times higher than females. The disorder was also more frequent among white, highly educated, married, and employed subjects, and it was associated with anxiety disorders. However, the study derived the diagnosis from an interview originally not intended to diagnose PDs. This could mean that they identified adaptive obsessive-compulsive traits rather than a PD. Passive-Aggressive Using the PDQ, Zimmerman and Coryell12 found a low rate (0.4%), while Reich et al,15 in their study, which included only 235 subjects, found no cases. The rate was higher with an interview, suggesting that passive-aggressive persons may under-report on self-administered ques- tionnaires. Epidemiological studies carried out in psychiatric settings Table 3 lists the main prevalence studies of PD carried out in in-patient and out-patient psychiatric samples. To summarize, although the prevalence of PD among psychiatric out- patients and in-patients can be high, both in patients with only a PD and in those with an Axis I disorder (especially affective disorders), no final con- clusion can be reached because the available studies reported very

different prevalence rates. The differences are probably due to differences in sam- pling, diagnostic criteria, assessment methods, availability of mental health services, prevalence of Axis I disorders, and sociocultural factors. Even when authors use ICD or DSM criteria, they may have done so in different ways. There are, however, some consistencies across studies. The most prevalent PD seems to be borderline, both in in-patient and out-patient set- tings. The next most common PDs tend to be schizotypal and histrionic. These three disorders are also characterized by the lowest social function- ing. They are especially common in in-patient settings, as their symptoma- tology often results in hospitalization due to suicidal behaviour, substance abuse, and cognitive-perceptual abnormalities. In out-patient settings, dependent and passive-aggressive PDs are also common. In a study carried out among 2344 patients attending a public psychi- atric facility and having a DSM-III diagnosis of PD, cluster B patients Table 3. Prevalence rates of personality disorders (PDs) among psychiatric patients o Author and year Country Sample size Classification Assessment % with Remarks of publication and setting system instruments PD (Ref. no.) Allan, 1991 (43) UK 100 out-patients RDC Clinical 5 Alcohol abusers in treatment interview Alnaes & Torgensen, Norway 298 out-patients DSM-HI SIPD 81 97% had an Axis I diagnosis; about half 1988a (44,45) had an affective disorder Baer, etaL, 1990(46) USA 96 out-patients DSM-m SIPD 52 Obsessive-compulsive disorders. Dependent and histrionic PDs were the most common. Compulsive PD was found in only 6% of the sample. Berger, 1985 (35) Canada 486 out-patients DSM-HI Clinical 39 All patients seen in a private psychiatric assessment practice over a period of five years Castaneda & Franco, USA 1583in-patients DSM-IH Clinical 6/ Patients discharged from a psychiatric 1985 (47) assessment facility during one year; 101 received a primary diagnosis of PD Charney^fl/., 1981(48) USA 160 in-patients DSM-III Clinical 61 64 unipolar nonmelancholic depressives assessment 14 66 unipolar melancholic depressives 23 30 bipolar depressives Cutting etai, 1986(49) UK 100 in-patients RDC SAP 44 100 consecutive admissions with major psychiatric disorders. The proportion of patients with PD was comparable among different diagnostic groups (depressives 54%, schizophrenics 39%, manics 39%) Dowson & Berrios, UK 74 in-and DSM-HI-R PDQ-R Each patient had a mean number of 1991 (50) out-patients 4.5 PD diagnoses. Borderline (62%) and histrionic (61%) PDs were the most Fabregaefa/., 1991(34) USA 18,179 out-patients DSM-III Initial 12.9 Most frequent diagnoses were atypical, Evaluation antisocial and borderline. Subjects with Form PD were males, 35 years or younger, socially impaired. Friedman et al, 1983 (51) USA 53 in-patients DSM-III Clinical 87 Depressed in-patients; 36 (78%) met assessment criteria for borderline PD Fyer et al, 1988 (52) USA 598 in-patients DSM-III 76 item 54.1 Consecutive discharges from 501 in-patients checklist used 54.3 two psychiatric facilities. 23.2% to review and 19.8% of the two samples had medical records borderline PD Hyler & Lyons, 1988 (53) USA 358 DSM-III Specific 73.4 Patients in treatment with 287 (90% out-patients) assessment form US psychiatrists. The most common PD was borderline PD (21%), followed by compulsive PD (11%) JacksonetaL, 1991 (54) Australia 112 DSM-III-R SIPD 67 21% had one PD, 46% had >2 PDs. Schizophrenia associated with antisocial and schizotypal PDs Kass et al, 1985 (22) USA 609 out-patients DSM-III 4-point rating 51 Borderline was the most frequent PD format (11%) Kastrup, 1987 (55) Denmark 11.340 (in-patients) ICD-8 Clinical 18.3(a) a=revolving door patients, first assessment 16.7(a) diagnosis and last diagnosis 15.2(b) b=non revolving door patients, 15.7(b) first diagnosis and last diagnosis Kennedy etal, 1990(56) Canada 44 (in-patients) DSM-III-R MGMIBSI 93 Patients with eating disorders. Borderline, dependent and passive- aggressive PDs were the most common KioWetal, 1981(57) USA 117 (in-patients) DSM-III DIB 18 Assessment focused on borderline PD Loranger, 1990 (38) USA 5143 (a) DSM-II (a) Clinical 19.1 Diagnoses made according to the DSM-II assessment in the years 1975-79 5771 (b) (in-patients) DSM-III (b) 49.2 Diagnoses made according to the DSM-III in the years 1981-85 Table 3. (contd.) Author and year Country Sample size Classification Assessment %with Remarks of publication and setting system instruments PD (Ref. no.) Loranger etal., 1991 (58) USA 84 (in-patients) DSM-III PDE 58.3(a) Patients evaluated at entry (a) and at 50(b) follow-up (b). Borderline, avoidant, dependent and masochistic PDs were the most common McGlashan, 1986 (59) USA 532 (in-patients) DSM-III Clinical 32 Patients who met DSM-III criteria or assessment Gunderson' s criteria for borderline PD Mezziche/ al., 1982(60) USA 1111 (in-and DSM-III & ICD-9 Initial 21.4 For 33 (3%) patients an Axis II diagnosis out-patients) Evaluation Form was primary Mezzichef al., 1990(61) USA 4,141 (38% in-patients, DSM-III & ICD-9 Initial 14.0 PD first cluster=7%; PD second 62% out-patients) Evaluation Form cluster=45%; PD third cluster=19%; PD fourth cluster=30%. Most frequent Axis I diagnoses: somatoform disorders (36%) and substance abuse (25%) Naceetal.,l991(62) USA SCID-II 57 100 middle-class in-patient substance abusers Nurnberg etal, 1991 (63) USA 110 (out-patients) DSM-III-R Semistructured 62 Patients with any minor axis I diagnosis. assessment Avoidant (24%), borderline (20%) and histrionic (17%) were the most common PD Nussbaum & Rogers , Canada 82 (in-patients) DSM-III-R SCID-PQ The SCID-PQ yielded very few false 1992(64) negatives and moderate false positives. Oldham etal, 1992 (65) USA 100 (in-patients) DSM-III-R SCID-II Patients assigned 290 PD diagnoses. Borderline, avoidant and dependent PDs most common. Oldham & Skodol, USA 129,268 (in-and DSM-III & ICD-9 Clinical 10 All patients served by the New York State 1991 (66) out-patients) assessment Office of Mental Health in one year. Of all PD patients, 17.2% had a diagnosis of borderline PD. Schizoaffective disorders, major affective disorders, dysthymia, substance abuse were more common among PD patients Pfohl etai, 1986(67) USA 131 (in-patients) DSM-III SIPD 51 Histrionic (30%) and borderline (29%) most common. 54% of the PD had two or more PDs Pilgrim & Mann, UK 120 (in-patients) ICD-10 SAP 36 First admissions in one year. Anxious and 1990(68) impulsive PDs most common. Pilkonis & Frank, USA 119 (out-patients) DSM-III Hirschfeld- 48 Patients with recurrent unipolar 1988(69) Klerman depression. Most common PDs were Personality avoidant (30.4%) and compulsive Battery, PAS (18.6%) Reich, 1987(21) USA 170 (out-patients) DSM-III SIPD 48.8 45% had a consensus diagnosis of PD. PDQ 60.0 More women with histrionic PD and MCMI 66.7 more men with paranoid, compulsive and antisocial PDs Reich & Troughton, USA 88(a) DSM-III SIDP 43 Panic patients assessed with the SIPD 1988(13) 82(b) SIPD 55 Out-patients assessed with the SIDP 40(a) PDQ 20 Normal controls assessed with the PDQ Ross et al., 1988 (70) Canada DIS 47 501 addicts. 47% had a diagnosis of anti- 501 (out-patients) DSM-III social PD RounsaviMe et al., USA SADS 7.7 Cocaine abusers. 7.7% had a diagnosis of 1991 (71) 298 (in- and out-patients) DSM-III-R antisocial PD Shea etai, 1990(72) USA PAF 74 Major depressives in the NIMH 239 (out-patients) DSM-III Treatment of Depression Collaborative Research Program. 57% of those with PD had a diagnosis of two or more PDs. Compulsive, avoidant, dependent and paranoid most frequent diagnoses. Tdble3.(contd.) 4 Author and year Country Sample size Classification Assessment %with Remarks of publication and setting system instruments PD (Ref. no.) Turner etal., 1991(73) USA 68 (out-patients) DSM-III-R SCID-II 37 Patients with social phobia. Over 75% received subthreshold ratings for one or more PDs. Avoidant and obsessive PD most common. Tyrer etal., 1983(74) UK 316 (all out-patients ICD-8 PAS 39.9 All patients had a diagnosis of neurosis. except 12pts) Anankastic personality disorder was the most common Zanarini era/., 1987(75) USA 43 (in-patients) DSM-III DIDP 81 97% of the PDs had two or more PDs. Borderline PD was most frequent (26%) Zimmerman etal., USA 66 (in-patients) DSM-III SIDP 57.6 Based on patient interview 1988 (76) 36.4 Based on informant interview Abbreviations: RDC, Research Diagnostic Criteria; DSM, Diagnostic and Statistical Manual of Mental Disorders; ICD, International Statistical Classification of Diseases Related Health Problems; SIPD, Structured Interview for Personality Disorders; SAP, Standardized Assessment of Personality; PDQ, Personality Diagnostic Questionnaire; MGMI, Million Clinical Multiaxial Inventory; BSI, Borderline Syndrome Index; DIB, Diagnostic Interview for Bordelines; SCID, Structured Clinical Interviews for DSM; PDE, Personality Disorder Examination; PAS, Personality Assessment Schedule; DIS, Diagnostic Interview Schedule; PAF, Personality Assessment Form; DIDP, Diagnostic Interview for Personality Disorders. 35 Epidemiology of DSM-III PDs were the most frequent and cluster A patients the least.34 There was highly significant demographic variation manifest across PD clusters. In the only study which investigated PD rates among those seen in a private psychiatric practice (N = 486), they were diagnosed in 39% of the patients seen.35 Borderline (9.7%) and obsessive-compulsive (8.2%) were the most frequently observed. Some studies have compared the hospital admission rates for PD over time, and they allow us to assess the impact of diagnostic changes. Mors36 has shown that in Denmark sex- and age-standardized rates of first-admitted borderlines significantly increased during the 16-year interval 1970-85. There was no sex difference, but the age group 15-34 especially contributed to the increase, which was particularly remarkable in urban areas, and might be explained in terms of a change in diagnostic habits. This hypothesis received support from another analysis of Danish admissions to psychiatric institutions in the years 1975, 1980, and 1985. In those years the increase in borderline diagnosis (5% to 20%) in men paralleled a decrease in the diagnosis of psychopathy (22% to 7%).37 The authors suggest that those previously diagnosed as psychopathic deviants were subsequently labelled borderlines. The shift in diagnosis was less marked for females. This same phenomenon, i.e., a change in diagnostic practice has been studied at one of the largest university-affiliated psychiatric hospitals in the USA.38 Comparing the diagnoses given to hospitalized patients in the last five years of the DSM-II era (N = 5143) with those given in the first five years of the DSM-III era (N = 5771), a marked increase was found in the diagnosis of PD, together with a decrease in the diagnosis of schizophrenia, and a corresponding increase in the diagnosis of affective disorders. The percentage of patients with a diagnosis of PD (19.1% to 49.2%) increased more than twofold. The most frequent diagnostic categories employed since the introduction of the DSM-III were atypical/mixed/other PD (33%) and borderline (27%). Another study assessed the proportion of patients with PD among all hospitalized cases of non-psychotic mental disorders in military personnel in the US Navy from 1981-1984.39 The overall sample included 27,210 cases. Among them, 4581 (16.8%) had a PD as the primary diagnosis. In New Zealand a survey was made of all patients admitted to psychiatric hospitals over a seven year period with an ICD-9 primary diagnosis of personality disorders (N = 6447).40 Despite a decrease in the total num- ber of admissions, the relative totals for each personality disorder remained consistent. The most common diagnosis was an unspecified 36 J. H. Reich and G. de Girolamo PD, and it accounted for 45% of the total sample. The next most com- mon was asthenic PD. In the US on a selected day in 1986, there were a total of 3893 persons under care in some in-patient psychiatric facility, with a primary diagno- sis of PD. This corresponded to 2.4% of the total number of in-patients on that date.41 In the same year there were 29,910 admissions with a pri- mary diagnosis of PD, 1.9% of all admissions. The median length of hos- pital stay for in-patients with a diagnosis of PD was nine days. Among all those under out-patient care on the same day, there were 81,731 or 5.9% of the total, with a diagnosis of PD. In the same year 136,903 peo- ple or 6.4% were admitted to out-patient care with a PD diagnosis. The epidemiological findings in treated samples are especially impor- tant if we bear in mind that the presence of a PD among those suffering from other mental disorders can be a major predictor of the natural his- tory and treatment outcome.6 Conclusions The epidemiology of PDs has not received the same amount of attention as that of many other psychiatric disorders. In the last few years the situ- ation has changed, and we now have data on the prevalence of PD in the community and in psychiatric facilities. Community data come primarily from three studies1012 with a total sample of about 1300 subjects from two countries, Germany and the US. There are excellent national and cross-national epidemiological data on antisocial personality disorder, based on the same diagnostic methods. There

are almost no data on other PDs from countries other than Germany and the US. The lack of studies from developing countries is especially noteworthy because the role of sociocultural factors has yet to be determined. One important methodological problem is that some PDs have a very low prevalence rate. Consequently, epidemiological surveys carried out among the general population may require very large samples in order to identify a sufficient number of cases to study demographic correlates and the association of PD with other psychiatric disorders. Many of the PDs are at an early stage of construct validation. Further research should probably follow the general recommendations for vali- dating a psychiatric disorder. These include the need to delineate a pro- posed disorder from other disorders. Given the overlap of the PDs, this will be a challenging task. Another criterion is external validation, and there are a number of psychological tests and behavioural indicators that 37 Epidemiology of DSM-III PDs might be used to establish construct validity. Biological markers will also be important in future research as another source of external validation. Another method of validation is to determine whether the course or natural history of PDs justifies their differentiation. Few such studies have been done, because of the time and cost of prospective designs, but longitudinal studies can provide information not available from cross- sectional ones. They could identify predictors of future PDs, modifying variables, and medical and social service needs. They also offer an opportunity to examine the effect of temperament as an important pre- disposing variable. Another issue that could be explored in this way is the temporal stability of PDs. Although as defined in the ICD-10 and DSM-III, PDs are long-lasting disorders, very limited data are available regarding this. For this reason it would be worth investigating the epi- demiology of PDs in different age groups, as an indication of the course of PDs. Longitudinal studies will also provide evidence for the validity of the concept of PD as constant maladaptive behaviour across time and environmental circumstances.42 Finally, treatment response is also a validator. Although PDs are con- sidered stable and long lasting, it is possible that effective treatments will ultimately be developed, as with other psychiatric disorders, and treat- ment response could also be used to validate the different types of PD. There has been a remarkable advance in our understanding of the epi- demiology of PDs in the last few years. As this continues, we should bet- ter understand not only the PDs, but also other mental disorders. References Casey, P.R. Epidemiology of personality disorders. In Tyrer, P. (ed.) Personality Disorders: Diagnosis, Management and Course. London: Wright, 1988. Merikangas, K.R. & Weissman, M.M. Epidemiology of DSM-III Axis II person- ality disorders. In: Frances, A.J. & Hales, R.E. (eds), APA Annual Review, vol. 5, Psychiatry Update, pp. 258-78. Washington, DC: American Psychiatric Press, 1986. Merikangas, K.R. Epidemiology of DSM-III personality disorders. In Michels, R. etal., (eds.). Psychiatry, vol 3, pp 1-16. Philadelphia: Lippincott, 1989. Weissman, M.M. The epidemiology of personality disorders: A 1990 update. Journal of Personality Disorders, 1993; 7,44-62. Andreoli, A., Gressot, G., Aapro, N., Tricot, L. & Gognalons, M.Y. Personality disorders as a predictor of outcome. Journal of Personality Disorders, 1989; 3: 307-20. Reich, J.H. & Green, A.I. Effect of personality disorders on outcome of treat- ment. Journal of Nervous and Mental Disease, 1991; 179: 74-82. 38 J. H. Reich and G. de Girolamo 7 Neugebauer, R., Dohrenwend, B.P. & Dohrenwend, B.S. Formulation of hypotheses about the true prevalence of functional psychiatric disorders among adults in the US. In Dohrenwend, B.P., Dohrenwend, B.S., Gould, M.S., Link, B., Neugebauer, R. & Wunsch-Hitzir, R. (eds.). Mental Illness in the United States: Epidemiological Estimates, pp. 56-92. New York: Praeger, 1980. 8 Perry, C. & Vaillant, G.E. Personality Disorders. In Kaghan, H.I., Sadock, B.J. (eds.). Comprehensive Textbook of Psychiatry, pp. 1352-86. Baltimore: William &Wirekins, 1989. 9 Casey, P.R. & Tyrer, PJ. Personality, functioning and symptomatology. Journal of Psychiatric Research, 1986; 20: 363-74. 10 Maier, W., Lichtermann, D., Klingler, T. & Heun, R. Prevalences of personality disorders (DSM-III-R) in the community. Journal of Personality Disorders, 1992; 6: 187-96. 11 Reich, J., Boerstler, H., Yates, W. & Nduaguba, M. 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The prevalence of specific psychiatric disorders among homeless individuals in the inner city of Los Angeles. Archives of General Psychiatry, 1988; 45: 1085-92. 33 Nestadt, G., Romanoski, A.J., Brown, C.H., Chahal, R., Merchant, A., Folstein, M.F., Gruenberg, E.M. & McHugh, P.R. DSM-III compulsive personality disor- der: An epidemiological survey. Psychological Medicine, 1991; 21: 461-71. 34 Fabrega, H., Ulrich, R., Pilkonis, P. & Mezzich, J. On the homogenity of person- ality disorder clusters. Comprehensive Psychiatry, 1991; 32: 373-85. 35 Berger, J. Private practice: The first five years. Canadian Journal of Psychiatry, 1985; 30: 566-71. 36 Mors, O. Increasing incidence of borderline states in Denmark from 1970-1985. Acta Psychiatrica Scandinavica, 1988; 77: 575-83. 37 Simonsen, E. & Mellergard, M. Trends in the use of the borderline diagnosis in Denmark from 1975 to 1985. Journal of Personality Disorders, 1988; 2: 102-8. 38 Loranger, A.W. 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American Journal of Psychiatry, 1981; 138: 1601-4. 49 Cutting, J., Cowen, P.J., Mann, A.H. & Jenkins, R. Personality and psychosis: use of the standardized assessment of personality, Acta Psychiatrica Scandinavica, 1986; 73: 87-92. 50 Dowson, J.H. & Berrios, G.E. Factor strucure of DSM-III-R personality disor- ders shown by self-report questionnaire: implications for classifying and assess- ing personality disorders. Acta Psychiatrica Scandinavica, 1991; 84: 555-60. 51 Friedman, R.C., Aronoff, M.S., Clarkin, J.F., Corn, R. & Hurt, S.W. History of suicidal behaviour in depressed borderline inpatients. America Journal of Psychiatry, 1983; 140: 1023-6. 52 Fyer, M.R., Frances, A.J., Sulivan, T., Hurt, S.W., Clarkin, J. Comorbidity of bor- derline personality disorder. A rchives of General Psychiatry, 1988; 45: 348-52. 53 Hyler, S.E. &Lyons, M. Factor analysis of the DSM-III personality disorder clusters: a replication. Comprehensive Psychiatry, 1988; 29: 304-8. 54 Jackson, H.J., Whiteside, H.L., Bates, G.W., Bell, R., Rudd, R.P. & Edwards, J. Diagnosing personality disorders in psychiatric inpatients. Acta Psychiatrica Scandinavica, 1991; 83: 206-13. 41 Epidemiology of DSM-III PDs 55 Kastrup, M. Who became revolving door patients? Findings from a nation-wide cohort of first time admitted psychiatric patients. Acta Psychiatrica Scandinavica, 1987; 76: 80-8. 56 Kennedy, S.H., McVey, G. & Katz, R. Personality disorders in anorexia nervosa and bulimia nervosa. Journal of Psychiatry, Res., 1990; 24: 259-9. 57. Kroll, J., Sines L., Martin, K., Lari, S., Pyle, R. & Zander, J. Borderline personal- ity disorder: construct validity of the concept. Archives of General Psychiatry, 1981; 38: 1021-6. 58 Loranger, A.W., Lenzenweger, M.F., Gartner, A.F., Susman, V.L., Herzig, J., Zammit, G.K., Gartner, J.D., Abrams, R.C. & Young, R.C. Trait-state artifacts and the diagnosis of personality disorders. 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1990. 62 Nace, E.P., Davis, C.W. & Gaspari, J. Axis II Comorbidity in substance abusers. American Journal of Psychiatry, 1991; 148: 118-20. 63 Nurnberg, G.H., Raskin, M., Levine, P.E., Pollack, S., Siegel, O. & Prince, R. The comorbidity of borderline personality disorder and other DSM-III-R Axis II personality disorders. American Journal of Psychiatry, 1991; 148: 1371-7. 64 Nussbaum, D. & Rogers, R. Screening psychiatric patients for Axis II disorders. Canadian Journal of Psychiatry, 1992; 37: 658-60. 65 Oldham, J.M. & Skodol, A.E. Personality disorders in the public sector. Hospital and Community Psychiatry, 1991; 42: 481-7. 66 Oldham, J.M., Skodol, A.E., Kellman, H.D., Hyler, S.E., Rosnick, L. & Davies, M. Diagnosis of DSM-III personality disorders by two structured inter- views: patterns of comorbidity. American Journal of Psychiatry, 1992; 142: 213-20. 67 Pfohl, B., Coryell, W., Zimmerman, M. & Stangl D. DSM-III personality disor- ders: Diagnostic overlap and inter consistency of individual DSM-III criteria. Comprehensive Psychiatry, 1986; 27: 21-34. 68 Pilgrim, J. & Mann, A. Use of the ICD-10 version of the standardized assessment of personality to determine the prevalence of personality disorder in psychiatric in-patients. Psychological Medicine, 1990; 20: 985-92. 69 Pilkomis, P.A. & Frank, E. Personality pathology in recurrent depression: nature, prevalence, and relationship to treatment response. American Journal of Psychiatry, 1988; 145: 435-41. 42 J. H. Reich and G. de Girolamo 70 Ross, H.E., Glaser, F.B. & Germanson, T. The prevalence of psychiatric disor- ders in patients with alcohol and other drug problems. Archives of Generql Psychiatry, 1988; 45: 1023. 71 Rounsaville, B.J., Anton, S.F., Carroll, K., Budde, D., Prusoff, B.A. & Gawin, F. Psychiatric diagnoses of treatment-seeking cocaine abusers. 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Archives of General Psychiatry, 1988; 45: 733-7. 43 International personality disorder examination (IPDE) Armand W. Loranger Background and History One of the aims of the World Health Organization (WHO) and US Alcohol, Drug Abuse and Mental Health Administration (ADAMHA) joint program on psychiatric diagnosis and classification was the devel- opment and standardization of diagnostic assessment instruments for use in clinical research around the world.1 The International Personality Disorder Examination (IPDE) is a semistructured clinical interview ori- ginally designed to assess the personality disorders (PDs) in the ICD-102 and DSM-III-R3 classification systems, and subsequently modified for compatibility with DSM-IV.4 The IPDE is an outgrowth and adaptation for international use of the Personality Disorder Examination (PDE) (Loranger, 1988).5 To facili- tate the development of the IPDE, beginning in 1985 several interna- tional workshops were convened. At these meetings WHO and ADAMHA officials, together with representatives of the international psychiatric community, discussed the format of the interview, the word- ing of items, and the development of a scoring manual. Frequent revi- sions were made to reflect the experience of interviewers with trial versions. Investigators at the various centres involved in the field trial described in this volume translated the instrument into the following lan- guages: Dutch, French, German, Hindi, Japanese, Kannada, Norwegian, Swahili, and Tamil. The translations were back-translated into English by a psychiatrist or psychologist who had not seen the original English version. Variations and problems in the back-translation were then reviewed with those who undertook the original translation, and correc- tions were made when indicated. Later, translations were made into other languages, including Danish, Italian, Spanish, Russian, and Estonian. Additional translations are contemplated. Particular problems arise when the interview is used with subjects who are illiterate and speak a regional or tribal dialect. Since written and spoken language are quite different in such populations, the interviewer 44 A. W. Loranger must frequently depart from the literal text and improvise an equivalent question on the spot, in order to maintain communication with the sub- ject. Although this is a potential source of error variance, the examiner's familiarity with the scope and meaning of the diagnostic criteria and with the intent of the original IPDE question, should keep such error within tolerable limits. Structure of the IPDE The IPDE is arranged in a format that attempts to provide the optimal balance between a spontaneous, natural clinical interview and the requirements of standardization and objectivity. At the beginning of the interview the subject is given the following instructions: The questions I am going to ask concern what you are like most of the time. I'm inter- ested in what has been typical of you throughout your life, and not just recently. If you have changed and your answers might have been differ- ent at some time in the past, be sure to let me know.' The questions flow in a natural sequence that is congenial to the clini- cian. They are arranged under six headings: work, self, interpersonal relationships, affects, reality testing, and impulse control. The headings are not only convenient labels, but they play an organizational or the- matic role. At times the overlapping nature of the six domains required a somewhat arbitrary allocation of questions. For efficiency and conve- nience sometimes a question extends beyond the scope of the section where it appears. For example, many obsessive-compulsive criteria are best assessed in the context of work functioning, but behaviour outside the realm of work is also considered, even though the questions appear in the 'work' section of the interview. The sections are usually introduced by open-ended inquiries that offer the subject an opportunity to discuss the topic as much as he chooses. This helps to develop a set for the questions that follow, and provides a transition from the focus of the previous section. Although they are not scored as such, these introductory remarks of the subject provide a back- ground against which to judge the clinical significance of some of the replies to the specific questions that follow. At times the comments also facilitate the task of the examiner in deciding whether to probe or pursue certain aspects of the subject's responses. The criterion and its number, together with the name of the disorder, appear above the questions designed to assess it. Since the questions are merely an attempt to get at the criterion, this serves to remind the exam- 45 IPDE iner what he is actually rating. When there is no major difference between an ICD and DSM criterion, they are assessed together by identi- cal questions. This occurs as often as possible to prevent the combined ICD-DSM version of the interview from becoming too long or unwieldy. Some criteria are followed by the designation partial, an indication that the item does not assess the entire criterion. This is done to preserve the topical focus of the interview. For example, it is more appropriate to inquire about an identity disorder in the sexual realm, when the subject of sex is being discussed, than to attempt to cover other manifestations of an identity disorder, such as uncertainty about values or career choice, at the same point in the interview. There appears to be no consensus about how long a behaviour should be present before it can be considered a personality trait. The IPDE has adopted the conservative convention that it should exist for a span of at least five years. Consideration was given to a three-year require- ment, but it was decided that might too frequently lead to confounding episodic mental illnesses or responses to unusual or special life situa- tions with the more enduring behaviour associated with personality. Some may feel this is too exacting, especially when applied to adoles- cents. Since users of the IPDE will differ in their predilection for making PD diagnoses in adolescents, those who prefer a three-year requirement may adopt it for that age group. They should specify, however, that they have departed from the standard instructions. The use of anything less than a five-year timeframe with subjects over 20 years of age is discouraged. ICD-10, DSM-III-R, and DSM-IV date the onset of the first manifes- tations of a PD to childhood, adolescence, or early adulthood. For that reason the IPDE takes the somewhat arbitrary position, that the require- ments for at least one criterion of a disorder must have been fulfilled prior to age 25, before that particular disorder can be diagnosed. Age 25 years rather than an earlier age was selected to allow more informed and accurate judgments about many of the adult-oriented PD criteria. Clinical tradition notwithstanding, it is possible that personality trans- formations may occur in midlife or old age, and that a true PD may emerge de novo at that time. In the absence of empirical data, rather than encourage premature closure on the subject, there is provision in the IPDE for an optional late onset diagnosis. The interview also provides the option of making a past diagnosis in someone who previously met the requirements, but does not evidence the behaviour currently (past 12 months). 46 A. W. Loranger Administration and scoring Much of the behaviour described in the criteria of ICD-10, DSM-III-R, and DSM-IV exists on a continuum with normality. The IPDE scoring is based on the convention that a behaviour or trait may be absent or nor- mal (0), exaggerated or accentuated (1), and criterion level or pathologi- cal (2). A few criteria are not applicable to certain subjects, and are scored 'NA\ A '?' scoring category is reserved for those rare occasions when a subject, despite encouragement, refuses to answer a question or states that he/she is unable to do so. It is not used to designate uncertainty on the part of the examiner about rating the item. No single formula was used in developing the guidelines in the scor- ing manual. They are based on interpretations of the criteria by the author of the instrument, and were revised after discussions with the clinicians who participated in the field trial. Clinical judgement, com- mon sense, and practical experience with the interview shaped the final version of the guidelines. The boxed text contains a sample item from the IPDE demonstrating the format, type of questions, and scoring guidelines. Initial replies of the subject that suggest a positive reply are rarely sufficient for scoring a criterion. They must be supplemented and sup- ported by convincing descriptions or examples. The examiner uses clini- cal judgement to determine the length of the descriptions and the number of examples. Although there is a standard set of probes, they must be augmented by an adequate clinical examination of the subject. The interviewer scores the IPDE item-by-item, as he progresses through the interview. The scores are combined for diagnostic purposes at the conclusion of the interview. Although this may be done clerically using a set of step-by-step algorithmic directions, the most efficient method is to use a program especially designed for personal computers. It is written with operator prompts, and the user responds to questions regarding the task to be performed and the management of the data, which may be sent to a printer and saved in a disk file. The entire proce- dure takes 5 to 10 minutes. Scope of the IPDE The IPDE is not designed to survey the entire realm of personality. Its purpose is to identify those traits and behaviours that are relevant to an assessment of the criteria for personality disorders in the ICD-10 and DSM-IV classification systems. It neglects many neutral, positive, and 47 IPDE Sample of IPDE item The questions I am going to ask concern what you are like most of the time. I'm interested in what has been typical of you throughout your life, and not just recently. If you have changed and your answers might have been different at some

time in the past, be sure to let me know. I. WORK If the subject has rarely or never worked, and is not a housewife (home- maker), student, or recent graduate, circle NA for 1 and proceed to 2. I would like to begin by discussing your life at work (school). How well do you usually function in your work (at school)? What annoyances or problems keep occurring in your work (at school)? 1. 0 1 2 ? 0 1 2 ? NA Is excessively devoted to work and productivity to the exclu- sion of leisure activities and friendships (not accounted for by obvious economic necessity) Obsessive Compulsive: 3 Do you spend so much time working that you don't have any time left for any- thing else? If yes: Tell me about it. Do you spend so much time working that you (also) neglect other people? If yes: Tell me about it. The examiner should be alert to the use of rationalizations to defend the behaviour. The fact that work itself may be pleasurable to the subject should not influence the scoring. There is no require- ment that the subject actually enjoy the work, although that is 48 A. W. Loranger often the case. Personal ambition, high economic aspirations, or inefficient use of time, are unacceptable excuses. Exoneration due to economic necessity should be extended only when supported by convincing explanations. Allowance should be made for short-term, unusual circumstances, e.g., a physician in training who has little or no control over his work schedule. The same person would not be excused if he persisted in excessive involvement in his work or career. Avoidance of interpersonal relationships or leisure activities for reasons other than devotion to work is not within the scope of the criterion. 2 Excessive devotion to work and productivity that usually prevents any significant pursuit of both leisure activities and interpersonal relationships. 1 Excessive devotion to work and productivity that occasionally pre- vents any significant pursuit of both leisure activities and interper- sonal relationships. Excessive devotion to work and productivity that usually prevents any significant pursuit of either leisure activities or interpersonal relationships but not both. 0 Denied or rarely or never leads to exclusion of leisure activities or interpersonal relationships. adaptive traits, because they are irrelevant to a PD assessment. It also does not cover other (Axis I) mental disorders. There are instruments available for the evaluation of most of those conditions. We recommend their use prior to the IPDE, to provide the examiner with background information that is likely to enhance the reliability and validity of the questioning, probing, and scoring process. When it is not available from such an interview or from other sources, the IPDE examiner is expected to conduct a mental status examination and to take a psychiatric history. The IPDE examines every subject for the presence or absence of all the PD criteria. It also provides a dimensional score for every subject on each disorder, regardless of whether or not they fulfill the criteria for the disorder. This additional information supplements that based on categor- ical diagnosis alone. Because PDs often reflect the exaggerated presence of traits that are continuously distributed in the population at large, the 49 IPDE dimensional scores are not only useful to the clinician, but they also pro- vide the research investigator with greater reliability and more versatility in data analysis. Appropriate subjects The IPDE is not intended for subjects below the age of 18, although with slight modifications some investigators have found it useful with those as young as age 15. The interview is not appropriate for those with severe depression, psychosis, below-normal intelligence, or substantial cognitive impairment. Whether it should be used with patients in remis- sion from a chronic psychotic illness is somewhat problematic. For example, can one distinguish residual schizophrenia or the interepisodic manifestations of a bipolar disorder from a PD? A number of investiga- tors have found the IPDE useful in studies of those disorders, and the decision is left to the discretion of the user. Limitations of the IPDE The IPDE is essentially a self-report instrument, and assumes that a per- son is capable of providing a valid description of disturbances in his per- sonality. However, an individual may be unaware of some of his traits. He may also be resistant to acknowledging behaviour, if it is socially undesirable or if he thinks its disclosure is likely to adversely affect his best interests. This is especially likely to occur in patients who wish to terminate treatment prematurely, or in those about to be discharged from a mental health facility. Others may exaggerate disturbances in their behaviour. This is sometimes observed in those who are frantically seek- ing help, or who are dissatisfied with their treatment or the amount of attention they are receiving. It may also be a reflection of certain person- ality traits. Although subjects may also feign traits or behaviour, particu- larly in compensation cases and some forensic and military situations, the IPDE discourages this by requiring documentation with convincing examples, anecdotes, and descriptions. Patients in a dysphoric state may have a selective recall or distorted perception of some personality traits. They may also confuse them with the symptoms of another mental disorder. There is evidence that the interest may be resistant to such trait-state artifacts in patients with mild to moderate symptoms, but additional research is required on this important subject. When possible, some investigators may wish to 50 A. W. Loranger postpone the assessment until the symptoms of other mental disorders have remitted. In ordinary clinical practice a family member or close friend is often used as an additional source of information to offset the limitations of the self-report method. We have experimented with various procedures for augmenting the subject's responses on the IPDE with data from other sources. Failure to acknowledge a behaviour, particularly one that is especially frowned upon by others, is sometimes followed on the IPDE by such inquiries as, 'Have people told you that you're like that?' Affirmative replies are then pursued with the question, 'Why do you think they've said that?' This approach can only be used selectively. If it were adopted in all situations where a behaviour has been denied, it would undermine the rapport between subject and examiner. We have also tried a parallel form of the interview in which an infor- mant was asked virtually the same questions about the patient. There were often discrepancies, and it was not always obvious who had pro- vided the more valid information. It proved difficult to formulate a set of practice guidelines stipulating the source to be used in scoring a particu- lar criterion. The problem is a complicated one, and a satisfactory resolu- tion awaits the availability of more empirical data on the subject, including attempts to identify those criteria that tend to produce discrep- ancies, and characteristics of the subject and informant that might be used to determine the preferred source of information. Meanwhile, the IPDE takes a practical approach to the informant problem with an additional scoring column for informant data. If the examiner has access to information from family, friends, mental health professionals, records, etc., that clearly contradicts the subject's responses regarding a particular criterion, then he/she may also score the criterion in the informant column provided two requirements are met. Firstly, he/she should have more confidence in that information than he/she does in the patient; and secondly, the other source must satisfy the identical scoring criteria that apply to the subject's response. Later, in entering ratings in the computer or transcribing them from the interview to the scoresheet, the scores based on the subject's report are bypassed in favour of those derived from the informant. Examiner Qualifications and Training The IPDE presupposes a thorough familiarity with the ICD-10 and DSM-III-R or DSM-IV classification systems of mental disorders, and 51 IPDE considerable training and experience in making psychiatric diagnoses. Like other semistructured clinical interviews, its reliability and validity are inseparable from the qualifications and training of the person using it. It is designed for experienced psychiatrists, clinical psychologists, and those with comparable training, who are capable of making independent psychiatric diagnoses without a semistructured interview. It is not intended for use by clinicians in the early phase of their training, or by research assistants, nurses, and medical or graduate students. Most clini- cians feel comfortable with the IPDE and achieve a basic proficiency after giving about 10 interviews. Those who wish to obtain the optimal training are encouraged to enroll in the course offered at the worldwide WHO training centres. References 1. Jablensky, A., Sartorius, N., Hirschfeld, R. & Pardes, H. Diagnosis and classifi- cation of mental disorders and alcohol- and drug-related problems: a research agenda for the 1980s. Psychological Medicine, 1983; 13: 907-21. 2. World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders, Diagnostic Criteria for Research. Geneva: World Health Organization, 1993. 3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, revised 3rd edn. Washington, DC: American Psychiatric Association, 1987. 4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, revised 4th edn. Washington, DC: American Psychiatric Association, 1994. 5. Loranger, A.W. Personality Disorder Examination (PDE) Manual. Yonkers: DV Communications, 1988. 52 Experiences with the IPDE Alv A. Dahl and Antonio Andreoli Personality disorders (PDs) have been considered among the least reli- able diagnoses in psychiatry. When DSM-III PD diagnoses are made by clinicians, their reliability has proved to be rather poor.1 The develop- ment of structured interviews for PD was, therefore, the natural next step in an effort to improve reliability. Loranger et al .23 developed the Personality Disorder Examination (PDE) to fill that need. The IPDE evolved from the PDE, and includes the PDs in both ICD-10 and DSM- III-R. Its features are described elsewhere in this monograph. After the completion of the International Pilot Study of Personality Disorders (IPSPD), the interviewers completed a questionnaire about their experiences with the IPDE.4 At a meeting of investigators in Geneva in 1991, considerable time was devoted to issues raised by responses to the questionnaire. We will present the main findings and solutions chosen, since they reflect the dynamic process involved in the development of the final version of the IPDE. Some centres sent a common reply to the questionnaire, while others provided the responses of the individual interviewers. They revealed a variety of experiences and attitudes towards the instrument and the prob- lems in diagnosing PDs. They are reviewed question by question. What is your general impression of the IPDE? The overwhelming majority of the respondents found the IPDE to be a useful instrument for diagnosing PDs. One could perhaps argue that this was inflated, because they had a major investment in the instrument. But many of the sites had also tried other ways of diagnosing PDs in the ICD- 9 and DSM-III classification systems, and they might simply have found the IPDE an effective way of doing it. Only minor modifications were suggested. In the IPSPD the mean time of the interviews was two hours and twenty minutes. About half of the participants found that it took too long. 53 Experiences with IPDE The investigators considered three solutions: (1) to administer the inter- view in two sessions; (2) to create separate modules for the ICD-10 and DSM-III-R PDs; and (3) to screen cases with a questionnaire with a low rate of false-negatives, thereby eliminating interviews with subjects unlikely to have a PD diagnosis. Another question raised by some respondents concerned the duration of the behaviour used to define PD. ICD-10 and DSM-III-R do not spec- ify the exact duration of the abnormal behavioural patterns constituting PDs, but both classifications use the term 'long-term'. ICD-10 states that the abnormal behaviour 'is stable and of long duration, having its onset in late childhood or adolescence,' while DSM-III-R says that it is 'char- acteristic of the persons's recent (past year) and long-term functioning (generally since adolescence or early adulthood).' There is some dis- crepancy then between ICD-10 and DSM-III-R regarding the onset of the maladaptive behaviour. The IPDE solved these problems by requir- ing that the behaviour associated with almost all the diagnostic criteria be present for at least five years, and at least one of the criteria be evident before age 25,

in order to diagnose that disorder. Concern was also expressed that a patient might have a disorder like depression that gives a distorted image of what he/she is usually like. A patient may also be unaware of some traits or unwilling to acknowledge them. The influence of depression is a well known problem in the evalu- ation of PD by self-report. A previous study with the PDE showed little influence of anxiety or depression on the categorical or dimensional assessment of PD.5 It may be reasonable to conclude the same for IPDE if experienced clinicians carefully question the patients and use their clinical judgement. Severely depressed patients, however, might have difficulties in remembering their habitual state due to the effect of depression. An alternative solution is to postpone the PD examination until the patient is euthymic or to interview a relative. Lack of awareness or lying about unfavourable or less socially acceptable behaviour is a general problem in diagnosing mental disorders, and is not peculiar to structured interviews. Although the questions flow naturally, they pre- sume that the subject is attentive, of normal intelligence, and motivated. What are specific points with regard to applicability of IPDE in your culture? Before the study several interviewers were concerned that the IPDE might reflect North American attitudes and social and cultural norms 54 A. A. Dahl and A. Andreoli which may not be valid elsewhere. This criticism was not widespread, and ultimately the IPDE proved relevant across cultural and social settings. Some investigators noted some problems of applicability. A few men- tioned, e.g., that questions concerning reckless driving, and physical abuse of family members were problematic in their culture. Some high school education was probability necessary for an adequate understand- ing of the IPDE questions. And in some countries the high rate of long- term unemployment made the questions related to work experience less meaningful. The following quotes illustrate experiences with the IPDE in different cultures: The pattern of occurrence of personality disorders is largely unexplored in the Indian context, and the IPDE may usher in empirical investigation into this area. Overall I am finding few problems of applicability of the IPDE to our culture of interest. Our sub- jects are mostly American urbanites who reside near the birthplace of the DSM-III-R itself. Therefore, one might expect that our subjects would share values and perspectives similar to those exemplified by the IPDE. This seems to be the case. Respondents who were not psychologically-minded had great difficulty with borderline questions about identity. Although patients suffering from mental subnormality were excluded, those respondents whose intelligence appeared to be at the lower end of normal had considerable diffi- culty with these concepts. In contrast, subjects from middle-class backgrounds performed much more satisfactorily. In French culture, people often answer not with specific examples, but more in terms of: 'I feel this way.' It is my impression that the IPDE asks for a kind of psychological-mindedness or self-reflection which is often not found in Holland. I also think that the place of leisure activities and social rela- tions compared to work is somewhat different in our culture, which could lead to an overdiagnosis of obsessive-compulsive personality disorder. If there is need to shorten the interview, please indicate the sections that can be omitted. All centres reported that the IPDE took a long time to administer, and the instrument can be shortened if only one of the two diagnostic systems is used. If only certain PDs need to be evaluated, it can also be shortened, but all PDs have to be examined to get complete differential diagnostic coverage. Several centres reported that they had not found any cases of DSM-III-R sadistic PD, and that the questions for that diagnosis could be omitted. It should be noted that in DSM-IV, sadistic, self-defeating, and 55 Experiences with IPDE passive aggressive PDs have been deleted, and this will shorten the IPDE significantly. What do you think about the validity of the information obtained by IPDE (as compared to your clinical judgement)? Most of the respondents reported that the validity of the IPDE was better than clinical judgement. Some patient denials and replies seemed doubt- ful to the examiners, and the IPDE does not allow clinical hunches. It may also be difficult to get valid answers to questions concerning items that are less socially desirable, e.g., the abuse of family members. The instrument assumes that the patient will be open and honest, but a num- ber of patients with apparent personality abnormalities did not receive an IPDE diagnosis. It was not clear whether these patients were deliberately denying characteristics, or they had no insight into their own behaviour. Do you think that the IPDE adequately covers information necessary to assess PDs? The overwhelming majority of the respondents believed that the IPDE provided enough information to assess the PDs in DSM-III-R and ICD-10. A strength of the instrument is that it insures that all criteria are addressed. There is a question whether some of the questions are sufficient to elicit the necessary information. The impact of acute mental states may also be problematic, and needs to be assessed by examining the relationship with other mental disorders. To deal with this problem, the IPDE recommends the use of an Axis I instrument prior to the IPDE, to provide the examiner with the clinical information that is likely to enhance the reliability and validity of the questioning, probing, and scoring process. When it is not available from such an interview or from other sources, the IPDE exam- iner must obtain the information requested on the first page of the IPDE interview under the heading 'Background information'. Several respon- dents explicitly stated that information from an informant or from other sources was necessary for the diagnosis of PD. What is your view of the IPDE interview on giving the interviewer a sense of satisfaction of completion? Most respondents reported that they had comprehensively probed all the psychopathology of PDs. However, many also described a feeling of 56 A. A. Dahl and A. Andreoli relief after having finished the interview, because they had been through a long and tedious task. Several reported a feeling of frustration, since they had collected a lot of information but did not know the diagnoses at the end of the interview. This required several additional minutes with a computer program, or even longer with the hand scoring algorithms. Conclusion A principal objective of the IPSPD was to field test and develop an inter- nationally acceptable structured interview for the DSM-III-R and ICD- 10 PDs. After the project, considerable feedback on the experience with the IPDE was provided. This chapter provides examples of that process, including some of the criticism. In the best tradition of international col- laboration, these issues were discussed and acceptable solutions agreed upon by the participants in the study. The process persuaded us that the IPDE is an internationally acceptable structured interview for assessing the PDs in ICD-10, DSM-III-R, and now DSM-IV. References Mellsop, G., Varghese, F., Joshua, S. & Hicks, A. The reliability of axis II of DSM-III. American Journal of Psychiatry, 1982; 139: 1360-1. Loranger, A.W., Susman, V.L., Oldham, J.M. & Russakoff, L.K. The personality disorder examination: a preliminary report. Journal of Personality Disorders, 1987; 1:1-13. Loranger A.W. The Personality Disorder Examination (PDE) Manual. Yonkers: DV Communications, 1989. Loranger, A.W., Hirschfeld, R.M.A., Sartorius, N. & Regier, D.A. The WHO/ADAMHA international pilot study of personality disorders: background and purpose. Journal of Personality Disorders, 1991; 5: 296-306. Loranger, A.W., Lenzenweger, M.F., Gartner, A.F., Susman, V.L. et al. Trait- state artifacts and the diagnosis of personality disorders. Archives of General Psychiatry, 1991; 48: 720-8. 57 Field Trial 58 Sampling, interviewers, interview procedures Werner Mombour Method of sample selection The subjects of the study were in-patients and out-patients enrolled in 14 participating mental health facilities located in 11 countries in North America, Europe, Africa, and Asia (Table 1). The sites were selected to provide a broad representation of different nations, languages, and cul- tures. An additional consideration was the availability of experienced investigators with an interest in personality disorders. Each centre was asked to attempt to enter approximately 50 patients in the study. To adequately explore the diagnostic utility of the interview an effort was made at each site to attempt to include approximately 30 patients with a personality disorder and 20 patients with a common men- tal disorder that was important in the differential diagnosis of personality disorders (PDs). The goal was to have an approximately equal represen- tation of patients of both sexes between the ages of 21 and 55. Sampling of consecutive admissions was not feasible, and cases were selected at the convenience of the investigators. All patients were screened by expe- rienced psychiatrists or clinical psychologists according to the following criteria. Exclusion criteria • Clinical evidence of toxic or organic brain disease. • Moderate to profound mental retardation. • Language or other communication difficulties preventing adequate assessment. • Alcohol- or drug-use likely to prevent an adequate examination. • Delusional disorders, acute transient, or other florid psychotic states. • Evidence that personality functioning may have been significantly changed by another psychiatric disorder, e.g., psychosis. 59 Sampling, interviewers, interview procedures Table 1. Sites of International Personality Disorder Examination field trial Center Country Institution Bangalore India National Institute of Mental Health and Neuro Sciences Geneva Switzerland Institutions Universitaires de Psychiatrie-Geneve Leiden Netherlands Rijksuniversiteit te Leiden London United Kingdom Institute of Psychiatry Luxembourg Luxembourg Centre Hospitalier de Luxembourg Munich Germany Max-Planck Institut fiir Psychiatrie Nervenklinik der Universitat Miinchen Bezirkskrankenhaus Kaufbeuren Nairobi Kenya Kenyatta National Hospital New York United States Cornell Medical Center Nottingham United Kingdom Stonebridge Research Centre Oslo Norway Universitetet i Oslo, Psychiatrisk Institutt Tokyo Japan Keio University School of Medicine Vienna Austria Psychiatrische Universitatsklinik Inclusion criteria • The presence of a common mental disorder important in the differential diagnosis of PDs or • Evidence of the following longstanding and persistent pattern of sympto- matology and behavior which in the context of the given culture is con- sidered an abnormality of personality due to the presence of: (a) Markedly disharmonious attitudes and behavior usually involving sev- eral areas of functioning, e.g., affectivity, arousal, impulse control, ways of perceiving and thinking, and styles of relating to others. (b) The abnormal behavior is enduring and not limited to episodes of mental illness. (c) The abnormal behavior pattern is pervasive and clearly maladaptive to a broad range of personal and social situations. (d) The above manifestations generally appear during childhood or adoles- cence and continue into adulthood. (e) The disorder is of sufficient severity to lead to considerable personal dis- tress and/or the disorder is usually, but not invariably, associated with significant impairment in occupational and social performance. 60 W. Mombour The screening clinicians utilized all available information on the patients and when necessary conducted their own interview. They sum- marized this information on a standard form that included a clinical diag- nosis according to both their local practice and ICD-10. IPDE training Each centre (with the exception of Nairobi, where only one interviewer was available in addition to the screening personnel), trained at least two psychiatrists or clinical psychologists in the administration of the IPDE. The initial training consisted of a two-day workshop conducted at each centre by the developer of the instrument and co-ordinator of the project (AW Loranger). These training sessions made extensive use of video- taped demonstration interviews. Thereafter the principal investigator at each centre assumed responsibility for the training. Each interviewer was required to complete a minimum of 10 practice interviews before partici- pating in the study. Scoring practices were also monitored during the study by circulating several videotaped interviews conducted in English. IPDE interviews To determine the interrater reliability of the IPDE, at each site an attempt was made to have 10 of the IPDE interviews observed and independently rated by another clinician. An effort was also made to have 25 of the patients at each centre reinterviewed with the IPDE by the same clinician several months later. The clinicians who conducted and observed the IPDE interviews were unaware of the diagnostic conclusions of the screening clinicians. Clinical evaluation The IPDE interviewer also conducted a general clinical evaluation of the patient. At several centers this included information derived from the following semistructured interviews: Diagnostic Interview Schedule

(DIS)-Leiden (The Netherlands); Schedule for Affective Disorders and Schizophrenia (SADS-L)-London (UK); and Structured Interview for DSM-III-R (SCID)-New York (USA), Nottingham (UK), Oslo (Norway), Tokyo (Japan). After the completion of the IPDE, the inter- viewer summarized all of this information on a Clinical Evaluation Form. 61 Description of centres participating in the IPDE field trial Aleksandar Janca and Charles Pull Bangalore Bangalore has been the capital of the southern Indian state of Karnataka (formerly Mysore) since 1830. The name comes from the word 'ben- dakalooru,' which means 'village of boiled grains' in the Kannada lan- guage. It is the fifth largest city in India, with about four million inhabitants consisting primarily of three cultural and linguistic groups: Kannada, Telugu, and Tamil. Bangalore was the headquarters of the British administration until 1881, and Britain retained its colonial and military presence there until independence in 1947. The city has an old section and several surrounding modern suburbs with many parks, wide streets, and a sprawl of military cantonments to the east. Often called the Garden City of India because of its salubrious climate, but more recently its rapid industrialization has also earned it the sobriquet, Silicon City. The National Institute of Mental Health and Neuro Sciences (NIMHANS) is the largest mental health institution in the area and the largest postgraduate training centre in the country. It was established in 1974 as an autonomous institution, that amalgamated the Mental Hospital and the All India Institute of Mental Health. There are 24 departments grouped into three major sections: behavioural sciences, basic sciences and neurosciences. There is an 805-bed hospital with pro- vision for 650 psychiatric and 155 neurological and neurosurgical patients. There is a multidisciplinary approach, which integrates service, training, and research in mental health and the neurosciences. The Department of Psychiatry of NIMHANS has collaborated with the Division of Mental Health of the World Health Organization (WHO) for more than a decade. The collaboration has been particularly success- ful regarding the diagnosis and assessment of mental disorders and their culture-specific characteristics. Research investigators in the department have translated several diagnostic instruments developed by WHO into Kannada, Tamil, and Hindi, and participated in their field trials. The Institute serves as a WHO training and reference centre for the 62 A. JancaandC. Pull Composite International Diagnostic Interview (CIDI), Schedule for Clinical Assessment in Neuropsychiatry (SCAN), and International Personality Disorder Examination (IPDE). In the IPDE field trial NIMHANS also served as a co-ordinating centre for several other insti- tutions from which subjects were recruited. These were King George's Medical College, Lucknow; Institute of Psychiatry, Madurai; Madurai Medical College, Madurai; Jawaharial Institute of Postgraduate Medical Education and Research, Ponchiderry; K.E.M. Hospital, Bombay; Madras Medical College, Madras; and G. S. Medical College, Bombay. Geneva Geneva, the capital of the Canton of Geneva, is situated between the Alps and Jura mountains where the Rhone river emerges from Lake Geneva. Earlier in its history it was the centre of the Calvinist Reformation, and today it is a centre of commerce, trade, banking, and insurance. Geneva is the European headquarters of the United Nations and its related divisions, as well as the home of many other international organizations. It is an international city, two-thirds of whose inhabitants are recent immigrants about equally divided between those from other Swiss cantons and foreigners from all over the world. Three public health institutions affiliated with the Department of Psychiatry of Geneva University Medical School provide mental health care to the adult population. Care is also provided by the emergency room of Geneva General Hospital and by approximately 160 private practitioners. This study was conducted at the out-patient department of the Eaux- Vives Psychiatric Centre, which is responsible for a residential area with a population of about 115,000. There are specialized out-patient clinics for schizophrenia and mood and personality disorders, and a walk-in clinic for emergency psychiatric care. The out-patient department treats about 300 chronic and 500 new patients a year. Two-thirds of new admissions have severe anxiety, mood or stress-related disorders, and the remainder present with psychotic and depressive disorders. The Eaux-Vives Psychiatric Centre is also a teaching institution affili- ated with the Department of Psychiatry of Geneva University and the Clinique de Psychiatrie Generate I. The Centre has developed a research program focused on crisis intervention in acute patients, personality dis- orders (PDs) as predictors of outcome, and the cognitive functioning of patients with borderline PD and major depression. 63 Centres participating in IPDE field trial Leiden/Delft Leiden is situated at the confluence of the Old and New Rhine rivers in the western Netherlands. It was first mentioned in AD 922 as a holding of the Utrecht diocese. It developed around a twelfth-century castle and received its name (Lugdunum Batavorum) in the sixteenth century from Janus Dousa, a statesman and defender against the Spaniards. The University of Leiden was founded in 1575 and the city became a centre of Dutch Reformed theology, science and medicine. It is the birthplace of many famous Dutch painters including Rembrandt, Jan van Goyen, and Jan Steen. The Department of Clinical and Health Psychology at the University of Leiden and the St. Joris Psychiatric Hospital in Delft participated in the study. Delft is a small city between Rotterdam and the Hague, famous for its handmade faience delftware. All subjects of the study were from St. Joris. London London is the largest port, and commercial and cultural centre of Great Britain and its Commonwealth. Founded by the Romans as Londinium, it experienced tremendous growth in trade and population at the end of the sixteenth century. Today it is one of the major centres of interna- tional trade and finance, and a tourist attraction for visitors from all over the world. Its museums, theatres and other cultural institutions make it one of the cultural capitals of the world. The Bethlem Royal and the Maudsley Hospital, known informally as the Joint Hospital, have treated the mentally ill for more than 600 years. Today the Joint Hospital is administered as a postgraduate teaching hos- pital, and with the Institute of Psychiatry make up a tripartite organiza- tion commonly referred to as the Maudsley. The out-patient department serves some 3000 new attenders each year, representing all the psychi- atric disorders. The hospital is responsible for a local catchment area in south-east London, south Southwark. In collaboration with the Institute of Psychiatry, the hospital has a wide range of specialty units, including those devoted to forensic psychiatry, alcoholism and the addictions, eat- ing disorders, epilepsy, child and adolescent psychiatry, and neuropsy- chiatry. It is also a referral centre for specialist services for patients from all over the country. The Institute of Psychiatry is affiliated with the University of London and offers advanced training for psychiatrists, psy- chologists, neurologists, and other scientific and paramedical workers. It 64 A. Janca and C. Pull also conducts pioneering research to advance the understanding and treatment of mental illness. Luxembourg The City of Luxembourg (meaning 'little fortress') was built as a fortress on a plateau above the Alzette river, and was a natural defensive position for the Romans and later the Franks. Today scenic parks have replaced earlier fortifications on the western fringe of the old town. The city is an important financial centre and hosts several agencies of the European Community. There are highly diversified industries concentrated in the suburbs. The Centre Hospitalier de Luxembourg is a general public hospital with a number of specialty departments. The Department of Psychiatry is one of the most active French-speaking WHO collaborating centres. It has been involved in many WHO research projects on the diagnosis, classification, and assessment of mental disorders. It has co-ordinated and tested the ICD-10 diagnostic criteria as well as numerous instru- ments developed by WHO. The hospital also serves as a training and ref- erence centre for the Composite International Diagnostic Interview (CIDI), Schedules for Clinical Assessment in Neuropsychiatry (SCAN), and the International Personality Disorder Examination (IPDE). In addi- tion to its use in the present study, the IPDE is used in the routine assess- ment of in-patients and out-patients with indications of a PD. Munich Munich is the capital of Bavaria and the third largest city in Germany. It traces its origin to an eighth century Benedictine monastery. Located on the Isar river it was founded in 1157 by Henry the Lion, Duke of Bavaria, who granted the monks the right to establish a marketplace (Miinchen means 'home of the monks'). Modern Munich is a city of great cultural and industrial importance, a major convention and financial centre, and one of the largest wholesale markets in Europe. Munich was represented in this study by the Max-Planck Institute for Psychiatry and the Department of Psychiatry of the University of Munich. A small number of patients from the Kaufbeuren mental hospital outside of Munich were also included. The Max-Planck Institute for Psychiatry is a research institute for psy- chiatry and related basic sciences, and a 120-bed hospital. There are more 65 Centres participating in IPDE field trial than 1000 in-patient admissions a year, and an out-patient department serving about 2000 psychiatric and 2000 neurological patients annually. The in-patient department consists of an intensive care unit (locked ward), several open wards, a crisis intervention ward, and a neurological ward. Current research is focused on biological psychiatry, including neuroendocrinology and molecular genetics. There is also a great interest in the diagnosis and assessment of psychiatric disorders. The Institute has translated and tested a number of WHO diagnostic instruments. The Department of Psychiatry of the University of Munich has an out- standing history dating back to Emil Kraepelin. It is now a part of the Munich Faculty of Clinical Medicine and comprises a 208 bed hospital, out-patient clinic, day and night clinics, and several affiliated department. Its staff comprises more than 300 professionals, including 97 physicians, psychologists, psychotherapists, and biochemists. The in-patient service cares for the inhabitants of Munich and its surrounding areas, and also admits patients from Upper and Lower Bavaria. It has 10 wards, including a research unit and one for the treatment of addiction. The out-patient department provides comprehensive care that includes a 24-hour emer- gency and liaison consultation service to the other hospitals of the Faculty of Clinical Medicine in Munich. There are also departments of neuro- chemistry, experimental and clinical psychology, psychotherapy and psy- chosomatics, neurophysiology and EEG, and forensic psychiatry. Patients are predominantly from working class backgrounds, but all socioeco- nomic groups are represented. They include mostly those with anxiety, depression, a history of suicide attempts, and personality disorders. Nairobi Nairobi is the capital of Kenya and one of the main trading centres in East Africa. The city was established at the end of the nineteenth century as a colonial railway settlement. It got its name from a waterhole known to the Masai people as Enkare Nairobi (cold water). The city attracted many migrants from various parts of rural Kenya and became one of the largest cities in tropical Africa. It is the principal industrial centre in the country and the railway is the largest single indus- trial employer. The study in Nairobi was conducted at three sites: Kenyatta National Hospital, Mathan Mental Hospital and the University of Nairobi Students' Health Centre. The Kenyatta National Hospital is the largest public hospital in the city of Nairobi and the majority of subjects for this 66 A. Jancaand C. Pull study were recruited from there. The Mathan Mental Hospital is the largest in-patient facility in Nairobi with 1500 beds, most of which are occupied by patients with psychotic symptoms. It also has a 200-bed secure unit which houses mostly forensic cases. The University Students' Health centre provides medical services to students of the University of Nairobi and has about 40 admissions a week of cases with some psychological problems. Patients of these institutions represent a whole range of sociodemo- graphic strata, although the majority belong to the working class. Most of the patients from the forensic unit of the Mathan Mental Hospital manifest some PD characteristics, while the patients from the other sites most commonly show mixed anxiety and depressive symptomatology, often with a history of suicide attempts. New York/White Plains In 1609 Henry Hudson, an Englishman employed by the Dutch to search for a new route to the Indies, sailed his vessel Half Moon up

the river that now bears his name. In 1626 the Dutch East India Company established a trading post on the present site of Manhattan, which they purchased from the natives for 60 guilders. It came under English rule in 1664 when Charles II seized it from the Dutch and gave it to the Duke of York. Situated on the Atlantic Ocean with one of the finest harbours in the world, in the nineteenth and early twentieth century New York was the gateway for most European immigrants to the US. Today, the city and its suburban communities has a population of more than 10 million, and is the financial, commercial and cultural capital of the US. With its unique ethnic mosaic it is arguably the most exciting and vibrant city in the world. The New York Hospital and its affiliated Cornell University Medical College comprise The New York Hospital-Cornell Medical Center, a world-renowned medical resource for patient care, research, education and training. Chartered by King George III in 1771, it has accepted men- tally ill patients since it opened in 1791 at the conclusion of the American Revolutionary War. The Department of Psychiatry maintains the Payne Whitney Clinic, a 100-bed facility adjacent to the main hospital in Manhattan, and the Westchester Division, a 300-bed hospital situated in a 200 acre park-like setting in suburban White Plains, where it has been located since 1894. Today White Plains has approximately 50,000 resi- dents, and is a thriving shopping area and business community housing the offices and headquarters of many leading companies. It is also the 67 Centres participating in IPDE field trial governmental seat of Westchester County with its population of almost one million. The Department of Psychiatry treats more than 10,000 patients a year in its in-patient and specialized ambulatory care programs. The patients represent the entire range of mental disorders, and reflect the ethnic and socioeconomic diversity of the region. The department has over 680 full- and part-time faculty members, who in addition to their clinical and edu- cational responsibilities also conduct research on many of the biological and psychosocial topics on the frontier of modern psychiatry. Nottingham The city of Nottingham was established in the sixth century AD by the Anglo-Saxons who colonized the area by the River Trent and gave the settlement the name of Snotingaham (the 'ham' or village of Snot's peo- ple). Nottingham, the county town of Nottinghamshire, lies at the heart of the East Midlands coalfields and has extensive rail, road, and air con- nections with the rest of the United Kingdom and Europe. The popula- tion of the city and adjacent boroughs is approximately 650,000. Nottingham has two universities and is the centre for a wide range of artistic and cultural activities. Nottingham's psychiatric services are divided into six catchment areas, each of which has a local mental health centre and an associated admission ward of 20 beds in one of two hospitals located in the north and south of the city. Patients in the study were selected from one of these sectors (East and Carlton), which has a resident population of 78,000 between the ages of 16 and 65. Those who required the services of the district-wide drug and alcohol unit or the rehabilitation and spe- cialized psychotherapy units were not included. All the psychiatric services of the East and Carlton sector are commu- nity based, with the exception of the admission ward. The psychiatric team is staffed by 1.5 consultant psychiatrists, three resident psychia- trists, one occupational therapist, five community psychiatric nurses, and four psychiatric social workers. The team operates from a purpose-built base which is located in the heart of the sector. It maintains very close links with the local community and is the first port-of-call for residents 16-65 years of age with mental disorders. There is no significant private practice in the area. Most psychiatric referrals are received from 53 pri- mary care physicians in the sector. A smaller proportion are referred from social services, housing, and other agencies. The catchment area is 68 A. JancaandC. Pull located in part of the inner city and is subject to very high levels of social deprivation and unemployment compared to the rest of the city. Oslo Oslo, founded in about 1050 by King Harald Hardaake, lies at the head of Oslo Fjord in the southeastern part of the country. After it was destroyed by fire in 1624, Christian IV of Denmark and Norway built a new town farther west under the walls of the Akershus fortress, and called it Christiania. The population grew in the nineteenth century partly because of the absorption of surrounding municipalities, and it replaced Bergen as Norway's largest and most influential city. It was renamed Oslo in 1925 and today is Norway's capital, largest city, and home of its leading cultural institutions. Oslo also has the largest and busiest harbour in the country, and is the centre of Norwegian trade, banking, shipping and industry. The study was conducted at the Psychiatrisk klinik, Vinderen, a clinic affiliated with the Department of Psychiatry of the University of Oslo. The clinic has primary responsibility for providing psychiatric services to approximately 80,000 inhabitants of sector-D west. This includes mostly the more affluent parts of the city, where psychiatric morbidity is less than elsewhere. The Psychiatrisk klinik works closely with general practitioners and the general hospital in the sector. Tokyo Tokyo lies on the Pacific coast of central Honshu Island. It has been inhabited since ancient times and was originally named Edo. It was renamed Tokyo ('eastern capital') in the nineteenth century. Today it is the capital of Japan and has a population of 12 million. It is the commer- cial, financial, and cultural centre of the nation. The locus of predomi- nantly light and labour-intensive industries, Tokyo is also a transportation and international traffic centre. The Keio University Hospital is located in Shinjuku-ku in the centre of Tokyo, surrounded by the beautiful garden of the Meiji Shrine and the Shinjuku Imperial Garden. It was established in 1917 under the leader- ship of Yukichi Pukuzawa, the founder of Keio University, and Shibasaburo Kitasato, the first dean of the School of Medicine. The hos- pital is affiliated with the Keio University School of Medicine, which was established in 1917 as part of the Keio Gijuku University founded in 69 Centres participating in IPDE field trial 1854. The hospital has gained a national reputation as one of the best medical centres in Japan. It has 1071 beds and serves over 3500 out- patients daily, more than 300 of whom are physician requests for consul- tations. Most patients are from the Tokyo area, but many come from elsewhere in the country. The Department of Neuropsychiatry has 31 beds, 200 annual admis- sions, and a 30- to 40-day length of stay. Most patients have mood, neu- rotic, or eating disorders. The out-patient department has 10 new admissions daily and cares for 180-200 patients. The department has a reputation as a centre for both psychotherapy and pharmacotherapy. The majority of patients are middle class and come from urban or suburban areas, although some are referred from all over the country. As a teaching hospital it trains 10-15 new residents a year. It has trained almost 500 psy- chiatrists, about 10 per-cent of those in Japan. The facility also has a long history of research, particularly in psychopharmacology, psychoimmunol- ogy, psycho-oncology, and the quality of life of psychiatric patients. Vienna Vienna is the capital of Austria and home of 1.5 million people, nearly one-fifth of the country's population. It is located on the Danube river and is a gateway between western and eastern Europe. The mainstays of its economy are trade and industry. It is a city of vast cultural achieve- ment, renowned for its baroque architecture and musical tradition. It was home to Haydn, Mozart, Beethoven, Schubert, Brahms, J. Strauss, Mahler, and Schonberg. Vienna was the seat of the Austro-Hungarian Empire until the beginning of the twentieth century, and the various states of the former empire have had a significant cultural and ethnic influence on this city. This study was conducted in the Department of Psychiatry of the University of Vienna, part of a large university hospital located in the centre of the city. There are wards for general psychiatric and psy- chotherapeutic treatment. There is a small day hospital and an out- patient clinic that treats approximately 5000 patients annually. They are referred from all districts of Vienna and to a lesser extent from the east- ern part of Austria. The national social insurance system insures free access to the hospital to the entire population. The subjects were recruited for the study from the out-patient clinic and psychotherapeutic wards. One patient was included from the day hospital. 70 Results Armand W. Loranger Course of the field trial The first patients entered the study in April 1988 and the last subject was examined in December 1990. All record forms were returned to the pro- ject coordinator (AW Loranger), who verified them for completeness and contacted the centers regarding missing data or apparent errors in recording. The information was then entered in a computer at the ADAMHA data processing facility at Rockville, Maryland. In August 1991 the investigators met at the World Health Organization (WHO) headquarters in Geneva to review the results of the data analysis. At the meeting they also discussed the replies to a questionnaire that had been sent to all of the interviewers about the strengths and limitations of the IPDE, including its user friendliness, cultural relevance, and apparent clinical validity. Patient sample At the conclusion of the study, 716 patients had been examined, 243 reexamined, and 141 of the IPDE interviews rated by an observer. The average interval between the initial and repeat IPDE examinations was six months, with approximately 85% of the repetitions occurring between two months and one year. Table 1 provides the sample sizes of the subjects at each centre, together with the number of IPDE examiners. Table 2 contains information about the educational level of the patients. Their clinical ICD-10 diagnoses, exclusive of personality disorders (PDs), are presented in Table 3. Personality disorder diagnoses The IPDE personality disorder diagnoses in the DSM-III-R and ICD-10 systems are presented in Table 4. For the 243 subjects who were exam- ined on two occasions, the diagnoses are based on the initial interview. Table 1. Sample sizes and IPDE field trial centres Patients IPDE City Centre Examiners Male Female In-patient Out-patient Bangalore National Institute of Mental Health and Neuro Sciences 3 31 16 7 40 Geneva Institutions Universitaires de Psychiatrie-Geneve 3 11 21 2 30 Leiden Rijksuniversiteit te Leiden 6 34 31 55 10 London Institute of Psychiatry 3 23 29 26 26 Luxembourg Centre Hospitalier de Luxembourg 5 28 24 46 6 Munich Max-Planck-Institut fur Psychiatrie 11 58 55 54 59 Nervenklinik der Universitat Miinchen Bezirkskrankenhaus Kaufbeuren Nairobi Kenyatta National Hospital 1 30 20 10 40 New York Cornell Medical Center 10 48 52 56 44 Nottingham Stonebridge Research Centre 4 26 24 0 50 Oslo Universitetet i Oslo Psychiatrisk Institutt 4 20 28 20 28 Tokyo Keio University School of Medicine 3 28 29 5 52 Vienna PsychiatrischeUniversitatsklinik 5 27 23 14 36 Total 58 364 352 295 421 72 A. W. Loranger Table 2. Educational level of patients at each centre Percentage of centre sample Site years of education <5 6-12 13-15 >16 Bangalore 2.2 42.2 35.6 20.0 Geneva 0 58.1 19.4 16.1 Leiden 1.5 60.0 30.8 7.7 London 11.5 50.0 21.2 9.6 Luxembourg 2.0 58.0 32.0 8.0 Munich 0.9 64.6 22.1 12.4 Nairobi 32.0 61.3 6.5 0 New York 1.0 17.0 43.0 38.0 Nottingham 2.0 86.0 6.0 4.0 Oslo 0 64.6 20.8 14.6 Tokyo 0 32.1 23.2 44.7 Vienna 0 62.0 32.0 6.0 Tables A. 1 to A. 12 in the Appendix list the IPDE diagnoses at each indi- vidual centre. Table 5 presents the frequencies with which the specific DSM-III-R disorders occurred in the same patients. Table 6 provides the same information for the ICD-10 disorders. IPDE interrater reliability and temporal stability Intraclass correlation coefficients1 were used to measure the examiner-observer agreement in scoring each of the 157 items on the IPDE, and their stability from the initial to repeat examinations. Since stability is influenced by the interrater agreement

in scoring a single interview, correlations with a correction for attenuation2 are included with the stability coefficients, to provide a more accurate estimate of sta- bility per se. Table 7 summarizes these correlations. Tables A. 13 and A. 14 in the Appendix present the measures of interrater reliability and stability for each PD criterion in DSM-III-R and ICD-10, together with the frequency of occurrence of the criterion in the sample of 716 patients. 73 Results Table 3. ICD-10 Disorders exclusive of personality disorders (N=696)* ICD-10 disorder No. of patients Substance use (15.4) 107 Schizophrenia and delusional schizophrenia (2.3) 16 persistent delusional (0.6) 4 acute and transient psychotic (0.7) 5 schizoaffective (0.3) 2 Mood (affective) manic episode (0.1) 1 bipolar (3.7) 26 depressive episode (9.9) 69 recurrent depressive (8.9) 52 persistent mood (12.0) 77 other mood (0.2) 1 Neurotic, stress related, somatoform phobic anxiety (6.2) 43 other anxiety (13.6) 95 obsessive-compulsive (6.5) 45 reaction to severe stress and adjustment (5.9) 41 dissociative (1.0) 7 somatoform (2.6) 18 other (0.7) 5 Physiological disturbances eating (6.6) 46 nonorganic sleep (0.3) 2 sexual dysfunction (0.3) 2 personality disorder only (32.8) 228 Includes multiple diagnoses in some patients. Diagnoses not available for 20 Nairobi patients. Intraclass correlation coefficients were also used to measure the examiner-observer agreement regarding the dimensional scores, the number of criteria met on each disorder, and their stability from the initial to repeat examinations. These correlations are presented in Table 8. 74 A. W. Loranger Table 4. IPDE DSM-III-R andICD-10 diagnoses (N=716)* DSM-III-R personality disorder No. of patients (%) Paranoid 42 (5.9) Schizoid 20 (2.8) Schizotypal 25 (3.5) Obsessive-compulsive 22 (3.1) Histrionic 51 (7.1) Dependent 32 (4.5) Antisocial 46 (6.4) Narcissistic 9 (1.3) Avoidant 79 (11.0) Borderline 104 (14.5) Passive aggressive 36 (5.0) Sadistic 2 (0.3) Self defeating 9 (1.3) +Not otherwise specified 92 (12.8) Any personality disorder 366 (51.1) ICD-10 personality disorder No. of patients (%) Paranoid 17 (2.4) Schizoid 13 (1.8) Dissocial 23 (3.2) Emotionally unstable impulsive 32 (4.5) borderline 107 (14.9) Histrionic 31 (4.3) Anankastic 26 (3.6) Anxious 109 (15.2) Dependent 33 (4.6) ++Other 49 (6.8) Any personality disorder 283 (39.5) Personality disorder diagnoses include patients with more than one type of personality disorder. +Did not fulfill diagnostic criteria for any specific personality disorder, but met 10 or more of the 110 DSM-III-R personality disorder criteria. ++Did not fulfill diagnostic criteria for any specific personality disorder, but met 10 or more of the 56 ICD-10 personality disorder criteria. 75 Results Table 5. Frequency of co-occurrence of DSM-III-R personality disorders in patients with a personality disorder (N=366) PAR SCD SCT ASP BOR HIS NAR AVO DEP OBC PAS SAD SFD PAR 42 4 5 8 16 13 1 9 3 4 8 0 1 SCD 20 6 0 2 0 0 5 1 0 1 0 0 SCT 25 0 6 1 0 4 2 1 1 0 2 ASP 46 16 10 2 5 2 0 9 1 0 BOR 104 26 7 18 16 4 16 1 5 HIS 51 7 8 10 3 9 0 2 NAR 9 1 2 0 3 0 0 AVO 79 14 7 12 0 5 DEP 32 3 4 0 2 OBC 22 5 0 2 PAS 36 0 4 SAD 2 0 SFD 9 Abbreviations: PAR, paranoid; SD, schizoid; SCT, schizotypal; ASP, antisocial; BOR, borderline; HIS, histrionic; NAR, narcissistic; AVO, avoidant; DEP, dependent; OBC, obsessive-compulsive; PAS, passive aggressive; SAD, sadistic; SFD, self-defeating. Table 6. Frequency of co-occurrence of ICD-10 personality disorders in patients with a personality disorder (N=283) PAR SCD DIS IMP BOR HIS ANA ANX DEP PAR 17 1 1 3 7 3 3 8 2 SCD 13 0 1 2 0 0 3 0 DIS 23 9 15 5 2 4 2 IMP 32 26 7 2 6 4 BOR 107 19 6 28 14 HIS 31 4 10 4 ANA 26 12 2 ANX 109 19 DEP 33 Abbreviations: PAR, paranoid; SCD, schizoid; DIS, dissocial; IMP, impulsive; BOR, borderline; HIS, histrionic; ANA, anankastic; ANX, anxious; DEP, dependent. 76 A. W. Loranger Table 7. Interrater reliability and temporal stability of 157 IPDE items Interrater reliability (N=141) Temporal stability (N=243) Intraclass R No. of Items % Cumul.% No of Items % Cumul. % 0.90-1.00 13 8.3 0 (2) 0 (1-3) 0.80-0.89 72 45.9 54.2 2 (13) 1.3 (8.3) 1.3 (9.6) 0.70-0.79 52 33.1 87.3 14 (42) 8.9 (26.8) 10.2 (36.3) 0.60-0.69 12 7.6 94.9 62 (62) 39.5 (39.5) 49.7 (75.8) 0.50-0.59 4 2.5 97.4 53 (27) 33.8 (17.2) 83.4 (93.0) 0.40-0.49 1 0.6 98.0 19 (5) 12.1 (3.2) 95.5 (96.2) <0.40 3 1.3 7 (6) 4.5 (3.8) Kappa3 was used to measure the interrater agreement and tem- poral stability of the PD diagnoses. Because of its instability in samples with an infrequent number of cases of a disorder, the recommendation was followed that it be calculated only when the prevalence of a disorder is at least 5%.4 To provide more opportunities for the calculation of kappa, it was also determined by combining definite and probable diag- noses. The IPDE assigns a probable diagnosis when a subject meets one criterion less than the number required for the diagnosis. An overall weighted kappa was also determined for all PDs, including those with a base rate of less than 5%. It was calculated by weighing each category of PDs by the total number of cases assigned a diagnosis in that category by either rater, regardless of whether or not the raters agreed about the diag- nosis. The numerator is the sum of the product of the diagnostic weight and kappa for each disorder; the denominator is the sum of the weights. The kappa values are presented in Table 9. References Ebel, R.L. Estimation of the reliability of ratings. Psychometrika, 1951; 16: 407-23. Nunnally, J.C. Psychometric Theory, pp. 219-20, 237-9. New York, NY: McGraw-Hill International Book Co, 1978. Fleiss, J.L. Statistical methods for Rates and Proportions, 2nd edn., pp. 217-20. New York: John Wiley & Sons Inc, 1981. Grove, W.M., Andreasen, N.C., McDonald-Scott, P., Keller, M.B. & Shapiro, R.W. Reliability studies of psychiatric diagnosis: theory and practice. Archives of General Psychiatry, 1981; 38:408-13. 77 Results Table 8. Interrater reliability and temporal stability oflPDE number of criteria met and dimensional scores* No. of criteria met Dimensional score Disorder Interrater Temporal Interrater Temporal reliability stability* reliability stability* (N=141) (N=243) (N=141) (N=243) DSM-III-R Intraclass R Paranoid .75 .58 (.67) .85 .68 (.74) Schizoid .83 .72 (.79) .86 .76 (.82) Schizotypal .82 .69 (.76) .87 .81 (.87) Obsessive-compulsive .82 .75 (.83) .89 .80 (.85) Histrionic .81 .75 (.83) .87 .78 (.84) Dependent .89 .67 (.71) .92 .72 (.75) Antisocial .88 .74 (.79) .94 .92 (.95) Narcissistic .83 .71 (.78) .90 .75 (.79) Avoidant .82 .71 (.78) .89 .77 (.82) Borderline .89 .84 (.89) .93 .87 (.91) Passive aggressive .92 .72 (.75) .89 .78 (.83) Sadistic .80 .61 (.69) .88 .76 (.81) Self-defeating .71 .74 (.88) .79 .75 (.84) ICD-10 Paranoid .78 .56 (.72) .87 .66 (.71) Schizoid .79 .62 (.78) .87 .74 (.80) Dissocial .88 .55 (.62) .92 .69 (.72) Emotionally unstable impulsive .87 .74 (.85) .89 .78 (.83) borderline .91 .82 (.90) .93 .86 (.90) Histrionic .84 .69 (.82) .88 .80 (.85) Anankastic .73 .74 (1.00) .86 .77 (.83) Anxious .83 .74 (.89) .88 .77 (.82) Dependent .88 .58 (.66) .91 .65 (.71) * Average interval between test and retest (temporal stability) was six months. tFor temporal stability, data in parentheses are corrected for attenuation. 78 A. W. Loranger Table 9. Interrater agreement (K), temporal stability (K), and base rate (%) oflPDE DSM-III-R and ICD-10 diagnoses* Interrater Agreement Temporal Stability Disorder (N=141) N=243 Definite Definite/Probable Definite Definite/Probable DSM-III-R Paranoid . . . (5%) .51 (12%) .24 (5%) .28 (10%) Schizoid . . . (3%) .87 (6%) . . . (2%) .68 (5%) Schizotypal . . . (1%) . . . (3%) . . . (3%) .68 (5%) Obsessive compulsive . . . (2%) .60 (6%) . . . (2%) . . . (4%) Histrionic .34 (6%) .66 (13%) .45 (5%) .46 (12%) dependent .70 (5%) .82 (9%) . . . (4%) .43 (9%) Antisocial . . . (5%) .73 (9%) .59 (5%) .62 (9%) Narcissistic . . . (1%) . . . (3%) . . . (1%) . . . (4%) Avoidant .71 (10%) .78 (17%) .48 (10%) .56 (19%) Borderline .80 (10%) .76 (16%) .70 (13%) .72 (19%) Passive aggressive . . . (2%) . . . (4%) . . . (3%) .41 (6%) Sadistic . . . (1%) . . . (1%) . . . (0%) . . . (2%) Self-defeating . . . (0%) . . . (3%) . . . (2%) .71 (7%) Any specific .59 (27%) .70 (46%) .62 (34%) .63 (51%) personality disorder Overall Weighted Kappa .57 .69 .50 .53 ICD-10 Paranoid . . . (2%) .43 (7%) . . . (2%) .30 (8%) Schizoid . . . (1%) . . . (5%) . . . (1%) . . . (3%) Dissocial . . . (4%) 1.00 (6%) . . . (2%) . . . (4%) Emotionally unstable impulsive . . . (4%) .79 (7%) . . . (4%) .60 (7%) borderline .76 (12%) .78 (16%) .65 (14%) .62 (15%) Histrionic . . . (3%) .64 (7%) . . . (2%) .53 (7%) Anankastic . . . (2%) .53 (6%) . . . (2%) .60 (7%) Anxious .72 (11%) .77 (22%) .64 (15%) .65 (24%) Dependent . . . (4%) .81 (13%) . . . (3%) .36 (11%) Any specific .64 (25%) .71 (43%) .59 (29%) .60 (44%) personality disorder Overall Weighted Kappa .65 .72 .54 .53 *Kappa calculated only when base rate >5% according to both raters; base rates in Table are means of both raters. Average interval between test and retest (temporal stability) was six months. Probable diagnosis assigned when patient met one criterion less than required number. 79 Discussion and conclusions Armand W. Loranger This investigation represents the first attempt to assess personality disor- ders (PDs) worldwide with contemporary methods of diagnosis. The semistructured interview (International Personality Disorder Examination-IPDE), developed within the World Health Organization (WHO) program on diagnosis and classification, was designed to assess PDs within the framework and guidelines of two distinct but overlapping classification systems. DSM-III-R, which was intended for use in the US, is primarily the product of American psychiatric opinion, while ICD-10, which is meant for worldwide use, reflects the views and needs of the international psychiatric community. Interrater Agreement To provide a valid diagnosis an instrument must first demonstrate a rea- sonable degree of interrater reliability. An international test of reliability such as the present one involves patients from a wide variety of national and cultural settings, who speak many different languages. The examin- ers also consist of a large number of psychiatrists and clinical psycholo- gists trained at many different facilities around the world. Therefore, this was an unusually exacting test of reliability to which no other interview for PDs has ever been subjected. The results, nevertheless, compare quite favourably with published reports on semistructured interviews that are used to diagnose the psychoses, mood, anxiety, and substance use disor- ders. Such comparisons, of course, must be viewed as rough approxima- tions. There are obvious differences in the heterogeneity of the patient samples, the base rates of the individual disorders, as well as variations in the methods used to measure reliability. Furthermore, many of these stud- ies have been conducted within one facility only, and rarely have they been undertaken outside the nation in which the interview was developed. With these caveats in mind, we compared the results of the present study with those of the SCID Axis I field trial.1 That study involved 390 80 A. W. Loranger patients at four locations in the US and one in Germany. The median kappa values for those individual disorders with a base rate of at least 5% were 0.64 for current diagnoses and 0.68 for lifetime diagnoses. In the present field trial, the median kappa values for the individual PDs (diag- nosis definite) with base rates of at least five per cent were 0.70 in DSM- III-R and 0.72 in ICD-10. The overall weighted kappa values in the SCID study were 0.61 for current diagnoses and 0.68 for lifetime diag- noses. In the present study, the overall weighted kappa values

for the definite diagnoses of the specific PDs were 0.57 in DSM-III-R and 0.65 in ICD-10. The median kappa values for an IPDE diagnosis that was def- inite or probable were 0.73 for DSM-III-R and 0.77 for ICD-10. The cor- responding weighted kappa values for a diagnosis that was definite or probable were 0.65 for DSM-III-R and 0.72 for ICD-10. The SCID study did not identify probable cases. The SCID study involved a test-retest design in which the interview was administered by different examiners at least one day but no more than two weeks apart. This is likely to result in lower reliabilities than when an examiner and observer rate the same interview, as in the present study. A similar test-retest design was not employed in the present study, because one of its objectives was to determine temporal stability over an extended period. There are practical and methodological con- straints associated with the too frequent repetition of a lengthy interview. The IPDE also fared well compared with other criteria-based inter- views for PDs that have been developed in recent years.23 However, reports of large-scale reliability studies conducted outside of the facili- ties where these other interviews were developed are rare or non-exis- tent. The other interviews also differ from the IPDE in several ways. They do not provide coverage of ICD-10; they are not available in so many languages; and they do not have a detailed, item-by-item scoring manual. Temporal stability The term 'personality' refers to an individual's usual or characteristic rather than transient or situational behaviour. Therefore, a PD instrument should not only demonstrate interrater reliability, but it should also have temporal stability. Before imputing a particular criterion to a subject, the IPDE requires a minimal duration of five years, including some manifes- tation during the current year (past 12 months). Since the patients in the study were examined after an average interval of six months, temporal 81 Discussion and Conclusions stability required that they provide essentially similar information on both occasions. The only exceptions were patients who might have failed to manifest the behaviour in both segments of the non-overlapping por- tions of the previous 12 months, or the rare patient who might have fallen a few months short of meeting the five-year requirement at the time of the initial interview. Naturally, these patients would adversely affect the measurement of stability. The determination of temporal stability is also influenced by the less-than-perfect reliability associated with the single administration of an instrument. Adjustments for that affect on the stabil- ity of the individual items, the number of criteria met, and the dimen- sional scores, were made by calculating additional correlations with a correction for attenuation. There are comparatively few reports48 on the temporal stability of the semistructured interviews that are used to make lifetime diagnoses of the psychoses, mood, anxiety, and substance use disorders. Table 1 Table 1 Temporal stability of SADS-L diagnoses* Andreasen Bromet Fendrich Rice Rice etal.4 etal.5 etal6 etal1 etal? Disorder (N=50) (N=391) (N=69) (N=50) (N=1669) Major depression .75 .41 .54 .56 .61 Mania .88 .48 .60 Hypomania .06 .09 .33 Generalized anxiety .15 .30 Phobic .33 .34 Separation anxiety .26 Panic .66 .37 Obsessive-compulsive .66 .27 Alcoholism .72 .73 .70 Drug use .56 Substance abuse .66 Any diagnosis .63 .62 *SADS-L indicates Schedule for Affective Disorders and Schizophrenia-Lifetime ver- sion. All coefficients are k values except the study by Andreasen et al4 which reported intraclass correlation. Four5"8 of the five studies involved longer time intervals than did one4 study. The time frame for those four studies were 18 months and 2, 5, and 6 years, respectively. 82 A. W. Loranger summarizes them for one popular instrument, the Schedule for Affective Disorders and Schizophrenia-Lifetime version (SADS-L). The findings indicate moderate, but at times disappointing, stabilities that are not con- sistently superior to many of those obtained in this study with the PDs. It should be noted, however, that four of the five studies involved longer time intervals than six months. The one study within that timeframe reported a kappa of 0.63 for the presence or absence of any SADS-L diagnosis. This compares with 0.62 in DSM-III-R and 0.59 in ICD-10 for the presence or absence of any specific PD on the IPDE. The studies in Table 1 did not report an overall weighted kappa, thus precluding comparisons based on that statistic. Another potentially relevant differ- ence is that in most of these studies, the initial and repeat interviews were conducted by different interviewers. One study,5 however, did not find significant differences in stability when the same and different inter- viewers were used; another study6 reported an inconsistent effect. There is very little literature on the temporal stability of criteria-based PDs diagnosed with semistructured interviews. There appear to be only three studies that involved more than a brief test-retest interval. One was based on an early trial version of the PDE,9 which is no longer extant. The other two1011 reported on the stability of the Structured Interview for DSM-III Personality Disorders (SIDP). Pfohl et al.10 repeated the SIDP in 36 depressed inpatients after 6 to 12 months. The kappa values, which ranged from 0.16 to 0.84, are problematic because of the small sample sizes of the individual disorders. Similar findings were obtained by van den Brink in the Netherlands.11 The belief that interviewers are perfectly interchangeable would seem naive in view of the potential influence that the age, sex, and personality of an interviewer might have on the information provided by a subject. The assumption made by those who use semistructured interviews is that such factors ordinarily are not a major source of error. In planning the present study, consideration was given to a design in which half of the interviews would be repeated by the same examiner and half by a differ- ent examiner. This would have helped to determine how much the inter- viewers themselves, in addition to their rating decisions, contributed to the instability of the measures. However, concerns about scheduling and the availability of interviewers influenced the decision to use the same interviewers whenever possible. As a result, 93% of the interviews were given by the same examiner on both occasions. A second interview, whether conducted by the same or a different person, may be contaminated by the experience of the first interview. 83 Discussion and Conclusions Repetitions can lead to boredom and decreased motivation. Patients may also believe that the interviews are no longer for their benefit but for that of the examiner. Repetitions can also produce fantasies that the inter- viewer is dissatisfied with the previous interview or is checking on the consistency of the responses. Patients may also refrain from providing as many positive replies as previously because of a heightened awareness that these invite further probing and prolong the interview. Elsewhere,12 I have argued that the problem of attempting to measure the precise degree to which interviewers are interchangeable is reminiscent of the Heisenberg principle in physics: one cannot measure the phenomenon without somehow tampering with it in the process. Another source of temporal instability is the possibility that patients in a dysphoric state may have a selective recall or distorted perception of certain personality traits. They may also confuse them with the symp- toms of another (Axis I) mental disorder. An earlier version of the PDE proved resistant to changes in symptoms of anxiety and depression during the course of treatment.9 In that study, the majority of patients had mood or anxiety disorders of mild to moderate severity. The finding has since been replicated with the DSM-III-R component of the IPDE (Loranger & Lenzenweger, 1992 unpublished). There is, however, a contradictory report based on a group of depressed patients treated with cognitive therapy.13 That study used an earlier version of the PDE and the authors failed to specify the professional status and training of the interviewers, a potentially relevant variable. It may require an experienced psychiatrist or clinical psychologist to distinguish personal- ity traits from transient pathological mental states and the symptoms of other disorders. The reliability and validity of the IPDE, like that of any semistructured interview, cannot be judged apart from the qualifica- tions of the interviewers. At times, semistructured interviews have assumed a mystique of their own, and that caveat all too often ignored. The IPDE is intended for use by those who have the clinical sophistica- tion and training required to make psychiatric diagnoses independently, i.e., without a semistructured interview. This is not to imply that the IPDE or any other PD interview is necessarily impervious to the influ- ence of abnormal mental states, particularly those characterized by severe symptoms. We are encouraged, however, by the evidence that some clinical states do not appear to invalidate the assessment of person- ality. In any event, no attempt was made to determine the extent to which trait-state artifacts may have affected the stability of the IPDE in the present study. 84 A. W. Loranger Categories and dimensions The prevailing systems of disease classification are categoric. They define the features of disorders, and ideally the categories have points of rarity with normality and other disorders. Although such nosologies sometimes fall short of the ideal, their value as shorthand forms of communication accounts for their widespread acceptance. However, proponents of what has come to be known as the 'dimensional' approach question the applic- ability of the categorical method to personality disorders.14 One argument is that if PDs are not truly dichotomous in nature, reliability should improve with the use of dimensions because their measurement would incorporate more information than that provided by categories alone. Critics sometimes overlook the fact that categories and dimensions need not be mutually exclusive, witness their harmonious coexistence in the classification of mental retardation and hypertension. Following that tradition, the IPDE was designed to provide categorical diagnoses and dimensional scores based on the categories. The results of the present study demonstrate the favorable effect of these scores on the reliability of the IPDE. This is illustrated, e.g., by paranoid personality, the dis- order with the least stability. Although the DSM-III-R kappa was only .24, the stability of the paranoid dimensional score was 0.68 (0.74 with correction for attenuation). The stability of all of the DSM-III-R dimen- sional scores ranged from 0.68 to 0.92 (0.74 to 0.95 corrected), with a median of 0.77 (0.83 corrected). The corresponding correlations for the ICD-10 dimensions ranged from 0.65 to 0.86 (0.71 to 0.90 corrected), with a median of 0.77 (0.82 corrected). These findings provide a striking example of the advantage of supple- menting a categorical conclusion about the presence or absence of a spe- cific PD with dimensional information about the traits that underlie the decision-making process. The IPDE dimensional scores include infor- mation about accentuated normal traits below the threshold required for a PD. A measure based on pathological traits alone consists of the num- ber of criteria that a patient meets on a particular disorder. Table 8 (see chapter 'Results') reveals that this coarser measure is almost invariably associated with lower reliabilities than the dimensional scores, although the differences are not usually great. Clinical acceptability and validity of the IPDE At the conclusion of the study, a questionnaire concerning the IPDE was completed by all of the interviewers and discussed at length at the meeting 85 Discussion and Conclusions of principal investigators in Geneva. The only significant reservation about the interview shared by a majority of the interviewers concerned its length. This was a necessary consequence of the decision to systemat- ically inquire about all of the PD criteria in the ICD-10 and DSM-III-R classification systems. The mean length of the interview was 2 hours 20 minutes, and there was considerable variation around that figure. If a patient acknowledged many criteria, the subsequent inquiry for confir- matory examples and anecdotes prolonged the interview. If few of the behaviors were endorsed, then the IPDE went comparatively rapidly. If it became evident that the interview was likely to exceed more than one and a half to two hours, an effort was made to administer it in more than one sitting to prevent erosion of the quality of the interview from fatigue or boredom. To offset the concern about the length of the interview and to make it more acceptable to a wider range of clinicians and

investigators, it was decided to issue it in modules and to update the DSM-III-R component to conform to DSM-IV. While the longer version of the IPDE assesses all of the disorders in ICD-10 and DSM-IV, separate modules are avail- able for those who wish to limit the examination to only one of the two classification systems. Those concerned with only certain selected disor- ders within one of the two systems can also restrict the interview to those items relevant to the disorders of interest to them. A self-administered screening version of the IPDE is also available. It is not intended to substitute for the interview, because the literature indicates that PD inventories and interviews do not provide equivalent diagnoses. The screening inventory merely makes it possible to avoid interviewing those who are unlikely to receive a PD diagnosis on the interview. A field trial was undertaken with an early screening version of the DSM-III-R module in a sample of 258 university students.15 The inventory produced few false-negative cases vis-a-vis the interview, but as expected it yielded a high rate of false-positives. Of course, the low literacy rate in some nations precludes its use with certain populations. Whereas reliability refers to the consistency with which a diagnosis is made, validity refers to the accuracy of the diagnosis. The problems associated with establishing the validity of either an ordinary clinical interview or a semistructured one such as the IPDE are formidable. What should one use as the 'gold standard?' It would be meaningless to vali- date the IPDE against clinical diagnosis without first having established the reliability if not the validity of the clinicians themselves. If clinical 86 A. W. Loranger diagnosis, as usually practiced, was 'as good as gold,' there would be no need to improve it with semistructured interviews. A common practice is to invoke construct validity by demonstrating that a diagnosis agrees with that based on other interviews or inventories. However, this has restricted meaning, because the instruments usually sample identical content and often employ similar methods. The use of the so-called LEAD standard (Longitudinal, Expert, and All Data)16 is also not without its problems. It is unlikely that many true 'experts' have the time or inclination to want to conduct a thorough examination and prolonged study of a large enough sample of patients to provide ade- quate representation of the various PDs and the differential diagnostic problems commonly encountered in ordinary clinical practice. The experts would also have to adhere to the same definition of a PD and diagnostic criteria, or there would be obvious artifactually based discrep- ancies. Inevitably the experts would also have to demonstrate how much they agree with one another. The ultimate validation of the IPDE may prove to be a pragmatic one. Does the interview provide more replicable and useful answers to ques- tions about etiology, course, and treatment than the assessments obtained from clinicians without benefit of the IPDE? The expectation is that it has the potential for doing so, because it is more likely to insure compre- hensive, standardized coverage of the information required for a diagno- sis. In theory the results of the examination should also be more generalizable and exportable than the clinical consensus of a panel of experts at one particular facility. There are obvious cultural variations in what is considered maladap- tive behaviour. Understandably one might question whether the PD criteria of DSM-III-R, which were developed for use in the US, are rele- vant or meaningful (valid) in other cultures. One might also wonder whether the ICD-10 criteria, which were designed for worldwide use, might be unduly influenced by Western psychiatric tradition. In the study no attempt was made to change the criteria themselves, in order to accommodate a particular culture. However, the clinicians were instructed to judge the meaning of the behaviour in the context of their culture. This did not prove to be a common occurrence. Examples include the DSM-III-R criteria pertaining to monogamous relationships (antisocial) and harsh treatment of spouses and children (sadistic). Surprisingly, the investigators at the various centres expressed few reser- vations about the applicability of either DSM-III-R or ICD-10 in their own nations. 87 Discussion and Conclusions Frequency of personality disorder types The study had a very limited and specific objective, namely, to deter- mine the reliability, stability, and clinical and cultural acceptability of a particular diagnostic instrument designed for worldwide use. In the absence of any prior evidence that PDs could be reliably and meaning- fully assessed on a worldwide basis, it would have been premature and ill-advised to have broadened the scope of the project. The development of an acceptable instrument for case identification was a necessary pre- requisite to any attempt at international collaborative or comparative studies of the PDs. The study was not intended to be an epidemiological survey of residents in the community or those under treatment. The sam- pling did not involve consecutive admissions, and there are obviously different thresholds associated with the request for mental health care in different cultures. Therefore, it would be imprudent to make too much of variations in the frequency with which the individual disorders were diagnosed at the various centres. It is noteworthy, however, that most of the specific personality dis- orders in the two classification systems were observed in the 11 nations represented in the study. It is also of some interest that the two most fre- quently diagnosed types in the sample as a whole are disorders that were not included in either ICD-9 or DSM-II. They are borderline (DSM-III- R) or emotionally unstable, borderline type (ICD-10), and avoidant (DSM-III-R) or anxious (ICD-10). At least one case of these two dis- orders occurred at every centre with the exception of Bangalore, which did not report an avoidant diagnosis. Two controversial disorders, sadistic and self-defeating, are not included in ICD-10, were relegated to the appendix of DSM-III-R, and do not appear at all in DSM-IV. Both were among the three least fre- quent diagnoses in the entire sample. Interestingly, the third, narcissistic, was not included in DSM-II and is still not recognized in ICD-10. It occurred in only 1.3% of patients in the study. This contrasts with pas- sive-aggressive, which is not included in either ICD-10 or DSM-IV but was diagnosed in 5% of study patients and appeared in all centers except Bangalore. Co-occurrence of mental disorders in the same patient Not only did the majority of patients have other mental disorders in addi- tion to PDs, but many also had more than one type of PD. Of the 366 patients with a DSM-III-R personality disorder diagnosis, 111 (30.3%) 88 A. W. Loranger had more than one personality disorder, including 55 (15.0%) with two, 32 (8.7%) with three, and 24 (6.6%) with more than three disorders. Of the 283 patients with an ICD-10 personality disorder diagnosis, 96 (33.9%) had more than one type of disorder, including 57 (20.1%) with two, 27 (9.5%) with three, and 12 (4.2%) with more than three disorders. What are the implications of a patient having more than one form of mental disorder, particularly more than one type of PD? In some instances this may merely reflect the fact that two or more disorders share similar symptoms or diagnostic criteria. For example, substance abuse may be indicative of poor impulse control, a characteristic of antisocial, emotionally unstable or borderline PD. Similarly, social withdrawal is a diagnostic criterion shared by both schizoid and avoidant PDs. Another implication may be prognostic or therapeutic, with one disorder modify- ing the course or outcome of another. There is evidence, for example, that depression is less responsive to treatment, when accompanied by a PD. Comorbidity may also be a consequence of the fact that two disorders share similar etiologies. Finally, at times comorbidity may also be an indication of a defective or less than optimal classification system. A fundamental problem in interpreting the meaning of the comorbid- ity findings from various studies, including this one, is that they are markedly influenced by the base rates of the disorders in the sample. These in turn are a function of the admission practices of the facilities from which the patients are drawn, not to mention the selection biases for inclusion in the studies themselves. Ideally, comorbidity should be determined from epidemiological studies based on probability samples from the community. Unfortunately these rarely if ever include a suffi- cient number of cases of most disorders, to provide definitive informa- tion about the true co-occurrence rates of the disorders in question. ICD-10 and DSM-III-R As previously noted, ICD-10 and DSM-III-R are different but overlap- ping classification systems. There are slight differences in nomenclature: anankastic/obsessive-compulsive, anxious/avoidant, and dissocial/anti- social. In ICD-10 borderline and impulsive are viewed as subtypes of emotionally unstable; schizotypal is located with schizophrenia and delusional disorders; and narcissistic, passive-aggressive, and the two disorders in the appendix of DSM-III-R, sadistic and self-defeating, do not appear. There are also several significant differences in the criteria in the two systems and some minor variations in their wording. Except for 89 Discussion and Conclusions emotionally unstable, ICD-10 requires four of seven criteria for a diag- nosis; and except for antisocial, DSM-III-R requires four or five from a list that varies from seven to nine criteria. Although there are fewer dif- ferences between ICD-10 and DSM-IV, many still remain. A more detailed comparison of ICD-10, DSM-III-R, and DSM-IV is beyond the scope of this chapter. However, mention should be made of the extent to which ICD-10 and DSM-III-R tended to produce similar results in the present study. Within the limitations imposed by the sam- ple sizes of the individual disorders, no statistically significant (p<.05) differences were observed in the base rates with which the correspond- ing specific PDs were diagnosed in the overall sample of 716 patients. There was a trend, albeit statistically not significant, for DSM-III-R to identify more cases of antisocial, paranoid, and histrionic behaviour and for ICD-10 to diagnose more cases of anxious/avoidant behaviour. Both systems provide a residual category for cases judged to have a PD that does not meet the requirements for any of the specific types. There is no method of identifying these patients without invoking some arbitrary standard. The IPDE assigns a residual diagnosis to anyone who does not meet the requirements for a specific disorder, but nevertheless accumu- lates 10 or more criteria from the various disorders. There are more opportunities to obtain the diagnosis in DSM-III-R than in ICD-10 because the former has 110 criteria and the latter only 56. It is not sur- prising, then, that approximately twice as many patients received a non- specific diagnosis of PD in DSM-III-R as in ICD-10 (12.8% vs 6.8%). This, of course, does not address the question of whether the two clas- sification systems actually identified the same patients as having a partic- ular disorder. That can be determined by the kappa statistic, particularly for those disorders with a prevalence of at least 5%. There are only two of them; the kappas are 0.66 (borderline) and 0.52 (anxious/avoidant), evidence of moderate but far from perfect agreement. With the distribu- tion of cases in the sample of 716 patients, these kappas were associated with 92% agreement regarding the diagnosis of borderline and 89% for anxious/avoidant. The kappa values for the remaining disorders should be viewed as relatively unstable because of the base rate problem. They range from 0.32 (dissocial) to 0.61 (anankastic/obsessive-compulsive), with a median of 0.52. The DSM-III-R and ICD-10 comparisons should not be affected by the less-than-perfect interrater reliability of the IPDE since the same examiner conducted the interview and rated the informa- tion on which the ICD-10 and DSM-III-R diagnoses for a particular patient were based. 90 A. W. Loranger The substantial disagreement regarding the dissocial and antisocial diagnoses is not entirely unexpected considering the different approaches the two classification systems have taken regarding the dis- order. The DSM-III-R emphasized lawbreaking and criminal acts, while ICD-10 is more concerned with generic concepts such as lack of em- pathy, inability to profit from experience, and inability to maintain enduring relationships. It is also possible to judge the overall agreement between DSM-III-R and ICD-10 for the eight disorders they share in common. This can be done by calculating an overall weighted kappa based on all of these

dis- orders, regardless of whether they meet the criterion of a 5% base rate. That kappa is .54, an indication of only moderate agreement. There appears to be sufficient disagreement regarding the cases of personality disorders identified by ICD-10 and DSM-III-R to justify the prior deci- sion of the WHO/ADAMHA (US Alcohol, Drug Abuse and Mental Health Administration) steering committee to develop an instrument that would accommodate both classification systems. The two, however, pro- vide roughly similar interrater agreement and temporal stability when assessed by the IPDE. Conclusions The IPDE was administered by 58 psychiatrists and clinical psycholo- gists to 716 patients in 11 countries in North America, Europe, Africa, and Asia. The interview demonstrated an interrater reliability and tem- poral stability roughly similar to instruments used to diagnose the psy- choses, mood, anxiety, and substance use disorders. Experienced clinicians also found the instrument user friendly, culturally relevant, and clinically meaningful. By providing a standard method of diagnosis and case identification, the IPDE should stimulate international PD research, and facilitate comparisons of the results of such worldwide investigations. References Williams, J.B.W., Gibbon, M., First, M.B., Spitzer, R.L., Davies, M., Bonus, J., Howes, M.J., Kane, J., Pope, H.G., Jr. Rounsaville, B. & Wittchen, H.-U. The Structured Clinical interview for DSM-III-R (SCID), II: Multisite test-retest reli- ability. Archives of General Psychiatry, 1992; 49: 630-6. Stangl, D., Pfohl, B., Zimmerman, M., Bowers, W. & Corenthal, C. A structured 91 Discussion and Conclusions interview for DSM-III personality disorders: A preliminary report. Archives of General Psychiatry, 1985; 42: 591-6. 3 Zanarini, M.C., Frankenburg, F.R., Chauncey, D.L. & Gunderson, J.G. The Diagnostic Interview for Personality Disorders: Interrater and test-retest reliabil- ity. Comprehensive Psychiatry, 1987; 28: 467-80. 4 Andreasen, N.C., Grove, W.M., Shapiro, R.W., Keller, M.B., Hirschfeld, R.M.A. & McDonald-Scott, P. Reliability of lifetime diagnosis: A multicenter collaborative perspective. Archives of General Psychiatry, 1981; 38: 400-5. 5 Bromet, E.J., Dunn, L.O., Connell, M.M., Dew, M.A. & Schulberg, H.C. Long- term reliability of diagnosing lifetime major depression in a community sample. Archives of General Psychiatry, 1986; 43:435^0. 6 Fendrich, M., Weissman, M.M., Warner, V. & Mufson, L. Two-year recall of lifetime diagnoses in offspring at high and low risk for major depression: The stability of offspring reports. Archives of General Psychiatry, 1990; 47: 1121-7. 7 Rice, J.P., McDonald-Scott, P., Endicott, J., Coryell, W., Grove, W.M., Keller, M.B. & Altis, D. The stability of diagnosis with an application to bipolar II disorder. Psychiatry Research, 1986; 19: 285-96. 8 Rice, J.P., Rochberg, N., Endicott, J., Lavori, P.W. & Miller, C. Stability of psy- chiatric diagnoses: An application to the affective disorders. Archives of General Psychiatry, 1992; 49: 824-30. 9 Loranger, A.W., Lenzenweger, M.F., Gartner, A.F., Lehmann Susman, V., Herzig, J., Zammit, G.K., Gartner, J.D., Abrams, R.C. & Young, R.C. Trait-state artifacts and the diagnosis of personality disorders. Archives of General Psychiatry, 1991; 48: 72-8. 10 Pfohl, B., Black, D.W, Noyes, R., Coryell, W.H. & Barrash, J. Axis I and Axis II comorbidity findings: implications for validity. In: Oldham, J.M., ed. Personality Disorder: New Perspectives on Diagnostic Validity, pp. 147-61. Washington, DC:American Psychiatric Press, 1991. 11 van den Brink, W. Meting van DSM-III persoonlijkheidspathologie: Betrouwbaarheid en validiteit van de SIDP-R as II van de DSM-III. Groningen: Drukkerij Van Denderen BV, 1989. 12 Loranger, A.W. Diagnosis of personality disorders: general considerations. In: Michels, R., ed. Psychiatry, vol 1 (chap. 15) pp. 1-14. Philadelphia, PA: JB Lippincott, 1991. 13 Stuart, S., Simmons, A.D., Thase, M.E. & Pillkonis P. Are personality disorders valid in acute major depression? Journal of Affective Disorders, 1992; 24:281-90. 14 Widiger, T.A. Categorical versus dimensional classification: Implications from and for research. Journal of Personality Disorders, 1992; 6: 287-300. 15 Lenzenweger, M,F., Loranger, A.W., Kornfine, L. & Neff, C. Detecting person- ality disorders in a non-clinical population: Application of a two-stage procedure for case identification. Archives of General Psychiatry. (In press). 16 Spitzer, R.L. Psychiatric diagnosis: are clinicians still necessary? Comprehensive Psychiatry, 1983; 24: 399-411. 92 Appendix Table Al Personality disorder diagnoses-Bangalore, India (N=47) No. (%) of patients IPDE Diagnosis Definite Definite/Probable DSM-III-R Paranoid 1 (2.1) 1 (2.1) Schizoid 2 (4.3) 2 (4.3) Schizotypal 9 (19.1) 9 (19.1) Obsessive-compulsive 0 (0.0) 0 (0.0) Histrionic 1 (2.1) 1 (2.1) Dependent 0 (0.0) 0 (0.0) Antisocial 3 (6.4) 3 (6.4) Narcissistic 0 (0.0) 0 (0.0) Avoidant 0 (0.0) 0 (0.0) Borderline 7 (14.9) 8 (17.0) Passive-aggressive 0 (0.0) 0 (0.0) Sadistic 0 (0.0) 0 (0.0) Self-defeating 0 (0.0) 0 (0.0) ICD-10 Paranoid 0 (0.0) 0 (0.0) Schizoid 1 (2.1) 1 (2.1) Dissocial 0 (0.0) 0 (0.0) Emotionally unstable impulsive 2 (4.3) 2 (4.3) borderline 2 (4.3) 2 (4.3) Histrionic 0 (0.0) 0 (0.0) Anankastic 0 (0.0) 0 (0.0) Anxious 0 (0.0) 1 (2.1) Dependent 0 (0.0) 0 (0.0) 93 Appendix Table A2 Personality disorder diagnoses-Geneva, Switzerland (N=32) No. (%) of patients IPDE Diagnosis Definite Definite/Probable DSM-III-R Paranoid 0 (0.0) 1 (3.1) Schizoid 0 (0.0) 1 (3.1) Schizotypal 0 (0.0) 1 (3.1) Obsessive-compulsive 1 (3.1) 2 (6.2) Histrionic 1 (3.1) 3 (9.3) Dependent 0 (0.0) 1 (3.1) Antisocial 0 (0.0) 1 (3.1) Narcissistic 0 (0.0) 0 (0.0) Avoidant 1 (3.1) 5 (15.6) Borderline 4 (12.5) 8 (25.0) Passive-aggressive 2 (6.2) 4 (12.5) Sadistic 0 (0.0) 0 (0.0) Self-defeating 0 (0.0) 3 (9.3) ICD-10 Paranoid 0 (0.0) 1 (3.1) Schizoid 0 (0.0) 0 (0.0) Dissocial 0 (0.0) 0 (0.0) Emotionally unstable impulsive 0 (0.0) 0 (0.0) borderline 5 (15.6) 6 (18.8) Histrionic 0 (0.0) 1 (3.1) Anankastic 0 (0.0) 2 (6.2) Anxious 5 (15.6) 5 (15.6) Dependent 1 (3.1) 6 (18.8) 94 Appendix Table A3 Personality disorder diagnoses-Leiden, Netherlands (N=65) No. (%) of patients IPDE Diagnosis Definite Definite/Probable DSM-III-R Paranoid 6 (9.2) 11 (16.9) Schizoid 1 (1.5) 5 (7.7) Schizotypal 2 (3.1) 2 (3.1) Obsessive-compulsive 3 (4.6) 5 (7.7) Histrionic 3 (4.6) 7 (10.8) Dependent 5 (7.7) 8 (12.3) Antisocial 2 (3.1) 3 (4.6) Narcissistic 0 (0.0) 4 (6.2) Avoidant 7 (10.8) 2 (18.5) Borderline 9 (13.8) 15 (23.1) Passive-aggressive 1 (1.5) 3 (4.6) Sadistic 0 (0.0) 2 (3.1) Self-defeating 1 (1.5) 4 (6.2) ICD-10 Paranoid 1 (1.5) 4 (6.2) Schizoid 1 (1.5) 4 (6.2) Dissocial 2 (3.1) 2 (3.1) Emotionally unstable impulsive 1 (1.5) 4 (6.2) borderline 8 (12.3) 11 (16.9) Histrionic 1 (1.5) 2 (3.1) Anankastic 4 (6.2) 10 (15.4) Anxious 9 (13.8) 18 (27.7) Dependent 2 (3.1) 7 (10.8) 95 Appendix Table A4 Personality disorder diagnoses-London, UK (N=52) No. (%) of patients IPDE Diagnosis Definite Definite/Probable DSM-III-R Paranoid 5 (9.6) 8 (15.4) Schizoid 1 (1.9) 2 (3.9) Schizotypal 3 (5.8) 5 (9.6) Obsessive-compulsive 1 (1.9) 1 (1.9) Histrionic 3 (5.8) 7 (13.5) Dependent 0 (0.0) 3 (5.8) Antisocial 9 (17.3) 10 (19.2) Narcissistic 0 (0.0) 2 (3.9) Avoidant 8 (15.4) 16 (30.8) Borderline 10 (19.2) 13 (25.0) Passive-aggressive 3 (5.8) 5 (9.6) Sadistic 1 (1.9) 2 (3.9) Self-defeating 0 (0.0) 2 (3.9) ICD-10 Paranoid 3 (5.8) 8 (15.4) Schizoid 0 (0.0) 2 (3.9) Dissocial 2 (3.9) 5 (9.6) Emotionally unstable impulsive 5 (9.6) 8 (15.4) borderline 12 (23.1) 13 (25.0) Histrionic 1 (1.9) 5 (9.6) Anankastic 1 (1.9) 3 (5.8) Anxious 13 (25.0) 23 (44.2) Dependent 1 (1.9) 4 (7.7) 96 Appendix Table A5 Personality disorder diagnoses-Luxembourg (N=52) No. (%) of patients IPDE Diagnosis Definite Definite/Probable DSM-III-R Paranoid 3 (5.8) 8 (15.4) Schizoid 2 (3.8) 5 (9.6) Schizotypal 1 (1-9) 2 (3.8) Obsessive-compulsive 2 (3.8) 5 (9.6) Histrionic 4 (7.7) 9 (17.3) Dependent 5 (9.6) 6 (11.5) Antisocial 1 (1.9) 1 (1.9) Narcissistic 0 (0.0) 2 (3.8) Avoidant 8 (15.4) 3 (25.0) Borderline 8 (15.4) 10 (19.2) Passive-aggressive 2 (3.8) 2 (3.8) Sadistic 0 (0.0) 0 (0.0) Self-defeating 0 (0.0) 1 (1.9) ICD-10 Paranoid 3 (5.8) 4 (7.7) Schizoid 2 (3.8) 3 (5.8) Dissocial 1 (1.9) 1 (1.9) Emotionally unstable impulsive 4 (7.7) 6 (11.5) borderline 11 (21.2) 13 (25.0) Histrionic 2 (3.8) 6 (11.5) Anankastic 4 (7.7) 6 (11.5) Anxious 13 (25.0) 17 (32.7) Dependent 2 (3.8) 8 (15.4) 97 Appendix Table A6 Personality disorder diagnoses-Munich, Germany (N=113) No. (%) of patients IPDE Diagnosis Definite Definite/Probable DSM-III-R Paranoid 12 (10.6) 25 (22.1) Schizoid 4 (3.5) 9 (8.0) Schizotypal 1 (0.9) 3 (2.6) Obsessive-compulsive 5 (4.4) 15 (13.3) Histrionic 15 (13.3) 20 (17.7) Dependent 7 (6.2) 17 (15.0) Antisocial 6 (5.3) 9 (8.0) Narcissistic 4 (3.5) 9 (8.0) Avoidant 14 (12.4) 25 (22.1) Borderline 22 (19.5) 28 (24.8) Passive-aggressive 6 (5.3) 9 (8.0) Sadistic 0 (0.0) 3 (2.6) Self-defeating 0 (0.0) 2 (1.8) ICD-10 Paranoid 5 (4.4) 12 (10.6) Schizoid 2 (1.8) 5 (4.5) Dissocial 2 (1.8) 6 (5.3) Emotionally unstable impulsive 8 (7.1) 15 (13.3) borderline 20 (17.7) 26 (23.0) Histrionic 11 (9.7) 18 (15.9) Anankastic 6 (5.3) 14 (12.4) Anxious 15 (13.3) 28 (24.8) Dependent 10 (8.8) 23 (20.4) 98 Appendix Table A7 Personality disorder diagnoses-Nairobi, Kenya (N=50) No. (%) of patients IPDE Diagnosis Definite Definite/Probable DSM-III-R Paranoid 2 (4.0) 3 (6.0) Schizoid 6 (12.0) 11 (22.0) Schizotypal 4 (8.0) 7 (14.0) Obsessive-compulsive 3 (6.0) 4 (8.0) Histrionic 4 (8.0) 5 (10.0) Dependent 3 (6.0) 5 (10.0) Antisocial 8 (16.0) 11 (22.0) Narcissistic 0 (0.0) 2 (4.0) Avoidant 7 (14.0) 12 (24.0) Borderline 0 (0.0) 5 (10.0) Passive-aggressive 12 (24.0) 16 (32.0) Sadistic 1 (2.0) 1 (2.0) Self-defeating 0 (0.0) 0 (0.0) ICD-10 Paranoid 2 (4.0) 4 (8.0) Schizoid 5 (10.0) 8 (16.0) Dissocial 5 (10.0) 7 (14.0) Emotionally unstable impulsive 2 (4.0) 4 (8.0) borderline 4 (8.0) 5 (10.0) Histrionic 5 (10.0) 7 (14.0) Anankastic 3 (6.0) 4 (8.0) Anxious 8 (16.0) 11 (22.0) Dependent 3 (6.0) 5 (10.0) 99 Appendix Table 8 A Personality disorder diagnoses-New York, USA (N=100) No. (%) of patients IPDE Diagnosis Definite Definite/Probable DSM-III-R Paranoid 2 (2.0) 6 (6.0) Schizoid 1 (1.0) 3 (3.0) Schizotypal 1 (1.0) 2 (2.0) Obsessive-compulsive 0 (0.0) 1 (1.0) Histrionic 8 (8.0) 17 (17.0) Dependent 2 (2.0) 7 (7.0) Antisocial 2 (2.0) 5 (5.0) Narcissistic 2 (2.0) 8 (8.0) Avoidant 7 (7.0) 13 (13.0) Borderline 15 (15.0) 20 (20.0) Passive-aggressive 5 (5.0) 10 (10.0) Sadistic 0 (0.0) 2 (2.0) Self-defeating 1 (1.0) 6 (6.0) ICD-10 Paranoid 0 (0.0) 4 (4.0) Schizoid 0 (0.0) 2 (2.0) Dissocial 4 (4.0) 6 (6.0) Emotionally unstable impulsive 1 (1.0) 4 (4.0) borderline 16 (16.0) 19 (19.0) Histrionic 3 (3.0) 9 (9.0) Anankastic 1 (1.0) 4 (4.0) Anxious 10 (10.0) 14 (14.0) Dependent 1 (1.0) 7 (7.0) 100 Appendix Table A9 Personality disorder diagnoses-Nottingham, UK (N=50) No. (%) of patients IPDE Diagnosis Definite Definite/Probable DSM-III-R Paranoid 5 (10.0) 8 (16.0) Schizoid 3 (6.0) 4 (8.0) Schizotypal 1 (2.0) 2 (4.0) Obsessive-compulsive 1 (2.0) 1 (2.0) Histrionic 2 (4.0) 3 (6.0) Dependent 1 (2.0) 3 (6.0) Antisocial 3 (6.0) 9 (18.0) Narcissistic 0 (0.0) 0 (0.0) Avoidant 4 (8.0) 8 (16.0) Borderline 5 (10.0) 6 (12.0) Passive-aggressive 1 (2.0) 2 (4.0) Sadistic 0 (0.0) 0 (0.0) Self-defeating 1 (2.0) 1 (2.0) ICD-10 Paranoid 1 (2.0) 10 (20.0) Schizoid 1 (2.0) 3 (6.0) Dissocial 2 (4.0) 5 (10.0) Emotionally unstable impulsive 1 (2.0) 4 (8.0) borderline 6 (12.0) 6 (12.0) Histrionic 0 (0.0) 0 (0.0) Anankastic 1 (2.0) 3 (6.0) Anxious 7 (14.0) 15 (30.0) Dependent 1 (2.0) 3 (6.0) 101 Appendix Table A10 Personality disorder diagnoses-Oslo, Norway (N=48) No. (%) of patients IPDE Diagnosis Definite Definite/Probable DSM-III-R Paranoid 2 (4.2) 6 (12.5) Schizoid 0 (0.0) 0 (0.0) Schizotypal 1 (2.1) 1 (2.1) Obsessive-compulsive 1 (2.1) 2 (4.2) Histrionic 4 (8.3) 7 (14.6) Dependent 4 (8.3) 8 (16.7) Antisocial 5 (10.4) 9 (18.8) Narcissistic 1 (2.1) 1 (2.1) Avoidant 5 (10.4) 9 (18.8) Borderline 10 (20.8) 16 (39.6) Passive-aggressive 1 (2.1) 1 (2.1) Sadistic 0 (0.0) 2 (4.2) Self-defeating 2 (4.2) 2 (4.2) ICD-10 Paranoid 0 (0.0) 8 (16.7) Schizoid 0 (0.0) 0 (0.0) Dissocial 1 (2.1) 1 (2.1) Emotionally unstable impulsive 4 (8.3) 5 (10.4) borderline 11 (22.9) 13 (27.1) Histrionic 4 (8.3) 6 (12.5) Anankastic 3 (6.3) 7 (14.6) Anxious 7 (14.6) 13 (27.1) Dependent 5 (10.4) 8 (16.7) 102 Appendix Table Al l Personality disorder diagnoses-Tokyo, Japan (N=57) No. (%) of patients IPDE Diagnosis Definite Definite/Probable DSM-III-R Paranoid 2 (3.5) 4 (7.0) Schizoid 0 (0.0) 3 (5.3) Schizotypal 1 (1.8) 3 (5.3) Obsessive-compulsive 2 (3.5) 7 (12.3) Histrionic 2 (3.5) 6 (10.5) Dependent 1 (1.8) 3 (5.3) Antisocial 0 (0.0) 1 (1.8) Narcissistic 1 (1.8) 2 (3.5) Avoidant 6 (10.5) 10 (17.5) Borderline 4 (7.0) 4 (7.0) Passive-aggressive 1 (1.8) 3 (5.3) Sadistic 0 (0.0) 0 (0.0) Self-defeating 0 (0.0) 0

(0.0) ICD-10 Paranoid 1 (1-8) 6 (10.5) Schizoid 1 (1.8) 1 (1.8) Dissocial 0 (0.0) 0 (0.0) Emotionally unstable impulsive 0 (0.0) 1 (1-8) borderline 4 (7.0) 5 (8.8) Histrionic 2 (3.5) 3 (5.3) Anankastic 2 (3.5) 5 (8.8) Anxious 10 (17.5) 21 (36.8) Dependent 0 (0.0) 4 (7.0) 103 Appendix Table A12 Personality disorder diagnoses-Vienna, Austria (N-50) No. (%) of patients IPDE Diagnosis Definite Definite/Probable DSM-III-R Paranoid 2 (4.0) 2 (4.0) Schizoid 1 (2.0) 3 (6.0) Schizotypal 2 (4.0) 3 (6.0) Obsessive-compulsive 3 (6.0) 6 (12.0) Histrionic 4 (8.0) 10 (20.0) Dependent 4 (8.0) 12 (24.0) Antisocial 2 (4.0) 5 (10.0) Narcissistic 1 (2.0) 1 (2.0) Avoidant 12 (24.0) 18 (36.0) Borderline 10 (20.0) 14 (28.0) Passive-aggressive 2 (4.0) 4 (8.0) Sadistic 0 (0.0) 1 (2.0) Self-defeating 4 (8.0) 7 (14.0) ICD-10 Paranoid 1 (2.0) 4 (8.0) Schizoid 0 (0.0) 2 (4.0) Dissocial 4 (8.0) 8 (16.0) Emotionally unstable impulsive 4 (8.0) 5 (10.0) borderline 10 (20.0) 10 (20.0) Histrionic 2 (4.0) 6 (12.0) Anankastic 1 (2.0) 9 (18.0) Anxious 12 (24.0) 19 (38.0) Dependent 7 (14.0) 11 (22.0) 104 Appendix Table A13 Frequency of occurrence, interrater reliability and stability ofDSM-III-R criteria Frequency of Reliability Stability occurrence (%) (R) (R) Criterion N=726 N=151 N=243* Paranoid 1 10 .70 .56 (.67) 2 16 .79 .59 (.66) 3 12 .81 .54 (.60) 4 21 .79 .56 (.63) 5 13 .75 .31 (.36) 6 17 .77 .49 (.56) 7 8 .77 .62 (.71) Schizoid 1 6 .71 .39 (.46) 2 21 .83 .68 (.75) 3 5 .74 .38 (.44) 4 9 .76 .49 (.56) 5 2 .33 .36 (.63) 6 22 .77 .63 (.72) 7 4 .57 .60 (.80) Schizotypal 1 18 .83 .63 (.69) 2 23 .86 .70 (.75) 3 10 .78 .66 (.75) 4 9 .86 .60 (.64) 5 2 .32 .63 (1.1) 6 22 .77 .63 (.72) 7 2 .79 .65 (.73) 3 .68 .64 (.78) 4 .72 .60 (.71) Antisocial Bl 14 .86 .85 (.91) B2 9 .87 .74 (.80) B3 8 .82 .77 (.85) B4 3 1.00 .51 (.51) B5 1 00 .47 (0) B6 3 .74 .59 (.69) 105 Appendix Frequency of Reliability Stability occurrence (%) (R) (R) Criterion N=726 N=151 N=243* B7 3 .89 .49 (.52) B8 4 .93 .60 (•62) B9 2 .73 .65 (-76) BIO 11 .89 .65 (.69) Bl l 12 .84 .72 (.78) B12 1 .89 00 (0) Cl 12 .82 .64 (.93) C2 17 .86 .80 (.86) C3 15 .86 .68 (•73) C4 10 .81 .75 (.83) C5 7 .74 .71 (.83) C6 11 .78 .67 (.76) C7 19 .87 .71 (•76) C8 6 .86 .63 (-68) C9 8 .55 .47 (.64) CIO 9 .73 .59 (.69) Borderline 1 17 .89 .65 (.69) 2 26 .86 .77 (.83) 3 28 .84 .59 (.64) 4 22 .81 .64 (.71) 5 27 .79 .79 (.89) 6 15 .74 .64 (.74) 7 28 .83 .68 (.75) 8 12 .82 .43 (.47) Histrionic 1 15 .82 .56 (.62) 2 5 .62 .47 (•59) 3 10 .79 .54 (•61) 4 10 .91 .75 (.79) 5 12 .88 .60 (.64) 6 18 .79 .60 (.67) 7 20 .77 .62 (.70) 8 3 .70 .56 (.67) 106 Appendix Table A13 (conf) Frequency of Reliability Stability occurrence (%) (R) (R) Criterion N=726 N=151 N=243* Narcissistic 1 23 .74 .61 (.71) 2 10 .85 .54 (.59) 3 7 .61 .51 (.65) 4 12 .77 .56 (.64) 5 12 .74 .56 (.65) 6 6 .74 .55 (.64) 7 12 .83 .56 (.61) 8 7 .89 .58 (.62) 9 8 .89 .52 (.55) Avoidant 1 33 .82 .63 (.69) 2 22 .77 .63 (.72) 3 20 .80 .48 (.54) 4 17 .89 .56 (.59) 5 18 .69 .58 (.70) 6 21 .91 .70 (.74) 7 13 .71 .50 (.60) Dependent 1 11 .86 .52 (.56) 2 10 .87 .57 (.61) 3 7 .84 .41 (.45) 4 10 .89 .65 (.69) 5 8 .62 .69 (.87) 6 14 .90 .45 (.47) 7 24 .87 .47 (.50) 8 18 .91 .50 (.53) 9 33 .82 .63 (.69) Obsessive-compulsive 1 15 .90 .48 (.50) 2 10 .84 .57 (.62) 3 14 .78 .58 (.66) 4 13 .90 .53 (.56) 5 23 .78 .62 (.70) 107 Appendix TableA13(cwzO Frequency of Reliability Stability occurrence (%) (R) (R) Criterion N=726 N=151 N=243* 6 10 .76 .55 (.63) 7 19 .82 0 (0) 8 4 .72 .54 (.64) 9 10 .85 .71 (.77) Passive-aggressive 1 15 .80 .56 (.63) 2 19 .91 .63 (.66) 3 10 .84 .63 (.68) 4 6 .85 .47 (.51) 5 8 .77 .54 (.61) 6 8 .86 .58 (.62) 7 12 .68 .55 (.65) 8 6 .76 .58 (.67) 9 12 .77 .68 (.77) Sadistic 1 2 .67 .26 (.32) 2 2 .86 .56 (.60) 3 2 .51 .40 (.56) 4 2 .72 .52 (.61) 5 3 .90 .50 (.53) 6 6 .65 .65 (.81) 7 4 .76 .40 (.46) 8 3 .77 .69 (.79) Self-defeating 1 14 .88 .67 (.71) 2 15 .80 .51 (.57) 3 6 .83 .62 (.68) 4 8 .73 .59 (.69) 5 7 .48 .46 (.67) 6 12 .80 .56 (.63) 7 7 .81 .61 (.68) 8 12 .61 .56 (.72) *For temporal stability data in parentheses are corrected for attentuation 108 Appendix 109 Table A14 Frequency of occurrence, interrater reliability and stability ofICD-10 criteria Frequency of Reliability Stability Criterion IPDE Occurrence (%) (R) (R) Item N=726 N=151 N=243* Paranoid 1 90 20 .79 .48 (.54) 2 82 21 .79 .56 (.63) 3 85,157 7 .71 .58 (•69) 4 67 11 .79 .56 (.63) 5 119 8 .77 .62 (.71) 6 86 18 .83 .63 (.69) 7 121 5 .75 .55 (•64) Schizoid 1 96 6 .69 .45 (.54) 2 93,101,155 10 .72 .30 (.35) 3 87 2 .33 .36 (.63) 4 114 9 .76 .49 (.56) 5 45,51 18 .78 .66 (.75) 6 48 22 .77 .63 (.72) 7 154 2 .32 .63 (1.1) Dissocial 1 63 7 .89 .58 (.62) 2 136 15 .84 .73 (•80) 3 50 12 .66 .60 (.74) 4 34,129 17 .80 .65 (.73) 5 137,139 9 .78 .60 (.68) 6 138 10 .81 .58 (.64) 7 98 15 .86 .64 (.69) Impulsive 1 125 17 .82 .64 (.71) 2 124 16 .85 .68 (.74) 3 106 28 .84 .59 (.64 4 99,116 13 .67 .64 (.78) 5 100 15 .81 .57 .63) 6 66 11 .79 .68 (.76) 7 27 17 .80 .62 (•69) Histrionic 1 94 10 .91 .75 (.79) 2 28 14 .90 .53 (.56) 3 105 18 .79 .60 (.68) 4 35 16 .76 .62 (.71) 5 38,88 23 .80 .57 (.64) 6 1,33 12 .83 .54 (.59) 7 62 10 .85 .54 (.59) Anankastic 1 23 23 .78 .62 (.70) 2 2,3,4 12 .86 .52 (.56) 3 1,33 12 .83 .54 (.59) 4 93 19 .82 0 (0) 5 60 14 .78 .58 (.66) 6 108 16 .75 .47 (.54) 7 31 9 .78 .63 (.71) 1 107 32 .88 .62 (.66) 2 30 28 .85 .67 (.73) 3 40 20 .90 .60 (•63) 4 56,88 29 .86 .62 (.69) 5 55 20 .80 .48 (.54) 6 111 13 .71 .50 (.59) 7 110 22 .83 .57 (.63) Dependent 1 24 10 .87 .57 (.61) 2 76 26 .81 .60 (.67) 3 75 18 .88 .49 (.52) 4 29 14 .81 .65 (.72) 5 104,112 16 .90 .48 (•50) 6 57 24 .87 .47 (.50) 7 25 14 .84 .64 (.70) * For temporal stability data in parentheses are corrected for attentuation 111 II International Personality Disorder Examination (IPDE) ICD-10 Module 112 Acknowledgements 113 Manual 114 History of the IPDE 114 ICD-lOandDSM-IV 115 Translations of the IPDE 115 Structure of the IPDE 116 Scope of the IPDE 117 Appropriate subjects 118 Limitations of the IPDE 118 Examiner qualifications and training 120 Administration of the IPDE 121 Scoring conventions 122 Recording the scores 124 Computer scoring 124 Handscoring 125 Frequently asked questions about the administration of the IPDE 125 Abbreviating the IPDE 127 Reliability and validity of the IPDE 128 References 129 ICD-10 criteria and corresponding IPDE Items 130 IPDE ICD-10 module screening questionnaire 134 IPDE ICD-10 module screening questionnaire scoring summary 137 IPDE ICD-10 module interview schedule 138 IPDE ICD-10 module answer sheet 205 IPDE ICD-10 module handscoring algorithms and summary scoresheet 206 113 Acknowledgements The IPDE was developed for the World Health Organization (WHO) by Dr. Armand W. Loranger in collaboration with the following colleagues from the international psychiatric community: Drs. Antonio Andreoli (Geneva), Peter Berger (Vienna), Peter Buchheim (Munich), S. M. Channabasavanna (Bangalore), Bina Coid (London), Alv A. Dahl (Oslo), Rene F. W. Diekstra (Leiden), Brian Ferguson (Nottingham), Lawrence B. Jacobsberg (New York), Aleksandar Janca (WHO), Werner Mombour (Munich), Yutaka Ono (Tokyo), Charles Pull (Luxembourg), Norman Sartorius (Geneva), and R. Onyango Sumba (Nairobi). The IPDE was developed in the framework of the Joint Project on Diagnosis and Classification of Mental Disorders, Alcohol- and Drug- related Problems carried out by the WHO and US National Institutes of Health (formerly Alcohol, Drug and Mental Health Adminstration). 114 Manual History of the IPDE One of the aims of the World Health Organization (WHO) and US National Institutes of Health (NIH) joint program on psychiatric diagno- sis and classification is the development and standardization of diagnos- tic assessment instruments for use in clinical research around the world.1 The IPDE is a semistructured clinical interview developed within that program, and designed to assess the personality disorders in the ICD-10 and DSM-IV classification systems. The IPDE is an outgrowth and modification for international use of the Personality Disorder Examination (PDE).2 To facilitate the develop- ment of the IPDE, beginning in 1985 several workshops were convened. At these meetings representatives of the international psychiatric com- munity discussed the format of the interview, the wording of items, and the development of a scoring manual. Translations were undertaken and frequent revisions made to reflect the experience of interviewers with trial versions. Finally, a field trial was undertaken in 1988 and 1989 at 14 participating centres in 11 countries in North America, Europe, Africa, and Asia.34 In August 1991 the principal investigators in the field trial met at WHO headquarters in Geneva to discuss the results and the experience of the interviewers with the IPDE. This resulted in some minor revisions of existing items. Subsequently additional modifications were made to accommodate the transition from DSM-III-R to DSM-IV. To offset con- cerns about the length of the interview, and to make it more acceptable to a wider range of clinicians and investigators, it was decided to issue the IPDE in modules. The complete interview would assess all of the disor- ders in both ICD-10 and DSM-IV. Separate modules would also be available for those who wished to limit the examination to one of the two classification systems. 115 ICD-10andDSM-IV ICD-10andDSM-IV DSM-IV5 was designed for use in the US and is primarily the product of American psychiatric opinion. ICD-106 is intended for use throughout the world and reflects the views and needs of the international psychi- atric community. The two are different but overlapping classification systems. There are slight differences in nomenclature: anankastic/obses- sive-compulsive, anxious/avoidant, and dissocial/antisocial. In ICD-10, borderline and impulsive are viewed as subtypes of emotionally unsta- ble, schizotypal is located with schizophrenia and delusional disorders, and narcissistic is not included. There are also some differences in the criteria required for various diagnoses. The IPDE field trial demon- strated that there was sufficient disagreement regarding the cases identi- fied as personality disorders in DSM-III-R and ICD-10 to require the administration of the entire IPDE if one wished to make diagnoses in both systems. Translations of the IPDE Investigators at the various centres involved in the field trial have trans- lated the instrument into the following languages: Dutch, French, German, Hindi, Japanese, Kannada, Norwegian, Swahili, and Tamil. Translations have also been made into other languages, including Danish, Estonian, Greek, Italian, Russian, and Spanish. Additional trans- lations are contemplated. The translations were backtranslated into English by a psychiatrist or psychologist who had not seen the original English version. Variations and problems in the back-translation were then reviewed with those who undertook the original translation, and corrections were made when indicated. Particular problems can arise when a semistructured interview like the IPDE is used with subjects

who are illiterate and speak a regional or tribal dialect. Since written and spoken language are quite different in such populations, the interviewer must frequently depart from the literal text and improvise an equivalent question on the spot, in order to maintain communication with the subject. Although this is a potential source of error variance, the examiner's familiarity with the scope and meaning of the diagnostic criteria and with the intent of the original IPDE question, should keep such error within tolerable limits. 116 Manual Structure of the IPDE The IPDE is arranged in a format that attempts to provide the optimal balance between a spontaneous, natural clinical interview and the requirements of standardization and objectivity. At the beginning of the interview the subject is given the following instructions: The questions I am going to ask concern what you are like most of the time. I'm inter- ested in what has been typical of you throughout your life, and not just recently. If you have changed and your answers might have been differ- ent at some time in the past, be sure to let me know.' The questions flow in a natural sequence that is congenial to the clini- cian. They are arranged under six headings: work, self, interpersonal relationships, affects, reality testing, and impulse control. The headings are not only convenient labels, but they play an organizational or the- matic role. At times the overlapping nature of the six domains required a somewhat arbitrary allocation of questions. For efficiency and conve- nience sometimes a question extends beyond the scope of the section where it appears. For example, many anankastic criteria are best assessed in the context of work functioning, but behaviour outside the realm of work is also considered, even though the questions appear in the 4 Work' section of the interview. The sections are usually introduced by open-ended inquiries that offer subjects an opportunity to discuss the topic as much as they choose. This helps to develop a set for the questions that follow, and provides a transi- tion from the focus of the previous section. Although they are not scored as such, these introductory remarks of the subject provide a background against which to judge the clinical significance of some of the replies to the specific questions that follow. At times the comments also facilitate the task of the examiner in deciding whether to probe or pursue certain aspects of the subject's responses. The criterion and its number, together with the name of the ICD-10 disorder, appear above the questions designed to assess it. Since the questions are merely an attempt to get at the criterion, this serves to remind the examiners what they are actually rating. Some criteria are fol- lowed by the designation partial, an indication that the item does not assess the entire criterion. This is done to preserve the topical focus of the interview. For example, it is more appropriate to inquire about an identity disorder in the sexual realm, when the subject of sex is being dis- cussed, than to attempt to cover other manifestations of an identity disor- der, such as uncertainty about values or career choice at the same point in the interview. There appears to be no consensus about exactly how long 117 Scope of the IPDE a behaviour should be present before it can be considered a personality trait. ICD-10 states that it should be stable and of long duration. Therefore, we have adopted the somewhat conservative convention that it should exist for a span of at least five years. Consideration was given to a three-year requirement, but it was decided that might too frequently lead to confounding episodic mental illnesses or responses to unusual or special life situations with the more enduring behaviour associated with personality. Some may feel this is too exacting, especially when applied to adolescents or young adults. Since users of the IPDE will differ in their predilection for making personality disorder diagnoses in adoles- cents, those who prefer a three-year requirement may adopt it for that age group. They should specify, however, that they have departed from the standard instructions. The use of anything less than a five-year time- frame with subjects over 20 years of age is discouraged. ICD-10 dates the onset of the first manifestations of a personality dis- order to late childhood or adolescence. For that reason we have taken the somewhat arbitrary position, that the requirements for at least one crite- rion of a disorder must have been fulfilled prior to age 25, before that particular disorder can be diagnosed. Age 25 years rather than an earlier age was selected to allow more informed and accurate judgements about many of the adult-oriented personality disorder criteria. Clinical tradition notwithstanding, it is possible that personality trans- formations may occur in midlife or old age, and that a true personality disorder may emerge de novo at that time. In the absence of empirical data, rather than encourage premature closure on the subject, we have made provision in the IPDE for an optional late onset diagnosis. We have also provided the option of making a past diagnosis in someone who previously met the requirements, but has not done so during the past year (12 months). Scope of the IPDE The IPDE is not designed to survey the entire realm of personality. Its purpose is to identify those traits and behaviours that are relevant to an assessment of the criteria for personality disorders in the ICD-10 and DSM-IV classification systems. It neglects many neutral, positive, and adaptive traits, because they are irrelevant to a personality disorder assessment. It also does not cover other mental disorders, because there are instruments available for them. We recommend their use prior to the IPDE, to provide the examiner with clinical and historical information 118 Manual that is likely to enhance the reliability and validity of the questioning, probing, and scoring process. When it is not available from such an inter- view or from other sources, the IPDE examiner should obtain that infor- mation from the subject at the beginning of the interview (under 'Background information'). The IPDE ICD-10 Module examines every subject for the presence or absence of all the ICD-10 personality disorder criteria. It also provides a dimensional score for all subjects on each disorder, regardless of whether or not they fulfill the criteria for the disorder. This additional information supplements that based on categorical diagnosis alone. Because personality disorders often reflect the exaggerated presence of traits that are continuously distributed in the population at large, the dimensional scores are not only useful to the clinician, but they also pro- vide the research investigator with greater reliability and more versatility in data analysis. Appropriate subjects The IPDE is not intended for subjects below the age of 18, although with slight modifications some investigators have found it useful with those as young as age 15. The interview is not appropriate for those with severe depression, psychosis, below-normal intelligence, or substantial cognitive impairment. Whether it should be used with patients in remis- sion from a chronic psychotic illness is problematic. For example, can one distinguish residual schizophrenia or the interepisodic manifesta- tions of manic-depression from a personality disorder? A number of investigators have found the IPDE useful in studies of those disorders, and the decision is left to the user. Limitations of the IPDE The IPDE is essentially a self-report instrument, and assumes that sub- jects are capable of providing valid descriptions of disturbances in their personality. However, individuals may be unaware of some of their traits. They may also be resistant to acknowledging behaviour, if it is socially undesirable or if its disclosure is likely to adversely affect what they believe to be their best interest. This is especially likely to occur in patients who wish to terminate treatment prematurely, or in those about to be discharged from a mental health facility. Others may exaggerate disturbances in their behaviour. This is sometimes observed in those who 119 Limitations of the IPDE are frantically seeking help, or who are dissatisfied with their treatment or the amount of attention they are receiving. It may also be a reflection of certain personality traits. Although subjects may also feign traits or behaviour, particularly in compensation cases and some forensic and military situations, the IPDE discourages this by requiring documenta- tion with convincing examples, anecdotes, and descriptions. Patients in a dysphoric state may have a selective recall or distorted perception of some of their behaviour. They may also confuse normal and abnormal personality traits with the symptoms of a mental disorder. There is evidence7 that the PDE was resistant to changes in the symp- toms of anxiety and depression that occurred during the course of treat- ment, when those symptoms were of mild to moderate severity. This is not to imply that some clinical states, particularly those accompanied by severe symptoms, do not invalidate the assessment of personality. Additional research is required on this important subject. When possible, some investigators may wish to postpone the assessment until the symp- toms of other mental disorders have remitted. In ordinary clinical practice, a family member or close friend is often used as an additional source of information to offset the limitations of the self-report method. We have experimented with various procedures for augmenting the subject's responses on the IPDE with data from other sources. Failure to acknowledge a behaviour, particularly one that is especially frowned upon by others, is sometimes followed on the IPDE by such inquiries as, 'Have people told you that you're like that?' Affirmative replies are then pursued with the question, "Why do you think they've said that?" This approach can only be used selectively. If it were adopted in all situations where a behaviour has been denied, it would undermine the rapport between subject and examiner. We have also tried a parallel form of the interview in which an infor- mant was asked virtually the same questions about the patient. There were often discrepancies, and it was not always obvious who had pro- vided the more valid information. It proved difficult to formulate a set of practical guidelines that stipulate the source that should be used in scor- ing a particular criterion. The problem is a complicated one, and a satis- factory resolution awaits the availability of more empirical data on the subject. Future studies may help identify those criteria that tend to pro- duce discrepancies, and the characteristics of subjects and informants that might be used to determine the preferred source of information. Meanwhile, we have adopted a practical, provisional solution to the informant problem. The IPDE has a second scoring column for informant 120 Manual data. If examiners have access to information from family, friends, men- tal health professionals, records, etc., that clearly contradicts a subject's responses regarding a particular criterion, then they may score the crite- rion in the informant column provided two requirements are met. Firstly, they should have more confidence in that information than they do in the subject; and secondly, the other source must satisfy the identical scoring guidelines that apply to the subject's response. Later, in entering ratings in the computer or transcribing them from the interview to the score- sheet, the scores based on the subject's report are bypassed in favour of those derived from the informant. While it is necessary to administer the IPDE with knowledge of a sub- ject's psychiatric history and current mental state, the examiner should avoid making detailed inquiries about the subject's personality prior to the interview. It is probably not advisable to confront subjects during the inter- view with discrepancies between their accounts and information obtained from others. Making them aware of the discrepancies could adversely affect rapport, and also create discord between the subject and informant. Examiner qualifications and training The IPDE ICD-10 Module presupposes a thorough familiarity with the ICD-10 classification system of mental disorders, and considerable train- ing and experience in making psychiatric diagnoses. Like any semistruc- tured clinical interview, its reliability and validity are inseparable from the qualifications and training of the person using it. It is designed for experienced psychiatrists, clinical psychologists, and those with compa- rable training, who are capable of making independent psychiatric diag- noses without a semistructured interview. It is not intended for use by clinicians in

the early phase of their training, or by research assistants, nurses, and medical or graduate students. The first step in training to use the IPDE is to study the interview and manual very thoroughly. Before the basics are mastered, the interview should be administered to several subjects primarily to get a 'feel' for it, and to make the instructions in this manual and the scoring guidelines more meaningful. Then the neophyte should examine a series of patients, following the instructions and scoring guidelines as closely as possible. This is best done with a colleague, someone who has already mastered the instrument or is also learning how to use it. These practice interviews should be followed by a critique, and a discussion of any problems in administration and scoring. Most clinicians will feel comfortable with 121 Administration of the IPDE the IPDE and have achieved a basic proficiency after having given about 10 interviews. As they examine more patients, they will find themselves making less use of the guides for questioning and scoring, but occasional reference to them is to be expected even by the seasoned examiner. We strongly recommend that those who wish to obtain the optimal training in the use of the IPDE, enroll in the course offered at one of the world- wide WHO training centres. Administration of the IPDE If the interview should take more than one to one and a half hours, there is danger that the examiner will not pursue responses with the same alert- ness and thoroughness, and that the subject's replies will become briefer and more perfunctory. In those circumstances the interview should be given on more than one occasion, if possible. However, interruptions in the middle of a section should be avoided. The IPDE can only be administered properly when the examiner con- ducts an adequate clinical examination of the subject with appropriate probing to solicit examples, anecdotes, and additional details. This requires a thorough knowledge of the scope and meaning of each crite- rion and a correct application of the scoring guidelines. Ultimately, many of these become familiar to examiners, and there is no need to con- stantly refer to them during the interview. Initial replies of the subject that suggest a positive rating are rarely sufficient for scoring a criterion. They must be supplemented and sup- ported by convincing descriptions or examples. Examiners must use their clinical judgement to determine the length of the descriptions and the number of examples that are required. When in doubt, they should always ask for more rather than less. However, they should avoid 'lead- ing the witness,' or being influenced by a 'halo' effect. For example, if the subject has already met three of the required four criteria for a diag- nosis, the examples regarding a possible fourth criterion should not be viewed any differently than if the subject had previously not met any cri- terion. Interviewers should not hesitate to tactfully inquire about appar- ent contradictions in responses. Although the examiners should score the interview as they go along, they should correct the scoring of an earlier item, when subsequent information elicited during the interview requires it. Recording the subject's responses verbatim is not required, but it can provide a permanent record of a considerable amount of useful informa- tion, that is not conveyed by diagnoses or dimensional scores alone. 122 Manual Scoring conventions Much of the behaviour described in the ICD-10 personality disorder cri- teria exists on a continuum with normality. The IPDE scoring is based on the convention that a behaviour or trait may be absent or normal (0), exaggerated or accentuated (1), and criterion level or pathological (2). A few items are not applicable to some subjects, and they are scored 'NA\ The '?' scoring category is reserved for occasions when subjects, despite encouragement, refuse to answer a question or state that they are unable to do so. It is not used to designate uncertainty on the part of the exam- iner about rating the item. Duration If the behaviour or trait has not been present for a timespan of at least five years it does not receive a positive score, even though it meets all the requirements concerning frequency, intensity, subjective distress, and social or occupational impairment. A positive score (except 'past') is also not given when the behaviour has not occurred at all during the past year (12 months). The only exceptions to the past year (12 months) rule are those behaviours that occur relatively infrequently, yet have considerable clinical significance. Those items (10,15, 26, 34, 55, 59, 60,61) are desig- nated by an asterisk next to the item number on the interview schedule. However, they too must have occurred at least once during the past five years to receive a positive score. Otherwise, like other items that meet all the requirements except past year (12 months), they should be scored 'past'. Age at onset The IPDE requires that behaviour indicative of at least one criterion of a personality disorder be present prior to age 25, before that particular dis- order can be diagnosed. The remaining criteria for the disorder may become evident after age 25, provided the requirement of five years duration is met. This rule exists for each individual disorder. However, when a subject meets all the requirements for a diagnosis except that regarding onset by age 25, an optional diagnosis may be recorded with the designation, 'late onset'. Timeframe and age at onset probes The examiner must use a predetermined set of probes to determine 123 Scoring Conventions whether a subject has met the duration and age at onset requirements. The probes may be selected to fit the particular responses and criteria, and may be varied to avoid monotony or stereotypy. Ordinarily examin- ers should devise their own probes only when the subject does not pro- vide adequate replies to the recommended ones. It is not necessary to ask subjects whether the behaviour has occurred during the past year. The assumption is that it has or they would either not have reported it, or noted that a change had taken place, since they are reminded to do so several times during the course of the interview. Of course, if examiners have reason to doubt that it has occurred during the past year, then they should question the subject about it. Duration and age at onset probes • How long have you been like that? • How long has that been going on? • How long have you been that way? • When did that start? • How old were you when that began? • At what age did that start? • Have you been that way for a long time? Frequency Scoring usually requires a knowledge of the frequency with which the subject manifests the behaviour, because it is often one of the grounds for distinguishing scores of '0', T , '2'. Some IPDE questions contain frequency information, e.g., 'Do you often change from your usual mood to feeling very irritable, etc.?' This should not be relied upon to establish the actual frequency. Replies acknowledging the presence of the behav- iour associated with the criterion require that the examiner ask how often it occurs by using one of the predetermined frequency probes. The sole exception is when subjects spontaneously supply the frequency in their replies. Frequency probes • How often are you like that? • How often does that happen? • How often do you behave like that? 124 Manual Recording the scores Required scoring Immediately after questioning the subject about a particular item, the examiner records the score in the first column. The second column is never used during the interview itself. It is reserved for information from infor- mants or records, when it is discrepant with the interview data, and the rater has more confidence in that than in the subject. The information, however, is subject to the same scoring guidelines as the subject's responses. If the subject does not meet the requirements stipulated in the manual for a positive score (1 or 2), the rater places a circle around '0'. If the subject meets all the requirements for a positive score (1 or 2), including onset prior to age 25, the rater circles the appropriate number (1 or 2). If the subject meets all the requirements for a positive score except age at onset, the rater underlines the appropriate number (1 or 2). If subjects insist they are unable to answer a question or refuse to do so, the rater places a circle around '? ' . If the criterion does not apply to the subject, the rater places a circle around 'NA'. Optional scoring If examiners wish to record a personality disorder that was present in the past, but no longer exists, they must use an additional set of scoring nota- tions in certain very specific situations. If a subject meets all the require- ments for a positive score, including that of five years duration and age at onset before 25, but has not displayed the behaviour at all during the past year (12 months), the rater should place an 'X' through the appropriate number (1 or 2). If a subject meets all the requirements for a positive score, including that of five years duration, except that onset has occurred after age 25, and the behaviour has not been present at all dur- ing the past year (12 months), the rater should underline the 'X'. It is important to remember that asterisked items (10, 15, 26, 34, 55, 59, 60, 61) are exempt from the requirement that they occur during the past 12 months. Therefore, those exempt items should be scored 'past' only when they occurred prior to but not during the past five years; otherwise they satisfy the requirements for a current disorder. Computer scoring The IPDE diagnoses and dimensional scores are determined after the 125 Frequently asked questions completion of the interview. The most efficient method is to use the computer scoring program*. The scores from the interview schedule or answer sheet are entered directly into a personal computer. The program is written with operator prompts, and the user responds to questions regarding the task to be performed and the management of the data, which may be sent to a printer and saved in a disk file. The entire proce- dure takes approximately 10 minutes. The printout provides the following information for each ICD-10 dis- order: criteria present or absent; number of criteria met; diagnosis - defi- nite, probable (one criterion less than the required number), negative, late onset (optional), past (optional); dimensional score; and number of criteria based on informants. The criteria met by the subject are also printed verbatim. The IPDE program will execute properly under either the BASICA program supplied with IBM PCs or GWBASIC supplied with MS-DOS, PC compatible systems, and requires a 2.0 or greater version of DOS. It is supplied on a single 360K diskette with accompanying software. The diskette also has a short batch file for installation on a hard disk drive. Handscoring The IPDE may also be handscored by clerical personnel. All of the scores are transcribed onto summary scoresheets that contain step-by- step algorithmic directions. Frequently asked questions about the administration of the IPDE Q. Do I ask every subject all of the questions on the IPDE? A. Ask every question that is flush with the left-hand margin unless directed otherwise. Indented questions preceded by I f Yes' or 'If No' are asked if the subject provides the appropriate response. When an indented ques- tion is asked, be sure to include any subsequent questions that are aligned with it. Q. Should the questions be asked verbatim? A. Yes. Do not change the wording or embellish the question with your own comments, a common error of beginners. The IPDE Computer Scoring Program for ICD-10 Diagnoses can be obtained from the Division of Mental Health and Prevention of Substance Abuse, World Health Organization, CH-1211 Geneva 27, Switzerland. 126 Manual Q. What do you do when subjects misunderstand a question or say that they do not understand it? A. Rephrase the question in your own words, so that you approximate the intent of the original question. In doing so be mindful of the criterion assessed by the question. Q. Is it

necessary to ask a question, if the subject has already provided the answer in response to a previous question? A. Never assume that you know the answer, because of a response to a simi- lar or related question. However, if the subject has already provided suf- ficient information, so that nothing would be gained from asking the question, and you are confident about scoring it, then it need not be asked. If you require more information or additional details, ask the question with an allusion to the subject's previous reference to it. Q. Do you score the subject's report, or base the score on your clinical impression? A. Score the report, except in those rare instances when directed otherwise. If the response appears to contradict a previous comment, ask the subject to explain the apparent contradiction. Q. Suppose the subject's behaviour during the interview seems to contradict the reply to a question? For example, the subject reports that he or she is rarely angry, yet displays obvious anger during the interview. A. Ask the subject to reconcile the apparent contradiction. This may lead to a revision of the previous response. If it does not, then score the response and not the behaviour during the interview. Remember, the latter may not be representative of the way the subject has been during the previous five years, particularly if he or she is currently in a dysphoric mental state. Of course, informant information is particularly useful in situations like this. Q. At the end of the interview several criteria are rated entirely on the basis of the subject's behaviour during the interview. Isn't this inconsistent with the use of a five-year timeframe in the remainder of the interview? A. Those criteria cannot be adequately assessed by self-report. Admittedly the features could be present during the interview without necessarily being characteristic of the subject. They also may not surface during the interview, yet be evident at other times. There is no other practical way of judging the presence or absence of these particular criteria, except to rely on informant information. 127 Abbreviating the IPDE Q. What about the criteria that are exempt from the 'past year' (12 months) requirement? A. The behaviour must have occurred at least once during the last five years. If it only occurred prior to the last five years, those employing the optional scoring for a 'past' personality disorder would score it posi- tively, using the appropriate notation. Q. If I elect to score a criterion as 'past', must I determine whether it over- laps in time with the other criteria that are scored positively for that dis- order? A. No. That would make the scoring too unwieldy, because the examiner would have to note the timeframe next to all positive ratings. The subject might also have difficulty recalling whether the behaviour associated with the various criteria overlapped in time. Q. Affirmative answers to questions that take the form, 'Have people told you that you're like that?,' are followed by, 'Why do you think they've said that?' How should replies to these follow-up questions be handled? A. Request examples, anecdotes, and descriptions. After any necessary probing, score the item according to the usual guidelines. Q. What if subjects endorse a trait or behaviour, but say that they are unable to provide examples? A. If despite encouragement they persist in saying so, then a positive score should not be given. This will result in occasional false-negative ratings, but experience suggests that to deviate from the rule would probably lead to an unacceptable number of false-positive ratings. If subjects really have the trait to a clinically meaningful degree, they should be able to provide anecdotes or examples. Abbreviating the IPDE This module of the IPDE is designed to assess all of the personality dis- orders in ICD-10, and the interview should be administered in its entirety whenever possible. Because of time constraints some users may be unable to give the complete interview to all subjects; others may be inter- ested in only certain specific disorders. In those situations two options are available. The first option is to omit the items that do not pertain to the disorders of interest. In doing so, however, the examiner should always be sure to include the introductory, open-ended questions at the beginning of each 128 Manual section, if there are questions in that section that pertain to the disorders that are being assessed. The second option is to use the self-administered 'IPDE Screening Questionnaire' to eliminate subjects who are unlikely to have a person- ality disorder or the particular disorders of interest. The screen is expected to produce a considerable number of false-positive but rela- tively few false-negative cases vis-a-vis the interview. The rates of case misidentification, however, are likely to vary considerably depend- ing on the base-rates of the disorders in the population in which it is employed. It is especially important to recognize that personality disorder ques- tionnaires and semistructured clinical interviews are not interchange- able.8 Therefore, under no circumstances should the 'IPDE Screening Questionnaire' be used to make a psychiatric diagnosis. Nor should it be used to calculate dimensional scores, with the expectation that they will be equivalent to those based on the IPDE itself. Reliability and validity of the IPDE The interrater agreement and temporal stability of the IPDE were studied at 14 clinical facilities in 11 countries in North America, Europe, Africa, and Asia. The field trial employed 58 psychiatrists and clinical psycholo- gists as interviewers and observers of 716 patients. The reliability and stability of the IPDE were roughly similar to what has been reported with instruments used to diagnose the psychoses, mood, anxiety, and sub- stance use disorders.4 Establishing the validity of semistructured clinical interviews has proved to be a more elusive undertaking, because of the absence of an acceptable gold standard. The use of clinical consensus as that standard is problematic without information about the reliability and validity of the clinicians themselves. The advantage of semistructured interviews like the IPDE, is that they have a certain procedural validity that makes their conclusions more readily exportable, and less susceptible to institu- tional and regional biases. In theory, they provide clinicians and investi- gators with a more uniform method of case identification, and thus facilitate the comparison and replication of research findings. It was the opinion of most of the clinicians who participated in the field trial, that the IPDE was a useful and essentially valid method of assessing person- ality disorders for research purposes. 129 References References Jablensky, A., Sartorius, N., Hirschfeld. R. & Pardes, H. Diagnosis and classifi- cation of mental disorders and alcohol- and drug-related problems: A research agenda for the 1980s. Psychological Medicine, 1983;13:907-21. Loranger, A.W. Personality Disorder Examination (PDE) Manual. Yonkers: DV Communications, 1988. Loranger, A.W., Hirschfeld, R.M.A., Sartorius, N. & Regier, D.A. The WHO/ADAMHA International Pilot Study of Personality Disorders: Background and purpose. Journal of Personality Disorders, 1991 ;5:296-306. Loranger, A.W., Sartorius, N., Andreoli, A., Berger, P., Buchheim, P., Channabasavanna, S.M., Coid, B., Dahl, A., Diekstra, R.F.W., Ferguson, B., Jacobsberg, L.B., Mombour, W., Pull, C , Ono, Y. & Regier, D.A. The World Health Organization/Alcohol, Drug Abuse, and Mental Health Administration International Pilot Study of Personality Disorders. Archives of General Psychiatry, 1994;51:215-24. American Psychiatric Association, Committee on Nomenclature and Statistics. Diagnostic and Statistical Manual of Mental Disorders, revised 4th edn. Washington DC: American Psychiatric Press, 1994. World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research. Geneva: World Health Organization, 1993. Loranger, A.W., Lenzenweger, M.F., Gartner, A.F., Lehmann Susman, V., Herzig, J., Zammit, G.K., Gartner, J.D., Abrams, R.C. & Young, R.C. Trait-state artifacts and the diagnosis of personality disorders. Archives of General Psychiatry, 1991;48:720-8. Loranger, A.W. Are current self-report and interview measures adequate for epi- demiological studies of personality disorders? Journal of Personality Disorders, 1992,6:313-25. 130 ICD-10 criteria and corresponding IPDE items F60.0 Paranoid personality disorder At least four of the following must be present: (1) excessive sensitivity to setbacks and rebuffs 38 (2) tendency to bear grudges persistently, e.g. refusal to forgive insults, injuries, or slights 34 (3) suspiciousness and a pervasive tendency to distort experience by misconstru- ing the neutral or friendly actions of others as hostile or contemptuous 35 (4) a combative and tenacious sense of personal rights out of keeping with the actual situation 31 (5) recurrent suspicions, without justification, regarding sexual fidelity of spouse or sexual partner 55 (6) persistent self-referential attitude, associated particularly with excessive self- importance 36 (7) preoccupation with unsubstantiated "conspiratorial" explanations of events either immediate to the patient or in the world at large 57 F60.1 Schizoid personality disorder At least four of the following criteria must be present: (1) few, if any, activities provide pleasure 42 (2) display of emotional coldness, detachment, or flattened affectivity 67 (3) limited capacity to express either warm, tender feelings or anger toward oth- ers 39,44 (4) an appearance of indifference to either praise or criticism 37 (5) little interest in having sexual experiences with another person (taking into account age) 53 (6) consistent choice of solitary activities 22 (7) excessive preoccupation with fantasy and introspection 18 (8) no desire for, or possession of, any close friends or confiding relationships (or only one) 19 (9) marked insensitivity to prevailing social norms and conventions; disregard for such norms and conventions is unintentional 66 F60.2 Dissocial personality disorder At least three of the following must be present: (1) callous unconcern for the feelings of others 29 (2) gross and persistent attitude of irresponsibility and disregard for social norms, rules, and obligations 61 131 ICD-10 criteria and corresponding IPDE items (3) incapacity to maintain enduring relationships, though with no difficulty in establishing them 20 (4) very low tolerance to frustration and a low threshold for discharge of aggres- sion, including violence 15,60 (5) incapacity to experience guilt, or to profit from adverse experience, particu- larly punishment 62, 64 (6) marked proneness to blame others, or to offer plausible rationalizations for the behaviour that has brought the individual into conflict with society 63 F60.3 Emotionally unstable personality disorder F60.30 Impulsive type At least three of the following must be present, one of which must be (2): (1) marked tendency to act unexpectedly and without consideration of the conse- quences 58 (2) marked tendency to quarrelsome behaviour and to conflicts with others, espe- cially when impulsive acts are thwarted or criticized 30 (3) liability to outbursts of anger or violence, with inability to control the result- ing behavioural explosions 43 (4) difficulty in maintaining any course of action that offers no immediate reward 11 (5) unstable and capricious mood 50 F60.31 Borderline type At least three of the symptoms mentioned in Impulsive type (F60.30) must be present, with at least two of the following in addition: (1) disturbances in and uncertainty about self-image, aims, and internal prefer- ences (including sexual) 5, 6, 7, 25, 56 (2) liability to become involved in intense and unstable relationships, often lead- ing to emotional crises 26 (3) excessive efforts to avoid abandonment 48 (4) recurrent threats or acts of self-harm 59 (5) chronic feelings of emptiness 45 F60.4 Histrionic personality disorders At least four of the following must be present: (1) self-dramatization, theatricality, or exaggerated expression of emotions 40 (2) suggestibility (the individual is easily influenced by others or by circumstances) 12 (3) shallow and labile affectivity 49 (4) continual seeking for excitement and activities in which the individual is the centre of attention 16,41 132 ICD-10 criteria and corresponding IPDE items (5) inappropriate seductiveness in appearance or behaviour 54 (6) over-concern with physical attractiveness 17 F60.5 Anankastic personality disorder Note: This disorder is often referred to as obsessive-compulsive personality dis- order. At least four of the following must be present: (1) feelings of excessive doubt and caution 9 (2) preoccupation with details, rules, lists, order, organization, or schedule 3 (3) perfectionism that interferes with task completion 2 (4) excessive conscientiousness and scrupulousness 14 (5) undue preoccupation with productivity to the exclusion of pleasure and inter- personal relationships 1 (6) excessive pedantry and adherence to social conventions 65 (7) rigidity and stubbornness 28 (8) unreasonable insistence by the individual that others submit to exactly his or her way of doing things, or unreasonable reluctance to allow others to do things 27

F60.6 Anxious [avoidant] personality disorder At least four of the following must be present: (1) persistent and pervasive feelings of tension and apprehension 52 (2) belief that one is socially inept, personally unappealing, or inferior to others 13 (3) excessive preoccupation with being criticized or rejected in social situations 24 (4) unwillingness to become involved with people unless certain of being liked 23 (5) restrictions in lifestyle because of need for physical security 51 (6) avoidance of social or occupational activities that involve significant interper- sonal contact, because of fear of criticism, disapproval, or rejection 4, 21 F60.7 Dependent personality disorder At least four of the following must be present: (1) encouraging or allowing others to make most of one's important life decisions 10 (2) subordination of one's own needs to those of others on whom one is depen- dent, and undue compliance with their wishes 33 (3) unwillingness to make even reasonable demands on the people one depends on 32 (4) feeling uncomfortable or helpless when alone, because of exaggerated fears of inability to care for oneself 46 133 ICD-10 criteria and corresponding IPDE items (5) preoccupation with fears of being left to care for oneself 47 (6) limited capacity to make everyday decisions without an excessive amount of advice and reassurance from others 8 F60.9 Personality disorder unspecified The IPDE assigns this diagnosis (definite) when someone fulfills 10 or more cri- teria from the various personality disorders, but does not meet the require- ments for the diagnosis (definite) of any specific disorder. It assigns this diagnosis (probable) when someone fulfills 9 criteria from the various person- ality disorders, but does not meet the requirements for the diagnosis (definite or probable) of any specific disorder. 134 IPDE ICD-10 module screening questionnaire Last Name First Name Middle I. Date Directions The purpose of this questionnaire is to learn what type of person you have been during the past five years. Please do not skip any items. If you are not sure of an answer, select the one- TRUE or FALSE-which is more likely to be correct. There is no time limit, but do not spend too much time thinking about the answer to any single statement. When the answer is TRUE, circle the letter T. When the answer is FALSE, circle the letter F. 135 Screening questionnaire 136 1 I usually get fun and enjoyment out of life. T F 2 I don't react well when someone offends me. T F 3 I'm not fussy about little details. T F 4 I can't decide what kind of person I want to be. T F 5 I show my feelings for everyone to see. T F 6 I let others make my big decisions for me. T F 7 I usually feel tense or nervous. T F 8 I almost never get angry about anything. T F 9 I go to extremes to try to keep people from leaving me. T F 10 I'm a very cautious person. T F 11 I've never been arrested. T F 12 People think I'm cold and detached. T F 13 I get into very intense relationships that don't last. T F 14 Most people are fair and honest with me. T F 15 I find it hard to disagree with people if I depend on them a lot. T F 16 I feel awkward or out of place in social situations. T F 17 I'm too easily influenced by what goes on around me. T F 18 I usually feel bad when I hurt or mistreat someone. T F 19 I argue or fight when people try to stop me from doing what I want. T F 20 At times I've refused to hold a job, even when I was expected to. T F 21 When I'm praised or criticized I don't show others my reaction. T F 22 I've held grudges against people for years. T F 23 I spend too much time trying to do things perfectly. T F 24 People often make fun of me behind my back. T F 25 I've never threatened suicide or injured myself on purpose. T F 26 My feelings are like the weather; they're always changing. T F 27 I fight for my rights even when it annoys people. T F 28 I like to dress so I stand out in a crowd. T F 29 I will lie or con someone if it serves my purpose. T F 30 I don't stick with a plan if I don't get results right away. T F 31 I have little or no desire to have sex with anyone. T F 32 People think I'm too strict about rules and regulations. T F 33 I usually feel uncomfortable or helpless when I'm alone. T F 34 I won't get involved with people until I'm certain they like me. T F 35 I would rather not be the centre of attention. T F 36 I think my spouse (or lover) may be unfaithful to me. T F 37 Sometimes I get so angry I break or smash things. T F 38 I've had close friendships that lasted a long time. T F 39 I worry a lot that people may not like me. T F 40 I often feel "empty" inside. T F 41 I work so hard I don't have time left for anything else. T F 42 I worry about being left alone and having to care for myself. T F 43 A lot of things seem dangerous to me that don't bother most people. T F 44 I have a reputation for being a flirt. T F 45 I don't ask favors from people I depend on a lot. T F 46 I oref er activities that I can do bv mvself. T F 47 I lose my temper and get into physical fights. T F 48 People think I'm too stiff or formal. T F 49 I often seek advice or reassurance about everyday decisions. T F 50 I keep to myself even when there are other people around. T F 51 It's hard for me to stay out of trouble. T F 52 I'm convinced there's a conspiracy behind many things in the world. T F 53 I'm very moody. T F 54 It's hard for me to get used to a new way of doing things. T F 55 Most people think I'm a strange person. T F 56 I take chances and do reckless things. T F 57 Everyone needs a friend or two to be happy. T F 58 I'm more interested in my own thoughts than what goes on around me. T F 59 I usually try to get people to do things my way. T F 137 IPDE ICD-10 module screening questionnaire scoring summary Last Name First Name Middle I. Date 1 Circle the item numbers not followed by F, if they were answered True. 2 Circle the remaining item numbers (those followed by F), if they were answered False. 3 If three or more items from a disorder are circled, the subject has failed the screen for that disorder, and should be interviewed. Clinicians and investiga- tors may wish to adopt lower or higher screening standards, depending on the nature of the sample, and the relative importance to them of errors of sensitivity (false-negative cases) vs. specificity (false-positive cases). The screen should not be used to make a diagnosis or to calculate a dimensional score for a personality disorder. F60.0 Paranoid: 2 14F 22 24 27 36 52 F60.1 Schizoid: 1F 8 12 21 31 46 55 57F 58 F60.2 Dissocial: 11F 18F 20 29 38F 47 51 F60.30 Impulsive: 19 30 37 53 56 F60.31 Borderline: 4 9 13 25F 40 F60.4 Histrionic: 5 17 26 28 35F 44 F60.5 Anankastic: 3F 10 23 32 41 48 54 59 F60.6 Anxious: 7 16 34 39 43 50 F60.7 Dependent: 6 15 33 42 45 49 138 IPDE ICD-10 module* interview schedule Last Name First Name Middle I. Sex: M F Examiner Date(s) Time Required for Interview Background information Optional if already known How old are you? Are you married? If no: Were you ever married? Do you have any children? Are your parents living? If yes: How old are they? If no: When did they die? Do you have brothers or sisters? If yes: How old are they? With whom do you live? How far along did you go in school? At what age did you finish school? What is your occupation? Have you had other occupations during your life? If yes: What? Tell me briefly why you are /here/in the hospital/in treatment/. Have you ever sought professional help for personal problems or a mental disorder at any (other) time in your life? If yes: Tell me about it. Copies of the IPDE ICD-10 Module can be obtained from the Division of Mental Health and Prevention of Substance Abuse, World Health Organization, CH-1211 Geneva 27, Switzerland. 139 Interview schedule The questions I am going to ask concern what you are like most of the time. I'm interested in what has been typical of you throughout your life and not just recently. If you have changed and your answers might have been different at some time in the past, be sure to let me know. I. Work If the subject has rarely or never worked, and is not a housewife/home- maker, student, or recent graduate, circle NA for 1 and proceed to 2. I would like to begin by discussing your life at work (school). How well do you usually function in your work (at school)? What annoyances or problems keep occurring in your work (at school)? 1. 0 1 2 ? NA 0 1 2 Undue preoccupation with productivity to the exclusion of pleasure and interpersonal relationships Anankastic: 5 Do you spend so much time working that you don't have time left for anything else? If yes: Tell me about it. Do you spend so much time working that you (also) neglect other people? If yes: Tell me about it. The examiner should be alert to the use of rationalizations to defend the behaviour. The fact that work itself may be pleasurable to the subject should not influence the scoring. There is no requirement that the subject actually enjoy the work, although that is often the case. Personal ambition, high eco- nomic aspirations, or inefficient use of time, are also unacceptable excuses. Exoneration due to economic necessity should be extended only when sup- ported by convincing explanations. Allowance should be made for short-term, unusual circumstances, e.g., physicians in training who have little or no con- trol over their work schedule. Avoidance of interpersonal relationships or leisure activities for reasons other than devotion to work is not within the scope of the criterion. 2 Undue preoccupation with work that usually prevents any significant pursuit of both leisure activities and interpersonal relationships. 1 Undue preoccupation with work that occasionally prevents any significant pursuit of both leisure activities and interpersonal relationships. Undue preoccupation with work that usually prevents any significant pursuit of either leisure activities or interpersonal relationships but not both. 0 Denied or rarely or never leads to exclusion of leisure activities or interper- sonal relationships. 140 Interview schedule 2. 0 1 2 ? 0 1 2 Perfectionism that interferes with task completion Anankastic: 3 Are you more of a perfectionist than almost anyone you know? If yes: Does it slow you down a lot or prevent you from getting things done on time? If yes: Tell me about it. Many subjects view themselves as perfectionistic, but do not have the trait to a pronounced degree or to the extent that it significantly interferes with their functioning. It is particularly important to verify that there is an effect on task completion or productivity. Perfectionism frequently prevents the completion of work, or interferes with productivity. Perfectionism occasionally prevents the completion of work, or interferes with productivity. Denied, rarely or never prevents the completion of work, or interferes with productivity. 141 Interview schedule 3. 0 1 2 ? 0 1 2 Preoccupation with details, rules, lists, order, organization, or schedule Anankastic: 2 Are you fussy about little details? If yes: Do you spend much more time on them

than you really have to? If yes: Does that prevent you from getting as much work done as you're expected to do? If yes: Tell me about it. Do you spend so much time scheduling or organizing things that you don't have time left to do the job you're really supposed to do? If yes: Tell me about it. The subject is so concerned with the method or details of accomplishing a task or objective, that they almost become an end in themselves, consuming much more time and effort than is necessary, and thereby preventing the task from being accomplished, or markedly prolonging the time required to achieve the objective. The subject need not display all of the features enumerated in the criterion. 2 Convincing evidence supported by examples that the behaviour frequently interferes with reasonable expectations of productivity. 1 Convincing evidence supported by examples that the behaviour occasionally interferes with reasonable expectations of productivity. 0 Denied, rare, or the consequences are insignificant. 142 Interview schedule 4. 0 1 2 ? NA 0 1 2 Avoidance of occupational activities that involve significant interpersonal contact, because of fear of criticism, disapproval, or rejection Anxious [avoidant]: 6 (partial) Do you usually try to avoid jobs or things you have to do at work(school), that bring you into contact with other people? If yes: Give me some examples. Why do you think you do that? The criterion is not so readily applicable to housewives/homemakers and ordi- narily should be scored NA with them. They have an opportunity to qualify on the other half of the criterion (21, avoidance of social activities). "Significant interpersonal contact" in this context means that the subject would likely be engaged in conversation with others. It does not refer to the mere physical presence of others in the same building or work area. The reason for the avoidance must be fear of criticism, disapproval or rejection. 2 Almost always avoids jobs or work(school) assignments that involve significant interpersonal contact. Subject provides one or more of these as the primary reason: fear of criticism, disapproval or rejection. 1 Often avoids jobs or work(school) assignments that involve significant inter- personal contact. Subject provides one or more of these as the primary reason: fear of criticism, disapproval or rejection. Almost always avoids jobs or work(school) assignments that involve significant interpersonal contact. Subject acknowledges one or more of the three rea- sons, but insists that they are not the primary reason. 0 Denied, infrequent, not supported by convincing examples, or avoidance is due to other reasons. 143 Interview schedule II. SELF Now let me ask some questions about the kind of person you are. How would you describe your personality? Have you always been like that? If no: When did you change? What were you like before? 5. 0 1 2 ? 0 1 2 Disturbances in and uncertainty about self-image Emotionally unstable; Borderline type: 1 (partial) Do you think one of your problems is that you're not sure what kind of person you are? If yes: How does that affect your life? Do you behave as though you don't know what to expect of yourself? If yes: Are you so different with different people or in different situations that you don't behave like the same person? If yes: Give me some examples. If no: Have others told you that you're like that? If yes: Why do you think they've said that? In this context "uncertainty about self-image" may manifest itself in different ways, any one of which, if obviously present, is sufficient for a positive score. Subjects may be uncertain about what kind of person they are, because their behaviour is so different at various times or with different people, that they do not know what to expect of themself. Their behaviour may be inconsistent, erratic, or contradictory. Or they may be chameleon-like and take on the iden- tity or personality of the particular person they are with at the moment. It is not necessary that subjects acknowledge or be aware that this is the source of distress or problems. Strikingly different behaviour or views of oneself con- fined to discrete episodes of illness are not within the scope of the criterion. However, changes in self-image or erratic behaviour indicative of an inconsis- tent sense of self, may be counted when they occur in conjunction with chronic anxiety or chronic depression. 2 Obvious and well documented persistent uncertainty about self-image, as described above. 1 Probable but less well documented persistent uncertainty about self-image, as described above. 0 Absent, doubtful, or not well supported by examples. 144 Interview schedule 6. 0 1 2 ? 0 1 2 Disturbances in and uncertainty about aims Emotionally unstable; Borderline type: 1 (partial) What would you like to accomplish during your life? Do your ideas about this change often? If yes: Tell me about it. Not asked of housewives/homemakers, adolescents, students, and those who have never or almost never worked. Do you often wonder whether you've made the right choice of job or career? If yes: How does that affect you? Asked only of housewives/homemakers. Do you often wonder whether you've made the right choice in becoming a housewife/home- maker? If yes: How does that affect you? Adolescents, students, and those who have never or almost never worked. Have you made up your mind about what kind of job or career you would like to have? If no: How does that affect you? The requirements for this criterion may be fulfilled in any one of several dif- ferent ways. Subjects may report that they cannot decide about their long-term goals or career choice, and that this has an obvious effect on the way they lead their life. They may deny that they are uncertain about them, but it may be obvious from their behaviour, which is characterized by persis- tently erratic or fluctuating consideration or selection of strikingly different careers or long-term goals. Persons 30 years of age or older who have not embarked on a career path (when one is available to them), or insist that they have no idea at all about what their long-term goals are, should receive a score of 2. The criterion should be scored conservatively with adolescents and not usually given to them. 2 Obvious and well documented persistent uncertainty about long-term goals or career choice. 1 Probable but less well documented or persistent uncertainty about long-term goals or career choice. 0 Absent, doubtful, or not supported by convincing examples. 145 Interview schedule 7. 0 1 2 ? 0 1 2 Disturbances in and uncertainty about internal preferences Emotionally unstable; Borderline type: 1 (partial) Do you have trouble deciding what's important in life? If yes: How does that affect you or the way you live your life? Do you have trouble deciding what's morally right and wrong? If yes: How does that affect you or the way you live your life? In this context "internal preferences" refers both to issues of ethics and moral- ity ("right and wrong") and to values (what is important in life). For a positive score both are not required. Subjects may qualify for either in two ways. They may report that they are so uncertain about internal preferences, that it causes subjective distress or problems in social or occupational functioning. Or they may, with or without acknowledgment or awareness of any uncertainty, demonstrate the phenomenon by extremely erratic or inconsistent behaviour indicative of uncertain values. 2 Obvious and well documented persistent uncertainty about internal prefer- ences as described above. 1 Probable but less well documented or persistent uncertainty about internal preferences as described above. 0 Absent, doubtful, or not well supported by examples. 146 Interview schedule 8. 0 1 2 ? 0 1 2 Limited capacity to make everyday decisions without an excessive amount of advice and reassurance from others Dependent: 6 Are you usually able to make ordinary, everyday decisions without asking others for advice or reassurance? If no: Give me some examples. Indecisiveness not associated with the need for advice or reassurance is not within the scope of the criterion, which concerns ordinary, everyday, types of decisions, and is not meant to include unusual, special, or major decisions. The essence of the criterion is the inability to make these ordinary decisions with- out seeking advice or confirmation from others. Both elements, advice and reassurance, are not required. 2 Frequently depends on others for an excessive amount of advice or reassur- ance before making decisions about ordinary matters, so that the decisions are not otherwise made. 1 Occasionally depends on others for an excessive amount of advice or reassur- ance before making decisions about ordinary matters, so that the decisions are not otherwise made. 0 Denied, rare, or examples not convincing. 147 Interview schedule 9. 0 1 2 ? 0 1 2 Feelings of excessive doubt and caution Anankastic: 1 Do you have a lot of doubts about things? If yes: Does that upset you or cause any problems for you? If yes: Tell me about it. Are you very cautious and afraid of making a mistake? If yes: Does that bother you or cause any problems for you? If yes: Give me some examples of what you mean. If the preceding item (8) was scored 1 or 2, the subject should be questioned carefully to establish that the reason for the excessive doubt is not solely the dependent's need for advice and reassurance from others. Caution is reflected by exceptional concern about making a mistake. Caution limited to concerns about physical security is not within the scope of the criterion. For a 2 score there must be evidence of both doubt and caution, and indications that they are sometimes a source of distress or problems. 2 Frequently shows excessive doubt and caution, and this sometimes causes dis- tress or problems in social or occupational functioning. 1 Frequently shows excessive doubt or caution, but not both, and this some- times causes distress or problems in social or occupational functioning. Occasionally shows excessive doubt and caution, and this sometimes causes distress or problems in social or occupational functioning. 0 Denied, rare, or examples unconvincing. 148 Interview schedule *10. 0 1 2 ? 0 1 2 Encouraging or allowing others to make most of one's important life decisions Dependent: 1 Do you let other people take charge of your life for you? If yes: Tell me about it. Do you let them make your important decisions for you? If yes: What decisions have they made for you? The essence of the criterion is that one encourages or allows others to assume responsibility for most major areas of one's life, such as decisions about the selection of schools, occupation, place of employment, spouse, friends, place of residence, etc. Merely seeking advice or reassurance is not within the scope of the criterion. The subject must abdicate responsibility for the decisions and leave them for others to make. The criterion should be applied conservatively to those under 25 years of age. Allowance should also be made for obvious ethnic and cultural factors. 2 Has allowed others to make several important decisions in at least two differ- ent areas of life. 1 Has allowed others to make at least two major decisions in one or more areas of life. 0 Denied or examples unconvincing. 149 Interview schedule 11. 0 1 2 ? 0 1 2 Difficulty in maintaining any course of action that offers no immedi- ate reward Emotionally unstable; Impulsive type: 4 Do you have trouble sticking with a plan or course of action, if you don't get something out of it right away? If yes: Does that ever cause problems for you or get you into trouble? If yes: Give me some examples. This refers to impatience and lack of perseverance when there is no immedi- ate reward. To be scored positively there must be evidence from convincing examples that this results in subjective distress or problems in social or occupa- tional functioning. Impatience associated with the pursuit of minor, everyday matters is not within the scope of the criterion. 2 Frequently has difficulty maintaining any course of action that offers no immediate reward. This sometimes causes subjective distress or problems in social or occupational functioning. 1 Occasionally has difficulty maintaining any course of action that offers

no immediate reward. This sometimes causes subjective distress or problems in social or occupational functioning. 0 Denied, rare, or examples unconvincing. 150 Interview schedule 12. 0 1 2 ? 0 1 2 Suggestibility (the individual is easily influenced by others or by circumstances) Histrionic: 2 Are you easily influenced by other people's suggestions? If yes: Do you ever go along with suggestions that get you into trouble? If yes: Give me some examples. Are you easily influenced by what's going on around you? If yes: Does that ever get you into trouble? If yes: Give me some examples. The essence of the criterion is the ease and frequency with which one's behav- iour is influenced by the conditions around one, or by the ideas and opinions of others rather than one's own. It is scored positively only if there are con- vincing examples that this suggestibility sometimes causes social or occupa- tional problems. 2 Is frequently suggestible. This sometimes causes social or occupational problems. 1 Is occasionally suggestible. This sometimes causes social or occupational problems. 0 Denied, rare, or examples unconvincing. 151 Interview schedule 13. 0 1 2 ? 0 1 2 Belief that one is socially inept, personally unappealing, or inferior to others Anxious [avoidant]: 2 Do you feel awkward or out of place in social situations? If yes: Give me some examples of what you mean. Do you believe that people find you uninteresting or unappealing? If yes: Tell me about it. Do you feel inferior to most people? If yes: Why do you believe that? Whether or not one is really socially inept, personally unappealing, or inferior to others is irrelevant. What counts is one's beliefs. All three aspects of the cri- terion are not required. It is particularly important to determine whether the beliefs are confined to isolated episodes of mental illness, in which case they are not scored as present. 2 Almost always feels socially inept, unappealing, or inferior to others 1 Often feels socially inept, unappealing, or inferior to others 0 Denied, rare, confined to isolated episodes of mental illness, or not supported by convincing examples 152 Interview schedule 14. 0 1 2 ? 0 1 2 Excessive conscientiousness and scrupulousness Anankastic: 4 Are morals and ethics much more important to you than they are to most people? If yes: Including people from your own background or religion? If yes: Give me some examples of what you mean. Are you (also) very concerned about rules and regulations? If yes: Give me some examples. Are you so strict or conscientious that you spend a lot of time worrying whether you have bro- ken any rules or done something wrong? If yes: Give me some examples. If no: Have people accused you of being too strict or rigid about what's right and wrong? If yes: Why do you think they've said that? It is not uncommon for people to view themselves as conscientious or subscrib- ing to a higher morality than others. This is insufficient grounds for a positive rating. There must be evidence of an excessive concern about rules, ethics, morality, or matters of right and wrong. This may express itself in extreme rigidity and inflexibility about such matters, undue concern or preoccupation with doing what is right, or excessive worrying about having broken rules or done something immoral or unethical. It is not necessary that subjects impose their scrupulosity or rigidity on others. It is particularly important to view the subjects' behaviour within the context of their cultural background and reli- gious beliefs or allegiances. Religious individuals should be judged in relation to others of the same sect, and scored positively only if members of the same religion would also view them as scrupulous or inflexible. The criterion should not be scored positively if the behaviour is present only during isolated episodes of depression or obsessive-compulsive disorder. 2 Usually is overconscientious, scrupulous, and inflexible about matters of morality, ethics, or values. 1 Occasionally is overconscientious, scrupulous, and inflexible about matters of morality, ethics, or values. 0 Denied, rare, confined to isolated episodes of depression or obsessive-compul- sive disorder, or not supported by convincing examples. 153 Interview schedule *15. 0 1 2 ? 0 1 Very low tolerance to frustration Dissocial: 4 (partial) Do you ever feel very frustrated or angry when you don't get what you want right away? If yes: When that happens does it ever cause problems for you or get you into trouble? If yes: Give me some examples. Subjects must indicate that they experience annoyance or anger when they cannot get what they want right away or have to wait too long for it. In order for the criterion to be scored positively the feeling of frustration must lead to behaviour that causes problems or gets the subject into trouble. The mere experience of anger or frustration is insufficient for a positive score. 2 Actions frequently directed toward obtaining immediate satisfaction, and feels frustrated when not immediately gratified. This sometimes leads to behaviour that causes social or occupational problems. 1 Actions occasionally directed toward obtaining immediate satisfaction, and feels frustrated when not immediately gratified. This sometimes leads to behaviour that causes social or occupational problems. 0 Denied, rare, does not cause social or occupational problems, or examples unconvincing. 154 Interview schedule 16. 0 1 2 ? 0 1 2 Continual seeking for activities in which the individual is the centre of attention Histrionic: 4 (partial) Do you ever have a strong need to be the centre of attention? If yes: Tell me about it. How do you feel when you're not the centre of attention? If no: Have people ever said you need to be the centre of attention? If yes: Why do you think they've said that? It is normal to desire a certain amount of attention. The criterion refers only to those who have an almost insatiable need for it. This is manifest by the frequency with which they pursue behaviours that are intended to ensure that they are the centre of attention, and the discomfort of one form or another that they experience when too much time elapses without their receiving the attention they crave. The criterion is not scored 2 unless the sub- ject acknowledges discomfort or distress, when the attention is not received. Frequently has a very strong need to be the centre of attention. When the need is not gratified, there is sometimes an experience of considerable dis- comfort or distress. Frequently has a very strong need to be the centre of attention. When the need is not gratified, there is rarely or never an experience of considerable discomfort or distress. Occasionally has a very strong need to be the centre of attention. When the need is not gratified, there is sometimes an experience of considerable dis- comfort or distress. Denied, the need for attention is reasonable, or the examples are unconvinc- ing. 155 Interview schedule 17. 0 1 2 ? 0 1 2 Over-concern with physical attractiveness Histrionic: 6 How important to you is your physical appearance? Do you like to dress so that you stand out in a crowd? Do you ever try to use your physical appearance to attract attention? If yes: Tell me more about it. In rating this criterion also consider subject's appearance during interview. The essence of the criterion is the use of one's physical appearance as a means of drawing attention to oneself. Denial of the behaviour and obvious mani- festation of it in the interview may be used as the basis for a positive rating, including a score of 2 if it is very striking and not due to hypomania. 2 Frequently uses physical appearance to draw attention to self. Denied but very striking in interview. 1 Occasionally uses physical appearance to draw attention to self. Denied but somewhat present in interview 0 Rarely or never uses physical appearance to draw attention to self. 156 Interview schedule 18. 0 1 2 ? 0 1 2 Excessive preoccupation with fantasy and introspection Schizoid: 7 Do you get much more enjoyment from daydreaming than you do from real life? If yes: Tell me about it. Do you (also) prefer to be alone with your own thoughts, rather than involved with other peo- ple or with what's going on around you? If yes: Tell me about it. This concerns a detachment from the outer world in favor of one's own inner mental life. In order to be scored 2 subjects should make it very clear that they overwhelmingly prefer or enjoy being alone with their own thoughts and imagination, rather than involved with other people and with what is going on in the world around them. 2 Overwhelmingly prefers to spend time with own thoughts or imagination, rather than with other people and with what is going on in environment. 1 Prefers, but not overwhelmingly so, to spend time with own thoughts or imagination rather than with other people and with what is going on in envi- ronment. 0 Denied, acknowledged but not supported by subject's description, or fantasy life and introspective reserve are not prominent. 157 III. INTERPERSONAL RELATIONSHIPS Now I would like to talk to you about the people in your life. Remember I'm interested in what has been typical of you throughout your life and not just recently, but if you have changed and are different from the way you used to be, be sure to let me know. Who are the most important people in your life? In what way are they important? During your life what kind of problems or difficulties have you had getting along with other people? 19. 0 1 2 ? 0 1 2 No desire for, or possession of, any close friends or confiding relation- ships (or only one) Schizoid: 8 Do you have any close friends or people you confide in? If yes: Tell me about them. If no: Would you like to? If yes: Tell me about it. If no: Is there anyone you have ever been close to or confided in? If yes: Tell me about it. The criterion also requires no desire for close friendships or confiding relation ships, and not merely their absence from one's life. 2 Neither desires nor has any close friends or confidants (or only one). 1 Probably neither desires nor has any close friends or confidants (or only one), but there is some doubt about this based on the subject's uncertainty or description of the nature of the friendships. 0 Denied or description unconvincing. 158 Interview schedule 20. 0 1 2 ? NA 0 1 2 Incapacity to maintain enduring relationships, though with no diffi- culty in establishing them Dissocial: 3 If 19 was scored 2, circle NA and go to 21. How long have these relationships lasted? To be scored positively there should be convincing evidence from examples that the subject has an inability to sustain friendships and relationships with others, excluding family members. In this context a spouse is not considered a family member. Not scored positively are those who claim never to establish friendships or relationships in the first place (NA), and those who through misfortune or events beyond their control (deaths, illness, moving, etc.) report the interruption of many relationships. Five years is considered evidence of an enduring relationship. 2 The subject has never maintained an enduring or longstanding relationship with anyone (excluding family members) since the completion of childhood. 1 The subject has maintained an enduring or longstanding relationship with only one person (excluding family members) since the completion of childhood. Examples suggest the likelihood that the subject has never maintained an enduring or longstanding relationship (excluding family members) since the completion of childhood, but they are less than totally convincing. 0 Denied, not supported by examples, or due to circumstances beyond the sub- ject's control. 159 Interview schedule 21. 0 1 2 ? 0 1 2 Avoidance of social activities that involve significant interpersonal contact, because of fear of criticism, disapproval, or rejection Anxious [avoidant]: 6 (partial) Some people almost always keep to themselves and rarely socialize. Are you like that? If yes: Tell me more about it. Why do you think you behave like that? For a positive score there must be evidence of an obvious avoidance of joint leisure activities, social

visits, parties, or participation in community, civic, or other organizations. Social contacts at work or with one's family do not exempt one from meeting the criterion. The reason for the avoidance must be fear of criticism, disapproval or rejection. 2 Almost always avoids social activities (outside of family or work) that involve significant interpersonal contact. Subject provides one or more of these as the primary reason: fear of criticism, disapproval or rejection. 1 Often avoids social activities (outside of family or work) that involve signifi- cant interpersonal contact. Subject provides one or more of these as the pri- mary reason: fear of criticism, disapproval or rejection. Almost always avoids social activities (outside of family or work) that involve significant interpersonal contact. Subject acknowledges one or more of the three reasons, but insists that they are not the primary reasons. 0 Denied, infrequent, not supported by convincing examples, or avoidance is due to other reasons. 160 Interview schedule 22. 0 1 2 ? 0 1 2 Consistent choice of solitary activities Schizoid: 6 Do you almost always choose the kind of activities that you can do all by yourself rather than with other people? If yes: Give me some examples. For a score of 2 there must be compelling evidence from examples that sub- jects almost always select activities (occupational and leisure) that they can do alone. The mere preference for such activities is insufficient. It must be acted on. Those who almost always choose solitary leisure activities but claim that their job occasionally prevents them from choosing solitary occupational activities should receive a score of 2. 2 Almost always chooses solitary occupational and leisure activities. Almost always chooses solitary occupational and leisure activities, except occa- sionally when the nature of the job prevents it. 1 Often chooses solitary occupational and leisure activities. 0 Denied or examples unconvincing. 161 Interview schedule 23. 0 1 2 ? 0 1 2 Unwillingness to become involved with people unless certain of being liked Anxious [avoidant]: 4 Are you willing to get involved with people when you're not sure they really like you? If no: Does that affect you or the way you live your life? If yes: Tell me about it. Many people acknowledge this tendency, but that is insufficient for a positive score. For a score of 2 the subject's description must make it clear that it has a significant impact, e.g., missing out on opportunities for potential friendships and relationships. 2 Usually unwilling to become involved with people unless certain of being liked, and this has an obvious effect on friendships and relationships. Occasionally unwilling to become involved with people unless certain of being liked, and this has some effect on friendships and relationships. 0 Denied, rare, or not supported by description. 162 Interview schedule 24. 0 1 2 ? 0 1 2 Excessive preoccupation with being criticized or rejected in social situations Anxious [avoidant]: 3 Do you spend a lot of time worrying about whether people like you? If yes: Are you afraid they'll criticize or reject you when you're around them? If yes: How much does this bother you? There is an inclination for subjects to confuse an ordinary, understandable concern about criticism or rejection in social situations with an excessive pre- occupation. It is particularly important that acknowledgement of the behav- iour be supported by convincing examples indicating that the concern is well beyond that experienced by most people in similar circumstances. 2 Frequently is concerned about being criticized or rejected in social situations. 1 Occasionally is concerned about being criticized or rejected in social situa- tions. 0 Denied, rare, or not supported by convincing examples. 163 Interview schedule 25. 0 1 2 ? 0 1 2 Disburtances in and uncertainty about internal preferences Emotionally unstable; Borderline type: 1 (partial) Do you have a lot of trouble deciding what type of friends you should have? If yes: Does that have an effect on your life or cause any problems for you? If yes: Give me some examples. Does the kind of people you have as friends keep changing? If yes: Tell me about it. This aspect of the criterion is met when subjects report that they are so uncer- tain about what type of friends they desire, that this causes significant distress or problems in their relations with others. A positive score is also given when subjects describes frequent or erratic changes in the type of friends they have, even if they don't acknowledge uncertainty about type of friends to have. Doubt about whether to have a particular person as a friend is not within the scope of the criterion, unless it is a particular instance of the more general uncertainty about the type of friends to have. 2 Obvious and well documented persistent uncertainty about type of friends to have, as described above. 1 Probable but less well documented persistent uncertainty about type of friends to have, as described above. 0 Absent, doubtful, or not well documented by examples. 164 Interview schedule *26. 0 1 2 ? 0 1 2 Liability to become involved in intense and unstable relationships often leading to emotional crises Emotionally unstable; Borderline type: 2 Do you get into intense and stormy relationships with other people with lots of ups and downs? I mean where your feelings about them run "hot" and "cold," or change from one extreme to the other. If yes: In those relationships do you often find yourself alternating between admiring and despising the same person? If yes: Give me some examples. In how many different relationships has this happened? For a positive score three features must be present: instability, strong feelings, and alternation between overidealization and devaluation. The latter does not require continuous switching from overidealization to devaluation. If the other requirements are met, it does not matter whether the behaviour is con- fined to specific types of relationships, e.g., those with parents, members of the opposite sex, etc. 2 Examples illustrating a pattern of unstable and intense relationships (more than one or two) characterized by alternating between the extremes of overidealization and devaluation. 1 Examples illustrating that one or two relationships were unstable, intense and characterized by alternating between the extremes of overidealization and devaluation. 0 Denied or not supported by convincing examples. 165 Interview schedule 27. 0 1 2 ? 0 1 2 Unreasonable insistence by the individual that others submit to exactly his or her way of doing things, or unreasonable reluctance to allow others to do things Anankastic: 8 Do you often insist that people do things exactly your way? If yes: Does that cause any problems for you or for others? If yes: Tell me about it. Are you reluctant to let people do things, because you're convinced that they won't do them your way? If yes: Does that cause any problems for you or for them? If yes: Tell me about it. For a positive score the behaviour must cause subjective distress or problems. 2 Frequent insistence that others submit to exactly his or her way of doing things. This sometimes causes subjective distress or problems. Frequent unreasonable reluctance to allow others to do things because of the conviction that they will not do them correctly. This sometimes causes subjec- tive distress or problems. 1 Occasional insistence that others submit to exactly his or her way of doing things. This sometimes causes subjective distress or problems. Occasional unreasonable reluctance to allow others to do things because of the conviction that they will not do them correctly. This sometimes causes sub- jective distress or problems. 0 Denied, does not cause distress or problems, or not supported by convincing examples. 166 Interview schedule 28. 0 1 2 ? 0 1 2 Rigidity and stubbornness Anankastic: 7 Are you very stubborn and set in your ways? If yes: Give me some examples of what you mean. Does this upset you or cause any problems? If no: Have people ever accused you of being that way? If yes: Why do you think they have? Resistance to the suggestions and views of others, and a reluctance to change one's ways under reasonable pressure from others to do so, should be taken as evidence of rigidity and stubbornness. For a positive score there should be indications that this sometimes leads to subjective distress or social or occupa- tional problems. Frequent rigidity and stubbornness that sometimes leads to subjective distress or social or occupational problems. Occasional rigidity and stubbornness that sometimes leads to subjective dis- tress or social or occupational problems. Denied, not associated with subjective distress or social or occupational prob- lems. 167 Interview schedule 29. 0 1 2 ? 0 1 2 Callous unconcern for the feelings of others Dissocial: 1 Some people are not too concerned about other people's feelings. Are you like that? If yes: Tell me more about it. If no: Has anyone ever told you that you're not concerned about other people's feelings? If yes: Why do you think they've said that? Many callous people may be unaware of it or fail to acknowledge it. Therefore, it is particularly important to adequately pursue the reasons for any accusations by others. 2 Usually is not concerned about the feelings of others. 1 Often is not concerned about the feelings of others. 0 Denied, infrequent or not supported by examples. 168 Interview schedule 30. 0 1 2 ? 0 1 2 Marked tendency to quarrelsome behaviour and to conflicts with oth- ers, especially when impulsive acts are thwarted or criticized Emotionally unstable; Impulsive type: 2 Do you have a habit of getting into arguments and disagreements? If yes: When are you likely to behave like that? Give me some examples. If no: Have people told you that you argue or disagree too much? If yes: Why do you think they have? To receive a positive score there must be evidence from examples that the quarrelsome behaviour and conflicts occur especially when the subject's impulsive acts are prevented, condemned, or criticized. 2 Frequently engages in quarrelsome behaviour and conflicts with others, espe- cially when impulsive acts are prevented, condemned, or criticized. 1 Occasionally engages in quarrelsome behaviour and conflicts with others, especially when impulsive acts are prevented, condemned, or criticized. Frequently engages in quarrelsome behaviour and conflicts with others, but not especially in relation to impulsive acts. 0 Denied, rare, not in relation to impulsive acts, or not supported by convincing examples. 169 Interview schedule 31. 0 1 2 ? 0 1 2 A combative and tenacious sense of personal rights out of keeping with the actual situation Paranoid: 4 Do you insist on standing up for your rights? If yes: Do you do this even when it means getting into a confrontation and arguing about something that many people would ignore? If yes: Give me some examples. If no: Have people accused you of being like that? If yes: Why do you think they have? Argumentative or disagreeable behaviour is not within the scope of the criterion, unless it occurs within the context of subjects' defending in an exaggerated or inappropriate fashion what they perceive to be their rights. 2 Frequently displays a combative and tenacious sense of personal rights out of keeping with the actual situation. 1 Occasionally displays a combative and tenacious sense of personal rights out of keeping with the actual situation. 0 Denied, rare, or not supported by convincing examples. 170 Interview schedule 32. 0 1 2 ? NA 0 1 2 Unwillingness to make even reasonable demands on the people one depends on Dependent: 3 Do you depend a lot on some people? If no: Score 32 and 33 NA, and go to 34. If yes: Do you ask them to help you or do things for you? Tell me about it. This refers specifically to reasonable demands on the people the subject depends on, e.g., spouse, parents, adult offspring, lover, friends, etc. It does not include such behaviour when it occurs with an employer, or outside the context of dependent relationships. 2 Usually unwilling to make even reasonable demands on the people the sub- ject depends on. 1 Occasionally unwilling to make even reasonable demands on the people the subject depends on. 0 Denied, rare, or not supported by convincing examples. 171 Interview schedule 33. 0 1 2 ?

NA 0 1 2 Subordination of one's own needs to those of others on whom one is dependent, and undue compliance with their wishes Dependent: 2 When you depend a lot on another person, do you give in too easily to what that person wants? If yes: Give me some examples of what you mean. Do you almost always put that person's needs ahead of your own? If yes: Tell me about it. As with the preceding item (32) this applies only to behaviour that occurs with those on whom the subject is dependent, e.g., spouse, parents, adult off- spring, lover, friends, etc. It does not include such behaviour when it occurs with an employer, or outside the context of dependent relationships. 2 Frequently subordinates own needs to those on whom subject is dependent, or unduly complies with their wishes. 1 Occasionally subordinates own needs to those on whom subject is dependent, or unduly complies with their wishes. 0 Denied, rare, or not supported by convincing examples. 172 Interview schedule *34. 0 1 2 ? 0 1 2 Tendency to bear grudges persistently, e.g., refusal to forgive insults injuries, or slights Paranoid: 2 Have you ever held a grudge or taken a long time to forgive someone? If yes: Tell me about it. Did you try to avoid or refuse to talk to the person? How long did you continue to act that way? Has this ever happened with anyone else? If yes: With how many people? As evidence of a grudge the subject should either try to avoid or refuse to speak to the person for more than a year. For a score of 2 there should be evi- dence of grudges against more than one or two people. The examples should establish that the reaction is obviously disproportionate. For example, a grudge against a parent responsible for child abuse or incest would not war- rant a positive score. 2 Has born persistent grudges, i.e., has been unforgiving of insults, injuries, or slights against several people. 1 Has born persistent grudges, i.e., has been unforgiving of insults, injuries, or slights against one or two people. 0 Denied or not supported by example 173 Interview schedule 35. 0 1 2 ? 0 1 2 Suspiciousness and a pervasive tendency to distort experience by mis- construing the neutral or friendly actions of others as hostile or con- temptuous Paranoid: 3 Has it been your experience that people often try to use you or take advantage of you? If yes: Give me some examples. Has anyone ever deliberately tried to harm you, ruin your reputation, or make life difficult for you? If yes: Give me some examples. In rating this criterion also consider subject's behaviour during interview. Affirmative replies to the questions that assess this criterion require consider- able probing and judgment on the part of the examiner, because there must be an assessment of the possible reality basis of the subject's reported experi- ences. Too much emphasis should not be given to accounts of isolated inci- dents. The focus should be on identifying a characteristic attitude on the part of the subject, suggesting an orientation or set toward the expectation of exploitation or harm. The subject's approach to the interview itself may be taken into consideration in the scoring, but should never be the sole basis for a score of 2. 2 Frequently expects, without sufficient basis, to be exploited or harmed by others. 1 Occasionally expects, without sufficient basis, to be exploited or harmed by others. Denied, but evident in interview. 0 Denied, rare, or not supported by convincing examples. 174 Interview schedule 36. 0 1 2 ? 0 1 2 Persistent self-referential attitude, associated particularly with exces- sive self-importance Paranoid: 6 When you enter a room full of people do you often wonder whether they might be talking about you, or even making unflattering remarks about you? If yes: Give me some examples. When you're in a public place or walking down the street, do you often wonder whether peo- ple might be looking at you, talking about you, or even making fun of you? If yes: Give me some examples. It is not uncommon for people to experience fleeting self-referential ideas when they first enter a large social gathering, particularly one involving unfa- miliar people. Such behaviour should not be considered within the scope of the criterion. There should be indications that the ideas are more than momentary. If it appears that they may be of delusional proportions, the sub- ject should be questioned carefully, since delusions of reference are excluded. 2 Frequently experiences ideas of reference. 1 Occasionally experiences ideas of reference. 0 Denied, rare, not supported by convincing examples, or delusional in nature. 175 IV. AFFECTS Now I am going to ask some questions about your feelings. Again I'm interested in the way you have been most of your life and not just recently. If you have changed and are different from the way you used to be, be sure to let me know. How do you usually feel? How do you usually feel deep down inside? What problems do you have with your feelings? 37. 0 1 2 ? 0 1 2 An appearance of indifference to either praise or criticism Schizoid: 4 When you're praised, do you show any reaction so that the people around you know how you feel? If yes: Tell me about it. What about when you're criticized? If yes: Tell me about it. For a positive score subjects must report the absence of any overt reaction, so that observers might conclude that they are indifferent to the praise or criti- cism. Apparent indifference to both praise and criticism is not required. 2 Almost always gives the appearance of being indifferent to praise or criticism. 1 Often gives the appearance of being indifferent to praise or criticism. 0 Denied, does not occur often, or not supported by subject's account. 176 Interview schedule 38. 0 1 2 ? 0 1 2 Excessive sensitivity to setbacks and rebuffs Paranoid: 1 Are you easily slighted or offended? If yes: Tell me about it. When you are slighted or offended, do you sometimes have too strong a reaction? If yes: Give me some examples. How do you react when things don't go your way? For a positive score the subject's examples should establish the presence of a characteristic inclination toward being slighted in situations where most peo- ple would not especially feel that way; or of reacting excessively to actual slights. This may occur as a consequence of what others say or fail to say, or what they do or fail to do. For a 2 score there must also be evidence of similar behaviour in response to setbacks, i.e., things not going one's way. 2 Frequently is easily slighted, or reacts excessively to actual slights. Also dis- plays similar behaviour in response to setbacks. 1 Occasionally is easily slighted, or reacts excessively to actual slights. Also dis- plays similar behaviour in response to setbacks. Frequently is easily slighted, or reacts excessively to actual slights, but not to setbacks. Frequently reacts excessively to setbacks, but not slights. 0 Denied, rare, or not supported by convincing examples. 177 Interview schedule 39. 0 1 2 ? 0 1 2 Limited capacity to express warm, tender feelings towards others Schizoid: 3 (partial) Some people rarely show affection or talk about it. Are you like that? If yes: Tell me about it. If no: Have people told you that you're not affectionate? If yes: Why do you think they've said that? Warmth, tenderness, or affection are the only emotions within the scope of the criterion, which concerns their display or expression, not the subjective experience of them. 2 Claims to rarely or never express affection. 1 Claims to occasionally express affection. 0 Frequently expresses affection. 178 Interview schedule 40. 0 1 2 ? 0 1 2 Self-dramatization, theatricality, or exaggerated expression of emotions Histrionic: 1 Do you almost always show your feelings in a very obvious way for others to see? If yes: Do you ever get carried away and exaggerate the way you feel? If yes: Give me some examples. Have people told you that you're dramatic? If yes: Why do you think they've said that? In rating this criterion also consider subject's behaviour during interview. Subjects should be questioned very closely if they acknowledge self-dramati- zation, but show no signs of it during the interview. Strikingly obvious theatri- cality or frequent exaggerated expression of emotions during the interview may justify a positive rating, including a score of 2, even if the subject denies the behaviour, provided there is no reason to suspect hypomania. 2 Acknowledges with supporting examples frequent self-dramatization and exaggerated expression of emotion, or displays it during the interview in an obvious and striking way. 1 Acknowledges with supporting examples occasional self-dramatization and exaggerated expression of emotion, or displays it to a limited degree during the interview. 0 Denied, rare, or not supported by convincing examples or behaviour during the interview. 179 Interview schedule 4 1 . 0 1 2 ? 0 1 Continual seeking for excitement Histrionic: 4 (partial) Do you need a lot of excitement in your life? If yes: Tell me more about it. Does needing excitement ever cause problems for you? If yes: Give me some examples. Proneness to boredom without obvious seeking of excitement is not within the scope of the criterion. For a positive score there should be evidence that the search for exciting forms of behaviour sometimes causes problems for the subject. 2 Frequently seeks excitement. This leads to the pursuit of exciting forms of behaviour that sometimes cause problems for the subject. 1 Occasionally seeks excitement. This leads to the pursuit of exciting forms of behaviour that sometimes cause problems for the subject. 0 Denied, not supported by subject's description, or rarely or never leads to exciting forms of behaviour that cause problems for the subject. 180 Interview schedule 42. 0 1 2 ? 0 1 2 Few, if any, activities provide pleasure Schizoid: 1 Are there any activities that you enjoy? If yes: Tell me about them. If no: Tell me more about it. It is particularly important to establish that the anhedonia is not limited to episodes of depression. Positive ratings should also not be given to those with dysthymia or persistent depression. 2 Claims to rarely, if ever, experience pleasure or joy. 1 Claims not to experience pleasure or joy most of the time. 0 Denied, infrequent, due to depression, or not supported by subject's descrip- tion. 181 Interview schedule 43. 0 1 2 ? 0 1 2 Liability to outbursts of anger or violence, with inability to control the resulting behavioural explosions Emotionally unstable; Impulsive type: 3 Do you sometimes get angrier than you should, or feel very angry without a good reason? If yes: Give me some examples. If no: Have people ever told you that you're a very angry person? If yes: Why do you think they've said that? Do you ever lose your temper and have tantrums or angry outbursts? If yes: Do you yell and scream in an uncontrolled way? If yes: Give me some examples. Do you ever throw, break, or smash things? If yes: Give me some examples. Do you ever hit or assault people? If yes: Give me some examples. The subjective experience of intense anger or psychodynamically inferred anger are not within the scope of the criterion. The anger must be either inap- propriate, or intense and uncontrolled. Overt verbal or physical displays of anger are required. 2 Frequently verbally displays inappropriate or intense, uncontrolled anger. Occasionally indulges in extreme physical displays of inappropriate or intense, uncontrolled anger. 1 Occasionally verbally displays inappropriate or intense, uncontrolled anger. On one or two occasions indulged in extreme physical displays of inappropri- ate or intense, uncontrolled anger. 0 Denied. 182 Interview schedule 44. 0 1 2 ? 0 1 2 Limited capacity to express anger towards others Schizoid: 3 (partial) If 43 is scored 1 or 2, score 44 0 and go to 45. When you're angry with someone, do you show it so that the person is aware of it? Tell me more about it This concerns the expression or display and not the experience

of anger toward others. 2 Claims to almost never express anger toward others, so that they are aware of it. 1 Claims to rarely express anger toward others, so that they are aware of it. 0 Expresses anger toward others or claim not supported by subject's account. 183 Interview schedule 45. 0 1 2 ? 0 1 Chronic feelings of emptiness Emotionally unstable; Borderline type: 5 Do you often feel empty inside? If yes: Does that upset you or cause any problems for you? If yes: Tell me about it. For a positive score there must be evidence that the emptiness is obviously dis- tressing to the subject or leads to maladaptive behaviour, e.g., substance abuse, self-mutilation# suicidal gestures, impulsive sexual activity, etc. Frequent feelings of emptiness that are obviously distressing or sometimes lead to maladaptive behaviour. Occasional feelings of emptiness that are obviously distressing or sometimes lead to maladaptive behaviour. Denied, rare, or not associated with obvious distress or maladaptive behav- iour. 184 Interview schedule 46. 0 1 2 ? 0 1 2 Feeling uncomfortable or helpless when alone, because of exaggerated fears of inability to care for oneself Dependent: 4 How do you usually feel when you're alone? If subject reports uncomfortable or helpless feelings: How much of a problem is that? How much does it actually bother you? Why do you think you feel that way? For a positive score subjects must experience significant and obvious discom- fort or helplessness when alone, or provide convincing examples that they go to great lengths to avoid being alone. The reason for this must be a fear of being unable to care for oneself. A feeling of loneliness as such does not receive a positive score. 2 Frequently feels very uncomfortable or helpless when alone, because of exag- gerated fear of inability to care for oneself. 1 Occasionally feels very uncomfortable or helpless when alone, because of exaggerated fear of inability to care for oneself. 0 Denied, rare, feelings insignificant, not supported by subject's description, or solely for other reasons, e.g., loneliness. 185 Interview schedule 47. 0 1 2 ? 0 1 2 Preoccupation with fears of being left to care for oneself Dependent: 5 Do you spend a lot of time worrying about the possibility that you may be left alone and have to care for yourself? If yes: Tell me about it. The criterion refers to a fear and not the actual event. An occasional or tran- sient concern is not within the scope of the criterion. There must be a long- standing preoccupation, not limited to an episode of illness. Positive scores should not be given if the preoccupation is due to special circumstances, such as those created by the serious illness or impending death of another, or the absence of other support systems, such as might occur in an elderly person with no surviving friends or family members. 2 Frequent unrealistic preoccupation with fears of being left to care for one- self. 1 Occasional unrealistic preoccupation with fears of being left to care for one- self. 0 Denied, rare, not supported by subject's description, or the fears have a defi- nite basis in reality. 186 Interview schedule 48. 0 1 2 ? 0 1 2 Excessive efforts to avoid abandonment Emotionally unstable; Borderline type: 3 Do you ever find yourself frantically trying to stop someone close to you from leaving you? If yes: Give me some examples. Unlike the previous Dependent item (47), which concerns preoccupation with fears of being left alone to care for oneself, this has to do with efforts on the part of the subject to avoid real or imagined abandonment. The efforts should be associated with obvious feelings of anxiety or agitation. 2 Frequent frantic efforts to avoid real or imagined abandonment. 1 Occasional frantic efforts to avoid real or imagined abandonment. 0 Denied, rare, occurs only in association with suicidal or self-mutilating behav- iour, or not supported by examples. 187 Interview schedule 49. 0 1 2 ? 0 Shallow and labile affectivity Histrionic: 3 Do your feelings often change very suddenly and unexpectedly, sometimes for no obvious rea- son? If yes: Give me some examples. Has anyone ever accused you of being a shallow person? If yes: Why do you think they have? In rating this criterion also consider subject's behaviour during interview. Unlike the next item (50), the emotions involved are not necessarily negative ones, such as anxiety, depression, and irritability, but may include enthusiasm, warmth, joy, etc. Denial of the behaviour and display of it in the interview is insufficient for a score of 2. Do not give a positive rating when the behaviour is due to a bipolar disorder. 2 Frequently displays rapidly shifting and shallow expression of emotions. 1 Occasionally displays rapidly shifting and shallow expression of emotions. Denied, but definitely displayed during interview. 0 Denied, rare, not supported by convincing examples, or due to a bipolar disor- der. 188 Interview schedule 50. 0 1 2 ? 0 1 Unstable and capricious mood Emotionally unstable; Impulsive type: 5 Do you often change from your usual mood to feeling very irritable, very depressed, or very nervous? If yes: When that happens how long do you usually stay that way? Give me some examples of what it's like when you're feeling that way. The subject need not report instability of all three moods: depression, irritabil- ity, and anxiety. For a positive score the description and examples should establish that the mood changes are not only frequent and shortlived (a few hours or days), but also of some intensity. 2 Frequently experiences affective instability. 1 Occasionally experiences affective instability. 0 Denied, rare, or not supported by examples. 189 Interview schedule 51. 0 1 2 ? 0 1 2 Restrictions in lifestyle because of need for physical security Anxious [avoidant]: 5 Some people have a very strong need to feel safe from physical harm. That may affect the way they live their lives or prevent them from doing a lot of things. Are you like that? If yes: Give me some examples. The restrictions on the way subjects live their life because of the need for physical security may involve a variety of areas: social, leisure, and occupa- tional. A positive score requires documentation with obvious examples. Vague generalities are insufficient. 2 The need for physical security has an obvious effect on the subject's lifestyle as reflected by convincing examples from different areas of life. 1 The need for physical security has a definite but less extensive effect on the subject's lifestyle. 0 Denied, insignificant, or not supported by convincing examples. 190 Interview schedule 52. 0 1 2 ? 0 1 2 Persistent and pervasive feelings of tension and apprehension Anxious [avoidant]: 1 Do you almost always feel tense or nervous? If yes: How much of an effect does it have on your life? Give me some examples. Are you the kind of person who is always worrying that something bad or unpleasant is going to happen? If yes: Is it very hard for you to get those thoughts out of your mind? If yes: How much of an effect does being a worrier have on your life? A positive rating should not be given if the tension and apprehension are lim- ited to isolated episodes of depressive, anxiety, phobic, panic, or obsessive- compulsive disorders. However, those with chronic anxiety disorders fall within the scope of the criterion. There must be convincing evidence that both tension and apprehension have an obvious effect on the subject's life. 2 Frequent experience of persistent and pervasive feelings of both tension and apprehension with an obvious effect on the subject's life. 1 Frequent experience of persistent and pervasive feelings of either tension or apprehension (but not both), with an obvious effect on the subject's life. Occasional experience of persistent and pervasive feelings of both tension and apprehension with an obvious effect on the subject's life. 0 Denied, rare, confined to episodic anxiety or depressive disorders, does not have an obvious effect on the subject's life, or not supported by subject's description. 191 Interview schedule 53. 0 1 2 ? 0 1 2 Little interest in having sexual experiences with another person (taking into account age) Schizoid: 5 The examiner should exercise discretion about inquiring about sexual behaviour in certain cultures. Where this might be inappropriate, the item should be scored ? Now a few questions about your sexual behaviour. There are some people who have little or no desire to have sexual experiences with another person. Are you like that? If yes: Tell me about it. The lack of sexual interest or desire should be longstanding and not due to old age or to physical or mental illness, including depression. Allowance should also be made for the possible effect of certain medications. 2 Almost never has any desire to have sexual experiences with another person. 1 Much of the time has no desire to have sexual experiences with another per- son. 0 Denied, does not occur much of the time, explicable by age, physical or mental illness, medications, or not supported by subject's description. 192 Interview schedule 54. 0 1 2 ? 0 1 2 Inappropriate seductiveness in appearance or behaviour Histrionic: 5 he examiner should exercise discretion about inquiring about sexual behaviour in certain cultures. Where this might be inappropriate, the item should be scored ?. Do you ever find yourself dressing or behaving in a sexually seductive way? If yes: What kind of things do you do? Have you ever been told that what you do is inappropriate? If yes: Tell me about it. If no: Have you ever been told that you do? If yes: Why do you think people have said that? In rating criterion also consider subject's appearance or behaviour during interview. For a score of 2 the subject must provide examples of obviously inappropriate seductiveness. The subject's appearance or behaviour during the interview may influence the rating, and may be sufficient for a score of 2, if it is not due to hypomania. 2 Frequently inappropriately sexually seductive in appearance or behaviour. Obviously inappropriately seductive in appearance or behaviour during the interview. 1 Occasionally inappropriately sexually seductive in appearance or behaviour. Frequently either somewhat flirtatious or seductive in appearance or behav- iour, but rarely inappropriately so. Somewhat inappropriately seductive in appearance or behaviour during the interview. 0 Denied, insignificant, or not supported by subject's description. 193 Interview schedule *55. 0 1 2 ? 0 1 2 Recurrent suspicions, without justification, regarding sexual fidelity of spouse or sexual partner Paranoid: 5 The examiner should exercise discretion about inquiring about sexual behaviour in certain cultures. Where this might be inappropriate, the item should be scored ? Asked only of those who have never been married. Have you ever had sexual relations with anyone? If no: Circle NA and go to 56. Have you ever been concerned about whether a sexual partner was unfaithful to you? If yes: Tell me about it. For a score of 2 there should be admission of more than brief, transient con- cerns about the sexual fidelity of one's spouse or partner. Subjects who admit to frequent suspicions, but who insist that it is justified, should be questioned very carefully. When in doubt about the possible reality basis of their account, the criterion should not be scored positively, unless there is evidence from other sources that the suspicions are pathological. 2 On a number of different occasions or with a number of different partners was obviously very concerned about fidelity, with no apparent justification. 1 On one or two occasions was obviously very concerned about fidelity, with no apparent justification. 0 Denied, rare, insignificant, or not supported by subject's account. 194 Interview schedule 56. 0 1 2 ? 0 1 2 Disturbances in and uncertainty about internal preferences (including sexual) Emotionally unstable; Borderline type: 1 (partial) The examiner should exercise discretion about inquiring about sexual behaviour in certain cultures. Where this might be inappropriate, the item should be scored ? Have you ever been uncertain whether you prefer a sexual relationship with a man or a woman? If yes: Tell me about it. Does this ever upset you or cause any problems for you? If yes: Tell me about it. Homosexuality or bisexuality as such

are not within the scope of the criterion unless they are associated with significant doubt or uncertainty about one's sexual orientation. This doubt or uncertainty causes subjective distress or problems with others. Has considerable doubt or uncertainty about sexual orientation. This fre- quently causes subjective distress. Has considerable doubt or uncertainty about sexual orientation. This some- times causes subjective distress. Denied, rare, does not cause subjective distress, or not supported by subject's account. 195 Interview schedule V. REALITY TESTING Now a question about some of your beliefs. 57. 0 1 2 ? 0 1 2 Preoccupation with unsubstantiated "conspiratorial" explanations of events either immediate to the patient or in the world at large Paranoid: 7 Do you spend time thinking about the possibility that there may be some kind of conspiracy going on around you or in the world at large? If yes: Does this bother you or have any effect on your life? If yes: Tell me about it. This should be scored conservatively. Passing suspicions or abstract ideas with little or no impact on the subject's behaviour are not within the scope of the criterion. For a positive score there should be a definite preoccupation that either produces emotional distress or has an obvious influence on the subject's behaviour. If people rather than events are the focus of the "conspiracy", then more than one person must be involved, and there must be communica- tion between or among them. Often preoccupied with unsubstantiated conspiratorial explanations. This sometimes produces emotional distress or has an obvious influence on the subject's behaviour. 1 Occasionally preoccupied with unsubstantiated conspiratorial explana- tions. This sometimes produces emotional distress or has an obvious influence on the subject's behaviour. Denied, rare, does not cause distress or influence behaviour, or not supported by subject's description. 196 Interview schedule VI. IMPULSE CONTROL I'm going to conclude the interview with some questions about impulsive and irresponsible behaviour. Have there been times when your behaviour hasn't conformed to what you believe or have been taught is right? If yes: Tell me about it. 58. 0 1 2 ? 0 1 2 Marked tendency to act unexpectedly and without consideration of the consequences Emotionally unstable; Impulsive type: 1 Some people have a habit of doing things suddenly or unexpectedly without giving any thought to what might happen. Are you like that? If yes: What kind of things have you done? This refers to the consequences of acting suddenly and unexpectedly on impulse. It is scored positively only if the subject can produce convincing examples of problems that have arisen or could have arisen as a result of this tendency. 2 Frequently acts suddenly and unexpectedly on impulse. This sometimes causes problems or could cause problems. 1 Occasionally acts suddenly and unexpectedly on impulse. This sometimes causes problems or could cause problems. 0 Denied, rare, or not supported by convincing examples. 197 Interview schedule *59. 0 1 2 ? 0 1 2 Recurrent threats or acts of self-harm Emotionally unstable; Borderline type: 4 Have you ever threatened to commit suicide? If yes: How many times? Tell me about it. Have you ever actually made a suicide attempt or gesture? If yes: How many times? Tell me about it. Have you ever deliberately cut yourself, smashed your fist through a window, burned yourself, or hurt yourself in some other way (not counting suicide attempts or gestures)? If yes: Tell me about it. The mere sharing of one's suicidal thoughts with another person does not ordinarily constitute a threat. There must be communication of an intent to commit suicide. The motive for making the threat is irrelevant. Suicidal ges- tures are counted whether or not they were serious or accompanied by a gen- uine wish to die. Acts of self-harm include wrist cutting, deliberately breaking glass with one's body, burning oneself, headbanging, and other deliberate forms of self-injury of a nonsuicidal nature. 2 On several occasions engaged in suicidal threats, gestures, or acts of self-harm. 1 Once or twice engaged in suicidal threats, gestures, or acts of self-harm. 0 Denied. 198 Interview schedule *60. 0 1 2 ? 0 1 2 A low threshold for discharge of aggression,including violence Dissocial: 4 (partial) Have you ever hit or physically abused anyone in your family? If yes: How many times? Tell me about it Have you ever hit anyone (else) or been in any (other) fights? If yes: How many times? Tell me about it. Do not count aggression or violence associated with legitimate efforts at defending oneself or others. Alcohol and drugs are not exonerating factors. 2 Several times has been involved in physical fights, assaults, or physical abuse of others. 1 Once or twice has been involved in physical fights, assaults, or physical abuse of others. 0 Denied, or required by job or to defend someone or oneself. 199 Interview schedule *61. 0 1 2 ? NA 0 1 2 Gross and persistent attitude of irresponsibility and disregard for social norms, rules, and obligations Dissocial: 2 Have you ever been unemployed? If yes: For how long? Why? Have you ever traveled from place to place without a job or definite purpose or clear idea of when the travel would end? If yes: Tell me about it. Have you ever defaulted on debts or failed to honor financial obligations? If yes: Tell me about it. Have you ever failed to provide financial support for other members of your family, when you were expected to do so? If yes: Tell me about it. Asked only of those with children. Have you ever failed to take adequate care of your children, or neglected their safety or physi- cal well-being? If yes: Tell me about it. If no: Has anyone ever accused you of any of those things? If yes: Why do you think they have? Asked only of males who have been separated or divorced. Have you ever failed to provide alimony (financial maintenance) or child support payments when you were expected to? If yes: Tell me about it. Are you inclined to lie if it serves your purpose? If yes: Give me some examples. If no: Have people accused you of lying or not telling the truth? If yes: Why do you think they have? 200 Interview schedule Have you ever used an alias? If yes: Why? Have you ever "conned" anyone? If yes: Tell me about it. Do you ever take unnecessary chances and risk harm or injury to yourself or others? If yes: Tell me about it. Have you ever driven a car while you were intoxicated with alcohol or drugs? If yes: How many times? Tell me about it. Have you ever been stopped by the police for speeding or reckless driving (when you were not intoxicated with alcohol or drugs)? If yes: How many times? Tell me about it. Have you ever been arrested? If yes: For what? Have you ever done anything (else) that you could have been arrested for, if you had been caught? If yes: What? This criterion is rated based on the application of clinical judgment to the replies to the questions. 2 Convincing evidence of gross and persistent behaviour indicative of irrespon- sibility and disregard for social norms, rules, and obligations. 1 Suggestive but less than convincing evidence of gross and persistent behav- iour indicative of irresponsibility and disregard for social norms, rules, and obligations. 0 No evidence or insufficient evidence for a positive rating. 201 Interview schedule 62. 0 1 2 ? NA Incapacity to experience guilt Dissocial: 5 (partial) If 60 and 61 are both scored 0f score 62-64 NA, and go to 65. How do you feel about (cite behaviour acknowledged in items 60 and 61)? Do you think you were justified in behaving that way? This criterion is rated based on a consideration of the history of dissocial behaviour viewed in conjunction with replies to questions regarding remorse or guilt. The examiner should cross-examine the subject closely to verify the authenticity of any alleged remorse or guilt. Regret because of the conse- quences for oneself, e.g.# imprisonment, is not remorse. The rating should ulti- mately be based on the application of clinical judgment to all of this information. 2 Convincing evidence that the subject lacks remorse or the capacity to experi- ence guilt. 1 Probable but less than convincing evidence that the subject lacks remorse or the capacity to experience guilt. 0 Appears to experience appropriate remorse or demonstrates the capacity to experience guilt. 202 Interview schedule 63. 0 1 2 ? NA 0 1 2 Marked proneness to blame others, or to offer plausible rationalizations for the behaviour that has brought the individual into conflict with society Dissocial: 6 Why do you think you behaved that way? Be sure to confront subject with all areas and examples of dissocial behaviour. The criterion is rated based on a consideration of the history of dissocial behaviour viewed in conjunction with the explanations of the behaviour offered by the subject. The examiner should cross-examine and confront the subject when necessary, to determine the validity of any attempts to blame others, or the plausibility of explanations for the behaviour. The rating is ulti- mately based on the application of clinical judgment to all of this information. 2 Convincing evidence that the subject is prone to blame others or to offer rationalizations for the dissocial behaviour. 1 Probable but less than convincing evidence that the subject is prone to blame others or to offer rationalizations for the dissocial behaviour. 0 Appears not to blame others or to offer rationalizations for the dissocial behaviour. 203 Interview schedule 64. 0 1 2 ? NA 0 1 2 Incapacity to profit from adverse experience, particularly punishment Dissocial: 5 (partial) The criterion is rated based on the application of clinical judgment to all of the information obtained in the interview that is relevant to the subject's his- tory of dissocial behaviour. 2 Convincing evidence that the subject is unable to profit from experience, par- ticularly punishment. 1 Probable but less than convincing evidence that the subject is unable to profit from experience, particularly punishment. 0 Appears to profit from experience, particularly punishment. 204 Interview schedule Rate the following criteria at the conclusion of the interview. Assign a score of 2 when the behaviour was present and obviously clinically significant. Score 1 if it was present but of uncertain clinical signifi- cance. 65. 0 1 2 ? 0 1 2 Excessive pedantry and adherence to social conventions Anankastic: 6 Rate ostentatious displays of learning and excessive formality in relating to interviewer. 66. 0 1 2 ? 0 1 2 Marked insensitivity to prevailing social norms and conventions; disregard for such norms and conventions is unintentional Schizoid: 9 Rate such phenomena as unkempt appearance, bizarre dress, unusual man- nerisms, and talking to oneself. When in doubt about the possible role of depression or intentionally rebellious or nonconformist behaviour, do not score 2. 67. 0 1 2 ? 0 1 2 Display of emotional coldness, detachment, or flattened affectivity Schizoid: 2 Rate unchanging facial expression, monotonous or unvarying vocal inflection, lack of expressive gestures, maintenance of a rigid, unchanging posture, poor eye contact, lack of apparent interest in examiner, failure to smile when almost everyone would. When in doubt about the presence or significance of these phenomena, including the possible role of psychotropic medications or depression, do not score 2. 205 IPDE ICD-10 module answer sheet Last Name First Name Middle 1. Date Subject Informant Subject Informant 1. 0 1 2 ? NA 0 1 2 35. 0 1 2 ? 0 ' 2 2. 0 1 2 ? 0 1 2 36. 0 1 2 ? 0 ' 2 3. 0 1 2 ? 0 1 2 37. 0 2 ? 0 ' 2 4. 0 1 2 ? 0 1 2 38. 0 2 ? 0 'I 2 5. 0 ' 2 ? 0 1 2 39. 0 2 ? 0 'I 2 6. 0 ' 2 ? 0 1 2 40. 0 2 7 0 I 2 7. 0 ' 2 ? 0 1 2 41. 0 2 7 0 I 2 8. 0 '1 2 ? 0 1 2 42. 0 41 2 7 0 I 2 9. 0 '1 2 ? 0 1 2 43. 0 1 2

7 0 1 2 10. 0 1 2 ? 0 1 2 44. 0 1 2 7 0 1 2 11. 0 1 2 ? 0 1 2 45. 0 1 2 7 0 1 2 12. 0 1 2 ? 0 1 2 46. 0 1 2 7 0 1 2 13. 0 1 2 ? 0 1 2 47. 0 1 2 7 0 1 2 14. 0 1 2 ? 0 1 2 48. 0 1 2 7 0 1 2 15. 0 1 2 ? 0 1 2 49. 0 1 2 7 0 1 2 16. 0 1 2 ? 0 1 2 50. 0 1 2 7 0 1 2 17. 0 1 2 ? 0 1 2 51. 0 1 2 7 0 1 2 18. 0 1 2 ? 0 1 2 52. 0 1 2 7> 0 1 2 19. 0 1 2 ? 0 1 2 53. 0 •1 2 7> 0 1 2 20. 0 1 2 ? 0 1 2 54. 0 1 2 :> 0 1 2 21. 0 1 2 ? NA 0 1 2 55. 0 •1 2 "> NA 0 1 2 22. 0 1 2 ? 0 1 2 56. 0 1 2 "> 0 1 2 23. 0 1 2 ? 0 1 2 57. 0 1 2 "> 0 1 2 24. 0 1 2 ? 0 1 2 58. 0 1 2 "> 0 1 2 25. 0 1 2 ? 0 1 2 59. 0 1 2 "> 0 1 2 26. 0 1 2 ? 0 1 2 60. 0 1 2 " 0 1 2 27. 0 1 2 ? 0 1 2 61. 0 •1 2 "> NA 0 1 2 28. 0 1 2 ? 0 1 2 62. 0 1 2 '> NA 0 1 2 29. 0 1 2 ? 0 1 2 63. 0 1 2 •> NA 0 1 2 30. 0 1 2 ? 0 1 2 64. 0 1 2 "> NA 0 1 2 31. 0 1 2 ? 0 1 2 65. 0 1 2 ' 0 1 2 32. 0 1 2 ? NA 0 1 2 66. 0 1 2 " 0 1 2 33. 0 1 2 ? NA 0 1 2 67. 0 1 2 ' 0 1 2 34. 0 1 2 ? 0 1 2 206 IPDEICD-10 module handscoring algorithms and summary scoresheet Directions Transcribe the scores from the IPDE interview schedule or answer sheet to the scoresheet as follows: 1. Follow the item sequence on the scoresheet not the interview. 2. If there is a score based on informants always transcribe it instead of the score recorded during the interview. Identify an informant score on the scoresheets by placing it in []. 3. If you used the optional X and X notation for recording past personality disor- ders, transcribe all such scores as 0 regardless of the actual score recorded on the interview schedule or answer sheet. 4. Enter scores of 0,?, NA, and circled scores of 1 and 2 in the first column (<25)# and underlined scores of 1 and 2 in the second column (> 25). 5. Begin by transcribing the scores for F60.0 Paranoid. Then follow the instruc- tions on the scoresheets. 207 Handscoring algorithms and summary scoresheet F60.0 Paranoid Criteria Items Onset <25 >25 (1) Excessive sensitivity to setbacks and rebuffs 38 (2) Tendency to bear grudges persistently 34 (3) Suspiciousness and tendency to distort 35 (4) Combative, tenacious sense of personal rights 31 (5) Suspiciousness regarding sexual fidelity 55 (6) Self-important self-referential attitude 36 (7) Preoccupation with conspiratorial explanations 57 Diagnosis: Definite Probable Negative Number of Criteria Met Dimensional Score Number of Criteria Based on Informant(s) 1. Count the number of scores in [ ]# and enter the total after Number of Criteria Based on Informant(s). 2. If there is no positive score (1 or 2) in column 1, enter 0 after Number of Criteria Met and Dimensional Score, check Diagnosis Negative, and go to next disorder, F60.1 Schizoid. 3. Add the scores in columns 1 and 2, and enter the sum after Dimensional Score. 4. If there is no score of 2 in column 1, enter 0 after Number of Criteria Met, check Diagnosis Negative, and go to next disorder, F60.1 Schizoid. 5. Count the number of 2s in columns 1 and 2, and enter the number after Number of Criteria Met. 6. If the number of criteria met is less than 3, check Diagnosis Negative, and go to next disorder, F60.1 Schizoid. 7. If the number of criteria met > 4, check Diagnosis Definite, and go to next dis- order, F60.1 Schizoid. 8. Check Diagnosis Probable, and go to next disorder, F60.1 Schizoid. 208 Handscoring algorithms and summary scoresheet F60.1 Schizoid Criteria Items Onset <25 >25 (1) Few, if any, activities provide pleasure 42 (2) Emotional coldness or flattened affectivity 67 (3) Limited capacity to express tender feelings and anger * (4) Appearance of indifference to praise or criticism 37 (5) Little interest in sexual experiences with another 53 (6) Constance choice of solitary activities 22 (7) Preoccupation with fantasy and introspection 18 (8) No desire for or possession of close friends 19 (9) Insensitivity to social norms and conventions 66 Diagnosis: Definite Probable Negative Number of Criteria Met Dimensional Score Number of Criteria Based on Informant(s) 1. Count the number of scores in [ ], and enter the total after Number of Criteria Based on Informant(s). 2. If there is no positive score (1 or 2) in column 1, enter 0 after Number of Criteria Met and Dimensional Score, check Diagnosis Negative, and go to next disorder, F60.2 Dissocial. 3. Add the scores in columns 1 and 2, and enter the sum after Dimensional Score. 4. If there is no score of 2 in column 1, enter 0 after Number of Criteria Met, check Diagnosis Negative, and go to next disorder, F60.2 Dissocial. 5. Count the number of 2s in columns 1 and 2, and enter the number after Number of Criteria Met. 6. If the number of criteria met is less than 3, check Diagnosis Negative, and go to next disorder, F60.2 Dissocial. 7. If the number of criteria met > 4, check Diagnosis Definite, and go to next dis- order, F60.2 Dissocial. 8. Check Diagnosis Probable, and go to next disorder, F60.1 Dissocial. * 39+44=4, score 2 39=1,44=0, score 0 39+44=3, score 2 39=0,44=1, score 0 39=1,44=1, score 1 39=0,44=0, score 0 When combining the partial components of criterion (3), it is only necessary that one of the items occurs in the past 12 months and before age 25 years, for the score to be entered in the <25 column. 209 Handscoring algorithms and summary scoresheet F60.2 Dissocial Criteria Items Onset <25 >25 (1) Callous unconcern for feelings of others 29 (2) Irresponsibility and disregard for social norms 61 (3) Incapacity to maintain enduring relationships 20 (4) Low tolerance to frustration; aggressiveness * (5) No guilt and ability to profit from experience ** (6) Marked proneness to rationalize behaviour 63 Diagnosis: Definite Probable Negative Number of Criteria Met Dimensional Score Number of Criteria Based on Informant(s) 1. Count the number of scores in [ ], and enter the total after Number of Criteria Based on Informants). 2. If there is no positive score (1 or 2) in column 1, enter 0 after Number of Criteria Met and Dimensional Score, check Diagnosis Negative, and go to next disorder, F60.30 Emotionally Unstable, Impulsive Type. 3. Add the scores in columns 1 and 2, and enter the sum after Dimensional Score. 4. If there is no score of 2 in column 1, enter 0 after Number of Criteria Met, check Diagnosis Negative, and go to next disorder, F60.30 Emotionally Unstable, Impulsive Type. 5. Count the number of 2s in columns 1 and 2, and enter the number after Number of Criteria Met. 6. If the number of criteria met is less than 2, check Diagnosis Negative, and go to next disorder, F60.30 Emotionally Unstable, Impulsive Type. 7. If the number of criteria met > 3, check Diagnosis Definite, and go to next dis- order, F60.30 Emotionally Unstable, Impulsive Type. 8. Check Diagnosis Probable, and go to next disorder, F60.30 Emotionally Unstable, Impulsive Type. * 15+60=4, score 2 ** 62+64=4, score 2 15+60=3, score 1 62+64=3, score 1 15+60=2, score 1 62+64=2, score 1 15+60=1, score 0 62+64=1, score 0 15+60=0, score 0 62+64=0, score 0 When combining the partial components of criteria (4) and (5), it is only neces- sary that one item occurs in the past 12 months and before age 25 years, for the score to be entered in the <25 column. 210 Handscoring algorithms and summary scoresheet F60.30 Emtionally Unstable, Impulsive Type Criteria Items Onset <25 >25 (1) Acts unexpectedly 58 (2) Quarrelsome when thwarted or criticized 30 (3) Liability to outbursts of anger or violence 43 (4) Not persistent when no immediate reward 11 (5) Unstable and capricious mood 50 Diagnosis: Definite Probable Negative Number of Criteria Met Dimensional Score Number of Criteria Based on Informant(s) 1. Count the number of scores in [ ], and enter the total after Number of Criteria Based on Informant(s). 2. If there is no positive score (1 or 2) in column 1, enter 0 after Number of Criteria Met and Dimensional Score, check Diagnosis Negative, and go to next disorder, F60.31 Emotionally Unstable, Borderline type. 3. Add the scores in columns 1 and 2, and enter the sum after Dimensional Score. 4. If there is no score of 2 in column 1, enter 0 after Number of Criteria Met, check Diagnosis Negative, and go to next disorder, F60.31 Emotionally Unstable, Borderline type. 5. Count the number of 2s in columns 1 and 2, and enter the number after Number of Criteria Met 6. If item 30 is not scored 2, check Diagnosis Negative, and go to next disorder, F60.31 Emotionally Unstable, Borderline type. 7. If the number of criteria met is less than 2, check Diagnosis Negative, and go to next disorder, F60.31 Emotionally Unstable, Borderline Type. 8. If the number of criteria met > 3, check Diagnosis Definite, and go to next dis- order, F60.31 Emotionally Unstable, Borderline type. 9. Check Diagnosis Probable, and go to next disorder, F60.31 Emotionally Unstable, Borderline type. 211 Handscoring algorithms and summary scoresheet F60.31 Emotionally Unstable, Borderline Type Criteria Items Onset <25 >25 (1) Acts unexpectedly 58 (2) Quarrelsome when thwarted or criticized 30 (3) Liability to anger or violence 43 (4) Not persistent when no immediate reward 11 (5) Unstable and capricious mood 50 (6) Uncertainty about self-image, aims, etc * (7) Intense and unstable relationships 26 (8) Excessive efforts to avoid abandonment 48 (9) Recurrent threats or acts of self-harm 59 (10) Chronic feelings of emptiness 45 Diagnosis: Definite Probable Negative Number of Criteria Met Dimensional Score Number of Criteria Based on Informant(s) 1. Count the number of scores in [ ], and enter the total after Number of Criteria Based on Informant(s). 2. If there is no positive score (1 or 2) in column 1, enter 0 after Number of Criteria Met and Dimensional Score, check Diagnosis Negative, and go to next disorder, F60.4 Histrionic. 3. Add the scores in columns 1 and 2, and enter the sum after Dimensional Score. 4. If there is no score of 2 in column 1, enter 0 after Number of Criteria Met, check Diagnosis Negative, and go to next disorder, F60.4 Histrionic. 5. Count the number of 2s in columns 1 and 2, and enter the number after Number of Criteria Met. 6. If the number of criteria 1-5 met > 3 and the number of criteria 6-10 met > 2, check Diagnosis Definite, and go to next disorder, F60.4 Histrionic. 7. If the number of criteria 1-5 met is less than 2 and the number of criteria 6-10 met is less than 2, check Diagnosis Negative, and go to next disorder, F60.4 Histrionic. 8. Check Diagnosis Probable, and go to next disorder, F60.4 Histrionic. * 5, 6, 7, 25, 56 two or more scores of 2, score 2 one score of 2, score 1 no scores of 2, but sum > 3,

score 1 all others, score 0 When combining the partial components of criterion 6, it is only necessary that one item occurs in the past 12 months and before age 25 years, for the score to be entered in the <25 column. 212 Handscoring algorithms and summary scoresheet F60.4 Histrionic Criteria Items Onset <25 >25 (1) Self-dramatization# exaggerated emotional display 40 (2) Suggestibility, easily influenced 12 (3) Shallow and labile affectivity 49 (4) Seeks excitement and attention * (5) Inappropriate seductiveness in appearance or behaviour 54 (6) Over concern with physical attractiveness 17 Diagnosis: Definite Probable Negative Number of Criteria Met Dimensional Score Number of Criteria Based on Informant(s) 1. Count the number of scores in [ ]# and enter the total after Number of Criteria Based on Informants). 2. If there is no positive score (1 or 2) in column 1, enter 0 after Number of Criteria Met and Dimensional Score, check Diagnosis Negative, and go to next disorder, F60.5 Anankastic. 3. Add the scores in columns 1 and 2, and enter the sum after Dimensional Score. 4. If there is no score of 2 in column 1, enter 0 after Number of Criteria Met, check Diagnosis Negative, and go to next disorder, F60.5 Anankastic. 5. Count the number of 2s in columns 1 and 2, and enter the number after Number of Criteria Met 6. If the number of criteria met is less than 3, check Diagnosis Negative, and go to next disorder, F60.5 Anankastic. 7. If the number of criteria met > 4, check Diagnosis Definite, and go to next dis- order, F60.5 Anankastic. 8. Check Diagnosis Probable, and go to next disorder, F60.5 Anankastic. * 16+41=4, score 2 16+41=3, score 1 16+41=2, score 1 16+41=1, score 0 16+41=0, score 0 When combining the partial components of criterion (4), it is only necessary that one item occurs in the past 12 months and before age 25 years, for the score to be entered in the <25 column. 213 Handscoring algorithms and summary scoresheet F60.5 Anankastic Criteria Items Onset <25 >25 (1) Excessive doubt and caution 9 (2) Preoccupation with detail 3 (3) Perfectionism 2 (4) Excessive conscientiousness and scrupulousness 14 (5) Undue preoccupation with productivity 1 (6) Pedantry and conventionality 65 (7) Rigidity and stubbornness 28 (8) Insistence on doing things own way 27 Diagnosis: Definite Probable Negative Number of Criteria Met Dimensional Score Number of Criteria Based on Informant(s) 1. Count the number of scores in [ ] f and enter the total after Number of Criteria Based on Informants). 2. If there is no positive score (1 or 2) in column 1, enter 0 after Number of Criteria Met and Dimensional Score, check Diagnosis Negative, and go to next disorder, F60.6 Anxious. 3. Add the scores in columns 1 and 2, and enter the sum after Dimensional Score. 4. If there is no score of 2 in column 1, enter 0 after Number of Criteria Met, check Diagnosis Negative, and go to next disorder, F60.6 Anxious. 5. Count the number of 2s in columns 1 and 2, and enter the number after Number of Criteria Met. 6. If the number of criteria met is less than 3, check Diagnosis Negative, and go to next disorder, F60.6 Anxious. 7. If the number of criteria met > 4, check Diagnosis Definite, and go to next dis- order, F60.6 Anxious. 8. Check Diagnosis Probable, and go to next disorder, F60.6 Anxious. 214 Handscoring algorithms and summary scoresheet F60.6 Anxious [avoidant] Criteria Items Onset <25 >25 (1) Persistent, pervasive feelings of tension 52 (2) Feels socially inept and inferior 13 (3) Preoccupied with criticism or rejection 24 (4) Social avoidance if doesn't feel liked 23 (5) Need for security restricts lifestyle 51 (6) Social avoidance due to fear of rejection * Diagnosis: Definite Probable Negative Number of Criteria Met Dimensional Score Number of Criteria Based on Informant(s) 1. Count the number of scores in [ ], and enter the total after Number of Criteria Based on Informant(s). 2. If there is no positive score (1 or 2) in column 1, enter 0 after Number of Criteria Met and Dimensionai Score, check Diagnosis Negative, and go to next disorder, F60.7 Dependent. 3. Add the scores in columns 1 and 2, and enter the sum after Dimensional Score. 4. If there is no score of 2 in column 1, enter 0 after Number of Criteria Met, check Diagnosis Negative, and go to next disorder, F60.7 Dependent. 5. Count the number of 2s in columns 1 and 2, and enter the number after Number of Criteria Met 6. If the number of criteria met is less than 3, check Diagnosis Negative, and go to next disorder, F60.7 Dependent. 7. If the number of criteria met > 4, check Diagnosis Definite, and go to next dis- order, F60.7 Dependent. 8. Check Diagnosis Probable, and go to next disorder, F60.7 Dependent. * 4+21=4, score 2 4+21=3, score 1 4+21=2, score 1 4+21=1, score 0 4+21=0, score 0 When combining the partial components of criterion (6), it is only necessary that one item occurs in the past 12 months and before age 25 years, for the score to be entered in the <25 column. 215 Handscoring algorithms and summary scoresheet F60.7 Dependent Criteria Items Onset <25 >25 (1) Allowing others to make one's important decisions 10 (2) Subordinates own needs to those on whom dependent 33 (3) Unwilling to demand from those on whom dependent 32 (4) Uncomfortable or helpless when alone 46 (5) Fears abandonment 47 (6) Needs excessive advice and reassurance 8 Diagnosis: Definite Probable Negative Number of Criteria Met Dimensional Score Number of Criteria Based on Inf ormant(s) 1. Count the number of scores in [ ], and enter the total after Number of Criteria Based on Informant(s). 2. If there is no positive score (1 or 2) in column 1, enter 0 after Number of Criteria Met and Dimensional Score, check Diagnosis Negative, and to go next disorder, F60.9 Personality Disorder, Unspecified. 3. Add the scores in columns 1 and 2, and enter the sum after Dimensional Score. 4. If there is no score of 2 in column 1, enter 0 after Number of Criteria Met, check Diagnosis Negative, and go to next disorder, F60.9 Personality Disorder, Unspecified. 5. Count the number of 2s in columns 1 and 2, and enter the number after Number of Criteria Met 6. If the number of criteria met is less than 3, check Diagnosis Negative, and go to next disorder, F60.9 Personality Disorder, Unspecified. 7. If the number of criteria met > 4, check Diagnosis Definite, and either fill out the Summary Scoresheet, or go to the optional diagnoses. 8. Check Diagnosis Probable, and go to next disorder, F60.9 Personality Disorder, Unspecified. 216 Handscoring algorithms and summary scoresheet F60.9 Personality Disorder, Unspecified Diagnosis: Definite Probable Negative Number of Criteria Met Dimensional Score Number of Criteria Based on Informant(s) 1. If there is a Definite Diagnosis for any specific personality disorder, check Diagnosis Negative, and either fill out the Summary Scoresheet or go to the optional diagnoses. 2. Add the number of scores entered after Number of Criteria Based on Informant(s) on the scoresheets for the specific disorders, excluding Impulsive disorder, and enter the total after Number of Criteria Based on Informants). 3. Add the number of criteria entered after Number of Criteria Met on the score- sheets for the specific disorders, excluding Impulsive disorder, and enter the total after Number of Criteria Met. 4. If the number of criteria met is less than 9, check Diagnosis Negative, and either fill out the Summary Scoresheet, or go to the optional diagnoses. 5. If the number of criteria met > 10, check Diagnosis Definite, and either fill out the Summary Scoresheet, or go to the optional diagnoses. 6. Check Diagnosis Probable, and either fill out the Summary Scoresheet, or go to optional diagnoses. 217 Handscoring algorithms and summary scoresheet Optional Past Personality Disorders Follow these steps with each disorder (except Emotionally Unstable and Unspecified) with no current Definite diagnosis: 1. Transcribe all the 2 scores recorded on the interview schedule or answer sheet with the X or X notation, by placing an X or X through the corresponding number in the Items column of the scoresheet for the disorder. Do not enter the scores in either column 1 (onset <25) or column 2 (onset >25). 2. If there are no 2 scores with an X or X notation, enter 0 in Table 1 under Number Criteria Met, and go to next disorder. 3. If the number recorded next to Number of Criteria Met on the scoresheet is 0, and there is no 2 score with an X (not X) notation, enter 0 in Table 1 under Number Criteria Met, and go to next disorder. 4. Count the number of 2 scores with an X or X in the Items column of the score- sheet, add the number recorded next to Number of Criteria Met on the score- sheet, and enter the sum in Table 1 under Number Criteria Met. 5. If the sum is > than the number in parenthesis, check Diagnosis Definite, and go to next disorder. 6. If the sum is one less than the number in parenthesis, check Diagnosis Probable. 7. Go to next disorder. Past Emotionally Unstable Disorder, Impulsive Type 1. If there is a current Definite diagnosis of Impulsive, go to Past Borderline dis- order. 2. Transcribe all the 2 scores recorded on the interview schedule or answer sheet with the X or X notation by placing an X or X through the corresponding num- ber in the Items column of the Impulsive scoresheet. Do not enter the scores in either column 1 (onset <25) or column 2 (onset >25). 3. If there are no Impulsive 2 scores with an X or X notation, enter 0 in Table 1 under Number Criteria Met, and go to Past Borderline disorder. 4. If the number recorded next to Number of Criteria Met on the Impulsive score- sheet is 0, and there is no Impulsive 2 score with an X (not X) notation, enter 0 in Table 1 under Number Criteria Met, and go to Past Borderline disorder. 5. Count the number of 2 scores with an X or X in the Items column of the Impulsive scoresheet, add the number recorded next to Number of Criteria Met on the scoresheet, and enter the sum in Table 1 under Number Criteria Met. 6. If the sum is less than 2, go to Past Borderline disorder. 7. If item 30 is not scored 2 and has no X or X notation in the items column, go to Past Borderline disorder. 8. If the number of criteria met > 3, check Diagnosis Definite, and go to Past Borderline disorder. 9. Check Diagnosis Probable and go to Past Borderline disorder. 218 Handscoring algorithms and summary scoresheet Past Emotionally Unstable Disorder, Borderline Type 1. If there is a current Definite diagnosis of Borderline, either fill out the Summary Scoresheet, or go to Late Onset disorders. 2. Transcribe all the 2 scores recorded on the interview schedule or answer sheet with the X or X notation by placing an X or X through the corresponding num- ber in the Items column of the Borderline scoresheet. Do not enter the scores in either column 1 (onset <25) or column 2 (onset >25). 3. If there are no Borderline 2 scores with an X or X notation, enter 0 in Table 1 under Number Criteria Met, and go to Past Unspecified disorder. 4. If the number recorded next to Number of Criteria Met on the Borderline scoresheet is 0, and there is no Borderline 2 score with an X (not X) notation, enter 0 in Table 1 under Number Criteria Met, and go to Past Unspecified dis- order. 5. Count the number of 2 scores with an X or X notation in the Items column of the Borderline scoresheet, add the number recorded next to Number of Criteria Met on the scoresheet, and enter the sum in Table 1 under Number Criteria Met. 6. If the number of criteria 1 -5 met is less than 2 and the number of criteria 6-10 met is less than 2, go to

Past Unspecified disorder. 7. If the number of criteria 1-5 met >3 and the number of criteria 6-10 met >2, check Diagnosis Definite, and either fill out the Summary Scoresheet or go to Late Onset disorders. 8. Check Diagnosis Probable, and go to Past Unspecified disorder. Past Unspecified Disorder 1. If there is a Definite diagnosis (current or past) for any personality disorder, either fill out the Summary Scoresheet or go to Late Onset disorders. 2. Add the numbers in Table 1 under Number Criteria Met, excluding Impulsive disorder, and enter the sum next to Unspecified. 3. If the sum is less than 9, either fill out the Summary Scoresheet or go to Late Onset disorders. 4. If the sum >10, check Diagnosis Definite, and either fill out the Summary Scoresheet or go to Late Onset disorders. 5. Check Diagnosis Probable, and either fill out the Summary Scoresheet or go to Late Onset disorders. 219 Handscoring algorithms and summary scoresheet Table 1 Number Criteria Diagnosis Diagnosis Met Definite Probable F60.0 Paranoid (4) F60.1 Schizoid (4) F60.2 Dissocial (3) F60.30 Emotionally Unstable, Impulsive type F60.31 Emotionally Unstable, Borderline type F60.4 Histrionic (4) F60.5 Anankastic.(4) F60.6 Anxious (4) F60.7 Dependent .(4) F60.9 Unspecified 220 Handscoring algorithms and summary scoresheet Optional Late Onset Personality Disorders Follow these steps with each disorder (except Emotionally Unstable and Unspecified) with no Definite diagnosis (current or past) and no score of 2 in column 1 (onset<25) of the scoresheet for the disorder: 1. Count the number of 2 scores in column 2 (onset >25) of the scoresheet and enter the number in Table 2 under Number Criteria Met. 2. If the number of criteria met > the number in parenthesis, check Diagnosis Definite, and go to next disorder. 3. If the number of criteria met is one less than the number in parenthesis, check Diagnosis Probable. 4. Go to next disorder. Late Onset Emotionally Unstable Disorder, Impulsive Type 1. If there is a Definite diagnosis (current or past) of Impulsive, go to Late Onset Borderline disorder. 2. If there is a score of 2 in column 1 (onset <25) of the Impulsive scoresheet, go to Late Onset Borderline disorder. 3. If there is no score of 2 in column 2 (onset >25) of the Impulsive scoresheet, go to Late Onset Borderline disorder. 4. Count the number of 2 scores in column 2 (onset >25) of the Impulsive score- sheet, and enter the number in Table 2 under Number Criteria Met. 5. If item 30 is not scored 2 in either onset column (<25 or >25), go to Late Onset Borderline disorder. 6. If the number of criteria met is less than 2, go to Late Onset Borderline disor- der. 7. If the number of criteria met >3, check Diagnosis Definite, and go to Late Onset Borderline disorder. 8. Check Diagnosis Probable, and go to Late Onset Borderline disorder. Late Onset Emotionally Unstable Disorder, Borderline Type 1. If there is a Definite diagnosis (current or past) of Borderline, go to Late Onset Unspecified disorder. 2. If there is a score of 2 in column 1 (onset <25) of the Borderline scoresheet, go to Late Onset Unspecified disorder. 3. If there is no score of 2 in column 2 (onset >25) of the Borderline scoresheet, go to Late Onset Unspecified disorder. 4. Count the number of 2 scores in column 2 (onset >25) of the Borderline score- sheet, and enter the number in Table 2 under Number Criteria Met. 5. If the number of criteria 1-5 met is less than 2 and the number of criteria 6-10 met is less than 2, go to Late Onset Unspecified disorder. 6. If the number of criteria 1-5 met >3 and the number of criteria 6-10 met >2, check Diagnosis Definite, and fill out the Summary Scoresheet. 7. Check Diagnosis Probable, and go to Late Onset Unspecified Disorder. 221 Handscoring algorithms and summary scoresheet Late Onset Personality Disorder, Unspecified 1. If there is a Definite Diagnosis for any specific personality disorder (current or past), check Diagnosis Negative, and fill out the Summary Scoresheet. 2. Add the number of scores entered after Number of Criteria Based on Informant(s) on the scoresheets for the specific disorders, excluding Impulsive disorder, and enter the total after Number of Criteria Based on Informant(s). 3. Add the number of criteria entered after Number of Criteria Met on the score- sheets for the specific disorders, excluding Impulsive disorder, and enter the total after Number of Criteria Met. 4. If the number of criteria met is less than 9, check Diagnosis Negative, and fill out the Summary Scoresheet. 5. If the number of criteria met >10, check Diagnosis Definite, and fill out the Summary Scoresheet. 6. Check Diagnosis Probable, and fill out the Summary Scoresheet. Table 2 Number Criteria Diagnosis Diagnosis Met Definite Probable F60.0 Paranoid (4) F60.1 Schizoid (4) F60.2 Dissocial (3) F60.30 Emotionally Unstable, Impulsive type F60.31 Emotionally Unstable, Borderline type F60.4 Histrionic (4) F60.5 Anankastic.(4) F60.6 Anxious (4) F60.7 Dependent .(4) F60.9 Unspecified 222 IPDE ICD-10 module summary scoresheet Last Name First Name Middle Initial Sex: Aae: Marital Status: Education: Occupation: Examiner Date(s) Time Required for Interview Summary Number Dimensional 9 Confidence ICD-10 Disorder Criteria Met Score Definite Probable Negative Rating F60.0 Paranoid F60.1 Schizoid F60.2 Dissocial F60.30 Emotionally unstable Impulsive type F60.31 Emotionally unstable Borderline type F60.4 Histrionic F60.5 Anankastic F60.6 Anxious F60.7 Dependent F60.9 Unspecified For each disorder check one: Definite, Probable, or Negative. If using the optional scoring, indicate next to the check mark, when a Definite or Probable diagnosis is past, late onset, or past late onset. Rate your level of confidence (1=High, 2=Moderate, 3=Low) in the validity of every diagnostic decision, using your clinical judgment, the IPDE interview, and other information when available. Index agreeableness 3 Axis I disorders 7,19 Axis II disorders 7 conscientiousness 3 Diagnostic and Statistical Manual, The (DSM) 5,6-7 diagnostic interview for borderlines 11 diagnostic instruments 10-15 dimensions 84 DSM-III-R 88-90 DSM-III personality disorder 74 (table) epidemiology 18-37 psychiatric settings 29-37 frequency of occurrence, interrater reliability, stability 104-7 (table) antisocial 104-5 (table) avoidant 106 (table) borderline 105 histrionic 105 narcissistic 106 obsessive compulsive 106-7 (table) paranoid 104 (table) passive-aggressive 107 (table) sadistic 107 (table) schizoid 104 (table) schizotypal 104 self-defeating 107 (table) DSM-IV115 extraversion 5 ICD (International Classification of Disease) 5 ICD-10 74 (table), 88-90,118 frequency of occurrence, interrater reliability, stability 108-9 anankastic 109 anxious 109 dependent 109 dissocial 108 histrionic 109 impulsive 108 224 Index paranoid 108 schizoid 108 ICD-10 disorders exclusive of personality disorders 73 (table) frequecy of co-occurrence with IPDE 73 (table) item location 130-3 anankastic 132 anxious (avoidant) 132 dependent 132 dissocial 130-1 emotionally unstable 131 histrionic 131 paranoid 130 schizoid 130 unspecified 133 ICD-10 module answer sheet 205 ICD-10 module handscoring algorithms 206-21 ICD-10 module interview schedule 138-204 affects 175-94 impulse control 196-204 interpersonal relationships 157 reality testing 195 self 143-56 work 139-42 ICD-10 module screening questionnaire scoring 134-6 summary 137 ICD-10 module summary scoresheet 206-21 International Personality Disorder Examination (IPDE) 3,7, 8-9,43-56 abbreviating 127-8 adequacy 55 administration 121 applicability to personal culture 53^4- appropriate subjects 49,118 categories 84 centres participating in field trial 61-9 Bangalore 61-2 Delft 63 Leiden 63 London 6 3 ^ Luxembourg 64 Munich 64-5 Nairobi 65-6 New York/White Plains 66-7 Nottingham 67-8 Oslo 68 Tokyo 68-9 Vienna 69 clinical acceptability 84-6 clinical evaluation 60 dimensions 84 educational level of patients 72 (table) examiner qualification/training 120-1 field trial course 70 225 Index field trial results 70-8 field trial sites 59 (table) frequency of co-occurrence of DSM-III-R personaltiy disorders 75 (table) general impression 52-3 history 114 ICD-lOseelCD-lO interrater agreement 79-80 interrater agreement, temporal stability of IPDE DSM-III-R ICD-10 diagnoses 78 (table) interrater reliability 72-6,77 (table) interviewer's satisfaction 55-6 interviews 60 item sample 47 late onset diagnosis 117 limitations 49-50,118-20 personality disorder diagnoses 70-2 questions about administration 125-7 reliability 128 sampling 58-60,70,73 (table) exclusion criteria 58 inclusion criteria 59-60 scope 117-18 scoring conventions 122-5 age at onset 122 age at onset probes 122-3 duration 122,123 frequency 123 frequency probes 123 timeframe probes 122-3 scoring recording 124-5 computer 124-5 hand 125 optional 124 required 124 self-administered 10, 85 shortened interview, omitted sections 54-5 structure 116-17 temporal stability 72,76 (table), 77 (table), 80-3 training 60 translations 43,115 validity 55, 84-6,128 International Pilot Study of Personality Disorder (IPSPD) 3 kappa 76, 78 (table), 84, 89 LEAD standard 86 Millon Clinical Multiaxial Inventory (MCMI) 13-14 neuroticism 3 personality 3-7 basic descriptions 3 ^ 226 Index Personality Assessment Schedule (PAS) 12-13 Personality Diagnostic Questionnaire (PDQ) 14,19 personality disorders 3, 52 antisocial (dissocial) 25-8 borderline 24-5 categories 8 classification 5 (table) compulsive 23 (table) co-occurrence of mental disorders 87-8 dependent 23 (table) diagnosis see personality disorder diagnosis dimensions 8 epidemiology 18 frequency 87 histrionic 21 (table), 24 narcissistic 24 paranoid 20,21 (table) passive-aggressive 23 (table), 29 prevalence rates 21-2 (table) relation to normal personality 5-6 sadistic 87 schizoid 20, 21 (table) schizotypal 20-1, 21 (table) self-defeating 87 personality disorder diagnoses 92-103 Bangalore 92 (table) Geneva 93 (table) Leiden 94 (table) London 95 (table) Luxembourg 96 (table) Munich 97 (table) Nairobi 98 (table) New York 99 (table) Nottingham 100 (table) Oslo 101 (table) Tokyo 102 (table) Vienna 103 (table) Present State Examination (PSE) 19 psychiatric diagnoses, progress in validation 8-9 psychotism 5 Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-L) 19 self-administered tests 10, 85 Standardized Assessment of Personality (SAP) 13 state-trait problems 7-8 Structured Clinical Interview for DSM-III-R (SCID-II) 12,19 Structured Interview for DSM-III-R Personality Disorders (SIDP-R) 11 Structured Interview for Personality Disorder (SIPD) 19, 82 Temperament and Character Inventory (TCI) 15 Tridimensional Personality Questionnaire (TPQ) 14-15

Gideon M. Hirschfi eld ● E. Jenny Heathcote Editors Autoimmune Hepatitis A Guide for Practicing Clinicians Editors Gideon M. Hirschfi eld, MB, BChir, E. Jenny Heathcote, MD, FRCP, FRCP(C) MRCP, PhD Department of Medicine Department of Medicine Toronto Western Hospital Toronto Western Hospital, University University Health Network Health Network, University of Toronto University of Toronto Ontario, Canada Ontario, Canada Centre for Liver Research jenny.heathcote@utoronto.ca Institute of Biomedical Research University of Birmingham, UK gideon.hirschfi eld@uhn.on.ca ISBN 978-1-60761-568-2 e-ISBN 978-1-60761-569-9 DOI 10.1007/978-1-60761-569-9 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2011939088 © Springer Science+Business Media, LLC 2012 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identifi ed as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Humana Press is part of Springer Science+Business Media (www.springer.com) Preface Autoimmune hepatitis is a relatively rare chronic infl ammatory disease of the liver, which is seen in adults and children, women and men, and across the world. It remains somewhat of a curiosity given the lack of specifi c diagnostic tests. Nevertheless, a pattern of clinical and laboratory presentation, coupled with an absence of alternative etiologies, remains a reliable way for clinicians to identify patients with this disease. Untreated mortality is high from severe disease, but fortunately immunosuppression with steroids and azathioprine in particular is very effective, and the outcomes for patients are now excellent, given appropriate diagnosis and prompt treatment. Nevertheless, with the recognized side effects of treatment it remains important for clinicians to be confi dent in their diagnosis, and to have clear strategies for how they manage their patients over the long term. With this in mind we set out to write a clinically useful textbook on autoimmune hepatitis, which hopefully addresses the common concerns encountered in routine practice. We have collected expert opinion from North America and Europe, which jointly collates evidence and practice into one readily accessible volume. Dr. Vierling initiates with a stimulating discussion of the pathogenesis of disease, while Dr. Heathcote reviews patient presentation in the twenty-fi rst century, something that continues to evolve. The use of serology in the diagnosis of disease is then reviewed by Dr. Bogdanos, whose chapter helps clinicians appreciate the benefi ts and limitations of autoim- mune serology. Dr. Michael Manns and Dr. Arndt Vogel provide some biologic insights into mimics of disease, while very practical guidance from expert adult (Dr. Montano-Loza) and pediatric (Dr. Mieli-Vergani and Dr. Vergani) clinicians is presented. Given that there are nuances to care, further insights into strategies for treatment nonresponders is provided by Dr. Peters and Dr. Mileti. Dr. Neuberger gives the perspective of the Transplant Hepatologist, since patients, despite adequate treatment, may still need the life-saving benefi ts of transplantation, while Dr. Heneghan and Dr. Westbrook help clinicians with the issues raised for patients contemplating pregnancy. Finally, two important chapters conclude this book, the fi rst by Dr. Levy, addressing side effects, and the second by Dr. Boberg, who tackles the often confus- ing but important area of overlap syndromes. v vi Preface Readers will therefore see that in assembling this group of authors the editors have set out to provide the breadth of opinion and knowledge that exists on the present day management of autoimmune hepatitis. It remains our hope that this book therefore fi lls an important niche for those looking after patients with autoimmune hepatitis. Birmingham, UK Gideon M. Hirschfi eld Contents 1 Introduction . 1 Gideon M. Hirschfi eld 2 The Pathogenesis of Autoimmune Hepatitis . 3 John M. Vierling 3 Clinical Presentation . 51 E. Jenny Heathcote 4 Confi rmation of the Diagnosis: Interpreting the Serology . 67 Dimitrios P. Bogdanos 5 Mimics of Autoimmune Hepatitis: Drug Induced and Immune Mediated Liver Disease. 93 Arndt Vogel and Michael P. Manns 6 When and How to Treat the Adult Patient . 115 Aldo J. Montano-Loza 7 When and How to Treat the Pediatric Patient . 135 Giorgina Mieli-Vergani and Diego Vergani 8 Strategies for Treatment Nonresponders: Second-Line Therapies and Novel Approaches . 147 Elizabeth Mileti and Marion Peters 9 Liver Transplantation for Autoimmune Hepatitis . 159 James Neuberger 10 Autoimmune Hepatitis and Pregnancy . 177 Rachel H. Westbrook and Michael A. Heneghan 11 Treatment Side Effects and Associated Autoimmune Diseases . 197 Cynthia Levy vii viii Contents 12 Managing the Patient with Features of Overlapping Autoimmune Liver Disease . 217 Kirsten Muri Boberg 13 Autoimmune Hepatitis: A Look Toward the Future . 235 Gideon M. Hirschfi eld Index . 237 Contributors Kirsten Muri Boberg Oslo University Hospital , Rikshospitalet, Oslo , Norway Dimitrios P. Bogdanos Institute of Liver Studies, King’s College, London School of Medicine , London , UK E. Jenny Heathcote Department of Medicine , Toronto Western Hospital, University Health Network, University of Toronto, Ontario, Canada Michael A. Heneghan Institute of Liver Studies, King’s College Hospital, NHS Foundation Trust , London , UK Gideon M. Hirschfi eld Department of Medicine , Toronto Western Hospital, University Health Network, University of Toronto, Ontario, Canada Centre for Liver Research, Institute of Biomedical Research, University of Birmingham, UK Cynthia Levy Division of Hepatology , University of Miami School of Medicine , Miami , FL , USA Michael P. Manns Department of Gastroenterology, Hepatology, and Endocrinology , Hannover Medical School , Hannover , Lower Saxony , Germany Giorgina Mieli-Vergani Department of Liver Studies and Transplantation , King’s College Hospital , London , UK Elizabeth Mileti Department of Pediatrics , Hospital of the University of California, San Francisco , San Francisco , CA , USA Aldo J. Montano-Loza Department of Gastroenterology and Liver Unit , University of Alberta , Edmonton , AB , Canada James Neuberger Liver Unit , Queen Elizabeth Hospital , Birmingham , UK Marion G. Peters Department of Medicine , Hospital of the University of California, San Francisco , San Francisco , CA , USA ix x Contributors Diego Vergani Department of Liver Studies and Transplantation , King’s College Hospital , London , UK John M. Vierling Department of Medicine and Surgery , Baylor College of Medicine , Houston , TX , USA Arndt Vogel Department of Gastroenterology, Hepatology, and Endocrinology , Hannover Medical School , Hannover , Lower Saxony , Germany Rachel H. Westbrook Institute of Liver Studies, King’s College Hospital, NHS Foundation Trust , London , UK Chapter 1 Introduction Gideon M. Hirschfi eld Keywords Immune-mediated liver disease • Liver failure • Immunosuppressive therapy • Hyperglobulinemia Gastroenterologists and hepatologists are usually charged with looking after autoimmune hepatitis (AIH), but because of its relative rarity few develop suffi cient exposure to patients to become true experts. This textbook is an attempt to provide all clinicians with a ready source of information when faced with the challenge of diagnosing and managing patients with this immune-mediated liver disease. As a chronic and relapsing infl ammatory disease of the liver, it may equally present as innocent liver biochemical changes, as it can fulminant liver failure. Disease is seen at all ages, in men and women, and across the world. When presenting classically, patients have markedly elevated transaminases, raised globulins, and circulating autoantibodies. The original patient descriptions remain apt even if increasingly patients present earlier in the course of their disease, and noted a predominance of young women, with an insidious, but prolonged and systemic disease, characterized by fever, arthralgias, and amenorrhea. After exclusion of viral, metabolic, and toxic injury, liver biopsy is usually required to confi dently confi rm the diagnosis, particularly before committing patients to immunosuppressive therapy and its attendant risks. No histologic features are in fact unique to AIH, but a plasma cell-rich interface hepatitis is often described. Variations to the classic presentation are not that uncommon, and many things may mimic the disease, including notably drug injury and Wilson disease. Such classic descriptions additionally apply to severe disease, but a growing challenge G. M. Hirschfi eld (*) Department of Medicine, Toronto Western Hospital, University Health Network, University of Toronto, Ontario, Canada Centre for Liver Research, Institute of Biomedical Research, University of Birmingham, UK e-mail: gideon.hirschfi eld@uhn.on.ca G.M. Hirschfi eld and E.J. Heathcote (eds.), Autoimmune Hepatitis: A Guide for Practicing 1 Clinicians, Clinical Gastroenterology, DOI 10.1007/978-1-60761-569-9_1, © Springer Science+Business Media, LLC 2012 2 G.M. Hirschfi eld is faced by clinicians seeing patients at earlier stages of disease, often without symptoms, or when patients with what appears to be something as common as fatty liver, have “overlapping” features serologically, or histologically that raise the specter of AIH. It is in these scenarios where the various proposed disease scoring systems can be of help. Historically, hyperglobulinemia was recognized in patients with cirrhosis in the 1940s, and there were early descriptions of liver disease blamed on persistent infection that would fi t for AIH with subacute hepatic necrosis. AIH was really “born” as a disease, initially with the given names “chronic active hepatitis” or “lupoid hepatitis,” after the fi rst clear descriptions some 60 years ago by Waldenstrom (1950) and Kunkel (1951). The disease became understood as an autoimmune one, albeit with potentially toxic or infectious triggers, and the label “lupoid hepatitis” arose because patients tested positive for LE (lupus erythematous) cells. AIH appears to nestle quite literally between the other two classic autoimmune liver diseases, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), a refl ection most probably that interface hepatitis, one of the characteristic histologic features, is a common fi nal pathway in liver injury. Yet it remains a somewhat perplexing disease, which lacks a specifi c diagnostic test, and requires astute and careful patient, labo- ratory, and histologic evaluation. The steady improvement over time in understanding this disease (or more likely a group of diseases, that appear as one) mirrors the improved diagnostic tests now core to modern day hepatology – liver biopsy, serum autoantibodies, viral serology, and imaging. Treatment has revolutionized outcomes, but the early descriptions of patients should always remind clinicians of the untreated natural history of severe disease. In the controlled trial of steroids from the Royal Free, the placebo group suffered 15 deaths over 72 months, from a total of 27 patients. The response of patients to steroids therefore, and subsequently other immunosuppressants such as azathioprine, has changed the disease dramatically, and AIH is now one of the most treatment responsive diseases in hepatology. Treatment side effects are not to be forgotten, and therefore careful refl ection from the clinician is required before either starting, or indeed stopping, treatment. The exquisite response to immunosuppression intrigu- ingly contrasts with the immune mediated biliary diseases PBC and PSC. AIH will always be a relatively challenging disease because of its rarity, its varied presentation, the absence of a single diagnostic test, the many potential disease mimics, and the presence of long-term treatment side effects. To the general physician broad guidance is important in helping them care for patients, although perhaps to the frustration of some, every expert has an individualized approach to patient care. Our goal in putting together this short book was to provide a general overview of the clinical aspects that challenge our management of AIH today. We have sought to provide chapters from recognized experts that either alone or in sequence, provide the general reader with an improved understanding of the disease. Duplication is inevitable but repetition does not hurt the practicing clinician, and individuals may wish to read chapters in isolation of others. Our authors have tried to

emphasize the important practical issues faced daily. Collectively, the editors and authors hope readers derive long-lasting value from this small contribution to the fi eld. Chapter 2 The Pathogenesis of Autoimmune Hepatitis John M. Vierling Keywords Innate immunity • Adaptive immunity • Antibodies • Autoantibodies • Endotoxin • Infl ammasome • Cytokines • Chemokines • T cells • CD4 T cells • CD8 T cells • B cells • Macrophages • Kupffer cells • Stellate cell • Myofibroblast Abbreviations PAMPs Pathogen-associated molecular patterns PRRs Pattern recognition receptors TLRs Toll-like receptors NOD Nucleotide-binding oligomerization domain receptors DAMPs Damage-associated molecular patterns LPS Lipopolysaccharide NK Natural killer cells NKT Natural killer T cells DCs Dendritic cells mDCs Myeloid dendritic cells pDCs Plasmacytoid dendritic cells APCs Antigen-presenting cells Ig Immunoglobulin LSECs Liver sinusoidal endothelial cells J. M. Vierling (*) Baylor College of Medicine , 1709 Dryden, Suite 1500, Houston , TX , USA e-mail: vierling@bcm.tmc.edu G.M. Hirschfi eld and E.J. Heathcote (eds.), Autoimmune Hepatitis: A Guide for Practicing 3 Clinicians, Clinical Gastroenterology, DOI 10.1007/978-1-60761-569-9_2, © Springer Science+Business Media, LLC 2012 4 J.M. Vierling IL Interleukin TCRs T cell receptors CDR Complementarity determining region aa Amino acid CD Cluster of differentiation Th T helper cell Tr1 CD 4 T regulatory 1 cell Th3 CD4 Th3 regulatory cell CTLs Cytotoxic T lymphocytes Tregs Regulatory T cells IFN Interferon FcR Fc receptor FasL Fas ligand CTLA-4 Cytotoxic T lymphocyte antigen-4 AIRE1 Autoimmune regulator 1 gene CYP Cytochrome P450 UGTs UDP-glucuonosyltransferases HAV Hepatitis A virus HBV Hepatitis B virus HCV Hepatitis C virus HEV Hepatitis E virus EBV Epstein–Barr virus HSV Herpes simplex virus CMV Cytomegalovirus Introduction Autoimmune hepatitis (AIH) is a progressive necroinfl ammatory disease of the liver of unknown cause [ 1 ] . As indicated by its name, it is regarded as a putative autoim- mune disease on the basis of shared features with classical autoimmune diseases and non-autoimmune-mediated infl ammatory diseases (Table 2.1 ). AIH is characterized by a female predilection, genetic factors that infl uence susceptibility, resistance and disease progression, nonorgan and organ-specifi c autoantibodies, hypergam- maglobulinemia (and/or isolated elevation of IgG), lymphoplasmacytic portal and periportal infl ammation, and responsiveness to immunosuppressive therapy [ 1 ] . The histopathological hallmark of AIH is interface hepatitis, in which T cells, plasma cells, and macrophages within portal tract infi ltrates invade the periportal paren- chyma, destroy hepatocytes by causing apoptosis, and secrete cytokines that stimulate fi brogenesis [ 1, 2 ] . The pathogenesis of AIH involves dynamic interplay of genetics, environmen- tal exposures, the immune repertoire and dysfunction of immunoregulation (Fig. 2.1 ) [ 3– 5 ] . In the absence of a defi ned etiology, pathogenetic mechanism(s) 2 The Pathogenesis of Autoimmune Hepatitis 5 Table 2.1 Comparison of autoimmune hepatitis, classical autoimmune diseases, and immune- mediated infl ammatory diseases Immune-mediated Autoimmune infl ammatory Feature Autoimmune hepatitis diseases diseases Disease-specifi c Based on Yes No autoantigenic autoantibodies: epitopes possible type 1, defi nite type 2 T cell autoantigenic reactivities poorly defi ned Autoantibodies Yes, type 1 and 2 Defi nite Yes Autoantigen Yes for type 2 Yes No immunization Unclear for type 1 generates auto reactive T cells and/or autoanti bodies and disease in animal models Female predilection Yes Yes No Affl icts children Yes Yes Yes and adults Strong HLA Yes Yes Yes associations Non-HLA Yes Yes Yes genetic associations Environmental Yes Yes Yes factors Organ-specifi c Yes Yes Yes disease Associated Yes Yes Yes, more limited immunological diseases Immunopathology Autoreactive T Autoantibodies, T cells, activated cells, Ig autoreactive macrophages T cells Responsive to Yes Yes Yes immunosuppression Examples Not applicable SLE, MS, Rheumatoid myasthenia arthritis, gravis, Grave’s psoriasis, thyroiditis, ulcerative colitis, Type 1 DM Crohn’s disease Abbreviations: I g immunoglobulin, S LE systemic lupus erythematosus, M S multiple sclerosis, DM diabetes mellitus 6 J.M. Vierling Fig. 2.1 Interactive factors of genetics, immune repertoire, immune regulation, and environment involved in the pathogenesis of autoimmune hepatitis or a disease-specifi c diagnostic laboratory test, AIH has been classifi ed into two types on the basis of its autoantibody profi les [1 ]. Type 1 is associated with ANA and/or SMA, while type 2 is characterized by anti-liver-kidney-microsomal type 1 (anti-LKM1). An autoantibody specifi c for AIH, anti-SLA, is highly specifi c for AIH and is observed in a minority of patients with either type 1 and 2 AIH [1 , 3 ] . The Liver as an Organ of Immunity The liver is now recognized as a primary site of innate immunity and regulation of systemic adaptive immunity [6 – 9 ] . Moreover, the innate immune system plays a key role in hepatic infl ammation and fi brosis [ 10– 12 ] . The liver contains large numbers of activated Kupffer cells and immature myeloid DCs (mDCs) and plas- macytoid DCs (pDCs) [1 3 ] in addition to a complex repertoire of intrahepatic lymphocytes that vary in quantity, function, and phenotype from counterparts in other organs (Fig. 2 .2 ) [7 , 8, 14 ] . NK, NKT, and g d (gamma delta) T cells congregate in the liver in proportions far greater than found in blood. In addition, most comple- ment proteins, all acute phase reactant proteins, the majority of circulating growth factors and cytokines are produced in the liver. The normal liver must achieve a balance between a hyporeactivity to food anti- gens, intestinal microbial products, and xenobiotics, while remaining capable of robust responses to pathogens and tumors. Intestinal PAMPs in portal venous blood 2 The Pathogenesis of Autoimmune Hepatitis 7 Fig. 2.2 The Liver as a Lymphoid Organ . Abbreviations: L SEC liver sinusoidal endothelial cell, S C stellate cell, KC Kupffer cell, D C dendritic cell, NK natural killer cell, N KT natural killer T cell constitutively activate TLRs on Kupffer cells, Liver Sinusoidal Endothelial Cells (LSECs), hepatocytes, DCs, and stellate cells, while bacterial peptidoglycans acti- vate intracellular NOD proteins [7 , 8, 10 ] . The net effect of these stimuli in the normal liver is NFk B-mediated production of the immunosuppressant cytokine IL-10. While Kupffer cells are hyporesponsive to physiological levels of LPS in portal blood, increased quantities of PAMPs and/or DAMPs result in TLR-mediated Kupffer cell secretion of proinfl ammatory IL-1b (beta), IL-6, IL-12, IL-18, and TNF a (alpha), along with physiological concentrations of the immunosuppressant IL-10. In contrast, LSECs are invariantly hyporesponsive to normal or pathophysi- ological concentrations of LPS. Thus, Kupffer cell responses to injurious stimuli change the dynamic balance between immunosuppressive and immunostimulatory cytokines. Hepatic stellate cells (HSCs) located in the space of Disse are the pri- mary source of normal matrix proteins and, when activated, secrete collagen result- ing in hepatic fi brosis [ 12 ] . TLR-mediated signaling in nonimmune cells, such as hepatocytes and cholangiocytes, also results in production of proinfl ammatory cytokines and chemokines that may contribute to the pathogenesis of infl ammatory liver disease [1 0 ] . Finally, Kupffer cells, LSECs, hepatocytes, and HSCs can also function as antigen-presenting cells (APCs) for intrahepatic activation of T cells [7 ] . Their APC functions coordinate the interplay of innate and adaptive immunity, and the cytokine milieu infl uences the type and magnitude of the T cell responses, while the migration of antigen-activated hepatic DCs to lymph nodes serve to activate nonhepatic T cells in lymph nodes. These activated T cells subsequently circulate in the blood and enter the portal tracts by transendothelial migration through the portal veins [ 15 ] . 8 J.M. Vierling Pathogenesis of Autoimmune Hepatitis: Interplay of Susceptibility, Immune Responses, and Immunoregulation The pathogenesis of AIH remains incompletely understood and the subject of investigation in both human beings and animal models. Figure 2.1 illustrates key features of autoimmunity pertinent to the pathogenesis of AIH. It is now clear that the pathogen- esis involves the interplay between the innate and adaptive immune responses in the liver (compared in Table 2 .2 ), genetic susceptibility, environmental triggering events, robust T helper cell, T cytotoxic cell and B cell responses to hepatic autoantigens or molecular mimics that are unrestrained by appropriate T regulatory cell control, and an infl amed hepatic microenvironment conducive to progressive fi brosis. Greater detail about the immunology involved in these processes can be found in the Appendix. Genetic Factors in Pathogenesis Multiple genes have been implicated in AIH, including those conferring susceptibility or resistance and others related to progression [3 , 4 ] . The involvement of multiple genes indicates that AIH is a complex genetic disorder in which the actions of multiple genes interact to produce and regulate immune responses to environmental agents, such as viruses or drug metabolites or possibly xenobiotics. While the complex interplay of genetics has been associated with susceptibility, resistance, and severity, no single allele appears to be obligatory or suffi cient for AIH to develop. Further exploration using genome-wide association scans in patients with AIH will undoubtedly refi ne and expand our knowledge in the near future. HLA Class I, II, and III Molecules Class I HLA Neither susceptibility nor resistance to AIH is conferred by HLA class I molecules that present antigens to the TCR of CD8 CTLs [ 3, 4 ] . Thus, the participation CTLs as effector cells in AIH does not appear to be determined by a genetically restricted TCR repertoire with a propensity for autoreactivity. In contrast, susceptibility to AIH is conferred by class II HLA-DR3 (see details below), which exhibits strong linkage disequilibrium with class I HLA-A, HLA-Cw, and HLA-B molecules. The extended haplotype of this linkage is referred to as A1-B8-DR3-DQ2 and the linked alleles are HLA A *0101-Cw*0701-B*0801-DRB1*0301-DQA1*0501-DQB1*0201 [ 3, 4 ] . Because of this linkage, HLA-DR3 patients preferentially have common class I HLA alleles, which could infl uence CTL effector function. Class I MICA or MICB genes also encode highly polymorphic ligands expressed by cells damaged 2 The Pathogenesis of Autoimmune Hepatitis 9 Table 2.2 Comparison of innate and adaptive immunity and role of the liver as an immunological organ Innate immunity Adaptive immunity Distinctive features Onset Rapid due to preformed Delayed due to requirement for antigen receptors for pathogens, activation, clonal proliferation, and endogenous molecules maturation of effector cell functions Specifi city PAMPs, DAMPs, reactive Epitopes of peptide antigens recognized oxygen species, activated by T cell receptors or B cell complement proteins, immunoglobulins apoptotic bodies Genetics Restricted, germline-encoded Complex with T cell receptors and antigen-binding domains of immunoglobulins produced by somatic recombination of gene segments Diversity Limited, evolutionarily Virtually infi nite conserved Memory None Memory T and B cell responses capable of amnestic reactivation Self-tolerance Discrimination of pathogens Positive and negative selection of T cell and endogenous DAMPs, receptor and B cell immunoglobulin rather than autoantigens to have restricted capacity to react with autoantigens Components Physical barriers Skin, mucosal epithelia, Intraepithelial lymphocytes of intestine antimicrobial proteins Cells Dendritic cells, monocytes, Professional antigen-presenting cells, macrophages (Kupffer a / b T cells, g / d T cells, natural and cells), neutrophils, NK inducible Treg cells, B cells cells, NKT cells Proteins C’ proteins, IFNa , b , g , IgM, IgG, IgA, IgE antibodies cytokines, chemokines Role of Liver as an Yes. Dendritic cells, Kupffer Yes. Antigen presentation by Immunological cells, neutrophils, NK hepatocytes, stellate cells, Kupffer Organ cells, NKT cells cells, LSEC. PD-L1/2 inhibition of IFNa , b , g , balance between activated CD8 T cells, site of CD proinfl ammatory and T cell elimination immunosuppressive chemokines Abbreviations: PAMPs pathogen-associated molecular patterns, D AMPs damage-associated molecular patterns, IFN interferon, NK natural killer, LSEC liver sinusoidal endothelial cell, PD-L1/2 programmed death ligands 1 and 2 by stress, infection, or neoplasia [1 6, 17 ] . When killer receptor NKG2D on NK cells, NKT cells, macrophages, g / d T cells, and CD8 T cells bind to MICA and MICB they induce apoptosis of the target cell. MICA and MICB map between the class I HLA B and class III TNF loci. While not associated with classic AIH, MICA alleles are associated with primary sclerosing cholangitis, suggesting a potential role for MICA in the pathogenesis of the PSC-AIH overlap syndrome [1 8 ] . 10 J.M. Vierling Class II HLA In contrast, both susceptibility and resistance alleles for AIH have been detected among the HLA D RB1 alleles that encode the b (beta)-chains of the class II molecules

that present peptide antigens to the TCR repertoire of CD4 T cells [ 3, 4 ] . Allelic dif- ferences result in amino acid substitutions in key areas of the fl oor and wall of the class II HLA antigen-binding groove and so dictate which specifi c antigens can appropri- ately bind and align in the groove (Fig. 2 .3 ). Since immunogenetic variations in DRB1 genes dictate the antigenic peptides that can be presented to T cells, their associations with susceptibility and resistance strongly suggest that class II molecules encoded by DRB1 genes preferentially bind the antigens that incite a CD4 T cell response in AIH (Fig. 2 .3 , Table 2 .3 ). In addition, D RB1 alleles may also infl uence disease severity and the probability of a concurrent extrahepatic autoimmune disease. Professional APCs simultaneously express class I and II HLA molecules and costimulatory molecules CD80/86 (B7.1/B7.2) and CD40 required for the func- tional activation of T cells [1 9, 20 ] . Positive and negative costimulation is provided by professional APCs to induce and, subsequently, quench adaptive immune responses (Fig. 2 .4 ). Activation of naïve CD4 T helper (Th0) cells is a critical step in cellular immunity because it generates four distinct Ag-specifi c cells defi ned by their secretion of mutually exclusive combinations of cytokines (Fig. 2 .5 ) [ 21 ] . Fig. 2.3 Immunogenetics of autoimmune hepatitis: HLA class I, II, and III regions, locations of amino acid sequence variations in the DRb -chain associated with susceptibility and resistance alleles, and non-MHC gene associations 2 The Pathogenesis of Autoimmune Hepatitis 11 Table 2.3 HLA DRB1 alleles associated with autoimmune hepatitis susceptibility and resistance aa DR b 13 aa DRb 86 aa DRb 71 Geographic distribution Susceptibility alleles DRB1*0301 S V K N. America–Europe DRB1*0401 H G K N. America–Europe DRB1*0404 H G R Japan DRB1*0405 H G R Japan DRB1*1301 S V E S. America Resistance allele DRB1*1501 R V A Japan S. America N. America Europe DRB1*1302 – G – S. America Abbreviations: a a amino acid, N North, S South, S serine, V valine, K lysine, H histidine, G glycine, R arginine, E glutamic acid Fig. 2.4 Positive and Negative Costimulation of T Cell Activation . Abbreviations: C D4 Th0 naïve CD4 T cell, A PC antigen presenting cell Type I Autoimmune Hepatitis In North American and European Caucasians, susceptibility to type 1 AIH is associ- ated primarily with HLA-DR3 (encoded by D RBI*0301 ) and DR4 (encoded by DRB1*0401 ) [2 2, 23 ] . Both of these b chains share a hexameric LLEQKR (single letter aa code) sequence at positions DRb (beta)67–72 and have a lysine (K in the single letter aa code) at position 71 (Table 2.3 ). In this population, the presence of K at position DRb (beta)71 is required for the binding and presentation of the 12 J.M. Vierling Fig. 2.5 Activation of naïve CD4 T cells resulting in differentiation into distinct subsets . The immunopathology of AIH indicates a predominance of CD4 Th1 effects, shown by the width of the arrows. Abbreviations: P AMPs pathogen-associated molecular patterns, M AC activated macrophage, NKT natural killer T cell, APC antigen presenting cell, TCR T cell receptor for antigen, Th0 naïve CD4 T helper cell, T h1 CD4 T helper 1 cell, Th2 CD4 T helper 2 cell, T h17 CD4 T helper 17 cell, T r1 CD4 T regulatory 1 cell, T h3 CD4 T helper 3 cell, I L interleukin, I FN interferon; T NF tumor necrosis factor, T GF b transforming growth factor b (beta) peptide antigen activating CD4 T cells and initiating AIH. D RBI*0301 is in strong linkage disequilibrium with D RB3*0101 , which also encodes K at position DR b (beta)71. Thus, patients with D RBI*0301 most often have two DRB alleles per haplotype with DRb (beta)71, which has been hypothesized to explain the greater disease severity observed in these patients based on a greater activation of their immune responses [2 4 ] . In contrast, D RB1*0401 is in strong linkage disequilib- rium with D RB4*0103 , which encodes arginine (R) at DRb 71. In comparison with patients with DRBI*0301 + DRB3*0101 , the single DRb (beta)71 allele in DRB1*0401 patients has been cited as an explanation for a lesser disease severity. In addition, the expression of both K and R at position DRb (beta)71 in patients with DRB1*0401 and D RB4*0103 might increase the diversity of peptide antigens presented. This possibility may explain the higher frequency of concurrent extra- hepatic autoimmune diseases in this haplotype. In Japan, Mexico, and China, the DRB1 alleles DRB1*0405 and DRB1*0404 are linked to susceptibility (reviewed in [ 4 ] ). Both alleles share the LLEQ-R motif with DRB1*0301 and D RB1*0401 but have arginine (R), rather than lysine (K) at posi- tion DR b (beta)71. Since both K and R are positively charged, the immunogenic peptide antigens binding and aligning at position DRb (beta)71 have been inferred to be negatively charged amino acids, such as aspartic acid (D) and conversely, class II molecules without a positive charge at position DRb (beta)71 should be unable to 2 The Pathogenesis of Autoimmune Hepatitis 13 present the antigens capable of inducing AIH. The fact that D RB1*1501 confers resistance to developing type 1 AIH in white North Americans and Europeans supports this hypothesis [2 2, 23 ] . This allele encodes alanine (A) instead of lysine (K) at DRb (beta)71, which has a neutral, rather than positive charge. In addition, DRB1*1501 also alters the extended hexameric motif by encoding isoleucine (I) for leucine (L) at DR b( beta)67. A recent Japanese genome-wide scan identifi ed 9 markers of susceptibility and 17 markers of resistance to AIH, in patients with and without HLA DR4 [2 5 ] . None were associated with disease severity. The association of D RB1*1301 with AIH in Argentine children and Brazilians argues against the unifying hypothesis that positively charged arginine (R) or lysine (K) at DRb (beta)71 is required for class II molecules to bind and present the peptide autoantigens involved in AIH [2 6, 27 ] . Specifi cally, D RB1*1301 encodes a ILEDER motif at positions DR b 67-72 with the negatively charged glutamic acid (E), aspartic acid (D), and glutamic acid (E) at positions DR b (beta)69, 70, and 71. Thus, peptide antigens presented by D RB1*1301 class II molecules must be distinctly different than those presented by class II HLA encoded by D RBI*03 01, DRBI*040 1, or DRBI*1301 , and appears to be associated with protracted hepatitis A virus (HAV) infections [ 28 ] . A meta-analysis of studies in Latin America reported that HLA DQ2 and D R52 were also susceptibility loci, while HLA DR5 and DQ3 were protective loci for AIH [2 9 ] . Specifi cally, the susceptibility alleles were DQB1*02, DQB1*0603, DRB1*0405, and DRB1*1301, while the protective alleles were DQB1*0301 and DRB1*1302. Table 2 .3 shows that susceptibility and protection are conferred by valine versus glycine in the DRb (beta)-86 position, respectively. The binding of peptide antigens to the antigen-binding grooves of class II HLA molecules involves attachment of several regions of the antigen, designated P1, P4, P6, P7, and P9 [3 0 ] . The crystalline structure of a D RB1*0401 molecule containing a bound peptide antigen indicates the peptide antigen should contain a negatively charged aspartic acid (D) or glutamic acid (Q) at position P4 to optimize the inter- action with the positively charged aa at DRB71 [ 31 ] . Since the hypervariable region 3 (HVR3) in the class II HLA molecule determines whether it can accom- modate a negatively charged antigenic aa at position P4, the HSVR3 may play an important role in the induction of AIH. It is equally important to recognize that class II HLA molecules encoded by alleles other than those with a statistically sig- nifi cant association with susceptibility might also express similarly charged amino acids at P4 and DRB71, resulting in the capacity to present autoantigen [ 24, 32 ] . This could explain the occurrence of AIH in patients lacking known HLA D RB1 alleles for susceptibility. Type 2 Autoimmune Hepatitis Susceptibility to type 2 AIH is associated with HLA-DR7 (D RB1*07 01) in Germany, Britain, and Brazil, while in Spain it is associated with DR3 (D RB1*0301 ) (reviewed in [4 ] ). This paradox may be explained by the fact that both D RB1* 0701 and 14 J.M. Vierling DRB1*0301 share strong linkage disequilibrium with D QB1*0201 , which may be the unifying immunogenetic determinant of susceptibility, while the contribution of DR7 may be related more to disease severity and progression [3 3, 34 ] . Class III HLA The class III region of the HLA region encodes C¢ 2, C ¢4 , TNFa (alpha)/ b (beta), and heat shock proteins. Homozygosity for the C¢ 4 null allele (C4AQ0) is associated with several autoimmune diseases, but its contribution to AIH is minor [ 35 ] . TNF a (alpha) is one of the principal proinfl ammatory cytokines and its genetic polymorphisms have been associated with AIH [3 6, 37 ] . TNFa (alpha) production after stimulation of peripheral blood leukocytes with endotoxin varies up to tenfold among normal people. The T NFA*2 allele commonly found in white northern Europeans is in linkage dysequilibrium with D RB1*03 alleles. Some studies indicate an association between overproduction of TNFa (alpha) and HLA-DR3, while others do not. However, combined expression of proinfl ammatory type cytokines (IL-2, IFN g (gamma) and TNFa (alpha) and type 2 cytokines (IL-4, -5, -6, -8, -10, and -13) is more commonly associated with the extended A1-B8-DR3-DQ2 haplotype and HLA-DR3 than is a pure type 2 cytokine profi le. Studies of TNFa (alpha) microsatellite, single nucleotide polymorphisms (SNPs) at position −308 have shown that substitution of adenine for guanine results in constitutive and induc- ible expression of proinfl ammatory TNFa (alpha). In North American and European patients with type 1 AIH, this SNP correlated signifi cantly with younger age, DRB1*0301, and inferior response to steroid immunosuppression [3 7 ] ; however, no correlation was observed in Japan [2 5 ] . Non-HLA Genes SNPs in non-HLA genes have also been implicated in the pathogenesis and/or progression of AIH. These genes encode CTLA-4, Fas, vitamin D receptor, and the autoimmune regulator 1 transcription factor. CTLA-4 CTLA-4 (CD152) is an inhibitory costimulatory molecule induced by activation of T cells to downregulate the activated T cell response by competitively binding to CD80/86 (B7.1/B7.2) on the APC surface with a 20-fold greater affi nity than the binding of the activating costimulatory molecule CD28 [3 8, 39 ] . Substitution of adenine for guanine at position 49 is strongly associated with autoimmunity, most 2 The Pathogenesis of Autoimmune Hepatitis 15 likely refl ecting inferior ability to downregulate T cell responses to autoantigens and their mimics [3 9 ] . The frequencies of the CTLA-4 genotypes vary signifi cantly between North American patients with type 1 AIH and healthy persons [ 40 ] , but these difference are absent in Brazilians [4 1 ] . Cytokines The functional roles of SNPs in proinfl ammatory cytokines (e.g., IL-1b (beta), IL-6, IFN g (gamma)), immunosuppressive cytokines (e.g., IL-4, IL-10, TGFb (beta)), chemokines, and pattern recognition receptors are under investigation in a variety of diseases. Although they have not been systematically studied, polymorphisms have been identifi ed in AIH for the promoter genes of IL-1, IL-6, and IL-10 [4 2 ] . Fas As noted earlier, binding of FasL (CD178) on CD8 CTLs to target cells expressing Fas (CD95) initiates target cell apoptosis. The Fas gene exhibits multiple SNPs, four of which have been associated with susceptibility for AIH in Japanese [4 3 ] . In white North American and European patients, substitution of adenine for guanine at position −670 in the T NFRSF6 has been associated with earlier onset of cirrhosis, and the adenosine–adenosine or adenosine–guanine genotypes more commonly have cirrhosis than the guanine–guanine genotype [4 4 ] . Vitamin D Receptor A SNP in the vitamin D receptor gene has been reported to be signifi cantly more common in patients with AIH than normal controls [4 5, 46 ] . It is now clear that vitamin

D and its receptor play important roles in regulation of the immune responses, and that vitamin D defi ciency is associated with autoimmunity [4 7, 48 ] . Further studies are required to defi ne its potential contribution to the pathogenesis of AIH. Autoimmune Regulator 1 A pproximately 20% of pediatric patients with Autoimmune Polyendocrinopathy- Candidiasis-Ectodermal Dystrophy (APECED) syndrome develop a hepatitis resem- bling type 2 AIH [4 9– 51 ] . The syndrome is an autosomal recessive disorder resulting from homozygous mutations in the Autoimmune Regulator 1 (A IRE1 ) gene. The AIRE1 gene is expressed in thymic medullary cells and encodes a transcription factor. Studies of AIRE1− /− knockout mice indicate that the AIRE1 16 J.M. Vierling gene prevents organ-specifi c autoimmunity by promoting expression of peripheral autoantigens in the thymus needed to delete autoreactive T cells. As a result, patients with APECED syndrome have a variety of autoimmune disorders, most commonly hypoparathyroidism and adrenal failure. However, spontaneous mutations in AIRE1 have been reported in three children with severe type 2 AIH and extrahepatic auto- immune disease and four children with type 1 AIH and positive family histories for autoimmunity [5 1 ] . The potential contributions of AIRE1 mutations or polymorphisms to the pathogenesis of classical AIH require further study. Gender AIH predominates in females with a female to male ratio of 4:1 [1 ] . Thus, female sex may facilitate, but not fully explain the pathogenesis of AIH. X-linked genetic abnormalities of immune function are generally devastating syndromes, unrelated to autoimmunity [ 5, 52 ] . The fact that the female to male ratio is the same for pedi- atric and adult patients with AIH and that the disease may manifest after menopause argues against estrogen being the primary risk factor [5 3 ] . Other hormones, including prolactin, growth hormone, progesterone, and testosterone may, along with estrogen, play roles in the greater immunological reactivity observed in women compared to men. The unique female experience of pregnancy may also facilitate induction or exacerbation of autoimmunity [5 4, 55 ] . Studies of fetal microchimerism indicate that it may jeopardize maintenance of self-tolerance; however, there is no evidence for its involvement in the pathogenesis of AIH. Overall, the heightened cellular and humoral responses characteristic of women suggest that female sex results in a heightened initiation response and a reduced immunoregulatory response to autoantigens in AIH. Environmental Factors in Pathogenesis Throughout life, exposures to pathogens, drugs, and xenobiotics are involved in the generation of individually unique immune repertoires, including natural and inducible Tregs [5 6 ] . The strong associations between the HLA-DR-DQ alleles responsible for the binding and alignment of antigens presented to CD4 T cells indicate that AIH is induced by the presentation of a restricted number of antigens by class II HLA molecules [3 , 4 ] . Indeed, analysis of the TCRs expressed by intrahepatic T cells in AIH shows oligoclonality, which indicates T cell activation by only a small number of antigens [ 57 ] . Viral infections and drugs or xenobiotic exposures are primary candidates for the triggering events in AIH, either through molecular mimicry or by presentation of hepatic autoantigens concentrated in apoptotic bodies [ 58 ] . 2 The Pathogenesis of Autoimmune Hepatitis 17 Viral Infections Multiple lines of evidence suggest that hepatic viral infections may trigger autoimmune reactions, including AIH in immunologically susceptible hosts. For example, sensitive techniques have identifi ed ANA and SMA in up to 50% of patients infected with HBV or HCV [5 9, 60 ] . Molecular mimicry between the proteins of both HBV and HCV and human nuclear and smooth muscle autoantigens has been identifi ed and may explain production of autoantibodies in these viral infections [ 59, 60 ] . In Europe, approximately 10% of pediatric HCV infections are associated with anti-LKM1 autoantibodies [6 1 ] . These fi ndings, however, do not imply that the pathogenetic mechanisms of host immune-mediated destruction of hepatocytes infected with HBV or HCV are directed against the autoantigens associated with AIH. It appears more likely that these autoantibodies are epiphenomena dependent on the balance between innate immune reactions and adaptive immune reactions at the time of viral infection. Since viral hepatitis caused by HAV, HBV, HCV, or HEV results in hepatocyte apoptosis, APC uptake of apoptotic blebs containing concentrated autoantigens of organelle membranes may explain the subsequent presentation of multiple hepatocyte autoantigens in class II HLA molecules [5 8 ] . In patients with the appropriate HLA DR or DQ alleles for presentation of autoantigens, TCR repertoire capable of concurrent recognition and ineffective immunoregulation, viral hepatitis could trigger AIH. In addition, other nonhepa- totrophic viruses, such as mumps, rubella, EBV, CMV, and HSV, cause a transient hepatitis that could also trigger AIH through the same apoptotic mechanism [6 2 ] . In support of this hypothesis, viral infections with HAV have been reported to trigger type 1 AIH [ 63 ] . HAV infection may play a disproportionate role in the triggering of AIH in Argentine children [ 28 ] and Brazilians. As noted earlier, susceptibility for AIH in these groups is associated with the HLA class II allele D RB1*1301 that has been asso- ciated with protracted HAV infection and development of AIH. Thus, it is possible that the DRB1*1301 allele may confer susceptibility for AIH by encoding class II molecules that are also able to present hepatic autoantigens from hepatocytes infected with HAV. In the case of type 2 AIH, molecular mimicry between viral antigens and anti- genic epitopes of CYP2D6 appears to be very likely. The immunodominant B cell epitope recognized by 93% of patients with type 2 AIH (CYP2D6 ) overlaps 193–212 with the epitopes recognized by 50% of HCV infected patients that have anti-LKM1 autoantibodies [6 4, 65 ] . These antibodies cross-react with homologous regions of both HCV peptides (NS5B HCV ) and CYP2D6 (CYP2D6 ). Similarly, 2985–2990 204–209 CMV (exon CMV ) contains epitopes cross-reactive with the immunodominant 130–135 CYP2D6 epitope [6 5 ] . Other antigenic epitopes of CYP2D6 (aa 254–271) also share homologies with HCV (E1 aa 310–324) and HSV1 (IE175 aa 156–175). Cross-reactive epitopes among CYP2D6, HCV, CMV, and HSV suggest that infections with HSV1, CMV, or self-limited HCV might generate cross-reactive anti- bodies capable of binding to CYP2D6. In the setting of transient liver injury in an 18 J.M. Vierling immunogenetically susceptible host, antibody-CYP2D6 complexes could be taken up by APCs, and in a milieu of favorable innate immune reactions, lead to a break in tolerance to both B cell and T cell epitopes of CYP2D6. Drugs and Xenobiotics as Triggers Drugs or xenobiotics may also serve as triggers for AIH [6 6 ] . In type 2 AIH, hepa- tocyte metabolism of drugs progresses through formation of metabolites conju- gated to CYP2D6. When immunogenetically susceptible individuals experience a conducive hepatic cytokine environment, these metabolites may be immunologi- cally recognized as haptens bound to carrier self-proteins such as CYP isoforms or UDP-glucuonosyltransferases (UGTs). Haptens alone cannot elicit an immune response, but when coupled to a protein carrier can trigger a response that includes cellular and/or humoral responses to the carrier protein portion of the complex. The duration of drug exposure and the number of epitopes recognized by a permissive TCR repertoire could then determine the magnitude of the T cell and B cell responses. Multiple medications, especially minocycline and nitrofurantoin, have been associated with type 1 AIH [6 7 ] . However, the role of xenobiotics in triggering type 1 AIH must remain speculative until autoantigenic T and B cell epitopes specifi c for type 1 AIH are identifi ed. Two alternative hypotheses of pathogenesis have been proposed: the danger hypothesis and the p-i-concept [ 68 ] . The danger hypothesis would require that the driving force in DILI resulting in AIH requires both drug metabolite modifi cation of self-proteins and generation of hepatocyte injury or stress, which constitutes the danger signal. The p-i-concept, which is defi ned as the “direct pharmacological interaction of drugs with immune receptors,” involves direct binding of a drug to the variable regions of TCRs and MHC molecules that trigger TCR signaling and costimulation of the HLA molecules without APCs. Immune Reactions and Regulation in Pathogenesis Histopathology The histopathology of AIH strongly indicates that the principal effector mechanisms of injury are cell mediated (Fig. 2 .7 ). Primary evidence for this comes from immu- nopathological studies of liver biopsies [2 , 69, 70 ] . These show that AIH is character- ized by dense infl ammatory infi ltrates of the portal tracts, composed of lymphocytes, variable numbers of plasma cells, activated macrophages and rare eosinophils, and an interface hepatitis caused by invasion of periportal hepatocytes with lymphocytes, macrophages, and small numbers of plasma cells [7 1 ] (Fig. 2 .6) . Immunohistochemical analyses have shown that the T cells have a (alpha)/b ( beta) TCRs and that CD4 T 2 The Pathogenesis of Autoimmune Hepatitis 19 Fig. 2.6 Immunopathology of portal infl ammation and interface hepatitis in autoimmune hepatitis . Portal infl ammatory infi ltrates differ in composition from the infl ammatory infi ltrates involved in periportal interface hepatitis cells predominate in portal tract infl ammatory infi ltrates, while CD8 CTLs are the major cell type infi ltrating periportal hepatocytes in areas of interface hepatitis [ 72 ] . As discussed earlier, the capacity of the portal tracts to serve as a lymphoid organ appears to facilitate localization of infl ammatory infi ltrates in the portal tracts in AIH, as well as other autoimmune liver diseases and chronic infections with HBV and HCV [7 3 ] . Cellular Immunity Oligoclonal T Cells and Liver-Specifi c Autoantigens In AIH, CD4 and CD8 a ( apha)/ b (beta) T cells are hypothesized to have TCRs that react with a limited number of hepatic autoantigenic peptides that are capable of binding in a genetically restricted number of HLA class II and I molecules [ 3, 4 ] . A corollary of this hypothesis is that only a restricted number of TCRs would be able to recognize these autoantigens and that subsequent expansion of a restricted number of clones from these activated CD4 and CD8 T cells would be oligoclonal TCRs. Analyses of the variable (V) regions of TCRs in T cells infi ltrating the livers of patients with type 1 AIH support the hypothesis by proving that hepatic infl ammatory infi ltrates in AIH contain T cell clones with a restricted number of TCRs (reviewed in [ 57 ] ). In addition, common aa sequences in the complementarity-determining 20 J.M. Vierling region 3 (CDR3) of the TCRs were identifi ed in some, but not all patients. This directly supports the notion that type 1 AIH is mediated by a reaction against a restricted number of autoantigens. Since autoimmunity is most often initiated by the loss of tolerance to a single antigen that later expands to include additional autoantigens (a phenomenon called epitope determinant spreading), it is particu- larly important to assess TCR V b (beta) regions in patients with recent onset of type 1 AIH. Studies of such patients have confi rmed the expectation that hepatic TCR V b (beta) diversity is highly restricted compared to peripheral blood T cells [ 74 ] . In addition, TCR CDRs were identical for each patient, but differed among patients. Studies using PCR techniques have also confi rmed that oligoclonal T cells accu- mulate in the livers of patients with type 1 AIH [7 5 ] . Of note, nearly all T cells from single clones were CD8 CTLs, while both CD4 and CD8 T cells were typically detected in patients infected with HCV. Another factor in the oligoclonal expansion of liver-infi ltrating T cells in AIH is their prolonged survival due to defective apoptosis [ 76, 77 ] . Protection from apoptosis appeared to be due to overexpres- sion of antiapoptotic bcl-2, which was observed in CD4 T cells in both the blood and in portal infl ammatory infi ltrates [ 77 ] . Liver-infi ltrating CD8 T cells did not overexpress bcl-2 [ 78 ] . In type 2 AIH, the immunodominant B cell epitope is CYP2D6 , and addi- 193–212 tional minor epitopes have also been defi ned [ 66 ] .

It is likely that epitope determinant spreading leads to sequential recognition of the minor autoantigens over time [ 79 ] . The CD4 T cell epitope, CYP2D6 , overlaps with one of the B cell epitopes, 266–285 CYP2D6 [ 80 ] . This suggests that the B cell capture and presentation of anti- 257–269 genic peptides to CD4 T cells may augment autoreactivity by expanding the number of autoreactive T cell clones [8 1 ] . Autoantigenic epitopes CYP2D6 , CYP2D6 , 193–212 217–260 and CYP2D6 encompass those recognized by B cells and both CD4 and CD8 305–348 T cells [3 3, 65, 82 ] . The restricted number of immunodominant hepatic autoantigenic epitopes recog- nized in the earliest phase of AIH would be likely be presented by an immunogeneti- cally restricted number of HLA class I and II molecules on mDCs. Normally, mDCs take up antigen and migrate to lymph nodes where they present antigens to CD4 Th0 cells and cross-present antigens to naïve CD8 T cells. In the unique immunological environment of the liver, antigen presentation to CD4 Th0 and naïve CD8 T cells can also occur in the sinusoids with Kupffer cells, stellate cells, LSECs, or hepatocytes as APCs [7 ] . During the chronic phases of hepatic infl ammation it is likely that nonau- toreactive T cells would also be recruited into the infl ammatory infi ltrates [ 83, 84 ] . This is a plausible explanation for a failure to detect shared CDR3 motifs during later phases of AIH [7 4 ] . Moreover, it indicates the need for caution in interpreting the presence of CD8 T cells as evidence of antigen-specifi c CTLs. The presence of intense immunopathology in AIH and plasma cells within the portal and periportal infl ammatory infi ltrates provides circumstantial evidence for a dynamic balance of CD4 T cell mass composed of CD4 Th1 > Th2. While little is known about the role of Th17 T cells in AIH, tantalizing observations suggest that they could play important roles in pathogenesis [8 5, 86 ] . As noted earlier, CD4 2 The Pathogenesis of Autoimmune Hepatitis 21 Th17 cells are proinfl ammatory cells involved in several types of organ-specifi c autoimmunity . In human livers, Th17 cells have been observed in chronic graft- versus-host disease [8 7 ] and the peribiliary infi ltrates of primary biliary cirrhosis [ 86 ] . In contrast, Th17 cells selected against self-antigens in the thymus of mice spontaneously migrated to the liver and suppressed chemical-induced hepatitis by secreting IL-22 [8 8 ] . The role of Th17 cells in the pathogenesis of AIH is unknown but should be studied. Role of g (Gamma)/ d (Delta)T Cells Although the majority of liver infi ltrating T cells express the a (alpha)/ b (beta) TCR, the livers of patients with AIH contain larger proportions and absolute numbers of T cells with a g (gamma)/d (delta) TCR than observed in other autoimmune or non- autoimmune liver diseases [5 7, 89, 90 ] . g (gamma)/d (delta) T cell clones established from the liver biopsies of children with AIH exhibited increased non-HLA restricted cytotoxicity against a human hepatoma line, indicating a possible role in non-HLA restricted, non-antigen-specifi c hepatocytolysis [9 0 ] . Involvement of g d (gamma delta)T cells in the pathogenesis of the autoimmune disease, multiple sclerosis [9 1 ] suggests that they may also play a role in AIH. Role of Macrophages Activated macrophages are present in portal infi ltrates and at sites of interface hepa- titis [ 2, 69– 71 ] . In addition, Kupffer cells in the sinusoids are perpetually activated tissue macrophages [7 ] . Peripheral blood monocytes from children with AIH have an activated phenotype characterized by overproduction of TNFa (alpha) and IL-10 and overexpression of TLR4, the receptor for LPS [9 2 ] . The activation of mac- rophages in the liver is most likely driven by the proinfl ammatory cytokine milieu and exposure to bacterial cell wall products, such as LPS, in portal venous blood. Activated macrophages can mediate cytotoxic effects by cell contact or through TNF a -mediated apoptosis of target cells [9 3 ] . In addition, activated macrophages may also recruit infi ltrating Th17 cells [ 94 ] . Pivotal Role of Immunoregulation The activation of CD4 and CD8 T cells with appropriate positive co-stimulatory signals and antigen recognition by B cells results in a dynamic response of clonal proliferation, maturation, and development of effector functions (Fig. 2 .7 ). While normal immune responses are limited by negative costimulatory signals and natural Tregs, autoimmune diseases are characterized by failure of immunoregulation and perpetuation of immunopathology mediated by CD4 Th1 and Th2 cells, CD8 CTLs, activated macrophages, and autoantibodies. 22 J.M. Vierling Fig. 2.7 Generation of functional effector cells and antibodies by an immune response . The immunopathology of AIH indicates a predominance of CD4 Th1 effects and CD8 CTL activity along with activation of macrophages and plasma cells secreting IgG. Abbreviations: T h0 naïve CD4 T helper cell, Th1 CD4 T helper 1 cell, Th2 CD4 T helper 2 cell, Th17 CD4 T helper 17 cell, IL interleukin, C TL CD8 cytotoxic T lymphocyte, N K natural killer cell, M AC activated mac- rophage, B activated B cell secreting immunoglobulin, C ’ complement, A DCC antibody directed cellular cytotoxicity, I Cs immune complexes Treg Defi ciencies The hallmarks of autoimmunity are genetic susceptibility for reactions against autoan- tigens and failure of Tregs to maintain tolerance to autoantigens [ 5, 95 ] . Multiple observations indicate that the pathogenesis of AIH involves signifi cant impairment of the numbers of Tregs and their functions (Table 2 .4 ). At the time AIH is fi rst diag- nosed, both the quantity and function of natural Treg (CD4+CD25+FoxP3+) cells are defi cient [9 6, 97 ] . Successful treatment with corticosteroids and/or azathioprine partially restored the numerical and functional defi ciencies of natural Tregs [9 6, 97 ] . This observation strongly indicates that functional Treg defi ciency is produced, in part, by infl ammatory disease activity and the magnitude of deleterious effector cell functions. The mechanism(s) of restoration of Treg numbers and functions during immunosuppressive therapy are undefi ned. In children with either type 1 or type 2 AIH, the quantities of natural Tregs were signifi cantly inversely correlated with disease severity as well as with titers of anti-SLA and anti-LKM1 autoantibodies [ 97 ] . The inverse correlation with autoantibody titers has been interpreted as evidence of a pathogenetic role for autoantibodies (see below). Tregs isolated from children with AIH were also profoundly dysfunctional and unable to inhibit secretion of IFN g by CD4 or CD8 T cells [9 6, 97 ] . Thus, defi ciencies of natural Tregs facilitate 2 The Pathogenesis of Autoimmune Hepatitis 23 Table 2.4 Impaired immunoregulation in autoimmune hepatitis Type of Impairment Type 1 AIH Type 2 AIH Suppressor cell dysfunction [1 56 ] + ? Defective antigen-specifi c T cell suppression [1 57 ] + ? Decrease quantities and functions of CD4/CD25 + + Tregs [9 6, 97 ] Defective Treg control of CD4 and CD8 T cells [9 6, 97 ] + + Defective Treg promotion of regulatory cytokines [1 58 ] + ? Defective Treg control of monocytes [9 2 ] + ? pathological cellular and humoral immune responses in AIH. Even though treatment with immunosuppressive medications partially restored Treg functions, they never reached normal levels, suggesting that an underlying Treg defi ciency plays a permis- sive role in initiation of AIH. The numbers and functions of inducible Tregs have not been reported in AIH. Restoration of Treg Function While successful immunosuppressive therapy can increase the quantities and func- tions of natural Tregs in AIH, their restoration remains incomplete [9 6, 97 ] . Natural and/or inducible Tregs are attractive therapeutic candidates for control of AIH because they could control disease without a need for systemic immunosuppression. However, the proliferative capacity of natural Tregs is poor, and apoptosis limits the duration of their function. A recent study, however, proved that natural Tregs can be expanded ex vivo in healthy persons and patients with AIH [9 8 ] . Their proliferation was accompanied by increased FoxP3 expression and suppressor functions. In AIH, natural Tregs could also be generated de novo from a subset within a population of CD4+CD25− T cells [9 8 ] . The autoantigen specifi cities of these Tregs remain unknown but could be tested in type 2 AIH, in which the autoantigenic epitopes for CD4, CD8, and B cells are defi ned. Humoral Immunity Role of B Cells and Antibodies The dual functions of B cells are to produce antigen-specifi c antibodies and to serve as professional APCs capable of providing the costimulatory signals required for full T cell activation and receiving Th cytokines required for secretion of antibodies. In AIH, B cells receiving appropriate CD4 Th 1 and 2 cytokine stimulation, secrete increased amounts of IgG, resulting in an increased concentration of the IgG isotype and/or hypergammaglobulinemia, which are among the diagnostic criteria for AIH [1 ] . 24 J.M. Vierling The spectrum of autoantibodies has defi ned two types of AIH, and molecular studies with specifi c autoantigen epitopes [1 ] (see chapter by Bogdanos). Yet, the role of autoantibodies in the pathogenesis of hepatic injury and infl ammation remains unsettled [ 99 ] . One viewpoint is that autoantibodies are not involved in hepatocyte cytolysis [4 ] but may facilitate cellular immune reactions by forming immune complexes that can be phagocytosed, processed, and presented by APCs. In primary biliary cirrhosis, complexes of mitochondrial antigen and autoantibodies enhanced the capture of antigen and augmented cross-presentation by DCs to auto- reactive CD8 CTLs [8 1 ] . The contrary viewpoint invokes evidence that intracellular antigens have been detected on the surface membranes of hepatocytes that could be targets for autoantibody binding and hepatocyte cytolysis caused by ADCC and/or C ¢ -dependent mechanisms [3 ] . Regardless of a pathogenetic role for autoantibodies, classical AIH is associated with plasma cells in the portal and interface infi ltrates and increased secretion of IgG [1 ] . Persistence of plasma cells in the portal tracts predicts relapse after with- drawal of immunosuppression [ 100 ] . Since plasma cells are terminally differentiated B cells that secrete copious amounts of antibodies for only a few days [ 101 ] , their presence in portal and interface infl ammatory infi ltrates indicates that chemokines likely recruit and induce terminal differentiation of B cells [1 02 ] . However, portal infl ammatory infi ltrates containing plasma cells are found not only in AIH but also PBC [ 103 ] . However, plasma cells in the livers of patients with AIH predominantly contain IgG, while those from PBC livers contain IgM [1 03 ] . Neither the mecha- nisms responsible for hepatic plasma cell accumulation nor the antigen specifi cities of their antibodies have been defi ned. Autoantibodies and Type I AIH Both ANA and SMA (with or without f-actin specifi city) are non-organ, non-species, and non-disease-specifi c autoantibodies in type 1 AIH [ 99 ] . They serve as indicators of a genetic predisposition to autoimmunity but likely have no pathogenetic role. Autoantibodies reacting with ASGPR, a molecule expressed on the surface of hepa- tocytes, occur in 50–76% of patients with type 1 AIH (as well as in patients with PBC, PSC, or viral hepatitis) and in 85–88% of patients with active AIH disease [ 104 ] . Since the titer correlated inversely with disease activity, it can be used to monitor therapeutic responses [1 05 ] . From 65 to 92% of patients with type 1 AIH also have perinuclear antineutrophil cytoplasmic antibodies (pANCA); however, the neutrophil autoantigen(s) actually appear to be nuclear rather than cytoplas- mic [1 06 ]. Approximately, 10–30% of type 1 patients also have anti-SLA-LP autoantibodies targeting the UGA suppressor tRNA-associated antigenic protein (tRNAS er/Sec ) that was recently renamed SepSecS [1 07 ] . Anti-SLA autoantibodies are specifi c for the disease AIH and are found in patients with either type 1 or 2 AIH [ 99 ] . In the past, antibodies reactive with so-called Liver Specifi c Protein (LSP) were implicated in antibody-mediated pathogenesis [3

] . However, rather than being a specifi c protein, LSP contains an array of both liver specifi c (e.g., ASGPR and alcohol dehydrogenase [ADH]) and non-organ-specifi c antigens. 2 The Pathogenesis of Autoimmune Hepatitis 25 Indirect evidence has suggested that autoantibodies against autoantigens on surface of hepatocytes might cause hepatocytolysis, either through ADCC or C¢ - mediated mechanisms [1 08 ] . Evidence that hepatocytes isolated from AIH biopsies were coated with Ig provided circumstantial support [1 09 ] . The correlation between the titers of antibodies specifi c for the ASGPR and ADH and the biochemical and histological severity of type 1 AIH also suggested a potential pathogenetic role [ 108 ] . The more severe course of disease in patients with either type 1 or 2 AIH with anti-SLA autoantibodies has also been attributed to a role in pathogenesis [1 10 ] . However, it is also plausible that the correlation between severity and autoantibody titers refl ects dual consequences of pathogenetic infl ammation and cytokines, rather than their cause. To explore the role of autoantibodies in type 1 AIH requires identifi cation of type 1-specifi c B cell autoantigenic epitopes and studies of animals immunized with the autoantigen(s). Seven human hepatocyte-specifi c candidate antigens were recently identifi ed that reacted with antibodies in the sera of patients with type 1 AIH [1 11 ] . Further characterization of these atypical “autoantibodies” should be performed. Autoantibodies in Type 2 AIH In type 2 AIH, primary and secondary B cell epitopes have been identifi ed on the full-length CYP2D6 molecule (see above), and a potential for molecular mimicry with viral B cell epitopes has been defi ned [3 , 4 ] . Molecular modeling has also shown that the B cell epitopes are exposed on the surface of the intact, conforma- tional CYP2D6 molecule [ 112 ] . In contrast to evidence of expression of CYP2D6 on the surface membranes of isolated rat hepatocytes [1 13 ] , studies using immuno- electron microscopy and fl ow cytometry failed to detect CYP2D6 on the surface of human hepatocytes [1 14, 115 ] . Thus, no direct evidence exists for a pathogenetic role of anti-LKM1 antibodies in human hepatocyte cytolysis. As noted earlier, autoantibodies against “atypical autoantigens” in the plasma membranes of hepato- cytes in the sera of type 1 patients might also be present in type 2 disease. Role of Cytokines in Hepatic Fibrosis and Progression to Cirrhosis Activation of stellate cells in the periportal, pericellular space of Disse leads to progressive periportal fi brosis in sites of interface hepatitis containing apoptotic hepatocytes, infl ammatory effector cells, proinfl ammatory cytokines, LPS, and reactive oxygen species [1 2, 116 ] . Specifi cally, stellate cells are activated to become myofi broblasts by binding of their innate immune PRRs with apoptotic bodies, DAMPs, LPS, reactive oxygen species and the cytokines IL-10 and TGFb (beta) secreted by Kupffer cells, LSECs, and infi ltrating T cells. Myofi broblasts produce collagen, matrix metalloproteinases that alter and degrade matrix proteins and migrate in response to chemokines. Myofi broblasts also express a high density of 26 J.M. Vierling CD1d, indicating that they can activate NKT cell secretion of IFN g , IL-2, IL-4, TNF a (alpha), G-M-CSF, and chemokines. Proliferation of myofi broblasts is driven by platelet-derived growth factor. Thus, continued periportal infl ammation in the hepatic microenvironment creates a positive feedback loop of myofi broblast-mediated fi brosis and stimulation of proinfl ammatory cytokines results in bridging fi brosis between portal tracts or between portal tracts and central veins. It is likely that the microenvironment within the wave front of fi brosis is less immunosuppressant and more conducive to infl ammation than the adjacent hepatic parenchyma. This could explain the phenomenon of bridging fi brosis and, ultimately, its progression to cirrhosis. A Working Model of AIH Pathogenesis A working model of the immunopathogenesis of AIH can be constructed that explains the published observations regarding susceptibility, triggering events, auto- reactivity, failure of immunoregulation, perpetuation of CD4 Th1, CD8 CTL, and B effector cell responses to autoantigens and cytokine-mediated fi brogenesis required for progression to cirrhosis. This model emphasizes the critical importance of temporal relationships among these events. Genetic Susceptibility Since generation of peptide autoantigens for presentation by a restricted number of HLA class I and II molecules on APCs to a restricted repertoire of autoantigen-specifi c TCRs, immunogenetics involving HLA and non-HLA loci is a key requirement for AIH. Multiple other genetic infl uences, especially SNPs involved in innate immune responses, likely contribute to the probability of initiating an immune response against an autoantigen. Evolution of a Permissive Immune Repertoire While immunogenetics confers the HLA alleles necessary to recognize the putative autoantigen(s) in type 1 AIH and the CYP2D6 autoantigens recognized in type 2 AIH, the immune repertoire, including natural and inducible Tregs, determines whether presentation of autoantigenic peptides by HLA class I and II molecules results in activation of an immune response or anergy. Crucial components of the immune repertoire include (1) the number of functional autoreactive CD4 and CD8 T cells that escaped elimination during negative selection in the thymus; (2) the number of functional natural Tregs with the same autoantigen specifi cities as the autoreactive 2 The Pathogenesis of Autoimmune Hepatitis 27 CD4 and CD8 T cells; (3) the number of autoreactive B cells that escaped negative selection in the thymus; (4) the capacity for immunoregulatory expression of sup- pressive co-stimulatory CTLA-4 and PD-1; and (5) the susceptibility of activated CD4 and CD8 and Treg cells to apoptosis. Since age plays a crucial role in the cumu- lative generation of an immune repertoire, the status and reactivity of the repertoire most likely differs signifi cantly in childhood compared to adulthood. Environmental Triggers and Permissive Hepatic Microenvironment Hepatic viral infections or injurious exposures to xenobiotics or drugs are likely causes of hepatocellular stress, apoptosis, and/or necrosis that provide “danger signals” for initiation of innate and adaptive immune responses. However, the majority of adaptive immune responses in a normal liver are generated in a microenvironment of immunosuppressive IL-10, which biases T cells toward tolerance. Environmental triggers would be more conducive of AIH if they coincided with a period when the cytokine microenvironment favored CD4 Th1 and CD8 T cell activation. Since Kupffer cells respond to LPS and phagocytosed proteins and particles by secretion of proinfl ammatory cytokines IL-12, IL-18, and TNFa (alpha) and lesser amounts of immunosuppressive cytokine IL-10, their status is a likely determinant of whether a triggering event does or does not occur in a proinfl ammatory milieu. Production of INF g (gamma) by intrahepatic NK cells stimulated by hepatic cell injury and by acti- vation of CD4 T cells could help overcome the effects of IL-10 and promote further Kupffer cell secretion of IL-12 and IL-18 required for CD4 Th1 and CD8 T cell effector functions. Differentiated, hepatic-antigen specifi c CD4 and CD8 effector T cells activated by mDCs in regional lymph nodes would traffi c back to the portal tracts and provide positive feedback for a proinfl ammatory microenvironment. Presentation of Hepatocyte Autoantigens or Molecular Mimics Apoptotic bodies or blebs contain high concentrations of nuclear, organelle, and cytoplasmic autoantigens. Thus, receptor-mediated uptake of apoptotic bodies from hepatocytes by professional APCs would be expected to present hepatocyte-specifi c autoantigenic peptides in HLA class II molecules to CD4 Th0 cells. In addition, autoan- tigenic peptides would also be cross-presented in HLA class I molecules to naïve CD8 T cells. Alternatively, viral or xenobiotic triggers capable of causing suffi cient hepatocyte stress or injury to generate the necessary “danger signals” for an innate immune cellular and cytokine response might have aa sequences or a conforma- tional structure mimicking hepatic autoantigenic peptides. In this case, adaptive immune responses to the mimics would result in cross-reactions of effector CD4 Th and CD8 CTLs with autoantigens. 28 J.M. Vierling Activation of Autoreactive T Cells and B Cells While activation of autoreactive CD4 and CD8 T cells within the hepatic paren- chyma by Kupffer cells, LSECs, stellate cells, or hepatocytes could be short-lived and dysfunctional, the generation of autoreactive CD4 and CD8 T cells in regional lymph nodes by mDCs from the liver would be expected to result in traffi cking of differentiated, autoreactive effector T cells into the portal tracts. Following initia- tion of the immune response against autoantigens or mimics, epitope determinate spreading would result in activation of additional T cell clones by a restricted number of additional autoantigens. This would be fully consistent with the observation of both major and minor autoantigenic epitopes in CYP2D6 and the oligoclonality of TCRs observed in patients with AIH. The type and magnitude of the innate immune response to initial hepatocyte injury (Event 3) and the positive feedback of cytokines from lymph-node activated CD4 and CD8 T cells would dictate the dynamic balance among CD4 Th1, Th2, Th17, or inducible regulatory Tr1 and Th3 lineages toward CD4 Th1. This is most consistent with the intense immunopathology of AIH. Persistence of a population of CD4 Th2 cells would be predicted as a source of cytokines and chemokines for recruitment of B cells into the portal infl ammatory infi ltrates and for their terminal differentiation into plasma cells. CD4 Th1 predominance would also favor a robust CD8 CTL response against hepatocytes expressing autoantigens in class I HLA molecules. Finally, cytokines produced by CD4 Th1 and Th2 cells would provide continued help for secretion of IgG by activated B and plasma cells. Production of Autoantibodies Necrosis of hepatocytes would provide whole autoantigenic peptides to be bound and internalized by B cells bearing autoantigenic epitope-specifi c immunoglobulin receptors that had escaped negative selection. These B cells would then process and present autoantigenic peptide epitopes to CD4 and CD8 T cells. Presentation of peptide autoantigens to CD4 Th1 and Th2 cells would result in their activation and secretion of cytokines that promote clonal B cell expansion and secretion of autoantibodies. Failure of Immunoregulation The fact that AIH is a chronic disease without spontaneous remissions is testimony to the failure of cumulative immunoregulatory mechanisms. The inability to prevent activation of T and B cells to hepatic autoantigens or molecular mimics suggests that patients developing AIH have at least two primary immunoregulatory defects: (1) defi cient quantities of functional thymic-derived natural Tregs with hepatic autoantigen specifi city; (2) failure of thymic negative selection to eliminate B cells 2 The Pathogenesis of Autoimmune Hepatitis 29 expressing receptors for hepatic autoantigen epitopes. Perpetuation of chronic infl ammation in AIH may also involve defective expression of or response to suppres- sive costimulatory CTLA-4 and PD-1 and resistance of effector T and B cells. Intensifi cation of Immunopathology: Bias Toward CD4 Th1, CD8 CTL, and Activated Effector Mechanisms The immunopathology observed in liver biopsies is indicative of a proinfl ammatory milieu containing IL-1 b, IL-6, IFN g (gamma), and TNFa (alpha) favoring a predom- inance of CD4 Th1 and, possibly, TH17 cells over CD4 Th2 cells. Skewing of CD4 Th1 would promote CD8 CTL effector cells, which is consistent with the composi- tion of the portal tract infl ammatory infi ltrates and the enrichment of CD8 CTLs in the infi ltrates at sites of interface hepatitis. Although a role for Th17 cells has not been established in AIH, they could contribute to the intensity of infl ammation and perpetuation of dysfunctional immunoregulation. A proinfl ammatory milieu would also explain the increased numbers of activated macrophages observed in the portal tracts and periportal infi ltrates. Variability in the magnitude of the CD4 Th1 versus CD4 Th2 cytokine balance could explain why the numbers of plasma cells observed in the portal tracts or periportal infi ltrates are so variable. Regulation of Hepatocyte Cytolysis Since all hepatocytes theoretically could express autoantigens recognized by auto- reactive CD8 CTLs, global hepatocyte cytolysis could be life threatening. Indeed, this is the case in the minority of patients who present with acute liver failure due to AIH. The majority of patients, however, have a more indolent disease, which may refl ect the net effects of Kupffer cell-mediated immunosuppression and apoptosis of liver-infi ltrating CD4 and CD8 T cells. Kupffer cells immunosuppress activated CD4 and CD8 T cells by secreting IL-10 and expressing PD-L1/2 (CD274/273) to provide an inhibitory signal to T cells expressing PD-1 (CD27). Kupffer

cells also trap T cells and induce apoptosis by either the FasL (CD178) or TRAIL mecha- nisms. Concurrent loss of natural Tregs and PD-1 inhibitory signaling resulted in lethal intensifi cation of AIH in mice, indicating the importance of control of effector T cells in the hepatic microenvironment [1 17 ] . Evolution of Effector Cells and Cytokines Despite defi cits in immunoregulation and failure of appropriate apoptotic elimination of autoreactive CD4 T cells and CD8 CTLs in AIH, it is very likely that chronically infl amed livers undergo changes in the composition and proportion of effector cell populations and cytokines. These changes likely involve relative increases in 30 J.M. Vierling antigen-nonspecifi c effector cells and decreases in CD4 and CD8 antigen-specifi c T cells. g d (gamma delta)T effector cells have been cloned from liver-infi ltrating infl ammatory cells and likely induce apoptosis of hepatocytes exhibiting stress molecules, while providing a perpetual source of proinfl ammatory IFNg (gamma) and TNFa (alpha) to subvert the normal immunosuppressive microenvironment of the hepatic sinusoids. In a microenvironment of proinfl ammatory IFNg (gamma) and TNF a (alpha) and activated myofi broblasts expressing CD1d, it is also plausible that NKT cells become activated in the periportal sinusoids and secrete additional IFNg , IL-2, IL-4, TNF a( alpha), G-M-CSF, and chemokines. These in turn would facilitate recruitment and retention of CD8 CTLs without hepatic autoantigen specifi city. This speculation is supported by an experimental model in which CD8 CTLs with specifi city for nonhepatic antigens migrated to the liver and caused apoptosis of hepatocytes by engaging their Fas (CD95) molecules [1 18 ] . Positive Feedback for Fibrogenesis Resulting in Accelerated Bridging Fibrosis and Progression to Cirrhosis Infl ammatory T cells and activated macrophages within the wave front of fi brosis extending from the portal tracts into the hepatic parenchyma would be protected from inhibition provided by immunosuppressant IL-10 and inhibitory PD-L1/2 (CD274/273) and result in intensifi ed infl ammation and hepatocyte cytolysis. This in turn would provide the requisite proinfl ammatory cytokines, reactive oxygen species, and DAMPs to accelerate myofi broblast formation and replication. A positive feedback loop of myofi broblast-mediated fi brosis would result in rapid extension of bridges of fi brosis between portal tracts and between portal tracts and central veins. Continued bisection of the hepatic architecture by bridging fi brosis would ultimately trap hepatocytes and stimulate nodular regeneration characteristic of cirrhosis. Chapter Summary The liver is an immune organ, whose microenvironment infl uences both innate and adaptive immune responses. Genetic factors, both immune and nonim- mune, infl uence susceptibility and resistance to AIH. Environmental triggering events appear to initiate AIH in susceptible persons. Susceptibility requires an immune repertoire capable of responding to hepatic autoantigens or molecular mimics. Failure of immunoregulatory control of the autoimmune response, espe- cially by T regulatory cells, leads to the development of cytotoxic effector mechanisms and chronic hepatic infl ammation. Hepatic necroinfl ammation and cytokines induce progressive fi brosis leading to cirrhosis in the absence of immunosuppressive therapy. 2 The Pathogenesis of Autoimmune Hepatitis 31 Key Messages 1. The liver is an immune organ, whose microenvironment infl uences both innate and adaptive immune responses. 2. Genetic factors, both immune and nonimmune, infl uence susceptibility and resistance to AIH. 3. Environmental triggering events appear to initiate AIH in susceptible persons. 4. Susceptibility requires an immune repertoire capable of responding to hepatic autoantigens or molecular mimics. 5. Failure of immunoregulatory control of the autoimmune response, espe- cially by T regulatory cells, leads to the development of cytotoxic effector mechanisms and chronic hepatic infl ammation. 6. Hepatic necroinfl ammation and cytokines induce progressive fi brosis leading to cirrhosis in the absence of immunosuppressive therapy. Appendix Immune Responses: A Primer The following emphasizes general principles pertinent to understanding not only the immunopathogenesis of AIH but also the pathogenesis of other necroinfl amma- tory hepatobiliary diseases [1 0, 11 ] . The functions of the human immune response are to (1) recognize, (2) respond, (3) regulate, and (4) remember. These functions require coordinated responses from both limbs of the immune response: the innate or immediate response limb and the adaptive or antigen-specifi c response of T cells and immunoglobulins (Ig) produced by B cells [1 19– 121 ] . Innate Immunity This primal limb immediately reacts against microbial pathogens and cells altered by stress, infection, or neoplasia. Innate immunity is mediated by neutrophils, macrophages, dendritic cells (DCs), natural killer (NK), natural killer T (NKT) cells, antimicrobial proteins, and complement proteins [ 119, 122, 123 ] . The innate immune system plays a critical role in the regulation of adaptive immunity and in the development of autoimmune diseases [ 124, 125 ] . Importantly, the liver is now recognized to be a preeminent innate immune organ that also plays unique roles in adaptive immunity due to its cellular composition and microenvironment [ 6– 10, 14 ] . 32 J.M. Vierling Pattern Recognition Receptors (PRRs) and Pathogen-Associated Molecular Patterns (PAMPs) Macrophages, including Kupffer cells in the liver sinusoids, and DCs constitutively express evolutionarily conserved PRRs for equally conserved microbial PAMPs. Examples of microbial PAMPs include (1) lipopolysaccharide (LPS, or endotoxin) from cell walls of all Gram-negative bacteria; (2) lipotechoic acid from cell walls of all Gram-positive bacteria; (3) peptidoglycans, essential components of cell walls of all bacteria; (4) unmethylated, bacterial CpG dinucleotides; and (5) single- and double-stranded viral RNA. A family of PRRs, called “toll-like receptors” (TLRs), react with extracellular and intracellular microbial PAMPs [1 0 ] . Cytoplasmic PRRs called nucleotide-binding oligomerization domain (NOD) proteins react with intra- cellular bacterial PAMPs [1 26 ] . Other PRRs act as receptors for C¢ -coated pathogens or cells [1 23 ] , and still others mediate phagocytosis of apoptotic bodies [5 8 ] . Damage-Associated Molecular Patterns Damage-Associated Molecular Patterns (DAMPs) are nonmicrobial, endogenous molecules released from injured or necrotic (as opposed to apoptotic) cells that also engage and signal through TLRs, as well as intracellular infl ammasomes [1 27, 128 ] . Infl ammasomes are cytoplasmic multiprotein complexes that act as molecular scaf- folds for the activation of caspases required to generate proinfl ammatory cytokines IL-1 b and IL-18 [1 29 ] . Whereas initiation of immune responses have been attributed historically to microbes, it is now clear that DAMPs and infl ammasomes activated by endogenous stimuli play seminal roles in coordination of initial immune responses to “danger signals” and genetic predisposition to autoinfl ammatory diseases [1 30 ] . The infl ammatory response to DAMPs is central to the Danger Signal Hypothesis of adaptive immune responses, which postulates that immune reactions are triggered by APCs responding to a microenvironment of cell injury comprising reactive oxygen species, stress proteins, and necrotic debris [1 31 ] . These mechanisms are involved in the persistence of necroinfl ammation in sterile environments. Proinfl ammatory and Immunosuppressive Cytokines Activation of DCs and macrophages (including Kupffer cells) by PAMPs and/or DAMPs stimulates phagocytosis and generates production of chemokines and proinfl ammatory cytokines IL-1b ( beta), IL-6, IL-12, IL-18 and TNFa and immuno- suppressant cytokine IL-10 [1 1, 93, 119 ] . Bacterial peptidoglycans that enter the cell cytoplasm react with NOD proteins to induce immunosuppressive IL-10, which antagonizes both the production and function of proinfl ammatory cytokines [ 10 ] . Thus, a dynamic balance between production of cytokines promoting and inhibiting infl ammation ensues. 2 The Pathogenesis of Autoimmune Hepatitis 33 NK Cells NK cells lack T cell receptors (TCRs) for antigen recognition but have killer inhibitory receptors that prevent them from killing normal cells [1 6 ] . The major histocompat- ibility complex (MHC in all mammals and designated as HLA in human beings) class I genes, designated MICA or MICB (MHC class I chain-related genes A and B) encode highly polymorphic ligands that are expressed by cells damaged by oxidative stress, infection, or neoplasia. Natural killer group 2 member D receptors (NKG2D; found on NK cells, as well as NKT cells, macrophages, g d( gamma delta) T cells, and CD8 T cells) bind to MICA and MICB ligands and induce apoptosis [ 16, 17 ] . Activated NK cells also secrete interferon-gamma (IFNg ) , contributing to a proinfl ammatory milieu [1 32 ] . NK cells induce apoptosis by releasing perforin to open pores that target cell membrane and granzymes (serine proteases that enter the membrane pores and activate intracellular cysteine proteases resulting in a caspase cascade causing apoptosis). NK cells, along with macrophages and NKT cells, also express Fc receptors (FcR) for the Fc portions of antibodies activated by binding to cell surface antigens. FcR binding induces NK cell cytolysis of the tar- get cell, a process called antibody-dependent cellular cytotoxicity (ADCC) [1 6 ] . NKT Cells NKT cells exhibit properties of both NK cells and T cells [1 33 ] . The most common NKT cells have a b (alpha beta) TCRs, which have invariant specifi city for lipids and glycolipids presented by CD1d molecules on host cells. Activated NKT cells secrete large amounts of cytokines and chemokines, including IFNg (gamma), interleukin-2 (IL-2, the primary mitogen for proliferation of activated T cells), IL-4, tumor necrosis factor alpha (TNF a (alpha)), granulocyte-macrophage-colony stimulating factor (G-M-CSF), and chemokines (chemoattractant cytokines). The magnitude and duration of NKT cell secretion of these cytokines can greatly infl uence the type of adaptive immune responses generated in the vicinity. Adaptive Immunity This represents the response of T cells and B cells to specifi c foreign or autoanti- gens (Table 2 .2 and Fig. 2.7 ). The response of T cells is often called cell-mediated immunity and that of immunoglobulins (Ig) produced by B cells is referred to as humoral immunity. Normally, DCs and B cells act as APCs in lymphoid organs, and activated T and B cells subsequently enter the circulation and migrate through the tight junctions of endothelial cells to enter tissues or organs to mediate effector cell functions. In contrast, the liver is an active immunological organ with dynamic 34 J.M. Vierling interplay between innate and adaptive immunity, which included the ability to directly activate CD4 and CD8 T cells in the liver and to generate DCs that have phagocytosed hepatic antigens to activate CD4 and CD8 T cells in lymph nodes. T Cell Receptors and HLA Class I, II, and III Molecules T cells express TCRs that interact with peptide antigens presented in the antigen- binding grooves of HLA class I and II major molecules on professional APCs [1 9, 120, 121 ] . Professional APCs include activated macrophages, including Kupffer cells, DCs, activated B cells and in the liver, both LSECs and cytokine-activated hepatocytes [7 , 8 ] . CD4 TCRs react exclusively with exogenous antigenic peptides presented in the antigen-binding grooves of HLA class II molecules, while CD8 TCRs react to endogenous (including viral) antigenic peptides presented in the antigen-binding grooves of HLA class I molecules [ 134 ] . Most T cells have TCRs composed of a (alpha) and b (beta) chains and are called a b (alpha beta)T cells. A minority of T cells have TCRs composed of g (gamma) and d ( delta) chains and these g d (gamma delta) T cells bridge innate and adaptive immunity by recognizing antigenic molecules without HLA restriction [1 35, 136 ] . All TCRs contain an amino acid (aa) sequence in their variable (V) regions called a complementarity determining region (CDR). It is the aa sequence of CDR that dictates the TCR specifi city for peptide antigens presented by HLA class II and class II molecules. Similarly, the aa sequences of the antigen-binding groove and walls of HLA class I and II molecules determine which antigenic peptides can be bound and presented to TCRs. Since these sequences are encoded by highly polymorphic alleles, the capacity to present autoantigens to T cells is strongly related to the genetics of HLA genotypes [5 6 ] . In addition, only a restricted number of autoreactive T cells would be expected to have CDRs capable of binding autoantigens. The class III HLA region also encodes proteins important for the innate immune response, C¢ proteins 4 and 2, MICA, MICB, heat shock proteins, and TNFa (alpha) [ 137 ] . Having the null allele for C¢ 4 (C4AQ0) is strongly associated with autoim- mune diseases [9

5 ] . Selection of the Immune Repertoire and Natural T Regulatory Cells Immature T cells bearing both CD4 and CD8 co-receptors are exposed to a wide variety of autoantigens in the thymus. TCRs that bind either too weakly or too strongly to autoantigen–HLA complexes are deleted [1 38 ] . Thus, surviving T cells have inter- mediate capacities to react with autoantigen–HLA complexes. This confers a potential risk for autoimmune reactions in everyone. Surviving T cells then differentiate into 2 The Pathogenesis of Autoimmune Hepatitis 35 either CD4 or CD8 T cells based on whether their TCR recognizes antigen presented by class II HLA (CD4) or class II HLA (CD8). Prior to the fi nal conversion from CD4 and CD8 positivity to CD4 T cells, a variable proportion of the T cells begin to express repressor forkhead winged helix transcription factor box (FoxP3) and later differentiate into natural CD4 T regulatory (Treg) cells with the phenotype CD4+, CD25+, FoxP3+ [ 139 ] . CD25 is the receptor for the a (alpha)-chain of the T cell mitogenic cytokine IL-2. FoxP3 expression, the key determinant of natural Tregs, is subject to epigenetic control, which allows altered gene programs to be inherited by progeny cells [1 40 ] . Whether epigenetics contributes to dysfunction of Tregs associated with AIH is unknown. In theory, each TCR is expressed by both T cells capable of becoming effector cells as well as natural Tregs capable of suppressing each antigen-specifi c activated effector cell. From birth onward, the interplay between innate and adaptive immune responses to environmental stimuli of PAMPs and DAMPs [1 24 ] molds unique immune reper- toires, even in monozygotic twins. The most robust immune repertoires result from multiple microbial exposures early in life and are associated with protection from autoimmunity and allergy [ 95 ] . In contrast, reduced microbial exposures early in life have been associated with evolution of an immune repertoire with higher risk of both autoimmunity and allergy [ 141 ] . Costimulation Positive costimulation results in functional T cell activation results and from the binding of T cell receptors CD28 or CD152 (aka CD40 ligand, CD40L) to APC costimulatory molecules CD80/86 and CD40, respectively. Costimulated functional T cells subsequently express the negative costimulatory molecule cytotoxic T lym- phocyte antigen 4, CTLA-4 (CD152), which competes for binding to CD80/86 with a 20-fold higher avidity than CD28 and attenuates T cell activation. In addition to CTLA-4, costimulated T cells subsequently express a second negative costimulation molecule, programmed cell death-1 (PD-1, CD27), conferring an exhausted, hypo- functional T cell phenotype subject to functional inactivation after engaging with PD-ligands1/2 (PD-L1/2, CD274/273). Dynamic Family of CD4 T Cells Differentiation into specifi c subsets is controlled by lineage-specifi c transcription factors, which are under epigenetic control [1 42 ] . Thus, programs of gene expres- sion altered by epigenetics can be inherited by progeny cells. Th0 conversion to Th1 is stimulated by exogenous proinfl ammatory cytokines and LPS [2 1, 143 ] . Th1 cells secrete cytokines IL-2 (the most potent mitogen for proliferation of CD4 and CD8 T cells), IFNg ( gamma), and TNFb (beta). In contrast, Th0 to Th2 conversion is 36 J.M. Vierling induced by exogenous IL-4 and Th2 cells secrete IL-4, 5, 6, 10, and 13. Th0–Th17 conversion is stimulated in a microenvironment containing a combination of TGFb , IL-1 b , and IL-23. Th17 cells express IL-23 receptors and secrete IL-17, IL-21, and IL-22. Activation by a tolerogenic subset of pDCs converts Th0 to inducible Treg cells that secrete either immunosuppressive IL-10 (Tr1 cells) or TGFb (beta) (Th3 cells) [1 44, 145 ] . T he mutually exclusive cytokines secreted by Th1 and Th2 subsets create a dynamic Th1/Th2 balance by inhibiting both the proliferation and cytokine secre- tion of the other subset. Th1 cytokines promote proliferation of CD8 cytotoxic T lymphocytes (CTLs), Th2, Th17, and inducible Treg cells. In contrast, Th2 cytok- ines activate eosinophils and mast cells. Both Th1 and Th2 cells stimulate B cells to secrete antibodies: Th1 cells induce C’-fi xing IgG2a antibodies, while Th2 cells induce IgG1 and IgE. Th1 cells are preferentially produced in microenvironments with LPS and active innate immune production of IL-12, IL-18, and INF g (gamma). The Th1 cytokine IFNg ( gamma) also increases secretion of IL-12 by DCs and macrophages, creating a positive feedback loop promoting Th1 dominance. Th17 cells augment infl ammation and tissue damage in the autoimmune diseases, multiple sclerosis, type 1 diabetes and primary biliary cirrhosis, as well as in immune-mediated infl ammatory disorders, such as rheumatoid arthritis, psoriasis, and infl ammatory bowel disease [8 5, 86 ] . Secretion of IL-17 recruits neutrophils for clearance of pathogens, while IL-21 and IL-22 stimulate epithelial cell produc- tion of antimicrobial proteins and infl ammatory mediators. Thus, Th17 cytokines generate intense infl ammation and tissue injury. Both IFNg and IL-4, the primary cytokines produced by Th1 and Th2 cells, downregulate Th17 differentiation. Thus, a dynamic balance is established among Th1, Th2, and Th17 cells within sites of infl ammation. I nducible Treg cells generated by antigen-specifi c activation of CD4 T cells in the liver play immunoregulatory roles in animal models [1 44 ] . However, their role in humans remains debated [1 45 ] . CD8 T Cells Activated CD8 T cells are predominantly antigen-specifi c cytotoxic T lymphocytes (CTLs) [1 20, 121 ] . Naïve CD8 T cells are activated by TCRs reacting with specifi c peptide antigens presented in the antigen-binding grooves of class I HLA molecules of professional APCs. Since HLA class I molecules consistently contain endogenous, processed, self-proteins, the HLA class I antigen-binding grooves are always occu- pied. Cells infected with a virus also process and present viral antigenic peptides in HLA class I molecules. Professional APCs, including DCs, activated macrophages, Kupffer cells, LSECs, and B cells, can also phagocytose e xogenous antigens and present their processed peptides to CD8 T cells in HLA class I molecules. This phe- nomenon of cross-presentation is an important mechanism of CD8 T cell activation in the liver [ 7 ] . 2 The Pathogenesis of Autoimmune Hepatitis 37 With appropriate positive costimulation and IL-2 and growth factors produced by CD4 Th1 cells, CD8 T cell clones proliferate and differentiate into antigen- specifi c CTLs. A CD8 CTL does not require further costimulation to cause apoptosis of target cells by either the perforin-granzyme or the Fas-mediated mechanisms. While the perforin-granzyme mechanism of cytotoxicity predominates outside the liver, hepatocyte expression of inhibitory serpins limits this mechanism in the liver. Thus, CTL FasL (CD178) binding to target cell Fas (CD95) plays a dominant role in the apoptosis of Fas-expressing hepatocytes. Recently, CD8 T cells with innate immune functions, non-antigen-specifi c cyto- toxicity and suppressor Treg functions have also been identifi ed [8 4, 146, 147 ] . These non-antigen-specifi c, non-cytotoxic, cytokine-secreting innate CD8 T cells have been detected in chronic infl ammatory infi ltrates. These observations indicate that caution is necessary in assigning a cytotoxic role to CD8 T cells identifi ed by phenotype in sites of infl ammation. g (Gamma)/ d (Delta) T Cells Approximately 2–3% of T cells express a g d (gamma delta) TCR, and they are most abundant in gut mucosa, skin, genitourinary tract, and liver. Normally g d (gamma delta) T cells comprise 15–25% of T cells in the liver [7 , 8 ] . g d( gamma delta) T cells bridge innate and adaptive immune responses by being non-HLA restricted and capable of recognizing bacteria and fungi, nonpeptide microbial metabolites, and both stress-related and neoplastic cellular proteins [1 35, 136 ] . They kill by release of perforin-granzyme and secrete proinfl ammatory IFN g (Gamma) and TNFa (Alpha). Recently, g d (Gamma delta) T cells were noted to be involved in the pathogenesis of the autoimmune disease, multiple sclerosis [9 1 ] , and their isolation from liver infi ltrating T cells in children with AIH suggests a pathogenetic role [1 48 ] . B Cell Activation and Functions The dual functions of B cells are to produce antigen-specifi c antibodies and to serve as professional APCs capable of providing the costimulatory signals required for CD4 and CD8 T cell activation [1 49 ] . Naïve B cells express immunoglobulin (Ig) on their cell surfaces that serve as receptors for an antigenic aa sequence or epitope on unprocessed foreign or autoantigens. The epitope specifi city of each unique Ig is generated by recombination of gene segments that produce an Ig repertoire capable of binding a near infi nite variety of epitopes. Thus, the Ig of each B cell is analogous to the TCR of each T cell, and, like TCRs, the Ig repertoire is selected against autoantigens and B cells with autoreactivity are deleted. Binding of a specifi c antigen epitope to the B cell Ig initiates two events: (1) phagocytosis and processing of the entire antigen for presentation as peptides to CD4 38 J.M. Vierling and CD8 TCRs; (2) secretion of epitope-specifi c antibodies. When the antigen-HLA class II molecule on the B cell activates the TCR of a CD4 T cell, the subsequent Th1 and Th2 cells produce cytokines necessary for the B cell to secrete a soluble form of its surface Ig receptor, an epitope-specifi c antibody. Since whole antigens contain many peptides, the epitopes recognized by antibodies usually differ from those acti- vating the TCRs of CD4 and CD8 T cells. Thus, it is possible to have autoantibodies and T cell reactions against different epitopes of the same macro-antigen. Conversely, T cells may react to autoantigens in the absence of autoantibody production against overlapping B cell epitopes. Three other features of B cell responses are important in the coordination of innate and adaptive immune responses and disease pathogenesis. First, certain types of IgG and all IgM antibodies can activate C ¢ after they bind to their antigenic epitopes [ 150 ] . Thus, binding of these antibodies to an antigen on the surface of a cell or a pathogen causes C¢ -mediated lysis and can injure innocent bystander cells. In the liver, such collateral damage may provide a “danger signal” for additional infl ammation [ 131 ] . Second, IgG antibodies bound to antigenic epitopes become recognizable by a family of Fc receptors on NK cells, macrophages, DCs, neutro- phils, and mast cells. When Fc receptors of NK cells or macrophages engage IgG bound to a cell surface antigen, they kill the cell through ADCC. Fc receptors on macrophages also trigger production of proinfl ammatory cytokines. Third, binding of an antigen–antibody complex to the Fc receptor on DCs or macrophages (Fcg RI or CD64) leads to phagocytosis and peptide antigen presentation that enhances the generation of effector CD8 T cells [8 1 ] . Generation of T and B Effector Cell Responses The effector functions of T cells expressing PD-1 (CD27) can be functionally inac- tivated in the liver after engaging PD-L1/2 (CD274/273) expressed on Kupffer cells and stellate cells [7 ] . Immunoregulation of Immune Responses The ability to regulate and/or terminate immune responses is a key requirement for immune responses and maintenance of self-tolerance. Inhibitory costimulation through T cell CD152 (CTLA-4) and PD-1 is important in extinguishing immune responses to exogenous antigens. In addition, natural Treg [1 39 ] and inducible Treg cells [ 144, 145 ] play pivotal roles in terminating T cell-mediated reactions and suppressing autoreactive T cell clones that escape deletion in the thymus. Recently, CD8 Tregs have also been identifi ed and gd T cells may also mediate immunosuppression [1 46 ] . 2 The Pathogenesis of Autoimmune Hepatitis 39 T Regulatory Cells Natural Tregs are CD4+CD25+FoxP3+ and following selection as autoantigen reac- tive T cells in the thymus, they migrate to peripheral tissues [ 139 ] . As noted earlier, the expression of FoxP3 in natural Tregs is under epigenetic control, which might infl uence peripheral function of natural Tregs in AIH [1 40 ] . Inducible Tregs, desig- nated as T regulatory 1 (Tr1) cells secreting IL-10 and T helper cell 3 (Th3) cells secreting TGFb (beta), are generated from naïve CD4 Th0 cells activated by a subset of tolerogenic DCs that induce production of IL-10 and tolerogenic costimulatory molecules [ 144, 145 ] . IL-10 inhibits production

of proinfl ammatory TNFa (alpha) and IL-12, while TGFb (beta) inhibits Th1 responses and CD8 CTLs through its effects on the transcription factors and cytokines. In addition, non-antigen-specifi c CD8 Tregs secreting either IL-10 or TGF b( beta) or g d( gamma delta)T cells secreting both IL-10 and TGFb (beta) can suppress experimental murine autoimmune diabetes and antitumor activities of CD8 CTLs and NK cells [1 46 ] . Generation of non- antigen-specifi c CD8 Tregs is favored by a milieu containing IL-10, a principal cytokine in the hepatic lobule [8 ] . Since NKT cells and CD4 Th2 cells also secrete IL-10, they likely contribute to immunosuppressive regulation of cellular immunity. Since CD4 Tregs control the magnitude and duration of a cellular immune response, protracted immunopathology in AIH is indicative of inadequate Treg cell function. Regulatory Dendritic Cells Activation of mature mDCs leads to processing and presentation of peptide antigens and secretion of proinfl ammatory cytokines required to generate an adaptive T cell response. However, the hepatic microenvironment disproportionately contains immature mDCs and pDCs, which are poor stimulators of naïve T cells [7 , 8, 13 ] . pDCs produce large amounts of IFNa (alpha)/ b (beta)/g (gamma) and proinfl am- matory cytokines TNFa (alpha) and IL-6 involved in autoimmune diseases [1 51 ] . A subset of hepatic DCs in mice, referred to a liver regulatory DCs (LRDCs), can inhibit CD4 T cell proliferation through expression of CD274 (PD-L-1) and secretion of prostaglandin E2 and IFN g [ 152 ] . Infused LRDCs effectively inhibited AIH in a murine model, indicating a capacity for intrahepatic homing and immunoregulation. No human counterparts of LRDCs have been reported. Th17 Cells and Immunoregulation The interplay between natural Tregs and Th17 cells has been only partially defi ned, but it appears to infl uence immunoregulation [8 5, 153, 154 ] . For example, IL-2, the cytokine required for Treg proliferation and survival, suppresses Th17 differentiation. 40 J.M. Vierling Conversely, the presence of proinfl ammatory IL-1 b (beta) can negate IL-2 suppression of Th17. Of greater importance are the observations that Tregs can convert to Th17 cells in sites of infl ammation and that retinoic acid from gut DCs can abrogate infl ammation by suppressing Th17 cells and increasing Treg cells. In contrast to the general view that Th17 cells only promote infl ammation, natural Th17 cells selected in the mouse thymus actually downregulate peripheral infl ammation [8 8 ] . These thymic Th17 cells migrated spontaneously to the liver, gut, and lung. In the liver, Th17 secretion of IL-22 prevented experimental hepatitis caused by galac- tosamine and LPS. Thus, specifi c populations of Th17 cells with hepatotrophism and capacity to suppress hepatic infl ammation may be selected by exposure to self-antigens in the thymus. Liver as an Organ of Adaptive Immunity In addition to being a primary organ for innate immunity, the liver also plays impor- tant roles in adaptive immunity. Importantly, the portal tracts represent a distinct “lymphoid” compartment into which activated T cells are recruited by resident APCs [7 3 ] . The microenvironment of the portal tracts supports the accumulation of functional T cells, B cells, DCs, and macrophages and may explain why portal infl ammatory infi ltrates are observed universally in chronic, infl ammatory liver dis- eases [7 ] . Along with abundant mDCs, pDCs, Kupffer, NK, and NKT cells involved in innate immunity, the normal liver also contains enriched populations of CD8 a b (alpha beta) T cells, activated CD4 and CD8 T cells, g d T cells, memory T cells, and B cells [7 , 8 ] . The percentage of highly activated hepatic T cells is higher than in peripheral blood, but naïve T cells and B cells are underrepresented in the liver. Multiple hepatic cells serve as APCs for T cell activation, including several hepatic subsets of DCs, hepatocytes, LSECs, and stellate cells [7 , 8 ] . The architec- ture of the hepatic sinusoids permits T cells to make direct contact with not only Kupffer cells, LSECs, and a variety of DCs but also with hepatocytes and stellate cells through the fenestrations of the LSECs. Hepatic DCs have immature pheno- types consistent with the fact that they are less immunogenic than DCs in other tissues. However, hepatic DCs are more phagocytic and produce more cytokines than DCs in lymphoid tissues. Normally, CD4 T cell activation by hepatic APCs prefer- entially generates Th2 cells secreting immunosuppressive IL-10. It is unclear whether the hepatic microenvironment does or does not favor differentiation of inducible Tr1 and Th3 regulatory cells. In mice, the quantities of natural Tregs are decreased compared to those in lymph nodes, but CD8 T cells in the liver cause a rapid recruitment of natural Tregs. CD8 T cell activation by antigens presented solely by hepatocytes has been conclusively demonstrated, but it normally results in T cell inactivation or apoptosis. Stellate cells can also present endogenous antigens to T cells, resulting in an immunosuppressive response. In contrast, LSECs cross- present exogenous antigens in HLA class I molecules to activate CD8 T cells into CTLs. Kupffer cells expressing FasL and death receptors 4 and 5 (DR4, DR5 that 2 The Pathogenesis of Autoimmune Hepatitis 41 activate TNF-apoptosis-inducing ligand, [TRAIL]) trap senescent CD8 T cells from extrahepatic or intrahepatic sites and induce apoptosis by engaging Fas (CD95) [ 7 ] . CD4 or CD8 T cells that recognize antigens in the liver are exposed to both IL-10 and to inhibitory PD-L1/2 (CD273) expressed on both Kupffer and stellate cells. Adaptive immune responses against viral, neoplastic, or autoantigens in the liver can occur either directly in the liver or in regional lymph nodes [7 ] . The latter involves migration of mDCs that have phagocytosed antigens in the liver to regional lymph nodes where they present antigenic peptides to naïve CD4 and CD8 T cells. Direct T cell activation in the liver favors tolerance unless counteracted by a distinct proinfl ammatory cytokine milieu. In contrast, effector CD4 and CD 8 T cells acti- vated by hepatic DCs in lymphoid tissues enter the circulation and in the portal tracts after transendothelial migration across the endothelial cells of the portal veins. These activated cells exhibit effector functions in the proximal sinusoids at the interface of the portal tracts and hepatocytes [1 5 ] . However, the magnitude of their proinfl ammatory and cytotoxic functions is dictated by the sinusoidal milieu containing immunosuppressive IL-10 and by the expression of inhibitory PD-L1/2 (CD274/273) by Kupffer cells and stellate cells [1 55 ] . B cells normally comprise <10% of intrahepatic lymphocytes, and the majority of these B1 cells differ from splenic B2 cells by expressing CD5, characteristic of a subtype of innate B cells [ 7, 8 ] . B1 cells appear to connect the innate and adaptive limbs of immunity by being activated in a Th-independent manner and producing low affi nity IgM antibodies against glycoproteins, called natural antibodies. Nonhepatic CD5+ B cells also secrete IL-10, but it is unknown if their intrahepatic counterparts may also contribute to an immunosuppressive cytokine milieu. Alternatives to an Autoimmune Pathogenesis Since AIH is a necroinfl ammatory disease of unknown cause, it is important to consider the possibility of alternative mechanisms of pathogenesis. This requires scrutiny of AIH from different perspectives of pathogenesis and suggests testable hypotheses. The most plausible alternative to an autoimmune pathogenesis in AIH is an immunological response to an undefi ned, noncytopathic hepatotrophic virus whose mode of transmission and latency obscures its infectious nature. Consider a scenario in which HCV infections were not transmitted by blood transfusions and, therefore, an infectious etiology was unsuspected. Prior to development of diagnostic tests for HCV infection, patients with chronic hepatitis C were often misdiagnosed as AIH, especially those who had developed type 1 or type 2 autoantibodies through molecular mimicry. If a hypothetical virus did not replicate in response to corticos- teroid treatment, as does HCV, it might even appear responsive to immunosuppressive therapy. Recrudescence, which occurs after withdrawal of immunosuppression in AIH, would also be expected in chronic viral hepatitis . Finally, the restricted number of viral antigenic epitopes for T cell and B cells would also generate an oligoclonal response. However, a viral etiology would not be expected to have HLA associations 42 J.M. Vierling with susceptibility or resistance unless HLA dictated a difference in the probability that the infection would become chronic. An alternative to an autoimmune patho- genesis of AIH is that the disease is an immune-mediated infl ammatory disorder (IMID), similar to infl ammatory bowel diseases, rheumatoid arthritis, and psoriasis (Table 2 .1 ). In contrast to autoimmune diseases, IMIDs are not induced by immune responses to specifi c autoantigen(s) but, instead, are characterized by dysregulated interplay between innate and adaptive immune responses to environmental anti- gens, resulting in sustained tissue/organ-specifi c damage caused by infl ammation and proinfl ammatory cytokines, such as IL-12, IL-6, and TNFa (alpha). The tissue or organ specifi city of infl ammation results from the generation of chemokines and adhesion molecules that chemoattract and activate T cells, macrophages, and B cells. Autoantibodies are generated as epiphenomena and HLA associations refl ect a capacity for dysregulated infl ammatory responses. In this scenario, promi- nent roles for proinfl ammatory Th17 cells and g d (gamma delta)T cells would be expected. Apoptosis of hepatocytes could potentially induce autoreactive CD4 T cells to provide help for autoantibody production by autoreactive B cells. 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Longhi MS, Hussain MJ, Mitry RR, et al. Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis. J Immunol. 2006;176(7):4484–91. Chapter 3 Clinical Presentation E. Jenny Heathcote Keywords Asymptomatic autoimmune hepatitis • Advanced liver disease • Fulminant hepatic failure • Liver transplant • Immunosuppressive therapy Introduction Waldenstrom was the fi rst to describe what later became recognized as Autoimmune Hepatitis (AIH) [1 ] . No particular ethnicity precludes the development of AIH although its presentation may vary across the world. AIH may present at any age, from infancy through to the elderly. Although more common in women this disease must nevertheless be considered in the differential diagnosis of “hepatitis” in men. When AIH was fi rst recognized as a specifi c entity it was assumed that the disease was always symptomatic. Manifestations of advanced liver disease were usual at fi rst presentation. The recent introduction of routine screening blood tests indicates that some individuals may have “asymptomatic” AIH. At the other end of the spec- trum, the dramatic improvement in the understanding and management of Fulminant Hepatic Failure (FHF) has allowed the recognition of AIH as one of its many causes. Liver transplant saves the lives of most of those who need it, although recurrent AIH in the new liver may develop. It is important to recognize the change in demography over the last 40 years as the patients who were entered into any one of the three “classic” randomized control trials of immunosuppressive therapy (IST) for AIH [2 – 4 ] in the late 1960s do not necessarily represent the patient population seen in the physician’s offi ce or emergency E. J. Heathcote (*) Department of Medicine, Toronto Western Hospital, University Health Network, University of Toronto, Ontario, Canada e-mail: jenny.heathcote@utoronto.ca G.M. Hirschfi eld and E.J. Heathcote (eds.), Autoimmune Hepatitis: A Guide for Practicing 51 Clinicians, Clinical Gastroenterology, DOI 10.1007/978-1-60761-569-9_3, © Springer Science+Business Media, LLC 2012 52 E.J. Heathcote room today. Thus, it is wrong to assume that the therapies shown to be lifesaving in those with advanced liver disease benefi t all those given a diagnosis of AIH today, particularly those at the two extremes alluded to above. The Many Faces of Autoimmune Hepatitis The presentation of patients with liver disease subsequently shown to be due to AIH varies widely. Thus, AIH needs to be in the differential diagnosis of any acute (including fulminant) or chronic liver disease associated with a “hepatitis” (rarely with additional “cholestasis”). Recently, asymptomatic cases of AIH have been reported. An individual who presents de novo with hepatic decompensation or a background of inactive cirrhosis may have a “burned out” AIH. Occasionally another autoimmune liver disease may “overlap” with AIH (i.e., PBC or PSC) (see Chap. 12 ). Acute AIH Recurrent episodes of transient rises in serum transaminase levels are most often ascribed to a “viral” infection, a drug reaction – or left unexplained! There are no symptoms specifi c to acute AIH but as is usual with any hepatitis, fatigue is common and there may be an accompanying arthralgia or even a serum sickness-like syndrome. Abdominal discomfort is frequent but fever is unusual. As AIH is relatively rare in comparison to other causes of an acute hepatitis there are no long-term follow-up studies of patients who present acutely. Whether this disease always becomes chronic or may resolve for good remains unknown. There are many mimics of AIH (e.g., a toxic hepatitis secondary to new medication or herbal remedy, Wilson disease). A preceding viral infection is sometimes obtained from the history (e.g. acute hepa- titis A or C, measles, and EBV/CMV [ 5, 6 ] ). If the history taking and/or work-up at the time of fi rst presentation was incomplete it may be impossible to be sure that a prior “hepatitis” was viral or drug induced. In a series of 86 Italian patients given a diagnosis of AIH 26% presented acutely, and it was the negative viral serology, the higher g (gamma) globulin (26.9 versus 13.4 g/L) and the AST/ALT ratio (1.20 versus 0.61) which most helped to distinguish cases of acute viral hepatitis from acute AIH [7 ] . Those with an acute presentation are more likely to be jaundiced, and have high serum transaminase values. There may be no differences in levels of IgG, severity of liver disease on histology in terms of both activity and fi brosis which distinguish those who present acutely from those with a more indolent (chronic) presentation. A Japanese series of 53 cases of acute AIH were compared with 123 who were diagnosed with chronic AIH [8 ] , the former were younger (mean age 37 years com- pared to 56 years). In this series an acute presentation was defi ned as a sudden onset 3 Clinical Presentation 53 Table 3.1

Simplifi ed Diagnostic Criteria for Autoimmune Hepatitis Variable Cutoff Points ANA or SMA ³ 1:40 1 ANA or SMA ³ 1:80 or LKM ³ 1:40 2* or SLA Positive lgG >Upper normal limit 1 >1.10 times upper normal limit 2 Liver histology (evidence of hepatitis Compatible with AIH 1 is a necessary condition) Typical AIH 2 Absence of viral hepatitis yes 2 ³ 6: probable AIH ³ 7: defi nite AIH Adapted from Hennes EM. Hepatology 2008;48:169–76 *Addition of points achieved for all autoantibodies (maximum, 2 points). of jaundice and/or fatigue and/or anorexia with a serum bilirubin ³ 5 mg/dl and/or serum ALT ³ tenfold ULN. These authors found that serum IgG values of <2,000 mg/ dl and undetectable ANA were signifi cantly more likely than reported for the more classical (chronic) presentation. Retesting a few weeks later may reveal an increase in IgG and the appearance of ANA/SMA. In common with other reports of acute onset AIH, zone 3 necrosis seen on liver biopsy was present in half of those with the acute onset; a manifestation of AIH rarely observed in the liver biopsies of those with a chronic presentation. Confi rmation of Diagnosis of AIH To make a confi dent diagnosis of AIH, other diseases presenting similarly need to be sought. The International Autoimmune Hepatitis Group (IAHG) developed a complex scoring system [ 9 ] which has recently been considerably modifi ed (Table 3 .1 ). This simpler system [1 0 ] has been evaluated in well-characterized cases of AIH [ 11 ] but more extensive validation in “control” populations and in those with acute and fulminant AIH are needed. All these scores give a range for both a “probable” or “defi nite” diagnosis. In a patient in whom a liver biopsy is not feasible a “probable” diagnosis is suggested by high titer autoantibodies and an elevated IgG in serum. Unlike the earlier scoring systems “atypical” features such as an elevated alkaline phosphatase (ALP) or detectable AMA do not require one to subtract from the overall score: neither does this new score require specifi c val- ues for ALT or ALP. This latest scoring system refl ects the greater appreciation for the wide range of manifestations of this disease (e.g., AMA+ve AIH or asymptomatic inactive AIH). 54 E.J. Heathcote Table 3.2 Untreated versus treated demography asymptomatic AIH Treated (n = 15) Untreated ( n = 16) Mean age at presentation (years) 46.5 ± 12.57 (23–68) 51.2 ± 12.77 (31–5) Mean follow-up (years) 5.18 ± 4.8(0.8–16.9) 3.11 ± 4.7 (0.3–19.6) AST (<40 IU/L) 275 ± 375 234 ± 343 Bilirubin (<23 mM) 25 ± 29 15 ± 9.9 Albumin (35–50 g/L) 41 ± 5 43 ± 5 IgG (5–13 g/L) 21.3 ± 10.6 18.0 ± 8.1 Cirrhotic at presentation 1 (6.7%) 7 (43.8%) Mean AIH biopsy score 2.61 ± 1.88 1.56 ± 1.67% Endpoints 1 (6.7%) 2 (12.5%) Transplant 1 (6.7%) 0 Liver death 0 0 All death 0 2 (12.5%) Adapted from Feld JJ, Dinh H, et al. Hepatology. 2005;42:53–62 * p < 0.05 between the two values Chronic Autoimmune Hepatitis Individuals with chronic AIH often give a history of being told they have a persis- tent or a relapsing “hepatitis.” Specifi c symptoms may or may not be present. The nonspecifi c and intermittent nature of this disease means that chronic AIH often goes unrecognized from months to years following initial presentation. Negative viral serology and at least a ³ 1.2 × ULN for g (gamma) globulin and high titer ANA/ SMA are the laboratory features which could allow a “probable” diagnosis of AIH without a liver biopsy [1 0 ] . It is quite possible for an asymptomatic individual found to have a “transaminitis” to already have hematological evidence of liver failure (e.g., an elevated INR) yet be living a full and active life. When youngsters present in this fashion, it may be diffi cult to convince them that treatment (with all its untoward side effects) will be lifesaving. Despite lack of symptoms referable to their liver, a history in women of secondary amenorrhea may be obtained and physical examination may reveal spider nevi and/or a small liver with splenomegaly. In a case series where patients with asymptomatic AIH were compared to those who presented with symptoms, cirrhosis (mostly inactive) was evident in 25% of the asymptomatic patients and in 36% of those were symptomatic [1 2 ] . The survival of the symptomatic (all treated) and the asymptomatic group, half of whom were not treated was no different after 10 years of follow-up. The 10-year survival was 83% in those who had symptomatic disease and 80% in those without symptoms present at diagnosis (NS). The mean age at presentation was older in the asymp- tomatic group – 48.5 years versus 41.6 years for the symptomatic. Two of the three asymptomatic patients died of myocardial infarction. A background cirrhosis at the time of diagnosis regardless of the presence or absence of symptoms was associated with a signifi cantly reduced 10-year survival being 61.9% in cirrhotics versus 94% in noncirrhotics (Table 3 .2 ). 3 Clinical Presentation 55 Individuals may present de novo with both the symptoms and signs of hepatic decompensation (e.g. ascites, variceal hemorrhage, or chronic hepatic encephal- opathy) but with few or no serologic markers of AIH. In such cases liver biopsy generally shows an inactive cirrhosis. Such individuals are rarely given the correct diagnosis. The term “cryptogenic AIH” has been applied to subjects who have a chronic hepatitis but no detectable autoantibodies [ 13 ] (not to be confused with the end result of nonalcoholic fatty liver disease). However, despite the lack of detect- able autoantibodies, serum IgG levels were noted to be elevated in support of an autoimmune origin to their cirrhosis. Fulminant AIH A lthough an unusual presentation of AIH is one of the many potential causes of FHF, it is reported to be present in 8% cases with FHF [1 4 ] (Table 3.3 ). In the younger (predominantly but not always in children) population it is vital that a diag- nosis of Wilson disease be excluded [1 5 ] where typically jaundice is mostly due to an unconjugated hyperbilirubinemia secondary to hemolysis. The INR may be high and the ALT only moderately elevated. Subnormal values (corrected for age) of ALP may be the diagnostic “give away” in those with Wilson disease presenting acutely. Ocular examination showing Kaiser–Fleischer rings will often rapidly clinch the diagnosis. Table 3.3 Survival rate of seriousa acute liver failure according to etiology Survival rate Survival rate Total survival Etiology Total LDLT without LDLT with LDLT rate HAV 1 0 0/1 (0) – 0/1 (0) Acute HBV 1 0 0/1 (0) – 0/1 (0) SAE 6 0 1/6 (17) – 1/6 (17) HEV 1 0 0/1 (0) – 0/1 (0) Drugs 1 1 – 0/1 (0) 0/1 (0) Alcohol 1 0 0/1 (0) – 0/1 (0) AIH 4 1 2/3 (67) 1/1 (100) 3/4 (75) Cryptogenic 12 3 0/9 (0) 3/3 (100)* 3/12 (25) hepatitis Total 27 5 3/22 (14) 4/5 (80)** 7/27 (26) * P = 0.004 versus without LDLT ** P = 0.0089 versus without LDLT a Estimated to die by Muto’s formula (log it[l ] = 0.0649 × prothrombin time + 0.0357 × age − 2.81 × d irect/indirect bilirubin + 0.703 × log total bilirubin + 1.04 × [O−C][O−C]; acute form = 0, subacute form = 1.0, death rate (p ) = 1/1 + e− l ) When limited to patients with serious acute liver failure (ALF), the prognosis of cryptogenic cases with LDLT was signifi cantly better than that of patients without LDLT. A IH autoimmune hepatitis, HAV hepatitis A virus, H BV hepatitis B virus, H EV hepatitis E virus, LDLT living donor liver transplantation, SAE severe acute exacerbation of chronic hepatitis B infection Adapted from Takahashi SJ. Gastroenterol Hepatol. 2008;23:1216–22 56 E.J. Heathcote Table 3.4 C omparison of response to therapy of AIH patients with acute and chronic presentation Acute AIH (n = 10) Chronic AIH (n = 20) P value Clinical outcome Complete response 4 16 0.0433 Died 2 0 0.0449 OLT 3 2 0.10 Listed for OLT 1 2 Adapted from Kessler WR. Clin Gastroenterol Hepatol. 2004;2:625–31 As background liver disease in patients with AIH presenting with FHF may be acute or chronic, a liver biopsy (transjugular) is needed to demonstrate which is the case; zone 3 necrosis may be the clue to a diagnosis of acute AIH. Liver trans- plant is very often the optimal treatment for those with acute fulminant AIH [ 16 ] (Table 3.4 ). For those with evidence of chronic disease at presentation, introduc- tion of IST may be considered as initial treatment and in some this treatment prevents the need for liver transplantation. However, high dose IST poses a problem in such patients because it promotes both bacterial sepsis and disseminated fungal infection, particularly the latter may preclude a subsequent liver transplant should this be deemed necessary. Thus, potentially untoward consequences of instituting IST in FHF due to a chronic AIH need to be considered carefully prior to their introduction. A further study of 14 patients with AIH who presented with FHF reported that seven responded to IST and did not require liver transplant and six of seven nonre- sponders underwent liver transplantation. The stability of the markers of liver function distinguished the stable from unstable FHF [1 7 ] . In IST responders their pretreat- ment MELD score was £ 28 and they were more likely to be cirrhotic with a stable bilirubin value even in the face of a coagulopathy. In this series a response to steroid therapy was observed within 3–4 days of their introduction and precluded the need for transplant. In nonresponders their bilirubin and INR levels rose and review of their liver biopsy indicated submassive hepatic necrosis. All these studies empha- size the need for an immediate liver biopsy in cases of FHF to establish whether the liver disease is acute or acute on chronic, while the results of serologic testing are pending thus allowing the rapid introduction of optimal therapy. Recurrence of AIH Postliver Transplantation Recurrence of AIH is reported to occur in the liver allograft in 23% after a median interval of 26.4 months and this fi gure may increase to 41% at 10 years of follow-up [1 8 ] . Moderate to severe infl ammation and very high levels of IgG before transplanta- tion may be risk factors for recurrence postliver transplant [1 9 ] . It has been hypoth- esized that this observation indicates that it is the host that is susceptible (not the donor liver) as it is the host who appears unable to suppress their immune reactivity 3 Clinical Presentation 57 despite IST prior to transplant. Introduction of higher dose IST will usually induce a remission but on occasion retransplant is necessary. In a systematic review of recurrence of autoimmune liver disease following liver transplant, recurrent AIH was found in 22% [2 0 ] . Twenty-fi ve publications on recur- rence of autoimmune liver disease postliver transplant were identifi ed, 13 of which were suitable for inclusion in their systematic review. Recurrence of their prior autoimmune liver disease was diagnosed in 94 of 414 transplant recipients after a follow-up of 2 years±, yet the patients all remained asymptomatic. They were initially identifi ed biochemically but a conclusive diagnosis was made on liver biopsy: peripor- tal hepatitis ± a lobular hepatitis was identifi ed in those who reactivated their prior AIH. As typical pretransplant markers of AIH may persist posttransplant (IgG, AST/ALT and detectable autoantibodies), the method most likely to facilitate an accurate diagnosis of recurrent AIH posttransplant is liver biopsy. Overlapping Autoimmune Hepatitis and Sclerosing Cholangitis The overlap of AIH with a cholangitis has been best defi ned in a study of children diagnosed with AIH who as part of a prospective study underwent routine ERCP at fi rst presentation. Biliary changes on ERCP were found in half [ 21 ] . An earlier retrospective study reported similar fi ndings but with the primary liver disease being PSC. These children who were known to have a sclerosing cholangitis with both biochemical and histological features of cholestatic liver disease also had the sero- logic and histologic features of an

AIH [2 2 ] . The prevalence of an overlap between AIH and PSC in adults appears to be much less common although there are many isolated case reports. There are only two (albeit retrospective) studies which report MRC fi ndings in adult patients with a diagnosis of AIH: the results differ! The fi rst study reported that 10% of patients with a prior diagnosis of AIH (often longstanding) were found to have biliary features typical of PSC [2 3 ] . In another more recent study, these observations were not confi rmed and the authors drew attention to the fact that MRC may be misread as showing a pattern similar to PSC in the periphery of the liver in any patient with cirrhosis [2 4] . Nevertheless, overlaps certainly occur and small studies and case reports suggest that the outcome (in terms of the need for liver transplant) may be greater in those with this overlap although this observation may just be a conse- quence of reporting bias. A small Italian study indicated the survival of AIH versus AIH + PSC was better than for PSC alone [2 5 ] but this was not the case in another report [2 6 ] . It is noteworthy that the clinical presentation of those with AIH/PSC cannot be distinguished from AIH alone. Pruritus is rarely a predominant symptom in AIH except in some after estrogen therapy is prescribed. One case series of six patients with AIH, three of whom underwent an ERCP at the time of initial diagnosis (all normal) were subsequently shown to have typical cholangiographic features after their liver disease initially controlled with prednisone failed [2 7 ] . 58 E.J. Heathcote Overlapping Autoimmune Hepatitis and Primary Biliary Cirrhosis There are two circumstances when an overlap of AIH and PBC may be suspected. There are a number of case reports of individuals given a clear-cut diagnosis of PBC (cholestatic biochemistry, positive AMA, and classical fi ndings on liver biopsy) with a good biochemical response to UDCA who subsequently show a change in their biochemical pattern of disease more in keeping with a hepatitis with loss of AMA and appearance of ANA [2 8 ] . Such cases, albeit rare, clearly indicate that patients given a diagnosis of PBC may subsequently alter the pattern of their presumed autoimmune liver disease to that of AIH. Good response to IST is as is expected for AIH [2 9 ] . There are to date no well-described case reports of the reverse (i.e., individuals with AIH who subsequently change in the pattern of their disease to primary biliary cirrhosis). Reference is made to a few such individuals in one series of patients with PBC thought also to have AIH but no clinical description of their biochemical/histologic profi le was reported [ 30 ] . Transient appearance of AMA may be detected in patients with AIH [3 1 ] or with FHF of any cause [3 2 ] . The Mayo Clinic has reported that features of AIH may be present in about 12% of all those given a diagnosis of PBC when the International Autoimmune Hepatic Score (IAIH) was applied. The survival of individuals given a primary diagnosis of PBC yet with a positive IAIH score was worse, particularly in terms of the compli- cations of portal hypertension [ 33 ] . There are also reports of patients with clear-cut AIH who nevertheless test positive for antimitochondrial antibodies but without any clinical, biochemical, or histological evidence of the small duct disease typical of PBC [3 4 ] . In a series 15 such individuals who were followed for up to 26 years, no evidence of PBC was observed at any time despite persistent detection of AMA. Clinical Presentation AIH According to Ethnicity African Americans/Blacks Particularly relevant to a multicultural society (so often present in the West) is to appreciate that the clinical presentation of AIH varies widely according to ethnicity. In a study from the USA, African Americans were more often symptomatic at presentation (84%) versus 64% nonblacks in the USA [ 35 ] . In this series those with an acute presentation were more likely to be black (76%) than not (32%), and blacks had lower levels of albumin and higher INR values even though their disease appeared to be at a similar histologic stage to nonblacks. Blacks presented younger age (42 years) than nonblacks (45 years). In this study cirrhosis was a predictor of poor outcome and noncompliance with IST was higher in those with a bad outcome (Table 3 .5 ). 3 Clinical Presentation 59 Table 3.5 A IH in African Americans versus Caucasians: clinical, biochemical, and outcome data Blacks (37) Non-Blacks (64) P value Cirrhosis 57% 38% 0.061 Liver failure 38% 9% 0.001 Remission with IST 76% 90% 0.016 Referred liver transplant 51% 23% 0.009 Mortality 24% 6% Adapted from Verma S. Hepatology. 2007;46:1828–35 In another study from the USA, 27 African Americans with AIH were compared with 24 nonblacks who presented to the same institution with AIH. African Americans were found to have signifi cantly higher INR values at presentation likely because 85% were found to be cirrhotic: whereas cirrhosis was only present in 38% of Caucasians [3 6 ] . Response to IST was similar but higher doses of IST were needed to maintain African Americans in remission – this could be a consequence of their higher rate of background cirrhosis. There is little data on AIH in blacks outside of the USA. In a small study from the UK [3 7 ] which looked at the pattern of disease in 12 non-European, non-Caucasoid patients, half were African in origin. Their ages ranged from 12 to 39, their total serum bilirubin values at fi rst presentation ranged from 22 to 400 m (mu)mol/L and all had elevated ALP levels ranging from 850 to 230 iu/L (NR <130 iu/mL) simul- taneously levels of IgG were high, ranging from 25.3 to 70.7 g/L (NR <18). All but one of the six African patients tested positive for ANA and/or SMA. In this series of 12 patients three had histologic evidence of biliary changes, two were African. None tested positive for AMA and all had normal cholangiograms (only one of whom had a normal bilirubin at presentation). Only one of these six African patients had a good response to IST but none required a liver transplant. Need for liver trans- plant was limited to three of the four Asians in this case series. In another case series also from the UK [ 38 ] the authors describe the presentation of six Somalian males with type 1 AIH (all ANA/SMA+ve) – four of whom had cholestatic changes on liver biopsy. Only one had a complete response to IST, two failed to respond at all. Of these six patients, two-thirds despite their acute presenta- tion already had advanced liver disease. These three patients all had pericholangitis, ductopenia, cholestasis, and ductular proliferation on liver biopsy yet all three had a normal MRC or ERCP. Unfortunately, the authors did not report the long-term out- come of these Somalian men with a cholestatic form of AIH. In a small study of 37 patients presenting with FHF from the Sudan, 3 (8%) were thought to have AIH only one of whom survived (no liver transplant program was available) [3 9 ] . South America Czaja and colleagues from Brazil reported on the clinical manifestation of 115 Brazilians given a diagnosis of AIH and compared them to 161 cases in the USA [4 0 ] . In the Brazilian patients fewer had associated autoimmune diseases (17%) versus 60 E.J. Heathcote 38% in those from the USA. The Brazilian patients were younger at presentation and more often male. At presentation the Brazilian patients had both higher ALT values and gamma globulin levels. Recruitment patterns were very different in the two countries and this likely introduced bias into the study. North American Indigenous Peoples In a comprehensive study conducted in Alaska [4 1 ] , the prevalence (36/100,000) of defi nite AIH was much higher than that reported in Sweden (10.7 per 100,000) [4 2 ] . In Alaska, 40% of AIH presented acutely and the other 60% were mostly identifi ed at the time of screening blood tests. Although the age range at diagnosis ranged from 15 to 82 years they tended to be younger than reports from Norway [4 2 ] . In another report of AIH in Indigenous people in Canada, age at presentation was similar between First Nations People and those who were not. When 33 First Nations People given a diagnosis of AIH and were compared to non-FNP there were no distin- guishing features on presentation although both the grade and stage of liver disease on liver biopsy was found to be 3–4 in 10/17 (58%) FNP compared to 24/65 (34%) non-FNP – suggesting that more severe disease was present at fi rst diagnosis in FNP – this observation could be due to referral bias as many FNP live in rural areas which are hard to access [4 3 ] . South Asia AIH has in the past been considered rare in the Indian subcontinent but a report [4 4 ] from New Delhi indicated that of 1,358 patients with chronic liver disease 50 (3.43%) (1:3 males to females) were given a diagnosis of AIH. Almost all were described as being asymptomatic at presentation yet 83% were jaundiced! The mean values for bilirubin were 4.6 ± 4.9 mg/dl, AST 301 ± 267 iu/l, albumin 2.9 ± 0.6 g/l, and g (gamma)globulin 4.3 ± 0.8 g/l. At presentation 66% had splenomegaly and an active cirrhosis was present at initial referral in 76%. There was a 25% mortality over a mean follow-up period of 15.7 months. We are not told who received treat- ment or who maintained treatment. The fact that three-fourths presented for fi rst time with severe disease suggests that access to care may also be a factor leading to more advanced disease in this patient population. I n a subsequent report from a different centre in India [4 5 ] only 1.5% of their population of 2,401 patients given a diagnosis of chronic liver disease were thought to have AIH and only 34% were cirrhotic at the time of initial presentation – 79% of their patients had “defi nite” AIH according to the IAIH score. Mean duration of symptoms prior to diagnosis was 20.3 months (0.2–72). Age at presentation ranged 3 Clinical Presentation 61 from 6 to 68 years with a peak seen at 30 years. In this case series, 39% had associated autoimmune disease – diabetes, thyroiditis, and vitiligo being the most common. Of the 30 treated with corticosteroids ± azathioprine a clinical and biochemical response was seen in 70.8%. To their knowledge only one patient on immunosup- pressive medications developed acute liver failure and died. South East Asians In a small series reported from Taiwan [4 6 ] , 22 Chinese patients (M:F 1:2) 11 had a “defi nite” diagnosis and 11 “probable” according to the IAIH score – only fi ve were cirrhotic at the time of presentation (22%) despite a relatively long duration of symptoms prior to presentation, particularly in the women (91 ± 217 months). More than half of these Taiwanese patients had superimposed cholestasis (all AMA−ve) on a background of AIH in that either their serum levels for ALP > × 2ULN or they had evidence of a cholangiopathy on liver biopsy (no cholangiography performed). Nevertheless, all these patients responded well to IST (87.5%). Age at Clinical Presentation of AIH In a large (205 cases) series with AIH, a retrospective review of factors that distin- guished patients given a diagnosis over the age of 60 years was compared to those diagnosed under 30 years [ 47] . There was really only one overt difference separating age at presentation, HLA typing. In those over 60 years, DR3+/DR4− was present in 23% (58% £ 30 years) and the fi ndings for DR4+/DR3− were the reverse 47% in those >60 years versus 13% in those £ 30 years old. IAHG scores were similar. In terms of treatment response, the remission rates, relapse rates, and sustained remission rates were similar for these two age categories, but treatment failure in those

>60 years was only 5%, signifi cantly less than the 24% for those aged 30. This difference in failure to respond to therapy may be in part related to the distribution of HLA haplotypes although compliance with therapy may well have been another factor infl uencing outcome (Table 3 .6 ). Not surprisingly, liver transplant rates were higher in the young group (24%) whereas only 5% of those ³ 60 years were accepted for a liver transplant. Most reports on AIH in the elderly indicate that cirrhosis at fi rst diagnosis is more likely, suggesting that their diagnosis has been delayed. This may be because the general perception is (from studies published many years ago) that AIH is a disease of young women. Now it is evident that AIH may present at any age and thus should always be included in the differential diagnosis of someone with a 62 E.J. Heathcote Table 3.6 Clinical and HLA Findings in the Young and Elderly Age Groups at Presentation Patients ³ 60 years Patients £ 30 Clinical Features (N = 47) years (N = 31) Age (years) 69 ± 1a 25 ± 1 a Female 43 (91) 25 (81) Concurrent immune diseases 22 (47) 8 (26) Duration of symploms at accession (mo) 34 ± 7 32 ± 6 Symptoms £ 1 month duration 4 (8) 0 (0) Symptoms £ 6 month duration 16 (34) 4 (13) AST (nl, £ 31 U/L) 355 ± 48 510 ± 4 Bilirubin (nl, £ 1.1 mg/dL) 3.2 ± 0.6 3.7 ± 1 g -globulin (nl, 0.7–1.1 g/dL) 3.1 ± 0.2 3 ± 0.2 Immunoglobulin G (nl, 600–1500 mg/dL) 2812 ± 218 2630 ± 239 Cirrhosis at accession 15/46 (33)d 3/30 (10) d DR3 + /DR4 – 11 (23)c 18 (58) c DR4 + /DR3 – 22 (47)b 4 (13) b DR3 + -DR4 + 7 (15) 6 (19) IAHG Score 18.9 ± 0.3 18.4 ± 0.3 Adapted from Czaja AJ and Carpenter HA. Hepatology 2006;43:532–538 N ote: Numbers in parentheses are percentages. A ST serum aspartate aminotransferase level; I AHG International Autoimmune Hepatitis Group. Signifi cantly different from each other at level of a P < .0001, a P = .003, c P = .004, and d P = .03. “transaminitis.” If patients such as these do not undergo testing for IgG their correct diagnosis may be missed. Auto-antibody testing particularly ANA is less useful as with age the prevalence of ANA in the general population increases. In another study from Italy [4 8] , the pattern of disease in their patients >65 years given a diagnosis of AIH confi rmed the higher prevalence of HLA – DR4 (45% versus 18% in those <65 years) and they were more often asymptomatic. In this case series, the pattern on liver histology was not more severe in the elderly. This review also highlights the importance of considering a diagnosis of AIH in an older even in an asymptomatic patient identifi ed only by the incidental fi nding of elevated liver enzymes (AST/ALT). At the other end of the disease spectrum (i.e. adolescent and early adulthood), differences are observed in the distribution of HLA pattern in youngsters versus that of adults [ 4 9, 50 ]. In this study from Japan [4 9 ] , the authors compared clinical biochemical and histologic fi ndings in 15 youngsters (all <30 years) with 79 patients given a diagnosis of AIH between the ages of 40 and 50 years. The only signifi cant differences they observed was again in the distribution of HLA – DR4 (27% in children, 77% in adults) and presentation with an acute hepatitis (27% in children, only 4% in their adult group). 3 Clinical Presentation 63 The previously mentioned report by Gregorio et al. [2 1 ] indicated that chil- dren given a diagnosis of AIH on presentation had an approximately 50% chance they would at ERCP be noted to have an abnormal extrahepatic biliary tree – the fi ndings were not typical for PSC and the authors labeled these children as AIH plus “autoimmune sclerosing cholangitis.” Response to treatment was similar but the need for liver transplant appeared to be greater for those with additional biliary changes. Gender In a recent report on gender differences in “defi nite” AIH (extra two points for being female) from the UK, the authors confi rmed the usual greater prevalence of AIH in women [5 1 ] . Of 238 patients with AIH, there were 51 males. Females had a higher IAHG score than men at presentation (even though four points had to be deducted in seven females who tested AMA+ve because the old AIH score was employed). Relapse off IST was observed more often in men than women (71 versus 55%). Rates of cirrhosis at baseline were more common in men although death from any cause or need for liver transplantation was greater in the women. The author postu- lated that as estrogens enhance immune activity and androgens reduce it – this may in part relate to the differences in survival between men and women with AIH. This report also showed that independent of gender, cirrhosis at presentation (one-third) carried with it a worse prognosis. But the chance of a liver-related death was similar between males and females. Multivariate analysis indicated that the factors associ- ated with reduced survival in the entire cohort were jaundice, ascites, hematemesis, and grade on index biopsy. Men tended to present at a younger age and to have higher values of GGT. Chapter Summary 1. AIH can present in many ways from asymptomatic transaminitis to fulminant liver failure. 2. Careful exclusion of drug injury and Wilson disease particularly in young patients is important. 3. AIH is a chronic, relapsing and remitting disease: careful evaluation at baseline, nearly always including liver biopsy, is important before commit- ting patients to therapy. 64 E.J. Heathcote Useful Tips for Practitioners 1. AIH can present with systemic complaints including arthralgias, acne, and amenorrhea. 2. Immunoglobulins and autoantibodies may become positive later in the clinical course, and if the diagnosis remains in doubt these tests should be repeated. 3. A therapeutic response to treatment should be expected in more than 90% of patients: a failure to respond to treatment should lead to a re-evaluation of the diagnosis. Common Pitfalls in Practice 1. Budesonide is not appropriate in patients with cirrhosis and is not free of side effects. 2. Lack of compliance with therapy is the most common reason for a poor treatment response. 3. 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Chapter 4 Confi rmation of the Diagnosis: Interpreting the Serology Dimitrios P. Bogdanos Keywords Antibody • Autoantibody • Autoantigen • Autoimmunity • Clinician • D isease • Hepatitis • Liver • Primary biliary cirrhosis • Primary sclerosing cholangitis Abbreviations AIH Autoimmune hepatitis AMA Antimitochondrial antibody ANA Antinuclear antibody ANCA Antineutrophil cytoplasmic antibody ASGPR Asialoglycoprotein receptor c-ANCA Cytoplasmic antineutrophil cytoplasmic antibodies CYP Cytochrome ELISA Enzyme-linked immunosorbent assay HEp Human epithelioma (cells) IAIHG International Autoimmune Hepatitis Group IFL Indirect immunofl uorescence IgG Immunoglobulin G F-actin Filamentous actin FTCD Formiminotransferase cyclodeaminase LKM1 Liver kidney microsomal type 1 LC1 Liver cytosol type 1 p-ANCA Perinuclear antineutrophil cytoplasmic antibodies PBC Primary biliary cirrhosis D. P. Bogdanos (*) Liver Immunopathology , Institute of Liver Studies, King’s College Hospital , Denmark Hill , London , UK e-mail: dimitrios.bogdanos@kcl.ac.uk G.M. Hirschfi eld and E.J. Heathcote (eds.), Autoimmune Hepatitis: A Guide for Practicing 67 Clinicians, Clinical Gastroenterology, DOI 10.1007/978-1-60761-569-9_4, © Springer Science+Business Media, LLC 2012 68 D.P. Bogdanos PSC Primary sclerosing cholangitis SLA Soluble liver antigen SMA Smooth muscle antibody TBB5 Tubulin beta B5 Introduction Serological testing for autoantibodies plays an important role in the diagnosis and classifi cation of autoimmune hepatitis (AIH) [1 – 4 ] . Autoantibody testing can also help to distinguish this disease from autoimmune cholestatic diseases, such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) and facilitate diagnosis of overlapping conditions [ 1, 2, 5 ] . This chapter attempts to provide an overview of the autoantibody serology in patients with AIH that will be of value not only to hepatologists but also to those physicians and health care professionals who look after patients with this condition. Before ordering a test, the physician must have a clear indication of the outcome of the test (Fig. 4 .1 ). Worryingly, clinicians tend to rely on the results of autoantibody Unexplained hepatitis Clinician suspects AIH YES NO Autoantibody testing is NOT required Correlate with clinical, laboratory Perform IFL autoantibody test and histological findings Test Positive Test Negative Interpretation of a positive test Clinical suspicion remains Repeat testing – Recheck fresh sample YES NO Test Negative ANCA AMA Anti-LKM1 SMA ANA Still in a doubt? No further testing and/or anti-LC1 is indicated. Follow patient, and Request testing for other autoantibodies consider repeat Consider Consider Consider Consider IFL-ANCA, immunoassays for anti-SLA testing if there is PSC PBC AIH-2 AIH-1 & anti-CYP2D6 (anti-LKM1) clinical indication Test positive Test Negative Repeat testing - if positive consider AIH Additional testing for further autoantibodies is driven by specific clinical findings/diagnostic questions Fig. 4.1 Flow chart for autoantibody testing of individuals with unexplained hepatitis or clinical suspicion of autoimmune liver diseases. AIH autoimmune hepatitis, A MA antimitochondrial anti- body, ANA antinuclear antibody, A NCA antineutrophil cytoplasmic antibody, C YP2D6 cytochrome P4502D6, HEp-2 human epithelioma type 2 (cells), I FL indirect immunofl uorescence, F -actin fi la- mentous actin, F TCD formiminotransferase cyclodeaminase, L KM1 liver kidney microsomal type 1, LC1 liver cytosol type 1, PBC primary biliary cirrhosis, P SC primary sclerosing cholangitis, SLA soluble liver antigen, S MA smooth muscle antibody 4 Confi rmation of the Diagnosis: Interpreting the Serology 69 testing to make, rather than to confi rm, a diagnosis of AIH. The detection of particular autoantibody reactivities and identifi cation of their antigen specifi city may have both diagnostic and prognostic signifi cance [1 , 2 ] . However, their main indications for use are to confi rm a diagnosis of AIH in patients with suspected disease or to exclude the diagnosis in patients with uncertain clinical and laboratory fi ndings [ 1, 3, 4 ] . Autoantibody test results are also used to subclassify patients known to have AIH into serologically distinct groups (and to monitor disease activity or response to treatment over time under certain circumstances) [1 , 3, 4 ] . Hence, detection of AIH-related autoantibodies has assumed an important role in the diagnosis and management of patients with this disease. Although the results of autoantibody testing are often helpful, they can be misin- terpreted. AIH represents a small proportion of patients with liver diseases and as a consequence of that the tests per se have low positive predictive value; in practical terms, this means that a considerable proportion of the cases with detectable autoan- tibodies will not have AIH but another disease instead. Positive results for testing of antinuclear antibodies (ANA), for example, are seen more frequently in patients with systemic rheumatic diseases [6 , 7 ] . Moreover, ANA can be detected quite com- monly in patients with liver diseases unrelated to AIH and in a sizable number of healthy individuals which is increased as a result of aging [ 1, 2, 7, 8 ] . As few autoan- tibody specifi cities are highly specifi c for AIH, including anti-liver kidney microsomal type 1 (anti-LKM1) or antibodies against soluble liver antigen (SLA), most autoan- tibody tests alone are insuffi cient to establish the diagnosis of AIH [3 , 4 ] . For these reasons, the results of autoantibody testing must always be interpreted in the proper clinical context and in relationship to other laboratory test results [9 ] . The physician needs to be aware of the indications, sensitivity, specifi city, and cost of these tests. A better understanding of the diagnostic and clinical signifi cance of autoantibody reactivities will help the clinician to request the most relevant tests and to interpret correctly the report returned by the laboratory. Misuse of autoantibody test ordering or inappropriate interpretation of the results can result in clinical misjudgment, unwanted therapy, and increased health care costs [1 0 ] . Insuffi cient testing or unnec- essary repetition of liver-related autoantibody tests has been noted (local audits and personal communications), and may result in a cascade of inappropriate testing, costing the health care providers or the patients a large amount of money [1 0, 11 ] . The recent discovery of new AIH autoantigens and the development of new test assays have led to confusion over which tests to order, when to order them, and how to interpret the test results for the benefi t of the patient. An increasing number of physicians believe that the laboratory is responsible to assist the doctor to request the right tests, in the right order and at the right time. Conversely, the immunodiag- nostician’s view is that it is essential for the clinician to be aware of the tests offered by the laboratory and in a position to request the most appropriate autoantibody tests. The more the physician is aware of the signifi cance of individual autoantibody reactivities and the current laboratory practices, the greater the chance of correct autoantibody testing requests and meaningful clinical interpretation [2 ] . A diagnosis of AIH is not based on one test alone rather upon clinical history, physical examination, and histological and laboratory investigation [9 ] . AIH is 70 D.P. Bogdanos characterized by histological features of interface hepatitis, elevated transaminase levels, increase in immunoglobulin G (IgG) levels and circulating autoanti- bodies [9 ] . Autoimmune Serological Types of AIH Given suffi ciently sensitive immunofl uorescence (IFL) techniques (i.e. expert labo- ratories), autoantibodies can be detected in >95% of patients with AIH at diagnosis [ 1, 12 ] (Table 4.2 ). Those seronegative at presentation either have antibodies not detectable by IFL, like anti-SLA antibodies, or will develop autoantibodies over time [ 2, 13 ] . Autoantibody negative AIH is practically a nonexistent entity. The detection of diagnostic autoantibodies has allowed a subdivision in serologi- cally diverse groups with distinct clinical features and treatment outcome [4 , 14 ] : ANA and/or smooth muscle antibodies (SMA) defi ne type 1 AIH (AIH-1) whereas anti-LKM1 and/or anti-liver cytosol type 1 (anti-LC1) antibodies characterize patients with type 2 AIH (AIH-2). AIH-1 is the most common form accounting for 80–98% of AIH in developed countries. Usually the two patterns of serology are mutually exclusive, but if the serology is perplexed and includes positive tests for autoantibodies of both types, the disease manifestations resemble those of AIH-2 [ 15 ] . The subclassifi cation has signifi cant diagnostic and clinical implications. This is highlighted by the fact that accurate detection of anti-LKM1 antibodies in children with unexplained hepatitis is highly diagnostic of AIH-2, a condition which requires immediate attention and early administration of immunosuppressive therapy [1 5, 16] . A suggestion for a third type of AIH which is characterized by the presence of anti-SLA antibodies was not widely embraced and has been abandoned as in the great majority anti-SLA antibody positive cases fall within type 1 or type 2 AIH [ 17– 20 ] . Other forms of AIH, including the de novo appearance of AIH following liver transplantation for nonautoimmune liver diseases and recur- rence of AIH in transplanted cases, are infrequent and their serology is indistin- guishable from the conventional AIH types [2 1– 23 ] . A careful history for potential drug-induced liver injury is always important, as serology may also prove positive. Physicians should be aware that autoantibodies that occur only in AIH do not exist. Autoantibodies that were previously regarded as disease-specifi c markers, such as the anti-fi lamentous actin (F-actin) antibodies have been associated with a variety of diseases [2 4– 26 ] . The presence of ANA, SMA, anti-LKM1, and anti-SLA antibodies in patients who do not have AIH has diluted the strength of this very powerful clinical association. However, a more recent evaluation of these markers on well-defi ned patient groups demonstrated the autoantibodies to be robust in assisting the diagnosis of AIH in daily clinical practice [ 3, 12 ] . Thus, the results of autoantibody testing form part of the “simplifi ed” criteria

of the International Autoimmune Hepatitis Group (IAIHG) for the routine diagnosis of AIH [3 ] . In general, autoantibodies in AIH fl uctuate in titer and can disappear and re-appear in a proportion of cases during immunosuppressive treatment [1 , 2, 13 ] . Their presence 4 Confi rmation of the Diagnosis: Interpreting the Serology 71 per se does not establish a diagnosis nor does it indicate a specifi c treatment strategy which is not guided by the clinical setting. In the vast majority of newly diagnosed patients, the titer of autoantibodies is 1:80 or higher [3 ] . Relatively low titers are seen in a proportion of pediatric cases and in patients at drug-induced remission [1 3, 15 ] . There is no published evidence to support the use of autoantibody testing for routine use in the follow up of patients with AIH undergoing therapy. Autoantibody Testing There are many methods of testing autoantibodies, which can be a cause of error, confusion, or misinterpretation. (Table 4.1 ) The primary care physician must understand that “no test is perfect and no test is perfectly performed” [ 27 ] . Autoantibody test results in blood samples of the same patient’s reference serum may vary between different laboratories [2 , 10 ] . Re-testing of the same sample from the same laboratory can produce inconsistent results. The reasons for these discrep- ancies are numerous. Clinical laboratories use assay kits obtained from different manufacturers and this can lead to signifi cant assay-to-assay variations [1 0, 24, 25 ] . Worryingly, an inter-laboratory variation of results has been noted between different laboratories using the same kits and testing the same serum samples [1 0 ] . Thus, problems do exist between laboratory reporting, which partly depend on the variety of the screening tests and insuffi cient autoantibody assay standardization [ 2, 12 ] . These concerns have been addressed by the Committee of Autoimmune Serology of the IAIHG [ 12 ] . This international panel of experts has already published a series of recommendations for IFL methods used for autoantibody testing in patients with suspected or documented AIH [1 2 ] . A prominent issue remains that is with the signifi cant shift from IFL towards commercial enzyme-linked immunosor- bent assay (ELISA) and other enzyme immunoassays as screening tests for autoan- tibody detection [1 0, 12, 28 ] . This has raised concerns regarding the accuracy, reliability, and quality of most of these kits that is largely left to the discretion of the manufacturers. Routine testing for AIH-related autoantibodies has historically relied on IFL (other acronyms used include IFT: immunofl uorescence technique, IIFL: indirect immunofl uorescence, and IFA: immunofl uorescence assay) [4 , 12 ] . While IFL using animal tissue substrates has remained the mainstream method for the testing of a series of liver disease-related autoantibodies including SMA, AMA, and anti-LKM1 antibodies, the routine testing of ANA by IFL is currently based on human epithelial (HEp-2) cells, an epithelial cell line derived from a human laryngeal carcinoma [ 6, 29 ] . IFL is based on rodent substrates which usually include liver, kidney, and stomach [1 , 2, 12 ] . Some laboratories are preparing their own tissue substrates but most rely on commercial kits containing rat/mouse stomach/kidney composite blocks as substrates. Of concern is that several clinical laboratories purchase kits based on just employing kidney tissue which clearly limits costs both for the labora- tory and the clinics but it is potentially misleading in the diagnostic workup. 72 D.P. Bogdanos Table 4.1 Practical considerations for autoantibody testing in autoimmune hepatitis Before requesting the autoantibody tests • None of the tests are perfect and none of them are perfectly performed • Get to know your laboratory • Ask your laboratory to explain how they run the testing • Let them know you would like to be updated from time to time for new tests/assays • Keep an eye on the literature Requesting the autoantibody tests • Avoid unnecessary repeating of tests – check your records or previous results • Do not forget to send enough serum • Make sure you give enough clinical information when you ask for a specifi c autoantibody test • Minimize the risk of missing something important – asking for autoantibody testing by immunofl uorescence on a combination of rodent tissues • Do not forget: HEp-2 immunofl uorescence autoantibody testing is the “the gold standard” technique for rheumatologists but not for hepatologists • If the laboratory uses only ELISAs for autoantibody testing, the potential for “false negative” results is highly likely • Be prepared to be challenged for your autoantibody test preferences by the immunodiagnostician • Most laboratories should be able to perform the assays and issue the reports in 1–5 working days depending on the tests – ask for fast-track testing if necessary Clinical interpretation of the autoantibody test results – next steps • Do not assume that results will be consistent between different assays or laboratories • Always consider the possibility of “false positive” or “false negative” test results • Be careful with the interpretation of “weak” or “low” or “borderline positive” results • Check the “small letters” of the report – they give details of immunofl uorescent patterns and autoantibody titers/concentrations – ask if necessary • If the results are not in agreement with your clinical fi ndings, discuss this with the diagnosti- cian – you will be amazed at how much care they may take to address your concerns. They can recheck the sample • If there is still a doubt about a result, recheck the test on a fresh sample or ask to be repeated using another method (usually molecularly based assay) • If the laboratory cannot perform additional or specialized tests, ask for testing to other laboratories if necessary • Do not keep requesting antibodies without proper justifi cation on the ordering forms – the laboratory must understand your concerns • Do not forget that many autoantibodies associated with AIH can be found in overlapping conditions like primary biliary cirrhosis and primary sclerosing cholangitis • Ask for repetition of testing for results reporting the presence of anti-LKM1, anti-LC1, anti-CYP2D6 (anti-LKM1), anti-FTCD (anti-LC1), or anti-SLA – these antibodies are relatively infrequent and you must make sure that the tests are “true positive” or “true negative” While clinicians do not necessarily need to be aware of all the technical aspects of the assays, it is important that they at least know the substrate used for IFL testing. This is important because the titers described with rodent tissues are frequently dissimilar of those described using HEp-2 cells [ 7 ] . In adults, signifi cant titers equal or exceed 1:40 dilution by IFL based on rodent tissue substrates whereas on the HEp-2 cells, titers of 1:80 or higher are considered signifi cant, especially for ANA. 4 Confi rmation of the Diagnosis: Interpreting the Serology 73 In children, titers of 1:20 for ANA or SMA and 1:10 for anti-LKM1 are considered signifi cant in patients with a reasonable suspicion of AIH [3 , 12 ] . In practice, positive sera should be titrated to extinction and the autoantibody titer provides diagnostically relevant information. Within the “simplifi ed” criteria for the diagnosis of AIH issued by the IAIHG which is designed for routine clini- cal practice, emphasis is placed on the need to report autoantibody titers [3 ] . Thus, ANA or SMA IFL titers of 1:40 attract 1 point whereas ANA or SMA titers ³ 1:80 or anti-LKM1 of 1 ³ 40 attract 2 points, the sum of both results being limited to 2 points [3 ] . Other parameters include elevated immunoglobulin G (1 or 2 points depending on the level of increase), histology compatible with or typical of AIH (1 or 2 points), and exclusion of viral hepatitis (2 points) [3 ] . A reliable diagnosis of probable AIH can be made at a cutoff point greater than 6 points and a defi nite AIH at 7 points or higher [ 3] although validation studies which include a wide spectrum of other liver diseases are still needed. Selection of 1:80 or even 1:160 as a starting screening dilution expands the number of “false-negative” and can delay the early diagnosis and prompt treatment of cases with clinical suspicion of AIH [2 ] . More troubling is the appreciation that an increasing number of physicians considers that titers of 1:40 or 1:80 often have minimal clinical signifi cance. On the other hand, results (mainly for ANA) reporting titers of 1:40 or 1:80 are commonly misused by inexperienced primary care physi- cians to screen for AIH using costly or risky diagnostic procedures, e.g., imaging techniques or liver biopsy, for no clear purpose and when the diagnostic suspicion is extremely low. Diagnostic Relevance of Autoantibodies in AIH Testing for a panel of autoantibodies relevant to AIH should be requested in all patients with abnormal liver function tests of unknown etiology and/or symptoms and signs of unexplained acute or chronic hepatitis [ 1– 3, 30– 32 ] (Fig. 4.1 and Table 4 .2 ). There are no published data to support a role for autoantibody testing for population screening. These tests should not be used for generic screening purposes in asymptomatic individuals. Autoantibody testing in fi rst-degree relatives of patients with AIH is only encouraged in the appropriate clinical circumstances. Antinuclear Antibody Testing The ANA test also known as immunofl uorescence ANA (IF-ANA) or fl uorescent (F-ANA) test is widely available and is based on the detection by IFL of antibodies directed against a variety of antigens localized to the cell nucleus [6 , 7 ] . This autoan- tibody is readily detectable as nuclear staining in all the tissues of the rat or murine substrate [7 , 12, 33 ] . On the liver tissue substrate it is possible to identify different 74 D.P. Bogdanos Table 4.2 Primary (open square), secondary (open triangle), and optional (open circle) tests in patients with autoimmune liver diseases Tentative diagnosis Autoimmune Primary Biliary Primary Sclerosing Hepatitis Cirrhosis Cholangitis Tests IFL (rodent triple tissue) IFL (fi xed neutrophils) IFL (HEp-2) Anti-SLA Anti-CYP2D6 (LKM1) Anti-FTCD (LC1) Anti-F-actin Anti-sp100 Anti-gp210 Anti-MPO Anti-PR3 IFL immunofl uorescence, H Ep-2 human epithelioma cells, S LA soluble liver antigen, CYP2D6 cytochrome P4502D6, LKM1 liver kidney microsomal type 1, FTCD formiminotransferase cyclo- deaminase, F -actin fi lamentous actin, M PO myeloperoxidase, PR3 proteinase 3 nuclear patterns but these are best seen by F-ANA tests based on HEp-2 [2 , 12, 33 ] . The typical fl uorescent patterns of ANA give homogenous, speckled, nucleolar, centromere, nuclear-dot, rim-like membranous (nuclear envelope) staining [2 , 5, 6, 34 ] . The latter two facilitate the diagnosis of PBC-specifi c ANA and are helpful in distinguishing the autoantibody serology of PBC to that of AIH [ 2, 5, 34 ] . Antimultiple nuclear dot antibodies react with the nuclear body sp100 protein and anti-rim-like membranous antibodies recognize the nuclear envelope gp210 antigen (reviewed elsewhere [2 , 5, 34 ] ). Results of F-ANA are usually reported as both titer and pattern [ 7, 12 ] . As a general rule, titers of 1:160 or higher are more likely to represent true positives and do not need to be repeated [3 5 ] . Elevated titers and certain patterns carry signifi cant diagnostic connotations [ 1 , 2, 6] . These titers correspond to autoantibodies of the IgG class as the IFL procedure used antihuman IgG rather than antihuman immuno- globulin as revealing agent [7 ] . Most reports include a brief description that states whether the ANA test result is negative or positive at the cutoff dilution. Negative F-ANA test results imply lack of noticeable nuclear fl uorescence or clinically irrelevant fl uorescent patterns at low titers. A result is considered positive when the nuclei display a specifi c pattern. In case of the co-existence of several patterns those reported are the most prominent. The report usually includes a single titer which corresponds to that of the strongest pattern. 4 Confi rmation of the Diagnosis: Interpreting the Serology 75 Clinical Interpretation of ANA Testing The ANA test is mainly used as a tool for the diagnosis of autoimmune rheumatic conditions. This test is positive in more than 95% of patients with systemic

lupus erythematosus, 60–90% of patients with systemic sclerosis, and 40–70% of patients with Sjögren’s syndrome [6 ] . ANA is also useful for the diagnosis of patients with idiopathic inflammatory myositis (30–80%), drug-induced SLE, and mixed connective tissue disorders (approximately 100%) [ 6, 7 ] . Outside liver diseases, the ANA test result can be positive in a number of other rheumatic and nonrheumatic disorders including rheumatoid arthritis, Raynaud phenomenon, thyroid disease, malignancies, multiple sclerosis, and infectious diseases [6 , 7 ] . The prevalence varies widely depending on the condition, the study population, and the methodological approach [6 , 7 ] . Relatively low positive F-ANA results occur in variable percentages of healthy individuals [ 35 ] . Female sex and increasing age tend to be more commonly associated with positive F-ANA based on HEp-2 cells [3 5 ] . ANA testing constitutes a major part of the diagnostic testing for autoimmune liver diseases and is present in patients with AIH-1, PBC, PSC, de novo AIH postliver transplant [ 1, 2, 5, 13, 22 ] . ANA tests are also positive in patients with viral hepatitides or infections with hepatotrophic viruses, acute liver failure, nonal- coholic steatohepatitis, alcoholic liver disease, and hepatocellular carcinoma [2 ] . The fact that ANA can be detected in considerable number of patients with various autoimmune and nonautoimmune liver disorders demonstrates why the ANA test alone is a poor test for screening purposes [6 , 36 ] . For example, if in the clinic a patient has a positive ANA test giving a speckled pattern, this result by itself will not be helpful in distinguishing between AIH and autoimmune cholestatic disease or other liver disease that can be associated with ANA positivity [1 , 7 ] . In AIH-1, a positive ANA test is an integral component of the diagnosis [3 , 4 ] . Amongst AIH-1 cases, 30–75% of them have a positive ANA test [1 , 13 ] . ANA alone is present in approximately 10–15% of the cases whereas ANA and SMA co-occur in ~50% of patients with AIH-1. According to internationally accepted diagnostic criteria, patients with a probable or defi nitive diagnosis of AIH have a positive ANA, SMA, and anti-SLA or anti-LKM1 antibodies [ 3 ] . Thus, when the clinician is faced with a patient with the clinical suspicion of AIH, it is customary to order autoantibody testing to assist the diagnosis [1 2 ] . The homogenous nuclear pattern is found in most cases (approximately 40–70%), the remainder displaying speckled or nucleolar patterns [1 , 13 ] . Because of recog- nition of considerable overlap between patterns and diseases and, and even more worryingly in order to simplify reporting, an increasing number of laboratories report autoantibody titer without description of the fl uorescent pattern. In AIH-1, the pattern and titer of F-ANA results are variable and do not nec- essarily refl ect disease activity [1 , 13 ] . That is to say that the titer of ANA does not necessarily increase when the disease progresses and that the autoantibody does not necessarily disappear as a response to immunosuppressive treatment [1 , 13, 37 ] . 76 D.P. Bogdanos F-ANA testing requires highly trained and experienced personnel, is time consuming, and cannot be fully automated, resulting in low throughput and increased staff costs. As an alternative, many laboratories screen sera for ANA by ELISA using plates that have absorbed nuclear extract from cell preparations or mixtures of purifi ed native or recombinant antigens [3 8] . The clinical usefulness of test results of “generic” ANA immunoassay tests has not been validated in patients with AIH-1 [ 12] . The laboratory should work closely with clinicians who order generic ANA tests. Proper interpretation of test results necessitates an understanding of the assay method and its limitations. For example, if an enzyme immunoassay-based test is negative and the laboratory cannot offer a complementary F-ANA test to substantiate the “true” negativity of the test, the physician should be made aware of this [7 , 39 ] . Other types of commercially available assays for use in clinical laboratories are those measuring reactivity to individual nuclear antigens. There are also “profi le” assays which incorporate a panel of diagnostically relevant tests in the same ELISA plate or line/dot immunoassay membrane [ 6, 7 ] . These kits are widely used in rheu- matic diseases but their diagnostic utility in AIH is unclear and attempts to incorporate such testing into diagnostic algorithms are discouraged [2 , 12 ] . By and large ANA testing by enzyme immunoassays cannot be recommended at present as a replacement for F-ANA testing in cases with suspected AIH by an accredited laboratory [1 2 ] . No single AIH-1 specifi c nuclear antigen has been identifi ed so far [ 1, 4 ] . Sera from AIH-1 patients can recognize a variety of nuclear antigens including single- stranded (ss) and double-stranded (ds)DNA, histones, chromatin, centromeres, Ro-SS-A and SS-B, and various other extractable nuclear antigens, with no individual specifi city or combination of specifi cities being characteristic of AIH [ 40, 41 ] . Their testing is useful primarily for clinical research purposes. A limited number of early studies have addressed the diagnostic and prognostic signifi cance of antibodies to individual ANA targets [1 3, 40– 42 ] . Anti-dsDNA antibodies have been reported in 23–64% of patients with AIH-1 depending on the assay used for their detection [ 42 ] . A preliminary study has indicated that patients with anti-dsDNA have higher serum levels of IgG and relapse more frequently during corticosteroid treatment compared to patients without anti-dsDNA antibody positivity [4 2 ] . However, the results of ELISA do not correlate well with those of IFL using Crithidia luciliae or the Farr immunoprecipitation assay which are required for their proper detection [ 42, 43 ] . Antibodies against histones appear only in patients with F-ANA positive test and occur more frequently in younger patients with higher aminotransferase levels than those lacking this antibody [ 13, 44 ] . Antibodies to chromatin are present in approximately 40% of patients with AIH-1 [ 40 ] . They occur more frequently in male than female patients and are associated with higher levels of serum IgG. A signifi - cant proportion of antichromatin antibody seropositive patients (~40%) loose this antibody marker during corticosteroid therapy [4 0 ] . These antibodies appear to be more frequent in patients with an active disease and in patients who relapse after treatment [4 0 ] . Notwithstanding these fi ndings, the clinical value of these antibodies has not been established. There is no systematic review that addresses the prognostic signifi cance of individual ANA reactivities and their routine testing is discouraged at this time [ 12 ] . 4 Confi rmation of the Diagnosis: Interpreting the Serology 77 Antismooth Muscle Antibody Testing Serum samples from AIH-1 cases with antismooth muscle antibodies (anti-SMA or SMA) typically stain the wall of arterial blood vessels (V), the mesangium of renal glomeruli (G), and fi bers surrounding the kidney tubules (T) giving the VG or VGT patterns [1 2, 45 ] . SMA also stains the smooth muscle of the gastric mucosa. The use of vinblastine-arrested cultured fi broblasts as a substrate for IFL has also revealed different fl uorescent patterns targeting mainly actin, tubulin, or intermediate fi la- ments [ 46 ] . The VGT pattern corresponds to the microfi lament (MF) staining of isolated fi broblasts and represents a cable pattern across the cell also known as “antiactin” [4 7 ] . These antibodies give a characteristic cytoskeletal pattern on vas- cular smooth muscle (VSM) 47 cells from rat embryonic thoracic aorta [2 4, 48 ] . It appears that the characteristic microfi lament pattern on VSM47 correlates strongly with that of VGT on rodent tissues and is easier to read. It is also highly specifi c for AIH-1, being present only in a minor proportion of pathological controls with positive SMA antibody positive tests [2 4, 48 ] . If these fi ndings are confi rmed on larger number of patients and in other laboratories, VSM47 cells can be proposed as a complementary substrate for the detection of AIH-1 specifi c SMA [2 4, 48 ] . Very few laboratories describe the SMA pattern of IFL on rodent tissue. Most clinicians are unfamiliar with the classifi cations of SMA and the relevant termi- nology. The clinician must be aware that autoantibody tests reporting a VGT or “antimicrofi lament” or “antiactin” SMA positive tests describe in practice the same autoantibody pattern. Efforts to achieve global harmonization of SMA autoantibody testing and results reporting are underway by the IAIHG. Ideally, a positive SMA test should be reported both as a particular staining pattern and as a titer. In the clinic, it is the presence of the antiactin pattern that the physician needs to know. In practice, the SMA test result is usually reported as positive or negative without a description of the pattern or the titer. Clinical Interpretation of SMA Testing SMA positive tests giving the “antiactin” IFL pattern have long been regarded highly specifi c for AIH-1, though some 3–40% of patients with this form of the disease test negative [ 1, 49 ] . The diagnostic utility of the SMA test largely depends on the clinical setting. As for F-ANA, the SMA test performed by IFL has been used for the assessment of patients with clinical and/or laboratory suspicion of AIH and has been incorporated in the diagnostic criteria for this disease by the IAIHG [3 , 4 ] . While the ANA test is positive in AIH and a group of diverse infl ammatory disor- ders, SMAs at high titer are mainly found in patients with AIH-1. Unlike ANA, these antibodies are infrequently present in patients with SLE or other autoimmune rheumatic diseases [4 6 ] . Of note, the anti-SMA test needs not to be confused with the SLE-specifi c anti-Sm antibody test. SMA positive tests are reported in a variety 78 D.P. Bogdanos of liver and nonliver diseases at varying frequencies but their titers and patterns differ from those seen in AIH [8 , 46, 50, 51 ] . SMA have been reported in 20–50% of cases with chronic hepatitis B and hepatitis C viral infection [8 , 50– 54 ] . SMA seropositivity has been reported in ~50% of PBC patients without evidence of co- existent AIH [4 9, 55 ] . SMA tests in these groups of patients show relatively low titers and a fl uorescence staining mainly of the V pattern. In non-liver-related condi- tions, SMA can be present in patients with malignant diseases and patients infected with cytomegalovirus. Unlike ANA, the incidence of SMA does not increase with age and is not higher in females compared to males [5 6 ] . SMA titres tend to become lower and may even disappear during immunosup- pressive treatment in a signifi cant proportion of patients with AIH-1 [ 13 ] . Their titer at diagnosis and their behavior over time do not predict disease outcome [ 13 ] . A longitudinal study of pediatric cases with AIH has reported a correlation of SMA titers with AST levels suggesting that the titers of these autoantibodies can be barometers of disease activity [3 7 ] . Attempts to identify a single, AIH-1 specifi c target of SMA have failed so far [4 9, 57] . Most of the studies have provided data suggesting that actin in its polymerized fi lamentous (F-actin) rather than its monomeric G actin form is a major target of SMA [4 6, 58– 60] . However, there is no molecular proof as yet that F-actin is indeed the only autoantigen associated with the AIH-specifi c VGT/MF pattern [2 5 ] . In recent years, commercial ELISA and dot/line immunoassays have been devel- oped to detect the presence of anti-F-actin antibodies [2 4– 26, 51 ] . The introduction of these assays has generated a series of studies investigating the diagnostic and clinical utility of this autoantibody and its relationship to the patterns of SMA. These studies show that the sensitivity and specifi city of the anti-F-actin antibody tests are lower than that of the SMA VGT

positive tests. Anti-F-actin antibodies are detected in up to 25% of cases with AIH-2, PBC, PSC, viral hepatitis, alcoholic liver disease, and celiac disease, a fi nding which is in sharp contrast to the high specifi city of the IFL VGT test. The results obtained with the IFL and molecular assays overlap considerably, but by no means completely and the discrepant cases vary among studies. The presence or absence of anti-F-actin antibodies does not appear to be prognostically useful at present. One can reasonably assume that based upon the results of these studies, at present anti-F-actin antibody kits are inadequate for autoantibody screening in patients with suspected AIH. Notwithstanding these observations, high titer anti-F-actin antibodies have good correlation with the SMA VGT immunofl uorescent staining and are associated with AIH-1. The prognostic signifi cance of these antibodies is not clear, though some early data indicate that anti-F-actin antibodies are more prevalent in patients who have younger age at presentation, a poorer response to treatment, and faster progression to liver failure compared to patients who are seronegative for this antibody [ 61 ] . A more recent study has reported anti-F-actin antibodies by ELISA in individuals with normal liver function and no other evidence of liver disease [6 2 ] . Larger clinical studies are necessary to provide outcome data to validate the rationale for testing of these antibodies in the clinic. 4 Confi rmation of the Diagnosis: Interpreting the Serology 79 Antiliver Kidney Microsomal Antibody Testing This antibody stains the Liver and Kidney and is absorbed out by the Microsomal fraction of liver homogenate. These three characteristics of the antibody have led to labelling it as anti-LKM antibody. [ 63, 64 ] . “Microsomal” is something of a misnomer as “microsomes” are the constituents derived mostly from the endo- plasmic reticulum wherein the anti-LKM autoantigens are located. These frac- tions are obtained by differential ultracentrifugation of liver homogenates and are mainly used for research purposes. Anti-LKM1 brightly characteristically stains the third portion of the proximal renal tubules and the cytoplasm of the hepatocytes but it spares cells of the gastric mucosa [1 , 2, 12, 63, 64 ] . Clinical Interpretation of Anti-LKM Antibody Testing Homberg et al. were the fi rst to suggest that anti-LKM antibodies defi ne a second type of AIH, which they named AIH-2 [1 4 ] . Anti-LKM antibody was soon renamed anti-LKM1 because other LKM immunofl uorescent patterns were detected in cases of tienilic acid-induced hepatitis (anti-LKM2) and chronic viral hepatitis D infection (anti-LKM3) [6 5, 66 ] . A fourth type of anti-LKM antibodies has been described in patients with AIH associated with autoimmune polyendocrinopathy-candidiasis- ectodermal dystrophy (APECED), in which the pattern of staining is indistinguishable from that of anti-LKM1 [6 7 ] . Confusing though it might be, type 1 anti-LKM is detected in type 2 AIH! Anti-LKM1 is a frequently misdiagnosed autoantibody, being commonly mis- interpreted as AMA and this information is important for the clinical interpreta- tion of the autoantibody test results [6 8– 70 ] . The confusion between AMA and anti-LKM1 arises because of the ability of these autoantibodies to stain the renal tubules [1 , 2 ] . The difference between the two patterns can be seen by a trained eye and is readily appreciated when the kidney tissue section contains both distal and proximal tubules [ 1 , 2] . AMA stains strongly the mitochondria-rich distal tubules which are smaller than the proximal tubules stained by anti-LKM1 anti- bodies [ 1, 2 ] . AMA also stains the gastric parietal cells within the stomach, which are spared by anti-LKM1, whereas AMA stains hepatocytes much less brightly than does anti-LKM1 [1 , 2 ] . This is why several clinical laboratories analyze samples using the three-tissue substrate instead of kidney/stomach or kidney tissue substrate alone. The combination of the three tissues allows better serologi- cal interpretation and minimizes the probability of diagnostic errors. The clinician must understand that the interpretation of staining fl uorescent patterns relies heav- ily on the experience and the skills of the reader. Quality assurance programs around the world have noted inability of several laboratories to report correctly the presence of anti-LKM1 antibodies by IFL [2 ] . Physicians must always be in a 80 D.P. Bogdanos position to challenge autoantibody test results reports which are inconsistent with their clinical fi ndings. For example, AMA is extremely rare in pediatric patients and children with PBC 15 yrs, when AMA is reported in a child with clinical and histological characteristics of AIH, the serological report is almost certainly incorrect [6 8, 70– 72 ] . Anti-LKM1 seropositivity strongly supports the diagnosis of AIH-2, particularly in the absence of HCV because these antibodies in isolation or combination with anti-LC1 (discussed later) are present virtually in all newly diagnosed AIH-2 patients [3 , 15 ] . In practical terms (by defi nition), the likelihood of a diagnosis of AIH-2 in a patient with anti-LKM1 antibody positivity and negative viral hepa- titis C markers is approximately 100% [3 , 4, 15 ] . Anti-LKM1 antibodies are reported in a proportion of adult (0–6%) or pediatric (0–11%) cases with chronic hepatitis C infection [ 1, 2, 51, 73, 74 ] . Thus, a clinician cannot simply rely on an anti-LKM1 antibody positive test to make a defi nite diagnosis of AIH-2. Experts in busy liver outpatient clinics may see chronic HCV infected patients with anti- LKM1 positive results unrelated to AIH-2. Some of those experience transami- nase fl ares and adverse reactions during antiviral treatment and need to be monitored at regular intervals [7 5 ] . A recent study in a large cohort of anti-LKM1 antibody positive suggests that antiviral treatment is as benefi cial in these patients as in anti-LKM1 negative HCV patients, and that the rare liver enzyme fl ares are suffi ciently controlled by corticosteroids, allowing continuation of antiviral therapy [ 75 ] . Compared with pediatric AIH-1 patients, those with AIH-2 tend to be younger, have partial IgA defi ciency, have higher levels of bilirubin and transaminases at diagnosis, and present more frequently with fulminant hepatic failure [1 5 ] . Early studies conducted on French and Italian patients support the contention that pediatric AIH-2 cases have more frequently aggressive disease compared to children with AIH-1 but this does not appear to be the case in series followed up at King’s College London [ 14, 15, 37, 76 ] . While the target antigens of ANA and SMA certainly need better defi nition at the molecular level, that of anti-LKM1 antibody has been clearly identifi ed in late 1980s as cytochrome P450 IID6 (CYP2D6), a member of the hepatic P450 microsomal family of enzymes [7 7– 80 ] . Subsequent studies have reported that the target of anti-LKM2 antibody is CYP2C9 [ 80 ] . The autoantigens of anti-LKM3 antibody are members of the uridine diphosphate glucuronosyl transferases (UGT) family of enzymes and those of the APECED-associated AIH anti-LKM antibody are the CYP1A2, CYP2A6, and CYP2D6 enzymes [8 0, 81 ] . The identifi cation of CYP2D6 as the target antigens of anti-LKM1 has enabled the development of enzyme immu- noassays based on the use of the recombinant antigen which have proven useful in assisting the detection of anti-LKM1 antibodies [1 , 2 ] . Usually, the titers of IFL- detected anti-LKM1 antibodies correlate with anti-CYP2D6 antibody concentra- tions by ELISA, but at times weak positive or borderline anti-LKM1 test results are true positive by anti-CYP2D6 antibody ELISA assays and such complementary testing can solve diagnostic uncertainties. The inability of these ELISAs to detect anti-LKM1 antibodies in patients with chronic hepatitis C virus infection compared 4 Confi rmation of the Diagnosis: Interpreting the Serology 81 to IFL and radioimmunoprecipitation is possibly because of the advantage of the latter assays to identify conformational epitopes undetectable by ELISA [ 82, 83 ] . Short CYP2D6 peptides used as antigenic preparations perform less well than those using full-length protein and their diagnostic use is limited [ 82, 84 ] . The laborato- ries must ensure that anti-LKM1 or anti-CYP2D6 positive tests are “true positives.” In case of a positive test, the physicians must be informed of the outcome of the test and the diagnostic importance of the fi nding. The experience of a West Coast American Liver Transplantation Center has shown that lack of timely anti-LKM1 detection can lead to labeling AIH-2 as cryptogenic cirrhosis [3 1, 69 ] . Misdiagnosis or late diagnosis ultimately leads to liver transplantation, or even death, for a condi- tion exquisitely responsive to immunosuppressive treatment and for an antibody that is easily detectable by commercially available ELISAs [2 , 15, 30, 69 ] . Antiliver Cytosol-1 Antibody Testing Anti-LC1 antibodies have been known for more than 20 years [8 5 ] . It is the second serological marker of AIH-2. When present in isolation it stains the cytoplasm and spared the cellular layer around the central veins of juxtavenous hepatocytes [1 , 12, 85] . In two third of the cases, however, anti-LC1 is obscured by the simultaneous presence of anti-LKM1 and cannot be detected by IFL [1 , 12, 85 ] . Alternative meth- ods for its detection include double dimension immunodiffusion, counter immuno- electrophoresis, and immunoblotting [8 6, 87 ] . The target antigen of anti-LC1 has been identifi ed as formiminotransferase cyclodeaminase [8 8, 89 ] Clinical Interpretation of Anti-LC1 Antibody Testing Anti-LC1 antibody can be the sole marker in one third of cases with AIH-2. Like anti-LKM1, anti-LC1 antibodies have been reported in a proportion of chronic hepatitis C virus infected patients, most of whom had anti-LKM1 antibody positive tests [8 6 ] . An Italian study conducted in a relatively small number of anti-LKM1- and/or anti-LC1-positive AIH-2 patients has indicated that reactivity to LKM1 was unaffected during treatment, whereas reactivity to LC1 disappeared or signifi cantly decreased (>50%) during remission and fl ared up during relapse, but this observa- tion requires confi rmation [9 0 ] . Nowadays, molecular assays for the detection of anti-FTCD antibodies are com- mercially available and can be used as alternative or complementary test to assist the diagnosis of anti-LC1. It has become evident that there is a wide variability in clinical practice regarding the utility of autoantibodies in the diagnosis and care of patients with AIH-2. A small number of clinical laboratories have implemented this test in their routine diagnostic testing. 82 D.P. Bogdanos Antineutrophil Cytoplasmic Antibody Testing ANCA is detected by IFL using as substrate human ethanol-fi xed neutrophils. Two patterns of staining can be recognized: a cytoplasmic (c-ANCA) and a perinuclear (p-ANCA). The classical p-ANCA staining is the result of an artifact caused by the ethanol fi xation of the neutrophils [ 91] . The fi xation procedure leads to the migra- tion of some positively charged cytoplasmic antigens to the negatively charged nuclear envelope, giving the characteristic p-ANCA staining. The classical p-ANCAs are serological markers of microscopic polyangiitis and their major tar- get autoantigen is myeloperoxidase. c-ANCAs are found in patients with Wegener’s granulomatosis and are directed mainly against proteinase 3. A third type of ANCA, called atypical p-ANCA is seen in patients with AIH-1, ulcerative colitis, and PSC [ 92 ] . Unlike classical c-ANCA and p-ANCA which recognize components of the neutrophilic cytoplasm, atypical p-ANCAs with antigen(s) localized within the nuclear envelope of neutrophils [ 93 ] . An experienced reader can differentiate between typical and atypical p-ANCA using both ethanol and paraformaldehyde- fi xed neutrophils [9 2, 94 ] . In our experience, atypical p-ANCA antibody positive tests must be checked by F-ANA and with specifi c assays for myeloperoxidase and proteinase 3. Clinical Interpretation of ANCA Antibody Testing Atypical p-ANCA have been reported in 50–92% in patients with AIH. A signifi cant number of laboratories do not report the presence of the atypical pattern. Most clinicians are unaware of the lack of clinical utility of atypical ANCA. The presence of atypical p-ANCA should not be measured for screening purposes in patients with suspected AIH. Atypical p-ANCA antibody positive samples recognize a 50-kDa nuclear pore complex antigen which has been identifi ed as the tubulin beta chain 5 (TBB5) [9 5, 96 ] . Antisoluble Liver Antigen Antibody Testing Anti-SLA (also

known as antisoluble liver antigen-liver pancreas) antibody has emerged as one of the most specifi c markers of AIH [1 7, 18, 96, 97 ] . This antibody cannot be detected by IFL and its testing has relied on molecular-based assays [1 7, 18, 97– 100 ] . It can be the only antibody present in a small group of patients with AIH, but most frequently is present in typical cases of AIH-1 [1 3, 17, 98, 101, 102 ] . The target antigen of anti-SLA antibodies is a selenocysteine synthase critical for the metabolism of selenocysteine called S ep ( O -phosphoserine) tRNA:S ec 4 Confi rmation of the Diagnosis: Interpreting the Serology 83 (selenocysteine) tRNA s ynthase or simply SepSecS, an acronym which has been approved by the Gene Nomenclature Committee of the Human Genome Organization (HUGO) [1 01, 103 ] . It is anticipated that it will take a long time for clinical immu- nology laboratories to become familiar with the formal name of the antigen. Commercial ELISA, immunoblotting, and dot or line immunoassays, which are increasingly replacing the inhibition ELISAs originally used for anti-SLA antibody detection, are currently used in routine practice [4 0, 99, 100, 102, 104, 105 ] . Clinical Interpretation of Anti-SLA Antibody Testing Depending on the geographic origin of the patients with AIH or the conventional assays used for their detection, anti-SLA antibodies are present in 5–22% of patients with AIH-1 [3 2, 102, 105 ] . Provided that a high sensitivity method is used for its detection, anti-SLA antibody is also present in up to 50% of patients with AIH-2 and also in patients with the pediatric form of autoimmune sclerosing cholangitis [ 19 ] . More recently, anti-SLA antibody has been described in 22% of patients with acute liver failure using a very sensitive, radiological assay but it is not clear whether the presence of these antibodies in patients with this condition refl ects an underly- ing component responsible for the induction of acute liver failure [1 9, 106 ] . In a similar fashion, a study based on a radioisotopic immunoprecipitation method has reported anti-SLA antibodies in chronic hepatitis C virus infected patients [1 07 ] . However, a series of studies using in house or commercially available molecular- based assays were unable to detect anti-SLA antibodies in this group of patients [1 9, 104, 106 ] . Recently, a multicenter study from France has reported that among 81 cases with true-positive anti-SLA antibody positive tests, 3 (4%) had evidence of chronic HCV infection unrelated to AIH [1 08 ] . The signifi cance of these fi ndings is far from clear, and the need to screen for this marker in this group of patients is uncertain at best. Some experts have proposed that testing of anti-SLA antibodies maybe useful to identify a subset of individuals initially thought to have cryptogenic cirrhosis [ 18, 30, 32 ] . Interestingly, the simplifi ed criteria proposed by the IAIHG have included anti-SLA in the routine autoantibody tests used for the diagnostic testing of AIH [3 ] . Whether this will work in practice remains to be seen. Most clinical laboratories are unlikely to implement this test for diagnostic use. Anti-SLA anti- bodies denote patients with a more severe course of AIH and a propensity for relapse during maintenance therapy or after corticosteroid withdrawal compared to those without anti-SLA antibodies [1 9, 30, 102 ] . There is no unanimity of opinion, but the presence of anti-SLA antibody may alter therapeutic strategy for a subset of patients. If further prospective studies confi rm a consistent relationship between anti-SLA antibody positivity and clinical indexes, it will be possible to use this antibody as a rational approach to monitor disease’s activity and outcome. 84 D.P. Bogdanos Antiasialoglycoprotein Receptor Antibodies Antibodies to liver membrane antigens received special attention in the 1980s and early 1990s since their concentration correlated with the histological severity of AIH. Attempts to identify antigens specifi cally expressed on the hepatocyte surface which could serve as targets in autoimmune liver diseases have led to the identifi ca- tion of the asialoglycoprotein receptor (ASGPR). ASGPR is a type II transmem- brane glycoprotein. Anti-ASGPR antibodies cannot be detected by IFL. The detection of these antibodies relies on molecularly based assays. A limited number of studies investigated the diagnostic and clinical utility of this marker. Early studies have reported the presence of anti-ASGPR antibodies in ~90% of patients with AIH but are also in up to 14% of patients with PBC, chronic hepatitis B and C, and alcoholic hepatitis. Thus, anti-ASGPR antibodies can co-occur with AMA, SMA, ANCA, and even anti-LKM1 antibodies. Persistence of anti-ASGPR was indicative of unresponsiveness to immunosuppressive treatment and reappearance was highly suggestive of relapse especially after corticosteroid withdrawal. Because of the diffi culty to establish a reliable assay, a commercial kit was not available and for many anti-ASGPR antibody testing was limited to academic research laboratories. A recent study has assessed the performance of a new commercial kit which detects anti-ASGPR antibodies by ELISA [1 09 ] . Anti-ASGPR antibody positive tests were reported in 70% of patients with AIH at diagnosis and in only 1/262 (0.4%) of the pathological and normal controls demonstrating a specifi city of 99.4% [ 109 ] . According to the authors, anti-ASGPR antibody levels signifi cantly correlated with transaminase and IgG levels. The number of patients and controls is relatively small to draw meaningful conclusions. Moreover, the correlations between disease’s activity indices and the levels of autoantibodies are modest. Thus, though interesting these data should be viewed as provisional and will need to be validated externally in larger cohorts. Conclusion In conclusion, a considerable number of autoantibody tests are available to assist the diagnosis of AIH. Not one of these tests is, however, perfect, and most of them have signifi cant constraints. Moreover, the interpretation of the autoantibody test results is not an easy task. The strength of most of these tests is their high negative predictive value, that is, they have the ability to exclude disease; for example, a negative SMA, ANA, anti-LKM1, or anti-SLA test makes AIH much less likely. Conversely, in a minority of autoantibody tests and under certain circumstances there is a high proba- bility of confi rming the presence of the disease, for example, anti-LKM1 is a good marker of AIH-2 in patients not-infected with viral hepatitis C. However, the predictive values are rarely suffi cient per se to be defi nitive regarding the diagnosis. Nevertheless, when used wisely, they can provide answers to differential diagnostic dilemmas. 4 Confi rmation of the Diagnosis: Interpreting the Serology 85 Chapter Summary 1. AIH is characterized by positive autoantibody tests: Type 1 is marked by a positive test result for antinuclear and/or antismooth muscle antibody and type 2 for antiliver kidney microsomal type 1 and/or antiliver cytosol type 1. 2. AIH is an unlikely diagnosis in patients with chronic hepatitis and true autoantibody negative tests; the results of autoantibody testing form part of the criteria for routine diagnosis of AIH. Most tests, however, lack prognostic value and repeated testing is discouraged. 3. Detection of autoantibodies is mainly performed by indirect immunofl uo- rescence or ELISA; the fi rst detects a broad array of autoantibody speci- fi cities of relevance to AIH while the second allows the identifi cation of reactivities to specifi c autoantigens and assists the diagnosis of the disease in suspicious cases with equivocal, undetermined, or perplexing immuno- fl uorescent patterns. Useful Tips for Practitioners 1. Avoid unnecessary repeating of tests without proper justifi cation worth- while if seen very early in course of disease. 2. Be careful with the diagnostic value and clinical interpretation of “borderline positive” autoantibody test results. 3. Combination of testing by indirect immunofl uorescence and molecularly based assays is unnecessary in the great majority of the cases. It can prove of help in cases with clinical suspicion of AIH and unspecifi ed fl uorescent patterns of borderline results. Common Pitfalls in Practice 1. Clinicians should not rely on autoantibody test results to make a diagnosis: their role is to confi rm the diagnosis. 2. In the correct context, moderate or low positive titers may still be of considerable diagnostic signifi cance. 3. Physicians should engage with the clinical immunology labs if results are not in agreement with the clinical or histological fi ndings. 86 D.P. Bogdanos References 1 . Bogdanos DP, Mieli-Vergani G, Vergani D. Autoantibodies and their antigens in autoimmune hepatitis. Semin Liver Dis. 2009;29:241–53. 2 . Bogdanos DP, Invernizzi P, Mackay IR, Vergani D. Autoimmune liver serology: current diagnostic and clinical challenges. World J Gastroenterol. 2008;14:3374–87. 3. Hennes EM, Zeniya M, Czaja AJ, Pares A, Dalekos GN, Krawitt EL, et al. Simplifi ed criteria for the diagnosis of autoimmune hepatitis. 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Autoimmunity. 2004;37:217–22. 108. Eyraud V, Chazouilleres O, Ballot E, Corpechot C, Poupon R, Johanet C. Signifi cance of anti- bodies to soluble liver antigen/liver pancreas: a large French study. Liver Int. 2009;29:857–64. 109. Hausdorf G, Roggenbuck D, Feist E, Buttner T, Jungblut PR, Conrad K, et al. Autoantibodies to asialoglycoprotein receptor (ASGPR) measured by a novel ELISA–revival of a disease- activity marker in autoimmune hepatitis. Clin Chim Acta. 2009;408:19–24. Chapter 5 Mimics of Autoimmune Hepatitis: Drug Induced and Immune Mediated Liver Disease Arndt Vogel and Michael P. Manns Keywords Hepatotropic viruses • Drug toxicity • Autoimmune reactions • Autoimmune diseases • Primary biliary cirrhosis Introduction The liver is the target of numerous acute and chronic infl ammatory processes. Major causes are hepatotropic viruses, toxicity of drugs and their metabolites, autoimmune processes, or genetic defects. Serological markers of autoimmunity can be detected in serveral of these disorders including alcoholic [1 ] and non-alcoholic fatty liver disease [2 , 3 ] , acute [4 ] and chronic [5 – 12 ] viral hepatitis, and drug-induced hepa- titis [ 13, 14 ] . It is however important to distinguish between autoimmune reactions and autoimmune diseases. The pathogenetic role of most, if not all, autoantibodies is still unclear and it is not known whether autoantibodies that are observed in pri- marily non-autoimmune liver disease contribute to tissue damage. In most liver dis- eases associated with serological markers of AIH, autoantibodies against phase I and phase II drug metabolizing enzymes may also be detected (Fig. 5 .1 ). Autoimmune reactions against members of the families of cytochromes P450 (P450) and UDP – glucuronosyltransferases (UGT) will also be discussed. A. Vogel • M. P. Manns (*) Department of Gastroenterology, Hepatology and Endocrinology , Hannover Medical School , Hannover , Germany e-mail: manns.michael@mh-hannover.de G.M. Hirschfi eld and E.J. Heathcote (eds.), Autoimmune Hepatitis: A Guide for Practicing 93 Clinicians, Clinical Gastroenterology, DOI 10.1007/978-1-60761-569-9_5, © Springer Science+Business Media, LLC 2012 94 A. Vogel and M.P. Manns Fig. 5.1 Detection of LKM-1 antibodies by immunofl ourescence Cytochrome P450 Family and Immune-Mediated Liver Injury Cytochrome P450 (CYP) is a very large and diverse superfamily of drug-metabolizing enzymes, which are predominately expressed in the liver, but which can also be found in several other organs such as testes, ovaries, adrenals, respiratory tract, lungs, kidney, brain, the small intestine, and in the adipose tissue of the breast. The initial nomenclature of CYPs relied on evolutionary relationships as depicted in phyloge- netic trees using number–letter–number combinations. The fi rst number designates a family that shared 40% or greater amino acid sequences. The subsequent letter denotes a particular subfamily within each family that contains CYPs that are at least 55% identical. The last number in the name identifi es the specifi c CYP enzyme. Recently, a web page has been constructed that contains a continuously updated list of allelic variants of CYP genes (h ttp://www.imm.ki.se/CYPalleles ). CYPs use a plethora of both exogenous and endogenous compounds as sub- strates in enzymatic reactions. They are also involved in the biosynthesis of steroids, fatty acids, and bile acids. Beside CYP3A and CYP2C, which represent 30% and 20% of all CYPs, other important isoenzymes are CYP 1A2 (13%), CYP2E1 (7%), CYP2A6 (4%), CYP 2D6 (2%), and CYP2B6 (0.4%) [ 15 ] . CYPs have been identifi ed 5 Mimics of Autoimmune Hepatitis… 95 as self-antigens in different forms of autoimmune reactions, including drug-related, viral, or autoimmune hepatitis. Though many studies investigated CYPs in autoimmune disease, the role of CYPs as self-antigens remains incompletely understood. In some cases, the capacity of CYPs to activate substrates to highly reactive metabolites that can bind to cellular marcomolecules including the CYP catalyzing the reaction may be an initiating step that triggers the immune response to the newly formed neoantigen. At least ten human CYPs are recognized by autoantibodies associated with either acute or chronic liver diseases. This text summarizes the current knowledge about the role of CYPs in different forms of hepatitis and underlines the importance of CYPs as potential self-antigens in disease pathogenesis. Possible mechanisms that induce loss of self-tolerance leading to autoimmune attack will be illustrated. CYPs in Autoimmune Hepatitis Autoantibodies against microsomal proteins form a heterogeneous group and are associated with several immune-mediated diseases including AIH, drug-induced hepatitis, the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), and chronic hepatitis C and D infection [ 16 ] . Antibodies to LKM fi rst discovered in 1973 by indirect immunofl uorescence are regarded as serological markers of AIH type 2 (Fig. 5 .2 ). They are reactive with the proximal renal tubule and hepatocellular cytoplasma [1 7, 18 ] . Subclassifi cation is achieved by ELISA and Western blot, preferably with recombinant antigens. The 50 kD antigen of LKM-1 was identifi ed as CYP2D6 by two independent approaches. The fi rst approach involved screening of human liver complementary DNA libraries and the identifi - cation of CYP2D6 by sequence analysis [ 19, 20 ] . The second approach used the specifi c inhibition of the enzymatic activity of the target protein for identifi cation, showing that LKM-1 autoantibodies inhibit the hydroxylation of bufuralol, a substrate of CYP2D6 in isolated liver microsomes. Extensive mapping studies identifi ed several epitopes recognized by sera of patients with AIH type 2 and HCV infection [ 21– 25 ] . LKM-1 antibodies in AIH mainly recognize short linear epitopes of CYP2D6 (CYP2D6 , CYP2D6 , and CYP2D6 ) [2 1– 23 ] (Fig. 5 .3 ). 196–218 254–271 321–351 Minor epitopes are CYP2D6 and CYP2D6 . Some of these epitopes exclu- 373–389 410–429 sively react with sera from patients with AIH (such as CYP2D6 ) or with sera 254–271 from patients with HCV (such as CYP2D6 ), whereas other are recognized by 200–214 LKM1 in both diseases (such as CYP2D6 ). 193–212 Whether anti-CYP2D6 antibodies are only of diagnostic value or also play a role in the pathogenesis of AIH remains unclear. Of note, 5–10% of the population are CYP2D6 defi cient and to date, AIH type 2 has never been described in CYP2D6- defi cient individuals suggesting that the expression of CYP2D6 might be a condition sine qua non for developing AIH type 2 [2 6 ] . Human CYP enzymes are primarily membrane-associated proteins located either in the inner membrane of mitochondria or in the endoplasmic reticulum of cells. 96 A. Vogel and M.P. Manns Fig. 5.2 Three-dimensional structure of CYP2D6 with known epitopes detected by AIH patients. Manns MP, Vogel A. Hepatology. 2006;43:S132–44. Used with permission Fig. 5.3 Cytchrome P 450 Enzymes and UDP-Glucuronosyltransferases as Autoantigens and their Disease Associations. Manns MP, Obermayer-Straub P. Hepatology. 1997 Oct;26(4): 1054–66. Used with permission 5 Mimics of Autoimmune Hepatitis… 97 One potential prerequisite for an immune-pathogenic relevance is that the antigenic regions of CYP2D6 are exposed on the external hepatocellular membrane, where antibodies that induce an immune reaction can detect them. Several studies indicate that CYP2D6 may access the cell membrane via a vesicular transport route from the endoplasmic reticulum [2 7 ] . Moreover, expression of CYP2D6 on the surface of hepatocytes can be detected by indirect immunofl uorescence and confocal laser microscopy of isolated rat hepatocytes probed with LKM-1 positive sera from patients with chronic hepatitis C or AIH type 2 [2 8 ] . Some studies revealed that antibodies directed against CYPs are able to inhibit the activity of the enzyme in vitro suggesting that these antibodies might have an additional biological signifi cance [2 4, 29 ] . However, this observation has not been confi rmed in in vivo experiments. Two amino acids (Asp-301 and Glu-216), which are relevant for substrates and inhibitors, are located in proximity to the main epitopes on CYP2D6. Thus, it is possible that antibody-binding to those epitopes results in an interference with the enzyme’s function [3 0 ] . Another option is an antibody-mediated conformational change of CYP2D6, which impairs its function. CYPs in the Autoimmune Polyendocrine Syndrome Type 1 (APECED) Autoimmunity against organ-specifi c CYP enzymes is also characteristic for APECED syndrome. APECED is a rare autosomal recessive disorder, which is char- acterized by an immune-mediated destruction of endocrine tissues, chronic candidiasis, and additional ectodermal disorders [3 1 ] . In the majority of cases candidiasis is the fi rst clinical manifestation to appear before the age of 5 years. This is followed by hypoparathyroidism before the age of 10 years, and later by the onset of Addison’s disease before the age of 15 years. Immunosuppressive therapy has been successfully used to treat various complications of APECED. In contrast to many other autoim- mune diseases, APECED is associated with mutations of a single gene, designated autoimmune regulator (A IRE ) [3 2 ] . AIRE up-regulates the transcription of certain organ-specifi c self-antigens in medullary thymic epithelial cells, and has a role in the negative selection of organ-specifi c thymocytes. So far, more than 50 different muta- tions of the AIRE gene have been identifi ed and are distributed throughout the entire non-coding and coding region [3 3, 34 ] . The variety of autoimmune diseases reported in patients with APECED suggests that AIRE might contribute to the etiology of other autoimmune disorders. Recent studies however indicate that common muta- tions in the AIRE gene do not play a major role in autoimmune liver diseases, and are therefore a unique feature of APECED [3 5, 36 ] . Chronic hepatitis affects only 10–18% of the patients. Similar to AIH-2, autoan- tibodies to CYP1A2 and CYP2A6 have been described as markers of liver disease in patients with APECED, but antibodies to tryptophan hydroxylase are the best predictors for hepatitis in APECED [3 7– 40 ] . Other organ-specifi c antibodies 98 A. Vogel and M.P. Manns detected in these patients are directed against CYPc21 (21-hydroxylase), CYPscc (side chain cleavage enzyme), and CYPc17 (17-hydroxylase) [4 1– 43 ] . While anti- bodies directed against CYPc17 and CYPscc correlate with hypergonadotropic hypogonadism, the combination of the antibodies against CYPc21, CYPc17, and CYPscc is associated with adrenal insuffi ciency. However, not only CYPs but also many other antigens such as tryptophan hydroxylase and tyrosin may also be self targets in APECED. CYPs in Hepatitis C Virus Infection Hepatic infection with the hepatitis C virus is known to induce several hepatic and extrahepatic autoimmune manifestations. Extrahepatic manifestations include mixed cryoglobulinemia, membrano-proliferative glomerulonephritis, polyarthritis, porphyria cutanea tarda, and Sjögren syndrome. Similar to AIH patients, sera of hepatitis C virus (HCV)-infected patients if looked for are frequently positive for ANA, SMA, and LKM. LKM-1 antibodies are found in 5–10% of patients with chronic HCV infection. Additionally, anti-CYP2A6-antibodies are reported in LKM-1-positive patients with HCV

[4 4 ] . In contrast to HCV infection, autoanti- bodies are rather infrequent in patients suffering from chronic hepatitis B. In light of pronounced differences in the capacity to induce autoimmune reactions, it seems unlikely that nonspecifi c reactions of the immune system, e.g., reactions against necrotic liver tissue, cause the phenomenon of virus-induced autoimmunity. It is more reasonable to assume that specifi c mechanisms are at work. Such processes may be cross-reactions of viral antigens with native hepatic antigens due to sequence similarity or as a consequence of mimicking tertiary structures. LKM-1 antibodies in AIH-2 and HCV-infection do not react identically. While LKM-1 antibodies in AIH primarily recognize small linear epitopes of CYP2D6, HCV-associated LKM-1 antibodies are more heterogeneous and detect mainly conformational epitopes of CYP2D6. However, some target-epitopes of LKM-1 antibodies in AIH-2 and HCV-infection overlap. For example, the major B cell epitope CYP2D6 was recognized by sera from 93% of patients with AIH-2 and 193–212 50% of patients with LKM-1 positive-HCV-infection [2 4 ] . The clinical relevance of these autoantibodies in patients with Hepatitis C is so far not completely understood. LKM in low titer is usually regarded as an epiphe- nomenon and only high antibody titers are considered to be a sign for a relevant autoimmune reaction. Nevertheless, it is reported that LKM-1-positive patients with a chronic hepatitis C may develop hepatic fl ares under the antiviral therapy with interferon. This phenomenon has been further investigated in smaller studies with 6 or 7 LKM-1-positive HCV-infected patients, in whom exacerbation was observed in 3/6 as compared to 1/7 without LKM-1 Ab [ 45, 46 ] . Recently, Ferri et al. tested a larger group of 26 LKM-1-positive patients and found that the exacerbation rate was negligible and reversible after immunosuppressive therapy [4 7 ] . 5 Mimics of Autoimmune Hepatitis… 99 CYPs in Drug-Induced Hepatitis Drug-induced hepatitis is albeit rare but sometimes may cause a life-threatening hepatitis if exposure to that drug is prolonged. Common to most patients is the metabolism of the drug by CYPs. A reactive metabolite is formed during the hydrox- ylation process, which may either bind to the active center of the CYP or which may leave the active center and covalently modify other hepatic proteins. Up to this point processes seem to be similar in all patients treated. However, in few susceptible patients drug-induced adducts are formed during these processes which are then recognized by the immune system as non-self. If this immune reaction is not sup- pressed, immune attacks directed against all cells, which harbor these modifi ed proteins may follow. This immune reaction may also be directed against native and modifi ed hepatic proteins. Since the induction of an immune reaction is the critical event in drug-induced hepatitis, the severity and onset of disease are essentially independent of drug dosage. Nevertheless, time is necessary for the induction of the specifi c immune response, therefore a signifi cant latency period is observed, which may vary from a few weeks to several months. After withdrawal of the drug, the targets of the immune response is no longer available and the hepatitis usually declines. The disease recurs upon re-challenge with the drug, this time after a shorter latency period and the “hepatitis” tends to be more severe upon re-exposure. Females tend to be more frequently affected by drug-induced hepatitis than men. Tienilic acid, a uricosuric diuretic withdrawn from clinical use in 1980, is one example for immune-mediated drug-induced hepatitis. One-tenth to 0.7% of patients treated with tienilic acid developed a hepatitis. [4 8 ] ; the reaction occurred with sig- nifi cant delay and liver damage was found to be dose independent. After discontinu- ation of the drug, liver damage resolved, but recurred after re-challenge [4 9 ] . Affected livers were infi ltrated with neutrophils, eosinophils, and lymphocytes. In 60% of patients suffering from severe hepatitis after administration of tienilic acid, a specifi c antibody directed against unmodifi ed liver and kidney microsomal proteins was detected, LKM-2 [ 50] . The molecular target of this LKM-2 autoantibody is CYP2C9, which is the major tienilic acid metabolizing enzyme. Based on the avail- able data, a hypothetical mechanism for LKM2 antibody induction in patients with tienilic acid-induced hepatitis has been proposed. Accordingly, tienilic acid is acti- vated by CYP2C9 during the degradation process to form a reactive sulfoxide, which binds to the enzyme and then forms a neoantigen resulting in the production of the LKM-2 autoantibody [ 51] . It is not known whether the LKM-2 autoantibodies are simply side-products of the underlying pathogenic process or whether they are directly involved in the pathogenesis of the disease. Dihydralazine has been shown to induce a hepatitis in some patients, which is characterized by antibodies that very specifi cally react with liver membranes (LM), but do not stain kidney sections. Subsequently, CYP1A2 was identifi ed as the molecular target of these autoantibodies [5 2– 54 ] . Dihydralazine-induced hepatitis affects more frequently females than males [5 5 ] . The hepatitis usually developed with a lag period of several months, resolved after discontinuation of treatment and 100 A. Vogel and M.P. Manns was re-induced upon re-challenge with the drug. A mechanism was proposed for the development of LM autoantibodies based on evidence that CYP1A2 act as the dihydralazine-activating enzyme. Dihydralazine is mainly metabolized via two pathways: One pathway is dependent of the N -acetyltransferase, resulting in an acetyl conjugate, the other one is an oxidative pathway, which is probably catalyzed by CYP1A2 and which contributes to the metabolic activation of dihydralazine. The latter leads to the formation of neoantigens, namely adducts with CYP1A2, which may induce an immune response and LM-antibody production. In 50% of the Caucasian population N -acetyltransferase activity is absent, resulting in a slow acetylator phenotype. Slow acetylators only can use the pathway mediated by CYP1A2 for detoxifi cation of dihydralazine. Their risk for adduct formation is higher and in accordance slow acetylators are strongly overrepresented in the patient population affected by dihydralazine hepatitis [5 5 ] . Halothane hepatitis is a rare but sometimes fatal complication of halothane anes- thesia. Studies in animals and humans have provided evidence for a complex multi- factorial basis for halothane-induced hepatotoxicity. Immunologic changes can be detected in a high percentage of cases of halothane hepatitis. A reductive and an oxidative pathway for halothane metabolism have been previously described. The reductive pathway is regarded as the cause of the mild form of liver injury that results from direct toxicity of halothane. In contrast, in the process of halothane oxidation by CYP2E1, the highly reactive trifl uoroacetylchloride is formed, which can bind to lysine residues of proteins forming trifl uoroacetyl (TFA) protein adducts [ 56 ] . These adducts may act as neoantigens and trigger an immune response. Subsequently, trifl uoroacetylated CYP2E1 was detected immunochemically in livers of rats treated with halothane [5 7 ] . Furthermore, high levels of autoantibodies that recognized purifi ed rat CYP2E1 but not purifi ed rat CYP3A were detected by enzyme-linked immunosorbent assay in 14 of 20 (70%) sera from patients with halothane hepatitis suggesting that immune responses to cell surface CYP2E1 could be involved in the pathogenesis of halothane hepatitis. Patients receiving anti-convulsants such as phenobarbital, phenytoin, or carbam- azepine, occasionally develop potentially life-threatening, idiosyncratic reactions [ 58 ] . Characteristically, the adverse effects occur within 3 months after the initiation of the therapy, and patients develop febrile illness affecting several organs and lymph nodes. The symptoms do not appear to be dose dependent. Some of the patients treated subsequently with other anti-convulsants may also develop adverse reactions against the other drugs [5 9 ] . Anti-microsomal antibodies have been found in sera of 9 out of 24 patients with hypersensitivity reactions after phenytoin treat- ment. These autoantibodies were neither detected in sera from healthy individuals nor in sera from patients treated with anti-convulsants without side effects. The antigen was constitutively expressed in rat liver and was inducible by phenobarbital treatment. Immunoblotting experiments conducted with a series of purifi ed rat cyto- chrome P450 showed that all sera tested from eight patients reacted with rat CYP3A1, and that sera from six patients reacted with CYP2C11. The human anti- gen however has not yet been identifi ed yet [ 60 ] . 5 Mimics of Autoimmune Hepatitis… 101 CYPs in Alcohol-Induced Liver Disease As only 10–20% of alcohol abusing patients develop liver disease, host factors may be important in alcohol-induced liver disease. There is growing evidence that infl ammatory reactions play an important role in the pathogenesis of alcoholic liver disease (ALD) and autoimmune reactions are frequently observed in these patients [6 1 ] . Autoantibodies directed toward alcohol dehydrogenase, hepatic asialoglyco- protein receptor, heat shock protein 65, and phospholipids are present in 25–50% of patients with alcoholic hepatitis or cirrhosis [6 2, 63 ] . The implication that immunity contributes to chronic infl ammation in ALD has further emerged from clinical and experimental evidence showing recruitment and activation of lymphocytes in the infl ammatory infi ltrates of ALD. Several investigations performed in different animal models and in humans revealed that patients with advanced ALD show a high prevalence of circulating IgG and T-lymphocytes to covalently modifi ed neoan- tigens [ 64– 66 ] . Mice exposed to alcohol generate persistent antibodies against acetaldehyde-protein adducts. The reactivity to the acetaldehyde-protein adducts is interestingly independent of the protein carrier used [6 6 ] . During ethanol oxidation by hepatic microsomes not only the reactive intermediate acetaldehyde is formed, but also other free hydroxyethyl radicals [6 7 ] . Using adducts of human serum albumin or bovine fi brinogen modifi ed by hydroxyethyl radicals, Clot et al. showed that both hydroxyethylated proteins were recognized by the patient sera and that binding was again independent of the protein carrier used [6 4 ] . Furthermore, the authors found that two populations of autoantibodies existed, because autoantibodies directed against hydroxyethyl domains did not cross-react with autoantibodies directed against acetaldehyde-modifi ed proteins. Incubation of liver microsomes with ethanol resulted in formation of four hydroxyethyl radical-derived liver antigens. Antibodies of most patients with alcoholic cirrhosis were bound by a 52 kd protein, which was later identifi ed as CYP2E1. The conclusion of this study was that CYP2E1 leads to formation of hydroxyethyl-adducts with CYP2E1 and three other proteins, which are recognized by the immune system resulting in formation of antibodies [ 65 ] . The titers of anti-CYP2E1 but not those of anti-CYP3A antibodies are interestingly associated with the severity of alcohol liver damage, and the inhibi- tion of CYP2E1-mediated ethanol metabolism by chlormethiazole prevented both liver injury and anti-CYP2E1 auto-reactivity [ 66 ] . The potential role of an autoim- mune response toward CYP2E1 in the pathogenesis of alcohol liver damage in humans is further supported by the demonstration that CYP2E1 is present on the surface of both rat and human hepatocytes [2 7, 68, 69 ] . Thus, both in immune- mediated drug-induced hepatitis and in alcoholic liver disease adduct-formation seems to be a crucial mechanism for establishing immune reaction against the metabolizing enzymes. Indeed, protein fragments modifi ed by drug metabolites have been shown to induce T-cell clones recognizing as “nonself,” short linear peptides derived from the native unmodifi ed protein. In turn, these T lymphocytes are capable of activating B lymphocytes to produce antibodies directed against both drug-modifi ed and non-modifi ed proteins [7 0, 71 ] . 102 A. Vogel and M.P. Manns Table 5.1 Viruses proposed as trigger for autoimmune hepatitis Virus Hepatitis C virus Autoimmune hepatitis type 2 induced by HCV and persisting viral clearance [1 09 ] Hepatitis A virus Identifi cation of hepatitis A virus as a trigger for AIH type 1 insusceptible individuals [1 10 ] Measles Autoimmune hepatitis type 1 after measles [1 11 ] Epstein-Barr-virus Epstein-Barr virus as a trigger for autoimmune hepatitis insusceptible individuals [1 12 ] Herpes simplex virus LKM-1 autoantibodies recognize a short linear sequence in P450IID6, a cytochrome P-450 monooxygenase [ 21 ] Herpervirus-6 Autoimmune hepatitis and adrenal insuffi ciency in an infant with human herpesvirus-6 infection [1 13 ] All the described forms of infl ammatory liver diseases have in common specifi c antibodies directed against CYP enzymes as diagnostic markers. The same CYPs may serve as

an autoantigen in different diseases (Fig. 5.1 ). I.e., anti-CYP2D6 anti- bodies can be found in patients with AIH and patients with hepatitis C, anti-CYP1A2 antibodies in APECED and dihydralazine-associated hepatitis, and anti-CYP2A6 anti- bodies in HCV and APECED (Table 5 .1 ). However, different sequences may serve as target epitopes or, in case of anti-CYP1A2 and dihydralazine- and APECED-mediated hepatitis, different ways of immunization may result in antibody induction. Role of Molecular Mimicry for Induction of Autoantibodies to CYP Enzymes Molecular mimicry is one of the favored, yet still controversial theories by which infectious agents may activate these cells against self-antigens. During the last two decades hundreds of articles have focused on epitope mimicry and have provided many arguments supporting this hypothesis but sound proof is elusive. According to the hypothesis a susceptible individual acquires an infection with an agent that has antigens immunologically similar to the host antigens which can induce an immune response when presented to T cells. As a result, the immune response generated cross-reacts with host tissues leading to tissue destruction. The immune responses can either be on the humeral (antibody) or T cell-mediated level or both. Several criteria need to be fulfi lled to establish evidence that molecular mimicry is involved in the pathogenesis of autoimmune diseases. (1) There has to be an asso- ciation between the infection and the autoimmune disease, which has to persist in the absence of the initiating microbe. (2) The cross-reacting epitopes should be identifi ed and the corresponding immunological cells such as antigen presenting 5 Mimics of Autoimmune Hepatitis… 103 cells and effector cells like T cells has to be determined during the infection and the autoimmune diseases. (3) It needs to be demonstrated that both the critical epitopes and the corresponding T cells are required and necessary to provoke the autoim- mune disease. There is evidence suggesting that molecular mimicry might also act as a trigger for induction of liver-specifi c autoantibodies. Sera of patients with different diseases can react to some extent with the same epitopes on CYPs as shown for CYP2D6 193–212 and HCV- and AIH-2-patients. Similarly, sequence homologies between HCV and the B cell epitope CYP2D6 as well as homologies between CYP2D6 and 254–271 common viruses like herpes simplex virus type 1 (HSV1), cytomegalus virus (CMV), Ebstein-Barr-Virus (EBV), and human adenovirus have been discovered [ 72, 73 ] . Furthermore, Ma et al. found that disease-specifi c CD4+ T cells in patients infected with HCV detect CYP2D6 , which in turn is homologous to the 313–332 sequence 794–801 of HCV [7 4 ] . Kammer et al. found a striking homology between the HCV core 178–187 peptide and CYP2A6 and CYP2A7 [7 5 ] . Intriguingly, HCV- induced cytotoxic T-cells recognize these CYPs and lyse cells transfected with a plasmid coding for the whole CYP2A6 protein. But a reaction against CYP2A6 and CYP2A7 at B-cell level could not be detected. These observations led to the sugges- tion that molecular mimicry may play a role in the pathogenesis of AIH-2. According to the “multiple hit-theory,” in genetically predisposed patients multiple contacts to viruses might induce a cross-reactive subset of T-cells and permit a loss of immuno- logical self-tolerance. This hypothesis might be expanded to incorporate cross- reactive responses involving various self-antigens specifi c for autoimmune diseases, which then lead to the development of multiple autoimmune diseases in the same patient. Studies by Choudhuri et al., for example, revealed that antibodies detecting the AIH-related antigen CYP2D6 can cross-react with carboxypeptidase H, 321–351 an autoantigen in type I diabetes and with CYP21, an autoantigen in Addison’s disease suggesting that autoimmunity to one CYP might spread to other CYPs via molecular mimicry [7 6 ] . The role of molecular mimicry in autoimmune reactions against CYP2D6 was further analyzed in a recently developed mouse model for AIH type 2 [ 77 ] . In this model “molecular mimicry” was compared to “molecular identity” in response to infection with an adenovirus, expressing the human CYP2D6 (Ad-2D6) [7 8 ] . Either wildtype FVB/N mice, which express mouse CYP isoenzymes with a structural and sequential similarity to human CYP2D6 (molecular mimicry) or transgenic CYP2D6 mice, which express in addition the identically human CYP2D6 (molecular identity), were infected with Ad-2D6. Infection of FVB/N mice led to a rapid development of persistent AIH with typical histological features like infi ltration of mononuclear cells and severe fi brosis as well as the formation of CYP2D6 antibodies and CYP2D6-specifi c T-cells. In contrast, liver damage in the transgenic mice progressed signifi cantly slower was less severe and was associated with lower antibody titers. Furthermore, a signifi cantly lower frequency (10–20×) of CYP2D6-specifi c T-cells was found in the transgenic mouse model. The authors concluded that the thresh- old of specifi c T-cells rather than the antibody titer is responsible for the severity of the disease. 104 A. Vogel and M.P. Manns Role of Cellular Autoimmunity to CYP Enzymes In the histological picture of AIH the main feature is a mononuclear cell infi ltrate, containing lymphocytes, plasma cells, and macrophages. Immunohistochemical studies revealed a predominance of CD4+ T-cells and a minority of CD8+ T-cells [7 9 ] . CD4+ T lymphocytes play a major role in infl ammation processes of autoim- mune hepatitis. Studies with lymphocytes demonstrated proliferation of T-Helper- cells specifi cally in response to human recombinant CYP2D6 [8 0 ] . In studies analyzing the proliferative response of mononuclear cells of patient sera after con- tact with CYP2D6 Löhr et al. found that eight of eight patients with AIH-2, 6 262–285 of 12 with AIH-1, and 4 out of 31 patients with chronic hepatitis C reacted with the antigen. After immunosuppressive treatment T cell response decreased [8 1 ] . Recent studies investigated T cell responses to peptides covering the whole CYP2D6 molecule. They demonstrated that multiple epitopes on CYP2D6 were detected by T-cells and that the production of cytokines was not uniform. The number of recog- nized epitopes as well as the quantity of cytokine production directly correlated with disease activity. The authors concluded that the T cell response to CYP2D6 is polyclonal, involves multiple effector cell types targeting different epitopes and is associated with hepatocyte damage [7 4 ] . There is growing evidence pointing to a crucial role of CD8+ autoreactive T-cells for liver cell injury. CYP2D6-specifi c CD8+ T-cells were shown to secret interferon-g and to be cytotoxic after recognition of CYP2D6-epitopes. In this study, frequency, IFN- production, and cytotoxicity of CYP2D6-specifi c CD8 T-cells were higher at diagnosis than during treatment. Furthermore, intensity of CYP2D6-specifi c CD8 T-cell responses correlated with disease activity [8 2 ] . Recently, a HLA B8/DR3 dependent impairment of T regulatory cell (Tregs) number and function has been considered as a permissive factor leading to auto- immune reactions [ 83 ] . Tregs are CD4+ CD25+ cells representing 5–10% of all CD4+ T-cells in healthy individuals [8 4 ] . They control the proliferation of autore- active T-cells by direct contact to the target cell and to a lesser extent by releasing cytokines. The number of Tregs inversely correlates with markers of the disease and LKM-antibody titers. Remarkably, the number of Tregs increases after the administration of corticosteroids [8 5, 86 ] . Uridine Diphosphate 5¢ -Glucuronosyltransferases and Immune-Mediated Liver Injury Uridine diphosphate 5¢ -glucuronosyltransferases are a superfamily of drug metabo- lizing enzymes located in the inner membrane of the endoplasmatic reticulum [ 87 ] . UGTs have evolved in vertebrate species and more than 50 isoforms have been so far identifi ed. The UGT enzymes catalyze the transfer of the glucuronic acid moiety of UDP glucuronic acid (UDPGA) to a wide range of acceptor molecules, including bilirubin, sex steroids, numerous prescribed drugs, and environmental toxins [8 8 ] . 5 Mimics of Autoimmune Hepatitis… 105 The sugar acid can be coupled to the substrate through the –OR, –SR, or –N.R ¢ R² forming a P-d -glucopyranosiduronic acid or glucuronide. This reaction leads almost always to inactive metabolites that are excreted into bile or urine. In their ability to glucuronize oxidized compounds, UGT enzymes complement the metabolic function of phase I enzymes such as CYPs, which are localized in the external membrane of the ER. The mammalian UGT1 gene superfamily currently has more than 117 members that can be divided into four families, UGT1, UGT2, UGT3, and UGT8 [8 9 ] . Based on an agreed system of gene nomenclature, members of the UGT superfamily have been named based on divergent evolution, with each gene given the symbol UGT, followed by a number representing the family, a letter to denote the subfamily, and a number for the individual gene within that family or subfamily similar to the nomen- clature of the CYP enzymes. Human UGT1 is located on chromosome 2q37 and spans approximately 200 kb, which is composed of 17 exons. To synthesize the fi nal UGT1 protein, one of 13 different exon-1 on the locus is spliced to four downstream exons (exon 2–5), common to all UGT1A isoforms. The exon-1 sequence of UGTs codes for the substrate-binding domain, while the four common exons code for the cosubstrate- binding domain. The human UGT2 gene family is located on chromosome 4q13 and is divided into two subfamilies, UGT2A and UGT2B. Similar to the UGT1 family, members of the UGT2B subfamily, which comprises several independent genes, share a high degree of similarity in the C-terminal portion of the protein and the highest degree of divergence in sequences encoded by exons 1. Although the liver is the main site of glucuronidation, expression of UGTs can also be found in extrahepatic tissues, including the kidney, lung, gastrointestinal tract, prostate, spleen, skin, and brain. Some isoforms appear to have a broad distribution, whereas others may be specifi c to the liver or may be restricted to specifi c extrahepatic tissues. UGTs in Hepatitis D Virus Infection The hepatitis D virus, an RNA viroid dependent on hepatitis B co-infection, was discovered in 1977 [ 17 ] . It was soon recognized that in 13% of Italian patients infected with HDV had LKM autoantibodies in serum, that differed from LKM-1 autoantibodies in autoimmune hepatitis type 2, and LKM-2 autoantibodies in dihydralazine-induced hepatitis directed. These antibodies gave a distinct immu- nofl uorescence pattern on rat liver-kidney cryostat sections with no or weak staining of the proximal renal tubules and stomach [9 0 ] . These autoantibodies were termed LKM-3. Just as in chronic hepatitis C a multitude of serum autoantibodies were subsequently identifi ed in sera of patients suffering from chronic HDV infection. In 1994, family 1 UDP glucuronosyltransferases (UGT-1) were identi- fi ed as molecular target of LKM-3 autoantibodies [9 1– 93 ] . This discovery now allows for the characterization of another form of virus-associated autoimmunity. As in HCV-associated LKM-1 autoantibodies, LKM-3 autoantibodies in HDV infection are present at lower titers than in AIH. LKM-3 autoantibodies appear to be specifi c for HDV and are not found in the sera of HCV infection [9 1, 94 ] . 106 A. Vogel and M.P. Manns These preliminary data indicate, that the immune response characterized by the molecular analysis of LKM-3 autoantibodies may differ in HDV-associated auto- immunity and AIH. Further studies are needed to evaluate the clinical and pathophysiological signifi cance of LKM-3 autoantibodies. UGTs in Autoimmune Hepatitis LKM-3 antibodies were subsequently also found in patients with AIH and can be regarded as rare markers of AIH [9 5 ] . Epitope mapping identifi ed a mayor epitope in the C-terminal region of the protein (AA 264–373). The signal was signifi cantly stronger when the N-terminal sequence was included in the clones indicating that the epitope is conformation dependent [9 6 ] . In addition to the mayor epitope, a minor epitope was found on a family II UGT, UGT2B13. Overall, LKM-3 antibodies have been shown to react with UGT1A1, 1A6, 1A4, and the UGT2B isoform. These antibodies can occasionally be the only marker of AIH, but most AIH type II patients test positive for LKM-1 antibodies. The molecular events leading to the formation of antibodies directed to UGTs are not known so far. In analogy to antibodies to CYPs, it can be postulated that UGTs might also lead to the formation of adducts thereby generating neoantigens that

trigger an immune response. Drug-Induced Liver Without Antibodies Directed Against CYP or UGT Enzymes Drugs such as minocycline [9 7– 99 ] , diclofenac [1 00, 101 ] , infl iximab [1 02 ] , propy- lthiouracil [1 03 ] , atorvastatin [1 04 ] , nitrofurantoin [1 05 ] , methyl dopa [1 06 ] , and isoniazid [ 107 ] can cause a syndrome that resembles AIH [1 08 ] with autoantibodies which however generally disappear after discontinuation of the drug and which usu- ally do not require treatment. Conclusion Autoimmune reactions against drug metabolizing enzymes are involved in several liver diseases of different origin, mainly seen in autoimmune hepatitis, viral hepatitis, and hepatitis induced by xenobiotics. In genetically predisposed individuals, antigen- antibody reactions and mislead cellular immune responses apparently lead to persistent and perpetuating liver damage. The immune reaction against self might be triggered by repeated virus-infections via molecular mimicry. However, the prime mechanism for breakdown of self-tolerance remains unclear and have to be addressed in future studies. 5 Mimics of Autoimmune Hepatitis… 107 Chapter Summary 1. Serological markers of autoimmunity can be detected in alcoholic and non-alcoholic fatty liver disease, acute and chronic viral hepatitis, and drug-induced hepatitis. 2. The liver contains the greatest abundance of phase I and phase II xenobi- otic-metabolzing enzymes in the body. In most liver diseases associated with serological markers of AIH, autoantibodies against cytochrome P450 (CYP) enzymes and UDP – glucuronosyltransferases (UGT) are detected. 3. The pathogenetic role of most, if not all, autoantibodies is still unclear and it is not known whether autoantibodies that are observed in primarily non- autoimmune liver disease contribute to tissue damage. Useful Tips for Practitioners 1. LKM-1-positive patients with a chronic hepatitis C may develop hepatic fl ares under antiviral therapy with interferon. However, antiviral treatment is as benefi cial in these patients as in anti-LKM1-negative patients, and the rare heptic fl ares can be effectively treated with corticosteroids. 2. Several drugs can cause a syndrome that resembles AIH with autoantibod- ies which however generally disappear after discontinuation of the drug and which usually do not require treatment. 3. Drug-induced hepatitis is rare but may cause a life-threatening hepatitis if exposure to that drug is prolonged. Since the induction of an immune reac- tion is the critical event in drug-induced hepatitis, the severity and onset of disease are essentially independent of drug dosage. Common Pitfalls in Practice 1. Antibodies directed against CYP enzymes may serve as diagnostic markers in several infl ammatory liver disease. These antibodies are not disease specifi c and the same CYPs may serve as an autoantigen in different diseases, i.e., anti-CYP2D6 antibodies can be found in patients with AIH and patients with hepatitis C, anti-CYP1A2 antibodies in APECED and dihydralazine associated hepatitis, and anti-CYP2A6 antibodies in HCV and APECED. 108 A. Vogel and M.P. Manns References 1. Czaja A, Carpenter HA. Validation of scoring system for diagnosis of autoimmune hepatitis. Dig Dis Sci. 1996;41:305–14. 2. Loria P, Lonardo A, Leonardi F, Fontana C, Carulli L, Verrone AM, et al. Non-organ-specifi c autoantibodies in nonalcoholic fatty liver disease: prevalence and correlates. Dig Dis Sci. 2003;48:2173–81. 3. Adams LA, Lindor KD, Angulo P. The prevalence of autoantibodies and autoimmune hepa- titis in patients with nonalcoholic Fatty liver disease. Am J Gastroenterol. 2004;99:1316–20. 4. Mackie FD, Peakman M, Ma Y, Sallie R, Smith H, Davis ET, et al. 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Am J Gastroenterol. 1996;91:2618–20. 112. Vento S, Guella L, Mirandola F, Cainelli F, Di Perri G, Ferraro T, et al. Epstein-Barr virus as a trigger for autoimmune hepatitis in susceptible individuals. Lancet. 1995;346:608–9. 113. Schmitt K, Deutsch J, Tulzer G, Meindi R, Aberle S. Autoimmune hepatitis and adrenal insuffi ciency in an infant with human herpesvirus-6 infection. Lancet. 1996;348:966. Chapter 6 When and How to Treat the Adult Patient Aldo J. Montano-Loza Keywords Autoimmune hepatitis • Corticosteroids • Prednisone • Azathioprine • Immunosuppressive treatments Introduction During the 1970s, three clinical controlled trials demonstrated the lifesaving properties of corticosteroid therapy in patients with autoimmune hepatitis (AIH) [1 – 3 ] ; and since then treatment with prednisone alone or a lower dose in combination with azathioprine has become the standard therapy for AIH [4 , 5 ] . However, not all patients with AIH respond to this therapeutic regimen, and of those who do, many relapse after corticosteroid withdrawal [6 , 7 ] . In addition, the success of corticosteroid treatment must be counterbalanced against the development of side effects to the medications [ 8, 9 ] . New pharmacological agents have emerged that may promise better immuno- suppression and tolerance than the conventional corticosteroid regimens [1 0, 11 ] . Indications for Treatment The indications for treatment of adult patients with AIH are based on the risk factors for disease progression, and for practical purposes can be classifi ed as absolute, relative or uncertain indications, and no indications for treatment. Special consider- ation should be made to the presence or absence of symptoms and patients with fulminant presentation of AIH. A. J. Montano-Loza (*) Division of Gastroenterology and Liver Unit, Zeidler Ledcor Centre, University of Alberta, Room 1-20B, 130 University Campus, Edmonton , AB , Canada 2X8 TV6 e-mail: aldo.montano-loza@ualberta.ca G.M. Hirschfi eld and E.J. Heathcote (eds.), Autoimmune Hepatitis: A Guide for Practicing 115 Clinicians, Clinical Gastroenterology, DOI 10.1007/978-1-60761-569-9_6, © Springer Science+Business Media, LLC 2012 116 A.J. Montano-Loza Table 6.1 Treatment indications for adult patients with autoimmune hepatitis Indications Findings Absolute Relative None Clinical Incapacitating Mild or no symptoms Asymptomatic with mild symptoms laboratory changes Relentless clinical Previous intolerance of progression prednisone and/or Fulminant presentation azathioprine Laboratory AST ³ tenfold normal AST 3–9-fold normal AST < threefold normal AST ³ fi vefold normal AST ³ fi vefold Severe cytopenias and g -globulin ³ normal and g -globulin (White blood cell count twofold normal < twofold normal below 2.5 × 109 /L or platelet count below 50 × 10 9 /L) Histologic Bridging necrosis Interface hepatitis Inactive cirrhosis Multi-acinar necrosis Focal interface hepatitis Portal hepatitis Decompensated inactive cirrhosis with variceal bleeding or hepatic encephalopathy AST = serum aspartate aminotransferase level Adapted from Montano-Loza AJ, and Czaja AJ [1 0 ] Absolute Indications Severe laboratory abnormalities defi ned as serum AST levels of at least tenfold the upper limit of the normal (ULN) or more than fi vefold ULN in conjunction with a serum g( gamma)-globulin level more than twofold ULN, incapacitating symptoms (fatigue and arthralgia), and histological changes of moderate-to-severe interface hepatitis are absolute indications for corticosteroid treatment. In addition, if bridging necrosis or multi-acinar collapse is seen on liver biopsy but the other criteria are absent, immediate corticosteroid therapy should be started (Table 6 .1 ). These patients progress to cirrhosis in 80% if untreated and

mortality could be as high as 60% at 6 months [ 1– 3 ] . Relative or Uncertain Indications Patients with laboratory and histological features that are less severe and not immediately life-threatening have not been studied by controlled clinical trials. The benefi t–risk ratio of corticosteroid treatment in these patients has not been thoroughly determined, and the institution of treatment is an individualized clinical decision that is generally infl uenced by the presence of symptoms and histological changes of mild–moderate interface hepatitis. Laboratory abnormalities of a mild-to-moderate degree are associated with cirrhosis in 49% within 15 years and a 10-year survival 6 When and How to Treat the Adult Patient 117 of 90%, and untreated patients with interface hepatitis have a 17% probability of cirrhosis within 5 years [1 2– 14 ] (Table 6 .1 ). Therefore, diagnosis of AIH does not compel therapy, and retrospective analyses of patients with mild disease have demonstrated the possibility of long-term survival without treatment [1 2– 14 ] . No Indication for Treatment The risk of the disease must be counterbalanced by the risks of the treatment, especially in patients with mild-to-moderate disease activity who are likely to be intolerant of the medication, such as those with advanced but inactive cirrhosis, post- menopausal osteopenia or vertebral compression, emotional lability or psychosis, poorly controlled hypertension, and diffi cult to control diabetes mellitus [8 , 9 ] . Patients with histological features of focal interface hepatitis, portal hepatitis or inactive cirrhosis, or advanced stages of liver decompensation in the absence of severe infl ammatory activity necessitate close observation (i.e. 3–6 months), symp- tomatic care, or be considered for liver transplantation (Table 6 .1 ) [ 12– 14 ] . Presence of Symptoms and Decision of Treatment AIH can be asymptomatic in as many as 34% of patients at presentation [1 4, 15 ] . Asymptomatic individuals are commonly men, and they have lower serum levels of aminotransferases and immunoglobulin G (IgG) at presentation than symptomatic patients. Histological features are similar between symptomatic and asymptomatic patients, and there is no signifi cant difference in the occurrence of cirrhosis [ 15 ] . Frequently, asymptomatic patients have inactive cirrhosis, and their survival is not enhanced by corticosteroid treatment. Asymptomatic patients without cirrhosis may have 10-year survival probabilities greater than 80% without treatment [1 4 ] . Disease severity as refl ected in the laboratory and histological features of infl ammatory activity and not the presence or absence of symptoms is the principal justifi cation for corticosteroid treatment. Asymptomatic patients commonly become symptom- atic [ 14, 15 ] . The absence of symptoms at presentation should not decide treatment in patients who otherwise satisfy criteria for severe disease [1 – 3 ] . Fulminant Autoimmune Hepatitis Several clinical descriptions of severe acute and fulminant AIH have emerged from small retrospective analyses within single institutions [ 16– 22 ] . The effi cacy of corticosteroids in the treatment of severe acute and fulminant AIH has not been established, but these experiences have suggested that the prompt institution of 118 A.J. Montano-Loza corticosteroid therapy may be benefi cial in 36–100% of such patients [1 7– 21 ] . The diagnosis of AIH should be considered in all patients with acute and chronic liver disease, including those patients with allograft dysfunction who have undergone liver transplantation for autoimmune [ 23, 24 ] and non-autoimmune conditions [ 25, 26 ] , and its presentation warrants an increase in immunosuppressive therapy. Conventional Treatment Schedules The preferred treatment schedule for adults with severe AIH is prednisone (pred- nisolone can be used in equivalent doses) in combination with azathioprine (50 mg/day generally used in North America and 1–2 mg/kg/day in Europe) [4 , 5 ] (Table 6 .2 ). Prednisone alone in higher dose is as effective as the combination regimen, but it is associated with a higher frequency of drug-related side effects (44 versus 10%) [2 7 ] . Prednisone should be tapered down slowly when at 20 mg/day as long as the ALT becomes close to normal, the reduction should be done by 5 mg every week or two until 10 mg per day are achieved; and even further reduction by 2.5 mg per week have been considered up to 5 mg daily. The maintenance regimen is then con- tinued until resolution of the disease, treatment failure, or drug-intolerance. It is usual that patients going into complete remission can be maintained in remission on azathioprine alone (Fig. 6 .1 ). In patients with advanced cirrhosis impairment of the conversion of prednisone to prednisolone may be present, but this impairment is insuffi cient to alter treatment response or mandate the administration of prednisolone [2 8 ] Table 6.2 Treatment schedules for adult patients with autoimmune hepatitis recommended by the AASLD Combination therapy Prednisone therapy Azathioprine NA EU Weeks administered Prednisone (mg daily) (mg daily) (mg/kg/day) Prednisone (mg daily) 1 30 50 1–2 60 1 20 50 1–2 40 2 15 50 1–2 30 Maintenance until 10 50 1–2 20 end point Relative Cytopenias Post-menopausal state Contraindications Pregnancy Osteoporosis Active malignancy Diabetes Short course (less than 6 months) Hypertension Thiopurine methyltransferase defi ciency Obesity Emotional lability AASLD American Association for the Study of the Liver Diseases, N A North America, E U Europe. Adapted from Montano-Loza AJ, and Czaja AJ [1 0 ] 6 When and How to Treat the Adult Patient 119 Fig. 6.1 Algorithm of therapy for patients with autoimmune hepatitis. The preferred initial regimen is prednisone alone or a lower dose of prednisone in combination with azathioprine. Outcomes after the initial therapy dictate changes in the initial treatment strategy. *Prednisolone can be used in equivalent doses. Lack of clinical trials. Adapted from Czaja AJ, and Manns MP [1 1 ] Some centers advocate for the use of maintenance low dose corticosteroid and/ or azathioprine monotherapy treatment in patients with AIH to avoid the high frequency of relapse after drug withdrawal but such schedules in adults may not be as successful as fi xed daily dose regimens in inducing histological resolution [2 7 ] . Treatment End Points Therapy should continue until remission, treatment failure, incomplete response, or drug toxicity. There is no prescribed minimum or maximum duration of treatment. The length of therapy should be based on a fi xed minimum duration that is usually associated with a complete response or on a variable duration that is individualized to the desired result and tolerance. The average duration of treatment required for disappearance of symptoms, normalization of laboratory indices, and histological resolution is 22 months [2 9 ] . Histological improvement lags behind clinical and laboratory resolution by 3–8 months, and therapy should be continued for at least 3 months beyond this point of improvement [3 0 ] . In Europe, treatment is main- tained for at least 2 years before considering drug withdrawal [3 1 ] . 120 A.J. Montano-Loza The ideal end point of therapy in patients with AIH is after resolution of all clinical, laboratory, and histological manifestations of disease activity [ 32– 34 ] . Normalization of serum aspartate aminotransferase (AST), g (gamma)-globulin, and IgG levels in conjunction with histological resolution reduces the relative risk of relapse after drug withdrawal by 3–11-fold [3 4 ] . The frequency of sustained remission after initial treatment is still low (approximately 25%), but 87% of patients who achieve an inactive state have normal laboratory indices prior to the termination of therapy. The normalization of tests and tissue does not protect against relapse, and 60% of patients who relapse do so despite prior disappearance on treatment of infl ammatory features [3 4 ] . The frequency at which corticosteroid treatment can induce resolution of the disease is unclear, and the pursuit of an idealized end point may be futile in some patients or may be associated with seri- ous drug-related side effects. Under such circumstances, management strategies must be individualized to patient tolerance. Liver biopsy evaluation before considering ending treatment is one approach to confi rm complete resolution of the disease. Up to 50% of patients with AIH and normal serum aminotransferases and g -globulin levels during therapy have interface hepatitis, and these patients usually relapse after cessation of treatment; therefore, their recognition by liver biopsy should indicate prolongation of immunosuppressive treatment. Thus, a liver biopsy is often suggested prior to termination of treatment in patients with AIH [4 , 5 ] . Termination of immunosuppressive treatment should be considered after at least 2 years, when serum aminotransferases and g (gamma)-globulin levels have been constantly normal. Termination of therapy after induction of remission should follow by gradual and monitored dose reduction over a 6-week period. The activity of the disease during and after drug withdrawal is assessed by the appearance of symptoms (fatigue and arthralgias) and laboratory indices (serum AST/ALT and g [gamma]- globulin levels). Laboratory tests should be done as often sometimes as every 3 weeks during drug withdrawal and for 3 months after termination of therapy. After that, laboratory test should be repeated every 3 months and then every 6 months for 1 year, and fi nally every year for life [4 , 5 ] . Nine percent of patients have worsening serum aminotransferases or bilirubin levels, unchanged or worse histological activity indices, and develop ascites or hepatic encephalopathy despite compliance with the treatment regimen [ 35, 36 ] . These individuals have treatment failure, and they are candidates for either high dose corticosteroid therapy after their original diagnosis has been reconfi rmed and different or superimposed diseases have been excluded. They commonly become candidates for liver transplantation [3 7 ] . Thirteen percent of patients with AIH improve but not to a point of complete resolution [3 8 ] . These individuals have an incomplete response, and they may rep- resent those patients who require indefi nite treatment and who remain at risk for disease progression. Serious side effects associated with corticosteroids or azathio- prine that require premature termination of treatment are present in 13% of patients with AIH [8 , 29 ] . 6 When and How to Treat the Adult Patient 121 Treatment Outcomes Approximately, 80% of treated patients satisfy remission criteria within 3 years [1 – 3 ] , and the life expectancies of treated patients exceed 85% at 10 years [ 39 ] and 74% at 20 years even in those with cirrhosis at baseline [ 40 ] . These survivals are comparable to those of an age- and sex-matched normal population from the same geographical region. Patients with cirrhosis respond as well to treatment as patients without cirrhosis, and they should be treated similarly with the same expectation of success [3 9 ] . Twenty-one percent of individuals who enter remission sustain this result long term after drug withdrawal (median interval of follow-up, 76 months), and an effort should be made to discontinue initial therapy in all patients with inactive disease [4 1 ] . Corticosteroid therapy may also reduce or prevent hepatic fi brosis [4 2, 43 ] . Fifty-six percent of patients have lower hepatic fi brosis scores on repeat liver biopsy performed after 55 ± 9 months of follow-up, and 33% have stable hepatic fi brosis during 62 ± 14 months of observation. Improvement in hepatic fi brosis occurs in association with reduction in liver infl ammation secondary to corticoster- oid therapy [ 44 ] . Case series studies have also suggested that cirrhosis may regress on treatment [4 2, 43 ] . Treatment of Suboptimal Responses Treatment failure is defi ned as deterioration during therapy, characterized by a progressive increase in serum aminotransferases or bilirubin at presentation. Consultation with an expert center is important. Management is individualized after compliance is confi rmed. This suboptimal response can be managed by administer- ing high dose prednisone alone (60 mg daily) or prednisone (30 mg daily) in conjunction with azathioprine (150 mg daily) (Table 6 .3 ) [ 45 ] . Doses of prednisone and azathioprine should be reduced by 10 and 50 mg respectively, for each month of laboratory improvement until conventional maintenance levels of drug are achieved. Seventy-fi ve percent of patients treated with this regimen achieve clinical and laboratory remission, but only 20% have histological resolution. These patients remain at risk for progressive liver disease and drug toxicity.

Drug toxicity requires premature dose reduction or discontinuation of the offending drug and continued use of the other tolerated medication in adjusted dose (Table 6.3 ). Corticosteroid-related side effects are the most common causes for drug withdrawal, and they include intolerable cosmetic changes or obesity (47%), osteoporosis with vertebral compression (27%), brittle diabetes (20%), and peptic ulcer disease (6%) [2 9 ] . Azathioprine can be administered as a corticosteroid- sparing agent with doses increased to 2 mg/kg daily. The emergence of a chole- static hepatitis, pancreatitis, rash, progressive cytopenia, or gastrointestinal symptoms indicates azathioprine toxicity and the need for its withdrawal. 122 A.J. Montano-Loza Table 6.3 Conventional and empiric treatments of suboptimal responses in autoimmune hepatitis Conventional treatments Possible empiric treatments Clinical event First choice Second choice Third choice Fourth choice Treatment failure Prednisone (30 mg daily) Prednisone (30 mg daily) and Cyclosporine (5–6 mg/kg daily) or Tacrolimus (4 mg twice and azathioprine (150 mg Mercaptopurine (1.5 mg/kg Prednisone (30 mg daily) and daily) daily) daily) Mycophenolate mofetil (2 g daily) Drug toxicity Azathioprine (2 mg/kg daily) P rednisone (20 mg daily) if Budesonide (3 mg twice daily) UDA (13–15 mg/kg if prednisone intolerance azathioprine intolerance daily) Incomplete response Prednisone maintenance A zathioprine maintenance (2 mg/kg Budesonide maintenance (3 mg twice UDA maintenance £ 10 mg daily if serum daily) if serum AST < threefold daily) (13–15 mg/kg daily) AST < threefold normal normal Relapse Azathioprine maintenance Prednisone maintenance reduced to Mycophenolate mofetil maintenance Cyclosporine mainte- (2 mg/kg daily) if serum £ 10 mg daily if serum (1 g twice daily) nance (5–6 mg/kg AST < threefold normal AST < threefold normal daily) UDA ursodeoxycholic acid Adapted from Montano-Loza AJ, and Czaja AJ [1 0 ] 6 When and How to Treat the Adult Patient 123 However, this complication is rare. Routine genotyping and phenotyping for thio- purine methyltransferase defi ciency prior to the institution of azathioprine therapy does not correlate with the occurrence, nature, or severity of the hematologic or somatic complications of azathioprine treatment, and the value of routine testing for this enzyme is uncertain [4 6– 48 ] . An incomplete response is arbitrarily declared after 3 years of conventional therapy without complete remission [ 5, 33 ] . Patients improve but not to a degree to satisfy remission criteria and they are at risk for drug-related side effects associated with standard doses of prednisone. Low dose prednisone or long-term maintenance therapy with azathioprine (2 mg/kg daily) is a treatment option (Table 6 .3 ). The emergence of new immune-modulating drugs in the liver transplant arena has led to their empiric use in the treatment of suboptimal responses to conventional therapies in AIH. These empiric applications are indicated in Table 6 .3 , but none has been evaluated in randomized control trials and are thus not incorporated into established treatment algorithms. Relapse After Drug Withdrawal Relapse occurs in 20–86% of patients depending on the laboratory and histological fi ndings prior to drug withdrawal [6 , 7, 34 ] . Generalized weakness, arthralgias, and increase in the serum AST level characterize this occurrence. Examination of liver tissue typically reveals moderate–severe interface hepatitis in patients in whom the serum AST level increases above threefold normal [3 0 ] . Re-treatment with the original regimen typically induces another remission, but relapse recurs in 79% within 6 months after drug withdrawal [ 7 ] . With each relapse and re-treatment, the frequency of drug-related side effects increases, as does the occurrence of cirrhosis, death from hepatic failure, or requirement for liver transplantation [4 1 ] . Thus these patients are candidates for alternative therapies with either low dose prednisone or long-term azathioprine maintenance (Table 6 .3 ). The low dose prednisone regimen requires fi rst the induction of clinical and laboratory remission on standard therapy and then reduction in the dose of prednisone by 2.5 mg each month of clinical and laboratory stability [ 48 ] . The lowest dose that prevents symptoms and keeps serum AST levels within the normal range is main- tained. More than 80% of patients can be managed on prednisone, 10 mg daily or less (median dose, 7.5 mg daily). Side effects associated with earlier conventional treatments improve or disappear in 85%; and in most cases new side effects do not develop and survival is unaffected. Maintenance therapy with azathioprine also requires the initial induction of clini- cal and laboratory remission by conventional treatments [4 9, 50 ] . The corticosteroid component is then withdrawn, and the dose of azathioprine may be increased to up to 2 mg per kg daily and maintained indefi nitely. Eighty-seven percent of adult patients managed in this fashion remain in remission during a median observation period longer than 60 months. Follow-up liver biopsy assessments reveal inactive or minimal 124 A.J. Montano-Loza histological disease in 94% of patients; corticosteroid-related side effects improve or disappear in the majority of cases; and the drug is generally well-tolerated. The most common side effects are steroid withdrawal arthralgias (63%), lymphopenia (57%), and myelosuppression (7%). Malignancies involving diverse cell types occur in 8% of patients, but their association with the treatment strategy is unclear [5 1 ] . Relapse does not prohibit permanent discontinuation of medication later in the course of the disease [ 41 ] . Twenty-eight percent of patients who relapse and are re-treated develop inactive disease and can be withdrawn from medication. The probability of a sustained remission after initial or subsequent therapy is 47% during 10 years of follow-up. As with other suboptimal responses in AIH, pharma- cological agents of theoretical but unconfi rmed effi cacy have been used empirically for the treatment of relapse. These novel but unendorsed treatments are indicated in Table 6.3 . Different Treatment Schedules The outcomes associated with conventional medications may be improved by alter- ing doses and routes of delivery. Under these circumstances, success is measured as a favorable balance between the response of the disease and the tolerance of the medication. Alternate day corticosteroid regimens may not induce histological remission of the disease in adults, but they may have fewer side effects than conventional schedules. Consequently, they may be an appropriate strategy for individuals with obesity, osteoporosis, and diffi cult to control diabetes [ 27 ] . Pulse therapy regimens based on oral medication have not been well tolerated in adults [ 51 ]. Therefore, it is appropriate and important to individualize therapies according to patient response and tolerance. Recommended schedules are not infl exible, and they must be adapted to suit the individual need. Screening of Patients Receiving Treatment Patients with AIH receiving prednisone or azathioprine should be aware of possible complications of these medications, and they should be introduced to appropriate adjunctive treatment programs to reduce the risk of drug-related complications. Such therapies should include regular weight bearing exercise program, vitamin D and calcium supplementation. The administration of bisphosphonates may be appro- priate for individual patients. Patients on long-term (>6 months) prednisone should be monitored for bone disease at baseline and periodically thereafter according to local protocol with bone densitometry of the lumbar spine and hip. Also, patients on prednisone should undergo periodic eye examinations during treatment looking for cataracts and glaucoma. Patients receiving azathioprine in any dose should be monitored at 3–6-month intervals for leucopenia and throm- bocytopenia. 6 When and How to Treat the Adult Patient 125 Lastly, patients with AIH should be protected against hepatitis B virus (HBV) and hepatitis A virus (HAV), and vaccination should be done as early as possible even before immunosuppression is started because of lower response rates [5 ] . Liver Transplantation for Autoimmune Hepatitis Liver transplantation is an effective treatment for the decompensated patient with AIH. Patient and graft survival after liver transplantation ranges from 83 to 92%, and the actuarial 10-year survival after transplantation is around 75% [ 23, 37, 52 ] . Recurrence of AIH is recognized in at least 17% of patients after 5 ± 1 years, espe- cially in individuals receiving inadequate immune suppression [2 2, 23, 37, 53 ] . Adjustments in the immunosuppressive regimen are usually able to suppress recurrent disease, and infrequently cirrhosis or graft failure occurs [2 2 ] . Patients transplanted for AIH may also have a greater frequency of acute and chronic rejection than patients transplanted for non-autoimmune conditions, and some but not all studies have suggested they may be more diffi cult to wean from corticosteroid therapy [5 3, 54 ] . These potential consequences have tempered efforts to rapidly withdraw corticosteroids after the procedure [ 54, 55 ] . De novo AIH can develop in 1–3% of adult recipients who undergo transplantation for non-autoimmune liver disease, and it can result in graft loss if not treated with corticosteroids [2 5, 26, 56 ] . Recent studies indicated that sirolimus (rapamycin) can be effective in controlling this process [ 57 ] . The pathogenic mechanisms resulting in de novo AIH are unknown, but they may refl ect reduced thymic clearance of autoreactive cells or impaired apoptosis of activated lymphocytes by the calcineurin inhibitors used in the post-transplantation period [5 8– 60 ] . The early response to corticosteroid treatment is predictive of the need for liver transplantation [6 1, 62 ] . Histological features of multilobular collapse and lack of improvement in laboratory indices within 2 weeks of corticosteroid treatment characterizes patients who die of liver failure within 6 months of presentation. A hyperbilirubinemia that does not improve or that worsens during this interval is highly predictive of early mortality and the need for liver transplantation [ 35 ] . Patients with high Model for End-stage Liver Disease (MELD) score who do not respond rapidly to corticosteroid therapy, especially those in whom there is an emerging cholestasis, should also be considered for liver transplantation [6 3 ] . New Drug Therapies for Autoimmune Hepatitis Drugs already exist that can interfere selectively with each co-stimulatory signal of lymphocytes activation, and agents that block transendothelial migration of T cells into target tissues are also in development [ 64– 66 ] . The specifi city of action of these new drugs in various combinations may have complementary effects that will provide greater effi cacy than current non-selective immunosuppressive regimens (Table 6 .4 ). 126 A.J. Montano-Loza Table 6.4 Promising drug therapies for autoimmune hepatitis Drug Dose Actions Experience Cyclosporine 5–6 mg per kg daily Calcineurin inhibitor; impairs transcription of Empiric fi rst-line therapy in adults; empiric IL 2; prevents T lymphocyte proliferation; salvage therapy increases hepatic TGF-b (beta) Tacrolimus 4 mg twice daily Calcineurin inhibitor; impairs transcription of Benefi cial in three small clinical experiences IL 2; limits expression of IL 2 receptors; increases hepatic TGF-b (beta) Mycophenolate 1 g twice daily Purine inhibitor; independent of thiopurine Benefi cial as steroid-sparing agent in fi ve mofetil methyltransferase; impairs DNA synthesis; small clinical experiences reduces T lymphocyte proliferation Budesonide 3 mg thrice daily Corticosteroid actions; high fi rst pass clearance Effective as frontline therapy of treatment- by liver; metabolites devoid of glucocorti- naïve mild disease; not in cirrhotics coid activity 6-thioguanine 0.3 mg/kg daily Active metabolites of azathioprine Effective in three patients intolerant nucleotides of azathioprine Rituximab 375 mg/m2 IV weekly × 4 weeks Chimeric monoclonal anti-CD20 antibody that Improvement in one patient with concomi- induces B lymphocyte depletion tant ITP, and six patients refractory or intolerant of standard therapy Ursodeoxycholic acid 13–15 mg per kg daily Reduces HLA class I expression; inhibits IL 2, Effective in eight Japanese patients with mild IL 4 and interferon- g (gamma) production; disease; not in severe disease inhibits apoptosis; eliminates hydrophobic bile acids IL interleukin, T GF- b (beta) transforming growth factor-beta, D NA deoxyribonucleic acid, I V intravenous, ITP idiopathic thrombocytopenic purpura Adapted from Montano-Loza AJ, and Czaja AJ [1 0 ] 6 When and How to Treat the Adult Patient 127 Cyclosporine A binds to cyclophilin and inhibits the phosphatase activity of calcineurin. Consequently, it impairs transcription of interleukin (IL)-2 and the downstream activation events dependent on this cytokine. In doses of 5–6 mg/kg daily, it has been used successfully as “salvage” therapy in patients who have failed or have been intolerant of conventional corticosteroid therapy, and it has also been used as fi rst-line therapy [6 7– 72 ] . However, cyclosporine A has

not been compared to conventional treatments in control-randomized trials, and its use, especially as a fi rst-line drug, remains controversial. Side effects of cyclosporine A include renal insuffi ciency, hypertension, and malignancy. Tacrolimus inhibits expression of the IL-2 receptor and as a result impairs cell cycle progression and expansion of cytotoxic T lymphocytes. At doses of 4 mg twice daily, it has improved serum aminotransferase and bilirubin levels at acceptable risk in a small, open-labeled treatment trial in which the drug was given for 3 months [ 73 ] . In another study, 11 patients who were treated an average of 25 months with doses of tacrolimus titrated to serum concentrations between 1.7 and 10.7 ng/mL (mean, 3 ng/mL) experienced signifi cant improvements in serum aminotransferase levels and histological activity indices [7 4 ] . Tacrolimus is an empiric therapy for the refractory patient, and it may allow corticosteroid withdrawal [7 5 ] . Clinical control and randomized trials are needed to fully justify this expensive and potentially toxic treatment option. Mycophenolate mofetil (MMF) is an ester prodrug of mycophenolic acid, and it inhibits inosine monophosphate dehydrogenase. Conversion of inosine monophos- phate to xanthosine monophosphate is impaired, and subsequently DNA synthesis is reduced as a result of depleted stores of guanine nucleotides and lymphocyte proliferation is inhibited. Four small studies, using a typical dose of 1 g twice daily, have demonstrated the potential value of MMF as a substitute for azathioprine in patients intolerant of the conventional drug regimens [7 6– 79 ] . These reports have been countered by another small study in which fi ve of eight patients receiving MMF had laboratory improvement but not resolution, histological improvement did not occur in four patients sampled during treatment, and successive liver tissue specimens in two patients showed progressive fi brosis. Furthermore, corticosteroids could not be withdrawn in any patient [ 80 ] . Another study with 15 patients with AIH demonstrated that administration of MMF, either as monotherapy or in com- bination with prednisone, results in biochemical and histologic improvement in patients who were previously prednisone and/or azathioprine intolerant or resistant without the development of signifi cant complications [ 81 ] . Recently, the largest cohort treated with MMF, including 39 patients with AIH showed a low frequency of response to treatment as only 14 patients (39%) achieved remission, defi ned as AST less than twice the upper limit of normal. In a subset analysis, the authors further demonstrated that most patients with prior non-response to azathioprine did not response to MMF either [ 82 ] . MMF may be useful in corticosteroid-responsive patients who require a non- steroidal maintenance regimen, whereas it may be less effective as a salvage therapy for corticosteroid-dependent or unresponsive patients. A potential advantage over 128 A.J. Montano-Loza azathioprine is the independence of MMF from the thiopurine methyltransferase pathway; therefore it may be an alternative for patients who could not tolerate azathioprine previously. Budesonide (3 mg thrice daily) is a second generation glucocorticoid with high fi rst pass clearance by the liver and metabolites that are devoid of glucocorticoid activity. Preliminary studies in patients with mild disease have suggested that it is useful in selected patients as a frontline treatment [8 3– 85 ] , and these small reports justifi ed the performance of a controlled clinical trial. Recently, a German study compared combined budesonide and azathioprine to prednisolone and azathio- prine treatment in 208 patients with AIH. The primary end point was to achieve complete remission without the typical steroids side effects, defi ned as acne, hir- sutism, diabetes, striae, glaucoma and facial swelling. In this study the outcome used was a combination of biochemical remission without the typical steroids side effects (47% versus 18%, P < 0.001). Furthermore, the frequency of biochemical remission was superior in the budesonide group (60% versus 39%, P = 0.001); however, for the long-term normalization of bilirubin and IgG, budesonide was not superior to prednisolone. There is controversy with respect to the prednisolone effect, as the remission rates seems poor when compared to the 90% remission rates achieved in previous studies [8 6 ] . Moreover, budesonide cannot be used in cirrhotics and has not been effective as a salvage therapy for patients who are refractory or on corticosteroid-dependent treatment [8 7 ] . 6-mercaptopurine (6-MP) is the active metabolite of azathioprine and a purine antagonist, but the drugs are not interchangeable equivalents. 6-MP, administered initially as 50 mg daily and increased to 1.5 mg per kg daily, has salvaged patients who have failed therapy with azathioprine, and it should be considered as empiric treatment in such patients [8 8 ] . Its advantage over azathioprine may refl ect differences in intestinal absorption and metabolism. 6-MP generates thioguanine nucleotides that can accumulate in hematopoietic tissue and cause myelosuppression, and its clearance involves the thiopurine methyltransferase pathway. 6-thioguanine nucleotides are the active metabolites of azathioprine, and they have been effective in three patients intolerant of the parent drug [8 9 ] . Their use in AIH represents a logical addition of the use of purine antagonists for this disease, and the strategy takes advantage of the downstream metabolic products of the parent drug to minimize intolerance and perhaps improve effi cacy. The discordance between blood levels, laboratory response, and treatment tolerance underscores the lack of effective dosing and monitoring schedules for the 6-thioguanine nucleotides and cautions against its premature clinical application. Rituximab is a chimeric monoclonal anti-CD20 antibody which can induce depletion of B lymphocytes by targeting their CD20 cell surface receptor. This interaction may affect complement activation, antibody-dependent cytotoxicity, and the induc- tion of apoptosis. Its rationale in AIH is based on a presumption that B-cell expan- sion and hyperactivity can be suppressed by blocking the CD20 cell surface receptor of these cells. The unregulated proliferation of activated plasma cells can result 6 When and How to Treat the Adult Patient 129 in the production of immunoglobulins that adhere to normal membrane constituents of the hepatocytes. These aggregates can then become targets of natural killer cells with Fc receptors, and the antigen–antibody complex on the hepatocytes surface can induce an antibody-dependent cytotoxicity. These presumptions have been sup- ported by the successful treatment of one patient with AIH and idiopathic thrombo- cytopenic purpura with the drug [9 0 ] . Moreover, a recent study described six patients with AIH intolerant of or refractory to prednisone and azathioprine who received rituximab 1,000 mg IV at days 1 and 15. In all cases rituximab was well-tolerated and there were no serious adverse events. All patients entered biochemical remis- sion and IgG and g -globulin levels signifi cantly improved [9 1 ] . These results sup- port the ongoing investigation of rituximab for AIH patients who are refractory to or intolerant of standard therapy. Ursodeoxycholic acid (13–15 mg/kg daily) has putative choleretic, cytoprotective and immunomodulatory actions that could benefi t patients with AIH. Its ability to reduce expression of class I human leukocyte antigens, reduce immunoglobulin production, inhibit IL-2, IL-4 and interferon-g production, impair nitric oxide syn- thetase, and reduce production of reactive oxygen species might attenuate the auto- immune response. Ursodeoxycholic acid has been used as primary therapy for mild AIH, and treatment with 600 mg daily for 2 years has resulted in clinical, laboratory, and histological improvement in eight Japanese patients [9 2 ] . Similar improvements have not been achieved in North American patients with severe disease who experi- enced relapse or treatment failure after corticosteroid therapy [ 93 ] . The role of ursodeoxycholic acid as primary or adjunctive treatment for AIH is limited, and its value may be in the treatment of individuals with the clinical phenotype of those in Japan who have mild or uncomplicated disease. None of the new drugs that have been used in AIH have been formally incorpo- rated into management algorithms, but each has been administered empirically with reported success and safety. These agents increase the treatment options for the diffi cult patient, who is refractory to conventional regimens or intolerant of fi rst-line medications, but they have not been established as effective treatments and their application is associated with an uncertain benefi t–risk ratio. Conclusion Progress toward a more rational therapy of AIH is being made because of a better understanding of pathogenic mechanisms and the emergence of potent site-specifi c immunosuppressive agents. Improved prognostic instruments and recognition of modifying genetic and regional factors will allow modifi cations of therapy to suit individual clinical situations. The drugs and science are available to improve treat- ment of AIH; nevertheless, reliable animal models of the human disease and a multi-center, collaborative network of clinical investigators are the remaining req- uisites for success. 130 A.J. Montano-Loza Chapter Summary 1. Autoimmune hepatitis may behave aggressively and can result in cirrhosis, mortality caused by liver failure, or the need for liver transplantation. 2. Prednisone alone or at a reduced dose combined with azathioprine remains the fi rst-line treatment for autoimmune hepatitis. 3. Not all patients with autoimmune hepatitis respond to corticosteroid therapy, and those who do can relapse after withdrawal of this therapy. Useful Tips for Practitioners 1. Therapy to the point when liver test results and histological fi ndings are normal reduces, but does not eliminate, the occurrence of relapse. 2. Termination of immunosuppressive treatment can be considered after at least 2 years of treatment, when serum aminotransferases and immuno- globulin levels have been persistently normal; an individualized approach is however needed. 3. Treatment failure warrants reassessment with regard to the accuracy of the original diagnosis and the exclusion of variant forms of hepatitis or concomi- tant alternative diseases. Common Pitfalls in Practice 1. The diagnosis of autoimmune hepatitis does not compel therapy, and retrospective analyses of patients with mild disease have demonstrated the possibility of long-term survival without treatment. 2. Treatment of patients presenting with inactive cirrhosis with immunosup- pressants is generally to be avoided. 3. 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Successful treatment of autoimmune hepatitis and idiopathic thrombocytopenic purpura with the monoclonal antibody, rituximab: case report and review of the literature. Liver Int. 2006;26:625–9. 91. Burak KW, Williamson-Coffey S, Swain MG, et al. Rituximab for refractory autoimmune hepatitis: interim results of a phase 1 study. Hepatology. 2008;48:S1093. 92. Nakamura K, Yoneda M, Yokohama S, et al. Effi cacy of ursodeoxycholic acid in Japanese patients with type 1 autoimmune hepatitis. J Gastroenterol Hepatol. 1998;13:490–5. 9 3. Czaja AJ, Carpenter HA, Lindor KD. Ursodeoxycholic acid as adjunctive therapy for problem- atic type 1 autoimmune hepatitis: a randomized placebo-controlled treatment trial. Hepatology. 1999;30:1381–6. Chapter 7 When and How to Treat the Pediatric Patient Giorgina Mieli-Vergani and Diego Vergani Keywords Children • Autoimmune hepatitis • Autoimmune sclerosing cholangitis • De novo autoimmune hepatitis post-liver transplant • Corticosteroids • Azathioprine • Calcineurin inhibitors • Mycophenolate mofetil • Ursodeoxycholic acid • Rituximab • Anti-IL2 receptor monoclonal antibody • Regulatory T cells Introduction Autoimmune hepatitis (AIH) is a progressive infl ammatory liver disorder affecting mainly females, characterized serologically by high levels of transaminases and immunoglobulin G (IgG), and presence of autoantibodies, and histologically by interface hepatitis, in the absence of a known etiology [ 1 ] . AIH responds satisfacto- rily to immunosuppressive treatment. If left untreated, it progresses rapidly to cirrhosis and liver failure. The clinical phenotype of AIH in children differs from that of adults [2 , 3 ] . The juvenile form of AIH is subdivided into two types according to the autoantibody profi le: type 1, positive for anti-nuclear (ANA) and/or anti-smooth muscle (SMA) G. Mieli-Vergani (*) Institute of Liver Studies , King’s College London School of Medicine at King’s College Hospital , London, SE5 9RS, UK Alex Mowat Professor of Paediatric Hepatology , Paediatric Liver Centre, King’s College Hospital , Denmark Hill , London, SE5 9RS, UK e-mail: giorgina.vergani@kcl.ac.uk D. Vergani Institute of Liver Studies , King’s College London School of Medicine at King’s College Hospital , London, SE5

9RS , UK G.M. Hirschfi eld and E.J. Heathcote (eds.), Autoimmune Hepatitis: A Guide for Practicing 135 Clinicians, Clinical Gastroenterology, DOI 10.1007/978-1-60761-569-9_7, © Springer Science+Business Media, LLC 2012 136 G. Mieli-Vergani and D. Vergani antibody, and/or type 2, positive for anti-liver kidney microsomal antibody type 1 (anti-LKM-1) or anti-liver cytosol type 1 (anti-LC1), autoantibodies rarely described in adult patients [4 ] . Both AIH types are associated with other autoimmune disorders (about 20%) and a family history of autoimmune disease (40%) [5 ] . Type 2 AIH can be part of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome, an autosomal recessive genetic disorder in which the liver disease is reportedly present in some 20% of patients [6 ] . The epidemiology of childhood AIH is unknown, but type 1 AIH accounts for two-thirds of the cases and presents usually during adolescence, while type 2 AIH presents at a younger age and also during infancy. In both types there is a female preponderance (75%) and IgG levels are usually raised at presentation, though 15% of children with AIH type 1 and 25% of those with AIH type 2 have normal levels [ 5 ] , especially those with an acute presentation. IgA defi ciency is common in AIH type 2 [5 ] . AIH in children is usually more advanced at presentation than in adults [7 ] . Severity of disease is similar in the two subtypes, though anti-LKM-1-positive chil- dren have a higher tendency to present as fulminant liver failure than those with type 1 AIH [5 ] . Most children with either subtype of AIH have an acute onset, indistin- guishable from severe acute infectious hepatitis, and over 40% already have cirrho- sis at diagnosis, the milder forms of the disease described in adults being rarely reported in childhood [1 , 8 ] . The aggressive course of juvenile AIH requires a low threshold of suspicion for this condition in children with unexplained abnormal liver function tests, so that treatment can be started early to avoid progression of disease and worse long-term outcome [9 ] . In pediatrics, sclerosing cholangitis is often associated with fl orid autoimmune features, including elevated titers of autoantibodies, in particular ANA and SMA, elevated IgG, and interface hepatitis [1 0 ] . Since these features are shared in common with AIH and are often not accompanied by elevated alkaline phosphatase or gamma glutamyl transpeptidase levels at disease onset, the diagnosis of sclerosing cholan- gitis relies on cholangiographic studies. In the absence of cholangiographic studies at presentation many of these children are diagnosed and treated as AIH, though the diagnosis of sclerosing cholangitis often becomes apparent during follow-up. This condition, referred to as autoimmune sclerosing cholangitis (ASC), is as preva- lent as AIH type 1 in childhood, but in contrast to AIH it affects equally boys and girls [1 0 ] . ASC responds satisfactorily to immunosuppression, at least in regard to the parenchymal infl ammation, if treatment is started early. Current International Autoimmune Hepatitis Group (IAIHG) diagnostic criteria [2 , 11 ] do not allow distinction between AIH and ASC. Treatment The goal of treatment is to obtain early complete remission to prevent disease pro- gression, and maintain it long term on the lowest dose of medication possible. 7 When and How to Treat the Pediatric Patient 137 Defi nition of Remission and Relapse Remission is defi ned as complete clinical recovery, normal transaminase and IgG levels, negative or very low titer autoantibodies (tested by immunofl uorescence on rodent liver stomach and kidney [1 2 ] ) and histological resolution of infl ammation. The histological response lags behind the biochemical response [1 3– 15 ] and clinical/biochemical remis- sion does not necessarily refl ect histological resolution. After a mean duration of 4 years of treatment, improvement of the intensity of portal infl ammation is observed in up to 95% of cases and is accompanied by an improvement of the fi brosis scores [1 4 ] . Histological regression of cirrhotic changes after immune suppressive treatment with steroids and azathioprine has been recently reported in a child with AIH type 1 [1 6 ] . Relapse is characterized by increase of serum transaminase levels after remission has been achieved. Relapse during treatment is common, occurring in about 40% of patients requiring a temporary increase in the steroid dose. An important role in relapse is played by nonadherence, which is common, particularly in adolescents [ 17 ] . In more aggressive cases, the risk of relapse is higher if steroids are adminis- tered on an alternate-day schedule, which is often instituted in the belief that it may have a less negative effect on the child’s growth. Small daily doses are more effec- tive in maintaining disease control and minimize the need for high-dose steroid pulses during relapses (with consequent more severe side effects). Importantly, these small daily doses have been shown not to affect fi nal height [1 8 ] . When to Treat AIH should be suspected and sought in all children with evidence of liver disease after exclusion of infectious and metabolic etiologies. Autoimmune hepatitis is exquisitely responsive to immunosuppression and treatment should be initiated promptly to avoid progression of disease. The aim of treatment is to reduce or eliminate liver infl ammation, to induce remission, improve symptoms, and prolong survival [1 9, 20 ] . The rapidity and degree of the response depends on disease severity at presentation. Although cirrhosis is reported to be present in 44–80% of children at the time of diagnosis [ 5, 8, 21 ] , mortality is low and most children remain clinically stable, with a good quality of life on long-term treatment. How to Treat With the exception of a fulminant presentation with encephalopathy, AIH responds satisfactorily to immunosuppressive treatment whatever the degree of liver impair- ment, with a reported remission rate around 80%. T here have been no randomized, controlled, treatment trials in children with autoimmune hepatitis, but several reports have documented the effi cacy of regimens similar to those used in adults [9 ] . 138 G. Mieli-Vergani and D. Vergani Standard Treatment Successful treatment is obtained in most cases of AIH with inexpensive, well-tested drugs. The mode of administration over time is key to success. Treatment of juvenile AIH is initiated with prednisolone (or prednisone) 2 mg/kg/day (maximum 40–60 mg/ day). This dose should be gradually decreased over a period of 4–8 weeks, guided by the decline of transaminase levels, to a maintenance dose of 2.5–5 mg/day [5 , 22, 23 ] . The target should be an 80% decrease of the transaminase levels by the fi rst 2 months of treatment, and not their complete normalization, which may take several months [5 , 24 ] . During the fi rst 6–8 weeks of treatment, liver biochemical tests should be checked weekly to allow frequent dose adjustments. The attempt to attain normal transaminase levels more rapidly would require a prolonged use of high-dose steroids with attendant severe side effects. The timing for the addition of azathioprine as a steroid-sparing agent varies according to the protocols used in different centers. In our center [ 5 ] , azathioprine is added if the transaminase levels stop decreasing on steroid treatment alone, or in the presence of steroid side effects, at a starting dose of 0.5 mg/kg/day, which in the absence of signs of toxicity is increased up to a maxi- mum of 2.0–2.5 mg/kg/day until biochemical control is achieved. In other centers azathioprine is added at a dose of 0.5–2 mg/kg/day in all cases after a few weeks of steroid treatment, when the serum aminotransferase levels begin to decrease. Whatever the protocol, 85% of the patients eventually require the addition of azathio- prine to steroids. Some centers use a combination of steroids and azathioprine from the beginning, but caution is recommended because azathioprine can be hepatotoxic, and should be used in severely jaundiced patients only when jaundice subsides. Measurement of thiopurine methyltransferase activity level before initiating azathioprine therapy has been advocated to predict azathioprine metabolism and toxicity. Measurement of the azathioprine metabolites 6-thioguanine and 6-meth- ylmercaptopurine has been reported to help in identifying drug toxicity and nonad- herence and in achieving a level of 6-thioguanine considered therapeutic for infl ammatory bowel disease [ 25 ] , though an ideal therapeutic level for AIH has not been determined. Prospective studies are needed. In adults, azathioprine alone has been shown to maintain remission in AIH type 1. A similar experience has been recently reported in pediatrics, successful with- drawal of steroids and maintenance of remission with azathioprine alone having been described in 18/37 children with AIH type 1 and 4/11 children with AIH type 2 in one center [2 6 ] and in 5/7 children with AIH type 1 in another [2 7 ] . Alternative Treatments Calcineurin inhibitors. The use of cyclosporine A to induce remission without high- dose steroid side effects has been advocated both in type 1 [ 28, 29 ] and 2 AIH [ 30 ] . In treatment naïve children, mostly with AIH type 1, Alvarez’ group reports attainment of remission using cyclosporine A alone for 6 months, followed by the addition of predni- sone and azathioprine [2 8, 29 ] . One month later, cyclosporine is discontinued. 7 When and How to Treat the Pediatric Patient 139 Cyclosporine is used at the dose of 4 mg/kg/day in three divided doses, increased every 2–3 days to achieve a whole-blood trough level of 250 ± 50 ng/ml for 3 months. If there is clinical and biochemical response in the fi rst 3 months, cyclosporine is reduced to achieve trough levels of 200 ± 50 ng/ml for the following 3 months, before discontinu- ing it. Normalization of transaminases was obtained in 94% of subjects treated, with 72% responding within the fi rst 6 months of treatment. Transition to azathioprine and low-dose prednisone after 6 months was possible in all patients and resulted in sustained remission in the majority for more than 2 years. Cyclosporine side effects included hypertrichosis (55%), gingival hyperplasia (39%), elevation of creatinine (8/84 chil- dren), and hypertension (3/84 children). Whether this mode of induction has any advan- tage over the standard treatment has yet to be evaluated in controlled studies. Tacrolimus, a second calcineurin inhibitor, is a more potent immunosuppressive agent than cyclosporine, with fewer cosmetic consequences, but signifi cantly higher toxicity. There is limited evidence supporting its role in the treatment of AIH apart from anecdotal reports in adults. There are theoretical disadvantages in the use of calcineurin inhibitors for the treatment of AIH, since these drugs have been shown to favor autoimmunity in experimental models both by depressing regulatory T-cell function and favoring thymus egress of self-reactive T cells [3 1– 35 ] . Calcineurin inhibitors may in fact be involved in the development of autoimmune reactions after transplantation, includ- ing de novo AIH after liver grafting [3 5 ] . Both cyclosporine A and tacrolimus are used as rescue treatment for diffi cult-to- treat cases, but since no large series in this subgroup of patients has been published, they should be used cautiously. Treatment of refractory cases . Mycophenolate mofetil (MMF) is the prodrug of mycophenolic acid. Its effect on purine synthesis leads to decreased T and B lym- phocyte proliferation. In patients in whom standard immunosuppression is unable to induce stable remission, or who are intolerant to azathioprine, mycophenolate mofetil at a dose of 20 mg/kg twice daily, together with prednisolone, has been used with success [3 6 ] . If there is a persistent absence of response or if there is intoler- ance to mycophenolate mofetil (headache, diarrhea, nausea, dizziness, hair loss, and neutropenia), the use of calcineurin inhibitors may be considered. Tacrolimus may be useful in combination with prednisolone as second-line therapy. Other treatments. No data are available on the effectiveness of budesonide or ursodeoxycholic acid (UDCA) in childhood AIH. Data on budesonide treatment in childhood AIH have been presented at an EASL meeting but await peer review. Treatment of Autoimmune Sclerosing Cholangitis ASC responds to the same immunosuppressive treatment described above for AIH. However, while steroids and azathioprine are benefi cial in abating the parenchymal infl ammatory lesions, they appear to be less effective in controlling the bile duct 140 G. Mieli-Vergani and D.

Vergani disease [1 0 ] . UDCA is usually added to steroids and azathioprine for the treatment of ASC, but whether it is helpful in arresting the progression of the bile duct disease remains to be established. In adults with primary sclerosing cholangitis high-dose UDCA has been reported as more benefi cial than standard doses [3 7 ] , but a randomized double-blind controlled study by the Mayo Clinic group shows that very high-dose UDCA (30 mg/kg/day) has a negative long-term effect [3 8 ] . It is prudent, therefore, to use doses not exceeding 15 mg/kg/day. Both AIH and, more commonly, ASC can be associated with infl ammatory bowel disease which should be investigated even in the absence of symptoms and appropriately treated. Duration of Treatment and Prognosis The optimal duration of immunosuppressive treatment for AIH is unknown. Treatment withdrawal is successful only if there is histological resolution of infl am- mation. Hence, cessation of treatment should be considered if a liver biopsy shows minimal or no infl ammatory changes after 1–2 years of normal liver function and biochemical tests, normal IgG levels and negative, or low titer autoantibodies. However, it is advisable not to attempt treatment withdrawal within 3 years of diag- nosis or during or immediately before puberty, when relapses are more common. It has been reported that 20% of patients with AIH type 1 can successfully and perma- nently stop treatment, while this is rarely achieved in AIH type 2 [ 5 ] . Long-term treatment is required for the majority of patients and parents and patients should be counseled accordingly. In the pediatric setting, an important role in monitoring the response to treatment is the measurement of autoantibody titers and IgG levels, the fl uctuation of which correlates with disease activity [ 39 ] . In particular, for patients with high IgG levels, their decrease is a reliable, objective and inexpensive measure of disease control. The prognosis of those children with AIH who respond to immunosuppressive treatment is generally good, with most patients surviving long-term with excellent quality of life on low dose medication. Development of end-stage liver disease requiring liver transplantation despite treatment, however, has been reported 8–14 years after diagnosis in 8.5% of children with AIH [5 ] . A question frequently asked by parents and teenage girls is the effect of treat- ment on pregnancy and its safety for the fetus. A few published reports demonstrate that treatment with steroids and azathioprine is safe for the mother and the baby and not associated with an increased risk of fetal defects or mortality [4 0– 42 ] . Liver Transplantation Liver transplantation is indicated in patients who present with fulminant hepatic failure (with encephalopathy) and those who progress to end-stage liver disease despite treatment (10–20%). The latter is more likely when established cirrhosis is 7 When and How to Treat the Pediatric Patient 141 present at diagnosis, or if there is a long history before the start of treatment. After transplantation, recurrent AIH develops in some 20% of cases [4 3 ] . Diagnosis of recurrent AIH is based on biochemical abnormalities, presence of autoantibodies, interface hepatitis on liver histology, and/or steroid dependence. Recurrence may occur even years after transplantation, and consequently maintenance of steroid- based immunosuppression at a higher dose than that used for patients transplanted for conditions other than AIH is generally recommended. Additionally, a form of graft dysfunction called de novo AIH, associated with positive autoantibodies, high IgG, histological features of interface hepatitis has been described in 6–10% of children transplanted for nonautoimmune disorders [3 5, 44 ] . This condition does not respond satisfactorily to anti-rejection regimens, but only to the standard treat- ment for AIH [3 5, 44 ] , or, in resistant cases, to rapamycin [4 5 ] . Future Treatment Options New immunosuppressive agents effective in the 10–15% of children who fail to respond to conventional corticosteroid treatment, and which may promote per- manent resolution of the disease in all patients are the ultimate goal for child- hood AIH. The armamentarium available to manipulate the immune system in the fi eld of organ transplantation and in other autoimmune diseases may ultimately provide important information for the treatment of autoimmune hepatitis and prompt multi- center, collaborative studies in large numbers of children. Immunosuppressant medications that may theoretically be useful in the treat- ment of AIH include selective monoclonal antibodies directed against the IL-2 receptor, a high number of activated lymphocytes bearing this receptor being char- acteristic of the active phase of the disease [ 46 ] . However, regulatory T cells also express IL-2 receptor and a fi ne balance will need to be found between curbing effector function while avoiding interfering with regulatory mechanisms. In view of the elevated level of IgG and high titers of autoantibodies, rituximab is a pos- sible mode of treatment for particularly aggressive cases. Rapamycin, reportedly successful in the control of post-transplant de novo AIH [4 5 ] , could also have a role in diffi cult-to-treat AIH. All the above drugs, however, in common with conventional immunosuppressive drugs, do not only suppress the autoimmune process causing liver damage, but also weaken the physiological immune responses, with consequent systemic side effects. Recent studies showing that a decrease in number and function of regulatory T cells (Tregs) characterizes childhood AIH, particularly when the disease is active [ 47– 49 ] , and that defective liver antigen-specifi c Tregs can be cultured, re-educated and expanded in vitro [5 0, 51 ] , lay the foundation for treatment based on adoptive transfer of re-educated antigen-specifi c Tregs. This would be able to treat, possibly cure, liver-directed autoimmunity without impairing the overall function of the immune system. 142 G. Mieli-Vergani and D. Vergani Chapter Summary 1. In childhood, autoimmune hepatitis has a particularly aggressive course and should be diagnosed and treated as early as possible to avoid rapid progression to cirrhosis and liver failure. 2. The goal of treatment is to obtain early complete remission (complete clinical recovery, normal transaminase and IgG levels, negative or very low titer autoantibodies and histological resolution of infl ammation) and maintain it long term on the lowest dose of medication possible. 3. The vast majority of children with autoimmune hepatitis respond to steroids, usually with the addition of azathioprine as a steroid sparing treatment. Alternative treatments should only be offered to diffi cult-to-treat patients. Medium and long-term prognosis of treated autoimmune hepatitis is excellent. Useful Tips for Practitioners 1. Autoimmune hepatitis should be considered in the differential diagnosis of all children with abnormal liver function tests. 2. An acute hepatitis with a fl uctuating course, negative for hepatitis A, B or C infection, is highly suggestive of autoimmune hepatitis. 3. Relapse of autoimmune hepatitis on treatment, in particular in teenagers, is usually due to poor adherence to treatment. 4. Progression of disease despite effective treatment suggests presence of bile duct disease (autoimmune sclerosing cholangitis). Common Pitfalls in Practice 1. To delay investigating children with a cryptogenic acute hepatitis in the belief that it is a benign condition. 2. To continue high-dose steroid treatment in autoimmune hepatitis until the transaminase levels return to normal: this will cause severe steroid side effects. The aim should be to achieve at least an 80% reduction of baseline transaminase levels within 6–8 weeks, and decrease the steroid dose weekly while the transaminase levels improve. Azathioprine should be added if the transaminase values plateau. 3. To give alternate days steroid treatment to children with autoimmune hepatitis in the belief that this will have less negative effect on growth. In children with severe disease, an alternate day steroid schedule is associated with a high relapse rate, requiring increased steroid doses, with attendant more severe side effects and growth impairment. 7 When and How to Treat the Pediatric Patient 143 References 1. Mieli-Vergani G, Heller S, Jara P, Vergani D, Chang MH, Fujisawa T, et al. Autoimmune hepa- titis. J Pediatr Gastroenterol Nutr. 2009;49(2):158–64. 2. Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31(5):929–38. 3. Pando M, Larriba J, Fernandez GC, Fainboim H, Ciocca M, Ramonet M, et al. Pediatric and adult forms of type I autoimmune hepatitis in Argentina: evidence for differential genetic predisposition. 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Azathioprine metabolite measurements in the treatment of autoimmune hepatitis in pediatric patients: a preliminary report. J Pediatr Gastroenterol Nutr. 2002;35(3):391–8. 26. Dumortier J, Arita CT, Rivet C, LeGall C, Bouvier R, Fabien N, et al. Long-term treatment reduction and steroids withdrawal in children with autoimmune hepatitis: a single centre expe- rience on 55 children. Eur J Gastroenterol Hepatol. 2009;21(12):1413–8. 27. Banerjee S, Rahhal R, Bishop WP. Azathioprine monotherapy for maintenance of remission in pediatric patients with autoimmune hepatitis. J Pediatr Gastroenterol Nutr. 2006;43(3):353–6. 28. Alvarez FCM, Canero-Velasco C, et al. Short-term cyclosporine induces a remission of auto- immune hepatitis in children. J Hepatol. 1999;30:222–7. 29. Cuarterolo M, Ciocca M, Velasco CC,

Ramonet M, Gonzalez T, Lopez S, et al. Follow-up of children with autoimmune hepatitis treated with cyclosporine. J Pediatr Gastroenterol Nutr. 2006;43(5):635–9. 30. Debray D, Maggiore G, Girardet JP, Mallet E, Bernard O. Effi cacy of cyclosporin A in children with type 2 autoimmune hepatitis. J Pediatr. 1999;135(1):111–4. 31. Gao E, Lo D, Cheney R, Kanagawa O, Sprent J. Abnormal differentiation of thymocytes in mice treated with cyclosporin A. Nature. 1988;336:176–9. 32. Bucy PB, Yan Xu X, Li J, Huang GQ. Cyclosporin A-induced autoimmune disease in mice. J Immunol. 1993;151:1039–50. 33. Wu DY, Goldschneider I. Cyclosporin A-induced autologous graft-versus-host disease: a pro- totypical model of autoimmunity and active (dominant) tolerance coordinately induced by recent thymic emigrants. J Immunol. 1999;162(11):6926–33. 34. Damoiseaux JG, van Breda Vriesman PJ. Cyclosporin A-induced autoimmunity: the result of defective de novo T- cell development. Folia Biol. 1998;44(1):1–9. 35. Mieli-Vergani G, Vergani D. De novo autoimmune hepatitis after liver transplantation. J Hepatol. 2004;40(1):3–7. 36. Aw MM, Dhawan A, Samyn M, Bargiota A, Mieli-Vergani G. Mycophenolate mofetil as rescue treatment for autoimmune liver disease in children: a fi ve-year follow-up. J Hepatol. 2009;51:156–60. 37. Mitchell SA, Bansi DS, Hunt N, Von Bergmann K, Fleming KA, Chapman RW. A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology. 2001;121(4):900–7. 38. Lindor KD, Kowdley KV, Luketic VA, Harrison ME, McCashland T, Befeler AS, et al. High- dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology. 2009;50(3):808–14. 39. Gregorio GV, McFarlane B, Bracken P, Vergani D, Mieli-Vergani G. Organ and non-organ specifi c autoantibody titres and IgG levels as markers of disease activity: a longitudinal study in childhood autoimmune liver disease. Autoimmunity. 2002;35(8):515–9. 40. Heneghan MA, Norris SM, O’Grady JG, Harrison PM, McFarlane IG. Management and outcome of pregnancy in autoimmune hepatitis. Gut. 2001;48(1):97–102. 41. Candia L, Marquez J, Espinoza LR. Autoimmune hepatitis and pregnancy: a rheumatologist’s dilemma. Semin Arthritis Rheum. 2005;35(1):49–56. 7 When and How to Treat the Pediatric Patient 145 42. Terrabuio DR, Abrantes-Lemos CP, Carrilho FJ, Cancado EL. Follow-up of pregnant women with autoimmune hepatitis: the disease behavior along with maternal and fetal outcomes. J Clin Gastroenterol. 2009;43(4):350–6. 43. Duclos-Vallee JC, Sebagh M, Rifai K, Johanet C, Ballot E, Guettier C, et al. A 10 year follow up study of patients transplanted for autoimmune hepatitis: histological recurrence precedes clinical and biochemical recurrence. Gut. 2003;52(6):893–7. 44. Kerkar N, Hadzic N, Davies ET, Portmann B, Donaldson PT, Rela M, et al. De-novo autoim- mune hepatitis after liver transplantation. Lancet. 1998;351(9100):409–13. 45. Kerkar N, Dugan C, Rumbo C, Morotti RA, Gondolesi G, Shneider BL, et al. Rapamycin successfully treats post-transplant autoimmune hepatitis. Am J Transplant. 2005;5(5):1085–9. 46. Lobo-Yeo A, Alviggi L, Mieli-Vergani G, Portmann B, Mowat AP, Vergani D. Preferential activation of helper/inducer T lymphocytes in autoimmune chronic active hepatitis. Clin Exp Immunol. 1987;67(1):95–104. 47. Longhi MS, Hussain MJ, Mitry RR, Arora SK, Mieli-Vergani G, Vergani D, et al. Functional study of CD4 + CD25+ regulatory T cells in health and autoimmune hepatitis. J Immunol. 2006;176(7):4484–91. 48. Longhi MS, Ma Y, Bogdanos DP, Cheeseman P, Mieli-Vergani G, Vergani D. Impairment of CD4(+)CD25(+) regulatory T-cells in autoimmune liver disease. J Hepatol. 2004;41(1):31–7. 49. Longhi MS, Ma Y, Mitry RR, Bogdanos DP, Heneghan M, Cheeseman P, et al. Effect of CD4+ CD25+ regulatory T-cells on CD8 T-cell function in patients with autoimmune hepatitis. J Autoimmun. 2005;25(1):63–71. 50. Longhi MS, Meda F, Wang P, Samyn M, Mieli-Vergani G, Vergani D, et al. Expansion and de novo generation of potentially therapeutic regulatory T cells in patients with autoimmune hepatitis. Hepatology. 2008;47(2):581–91. 51. Longhi MS, Ma Y, Mieli-Vergani G, Vergani D. Aetiopathogenesis of autoimmune hepatitis. J Autoimmun. 2010;34(1):7–14. Chapter 8 Strategies for Treatment Nonresponders: Second-Line Therapies and Novel Approaches Elizabeth Mileti and Marion Peters Keywords Alternative medications • Side effects • Mycophenylate mofetil • 6-Mercaptopurine • Cyclophosphamide • Budesonide • Defl azacort • Tacrolimus • Cyclosporine • Ursodeoxycholic acid • Infl izamab Introduction Conventional treatment of autoimmune hepatitis (AIH) with prednisone alone or in combination with azathioprine has been well studied over the last 40 years and found to be effective in approximately 80% of patients. The other 20% of patients are not successfully treated for various reasons including nonresponse, partial response, or noncompliance because they are unable to tolerate the side effects of these medications. Side effects of corticosteroids can be quite severe and include diabetes, hypertension, Cushingoid facies, behavioral changes, osteopenia, and growth retardation. These side effects are especially undesirable in children and the elderly. Azathioprine was initially studied as medication to maintain remission so that steroids could be weaned and side effects minimized. While azathioprine does allow for some steroid-sparing effects, it has its own adverse events which may limit tolerance to the medication. Over recent decades, newer immunosuppressive medications have become available mainly for use in transplantation. Figure 8.1 provides the dates they were fi rst reported for use in AIH. These medications have been evaluated for use in patients intolerant to fi rst-line therapy for AIH. As more studies and experience with E. Mileti Departments of Pediatrics , University of California , San Francisco, 94143-0538 , CA , USA M. Peters (*) Division of Gastroenterology, Department of Medicine , University of California, 513 Parnassus Ave, Room S-357, San Francisco, 94143-0538 , CA , USA e-mail: marion.peters@ucsf.edu G.M. Hirschfi eld and E.J. Heathcote (eds.), Autoimmune Hepatitis: A Guide for Practicing 147 Clinicians, Clinical Gastroenterology, DOI 10.1007/978-1-60761-569-9_8, © Springer Science+Business Media, LLC 2012 148 E. Mileti and M. Peters Fig. 8.1 Timeline of immunosuppressive medications usage for autoimmune hepatitis Table 8.1 Quality of studies reported using alternative therapies for autoimmune hepatitis Primary therapy Rescue therapy Drug Studies (n )* RCT* ( n ) Studies ( n ) RCT* (n ) MMF 0 0 Case series (36) 0 Budesonide Case series (13) Y* (203) Case series (11) 0 Tacrolimus Open-label prospective trial (21) 0 Case series (11) 0 Cyclosporine Open-label prospective trial in 0 Case series (10) 0 children (84) UDCA Retrospective study (65) 0 Case reports ns* (147) *( n ) = number of patients in largest study reported RTC = randomized controlled trial Y = RCT with signifi cant benefi t and fewer side effects than prednisone ns = RCT not signifi cant these medications continue to grow, the therapeutic approach to AIH is evolving. These alternative therapies include: mycophenolate mofetil, budesonide, cyclosporine, tacrolimus, cyclophosphamide, methotrexate, 6-mercaptopurine, not an immunosup- pressive acid, and infl iximab. These mostly immunosuppressive medications have generally been studied as second-line therapy after failure or intolerance of azathioprine and prednisone. There are few studies using these medications as alternative fi rst-line approach or for induction of remission prior to transition to prednisone and azathioprine. There are only two randomized controlled studies of new medications for AIH which are described below. This review will outline the data supporting use of these alternative therapies for AIH. Table 8.1 shows the quality of studies reported for each drug and whether the drug was studied as primary or rescue therapy. In parentheses is the number of subjects in the largest study reported. Table 8.2 shows the side effects of these alternative therapies. 8 Strategies for Treatment Nonresponders… 149 Table 8.2 Side effects of alternative therapies for autoimmune hepatitis Medication Side effects >10% 1–10% <1% Mycophenolate Asthenia, backache, cytopenias Severe neutropenia Lymphoma mofetil Electrolyte abnormalities, GI symptoms Gastrointestinal Malignant epithelial skin neoplasm Headache, insomnia, tremor hemorrhage Progressive multifocal leukoencephalopathy Hypercholesterolemia, hyperglycemia Pulmonary fi brosis Hypertension, nephrotoxicity Cyclophosphamide Alopecia, amenorrhea, GI symptoms Infectious disease Azoopermia Hemorrhagic cystitis Cardiomyopathy Interstitial pneumonia, leukopenia Stevens-Johnson syndrome Toxic epidermal necrolysis 6-Mercaptopurine Diarrhea hyperpigmentation of skin, rash Hepatotoxicity Hyperuricemia Myelosuppression Ulceration of intestine Methotrexate GI symptoms, mucositis, cytopenias Alopecia, photosensitivity, Acute neurologic syndrome Nephrotoxicity rash, pneumonitis, Alveolitis liver fi brosis, cystitis Erythema multiforme Budesonide Headache GI symptoms arthralgia Cataract, glaucoma, hypocortisolism Tacrolimus H eadache, insomnia, tremor, parasthesias, alopecia, Seizures Lymphoproliferative disorders, Leukoencephalopathy erythema, pruritus, GI symptoms, cytopenias, hypertension, diabetes, hyperlipidemia, nephrotoxicity, electrolyte abnormalities Cyclosporin Electrolyte abnormalities, gingival hyperplasia, Seizures Lymphoproliferative disorders headache, tremor, High triglycerides, hirsutism, hypertension, nephrotoxicity Ursodeoxycholic acid Backache, dizziness, GI symptoms Rash Infl iximab Abdominal pain, headache, nausea Fatigue, leukopenia, Acute coronary syndrome, drug induced lupus erythematosus, neutropenic disorder erythema multiforme, hepatosplenic T-cell lymphoma, hepatotoxicity, immune hypersensitivity reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis 150 E. Mileti and M. Peters Antimetabolites Mycophenolate Mofetil Mycophenolate mofetil (MMF) is a popular second-line immunosuppressive medication for the treatment of autoimmune hepatitis. MMF is a pro-drug that is converted to mycophenolic acid (MPA), a noncompetitive inhibitor of inosine mono- phosphate dehydrogenase. MPA blocks purine synthesis, thereby stopping DNA replication in T and B lymphocytes which are unable to use the salvage pathway. Initial small case series of patients who failed standard therapy reported success rates of 63–75% [1 , 2 ] . One of the fi rst studies to use mycophenolate mofetil, published in 2000, had seven patients who were either intolerant or failed treatment with prednisone and azathioprine. This study used 20 mg/day of prednisone and 1,000 mg MMF twice a day. Five of these seven patients (71%) had normalized transaminases after 3 months of therapy with subsequent decrease in prednisone dose from 20 mg/day to 2 mg/day. Hepatic activity index scores were measured in this study with median scores decreasing from 11 to 3 after 7 months of therapy. Side effects included leucopenia in one patient, which resolved after dose reduction of MMF [3 ] . A similar study reported biochemical remission in all fi ve patients on 1,000 mg MMF twice a day with continued steroid dose. All patients were able to decrease their steroid dose while on MMF [ 4 ] . A larger Canadian study reported normalization of ALT within 4.2 months in 13 of their 16 patients with MMF. Prednisone was able to be reduced in those who achieved biochemical remission [ 5 ] . One case series reported 34% dropout rates, due to side effects of the medica- tion [6 ] . The most recent study in children by Aw et al. evaluated mycophenolate mofetil as rescue treatment for AIH. Twenty-six children with median age 9.9 years were treated with MMF. Indications for use of MMF included failure to induce or maintain remission in 20 subjects and intolerance of side effects in the other six children. Sixty-nine percent of children in this study achieved biochemical remission in this study [ 7 ] . In contrast, Czaja et al. reported only 25% achieved biochemical improvement with MMF and 38% actually had worsening transaminases [8 ] . Similarly disap- pointing results were seen in the largest case series performed thus far with MMF. Hennes et al. studied 36 individuals who failed standard therapy: 27 were intolerant to the side effects of steroids and azathioprine, and nine were nonresponders to standard treatment. Overall, only 14 out of 36 subjects responded to MMF (39%) but the results varied based on the reason for switching to MMF. Those subjects who were intolerant to azathioprine had a better response to MMF (43% remission) compared with subjects who did not respond to azathioprine (25% remission). Nausea, vomiting abdominal pain, and diarrhea were the most common side effects seen in 31% of patients and four patients stopped therapy due to side effects [9 ] . No randomized controlled studies have been performed in treatment naïve or as rescue therapy in AIH. While MMF has gained popularity, there are no data to show that it is more effi cacious than azathioprine. 8 Strategies for Treatment Nonresponders… 151 6-Mercaptopurine 6-Mercaptopurine was one of the initial medications used to treat AIH in the early 1960s. Azathioprine is a derivative of 6-Mercaptopurine and both often used interchangeably. Despite being a derivative of azathioprine, 6-Mercaptopurine has a different side effect profi le and patients who are intolerant of azathioprine can sometime tolerate and respond to 6-Mercaptopurine and prednisone and be able to be weaned off prednisone [1 0 ] . Cyclophosphamide Cyclophosphamide has been used for AIH since the 1970s. Several case reports have been published with the use of cyclophosphamide for patients intolerant or unresponsive to standard therapy with normalization of liver enzymes on a regimen of cyclophosphamide and steroids [1 1, 12 ] . However, it is not often used because of incidence of side effects, especially hematologic effects. In addition to the above anti-metabolites, there are a few

case reports high- lighting the use of methotrexate in autoimmune hepatitis. Much like other anti- metabolites, methotrexate has shown promising results in limited case reports [ 13, 14 ] . Steroid Alternatives Budesonide Budesonide is a synthetic steroid with 90% fi rst-pass metabolism in the liver. It also has a 15-fold higher affi nity for the glucocorticoid receptor making it an attractive alternative to prednisone with potentially fewer side effects. Initial case series of 13 patients reported normalization of aminotransferases and the drug was well tolerated with fewer side effects [ 15 ] . A follow-up study of ten patients who were treatment-dependent were not stable on budesonide: remission was only seen in three patients and signifi cant side effects were noted [1 6 ] . The largest multicenter study of budesonide as an alternative to prednisone has been performed in 30 centers in Europe and Israel and was recently published [ 17 ] . This was a 6-month, prospective, double-blind, randomized, active-controlled, multi-center, phase IIb trial (RTC) of 203 (all but fi ve naïve) patients with AIH without evidence of cirrhosis. Treatment was randomized to 40 mg prednisone plus 1–2 mg/kg/day azathioprine or budesonide (3 mg tid) plus azathioprine with differing regimens for dose reduction subsequently. After 6 months, all patients 152 E. Mileti and M. Peters received budesonide and azathioprine for a further 6 months. Both prednisone and budesonide were decreased when biochemical remission was noted. A complete response was defi ned as biochemical remission (normal AST and ALT) as well as lack of steroid side effects at 6 and 12 months after therapy was started, i.e., a combined response. By intention to treat, a complete combined response was noted in 47.0% of 19/103 patients on budesonide compared to 18.4% on predni- sone-based therapy (p < 0.001). Biochemical remission at 6 months was seen in 60% of patients on budesonide and 38.8% of patients on prednisone (p = 0.001). Steroid-related side effects were higher in the prednisone group (53.4%) com- pared to budesonide (28%) (p < 0.001) [1 7 ] . These side effects included weight gain, headache, mood changes, muscle weakness, moon facies, hypertension, and insomnia. Steroid side effects also decreased from 44.8 to 26.4% at 12 months in those 87 patients who were initially given prednisone and then received budes- onide after 6 months (p < 0.002). Thus, budesonide is clearly benefi cial in achiev- ing biochemical remission as well as decreasing unwanted steroid side effects as shown in this RTC. The caveat is that not all clinicians treat AIH with such a high starting dose and the side effect profi le might not match their own clinical experience. Defl azacort There is only one study and case report of defl azacort, an oxazolinic derivative of prednisolone with fewer effects on bone and glucose metabolism. Fifteen patients stable on therapy were switched to defl azacort with or without azathioprine. No patient fl ared and 94% remained in sustained remission [1 8 ] . No further studies have been reported. Calcineurin Inhibitors Tacrolimus Tacrolimus is a macrolide that binds to an intracellular protein, FK506 binding protein. This bound complex competitively binds to and inhibits the phosphatase activity of calcineurin. Inhibition of calcineurin inhibits IL-2 transcription and subsequent T-lymphocyte activation. The initial study of tacrolimus was fi rst-line sole treatment in untreated AIH patients and was published in 1995. Twenty-one patients with biochemical and histological evidence of autoimmune hepatitis were started on tacrolimus. Mean duration of disease was 4 years and approximately half of the patients had cirrhosis prior to therapy. Subjects were treated with 3 mg of tacrolimus twice a day and levels were followed. Results showed a reduction in ALT level by 80% and a reduction in AST level by 70% after 3 months of therapy with 8 Strategies for Treatment Nonresponders… 153 normalization of levels by 1 year. Serum creatinine increased during this study from 0.9 to 1.3 mg/dL. The mean tacrolimus dose was 7.2 ± 0.8 mg/day. Four patients required liver transplantation [1 9 ] . Tacrolimus as rescue therapy has been reported in small case series with variable results. Aqel et al. reported 11 subjects refractory to standard therapy, who were subsequently treated with tacrolimus: ten subjects achieved clinical remission with normalization of transaminases. In one individual who did not achieve remission, rapamycin was added and remission was subsequently achieved [2 0 ] . In contrast, a Canadian study in 2005 of three subjects did not report such promising results with tacrolimus. Three patients received tacrolimus as monotherapy while an additional two patients received it in conjunction with MMF. None of the three subjects on tacrolimus alone achieved remission [ 5 ] . Finally, a study by Larsen et al. used low- dose tacrolimus in nine patients refractory to steroids and azathioprine or MMF. ALT normalized in all subjects and liver biopsies showed improvement in infl am- matory activity as determined Ishak score. These patients, however, were unable to be weaned off steroids completely [2 1 ] . No randomized controlled trials have been performed to date. Cyclosporine Cyclosporine is another calcineurin inhibitor. Cyclosporine binds to different intra- cellular proteins than does tacrolimus, called cyclophilins. The cyclophilin/cyclop- sporine complex can bind to calcineurin, thereby inhibiting its phosphatase activity. Like tacrolimus, the complex inhibits the action of calcineurin, required for tran- scription of cytokines, IL-2 in particular, which drive the T-cell proliferative response. Much like the other second-line medications, many of the studies related to cyclosporine have been small case series. The larger studies on cyclosporine for AIH have been performed in children and used to induce remission. The fi rst pub- lished use of cyclosporine for the treatment of autoimmune hepatitis was by Mistilis et al. in 1985 in a case report of a 51-year-old man who was unresponsive to corti- costeroids and was intolerant of azathioprine. He was placed on cyclosporine with normalization of his ALT [2 2 ] . Several other case reports followed showing similar results. A case series of six patients with type I autoimmune chronic active hepatitis unable to achieve remission with standard therapy and were intolerant to the side effects of the medications also showed promising results. Five out of the six patients had improved ALT levels, which were normal or near normal and remained in remission for up to 1 year. Post-treatment liver biopsies were performed in three subjects and all showed histological improvement [ 2 3 ] . The largest open-label trial of cyclosporine for autoimmune hepatitis was per- formed in medication naïve children as induction therapy. The study was initially reported in 1994 with 32 subjects and updated in 2006 with 84 subjects [2 4, 25 ] . This was a multi-centered clinical trial that enrolled 84 children prospectively. Subjects were started on cyclosporine at a dose of 4 mg/kg/day divided into three 154 E. Mileti and M. Peters daily doses. The dosing was adjusted to achieve blood concentration levels of 250 ± 50 ng/ml. Subjects remained on this for 3 months. Once transaminases had improved to three times the upper limit of normal, the dose was decreased to achieve blood concentrations of 200 ± 50 ng/ml for another 3 months. Prednisone and azathioprine were then started 6 months after diagnosis. Dosing for predni- sone and azathioprine were signifi cantly lower than usual therapy dose. Prednisone was started at 0.3 mg/kg/day in patients less than 20 kg and 0.5 mg/kg/day if greater than 20 kg. Azathioprine was started at 1.5 mg/kg/day divided into two daily doses. Cyclosporine was gradually decreased over 15 days as the other two medications were started. Prednisone was then reduced slowly 1 month later, and azathioprine was kept at the same dosage. Normalization of ALT was seen in 94% of subjects (79/84) by 1 year and no relapses were seen during treatment. Side effects of cyclosporine were transient but included hypertrichosis and gingival hyperplasia [2 5 ] . There have been open-label prospective studies and case series reporting use of cyclosporine both as fi rst-line treatment and as a rescue therapy for AIH. One pro- spective open-label study had 19 patients aged 15–46, ten previously on steroids and azathioprine at the start of the study. Subjects were started on cyclosporine at doses of 2–5 mg/kg/day divided twice a day and followed up for 26 weeks of treat- ment. Cyclosporine levels were monitored and kept between 100 and 300 ng/ml. If ALT was not decreased by at least 50% at 4 weeks of treatment, prednisone was added at 10 mg/day. After 26 weeks of treatment, subjects were placed back on prednisone 10 mg/day plus azathioprine at 1–2 mg/kg/day as a maintenance therapy. Fifteen of the 19 patients completed the 26-week course of cyclosporine. The four subjects that stopped cyclosporine prematurely did so because of side effects or nonresponse to treatment. Of the 15 subjects remaining, all had improvement in transaminases to normal or near normal levels [2 6 ] . Similar results were noted in other small case series [2 7, 28 ] . No randomized controlled trials of cyclosporine in AIH have been performed. Other Medications There are two other medications that have been used in patients with autoimmune hepatitis who have failed treatment, are nonresponsive or only have a partial response to azathioprine and prednisone. There are limited data on these agents. Ursodeoxycholic Acid Ursodeoxycholic acid (UDCA) is a 7a (alpha)-hydroxyl epimer of chenodeoxycholic acid that has been used in the treatment of cholestatic liver disease. It has been studied 8 Strategies for Treatment Nonresponders… 155 in primary biliary cirrhosis and is thought to may have immunomodulatory properties. Several papers have been published looking at the role of UDCA in AIH, including several case reports, a larger Japanese study looking at UCDA in initial therapy with and without steroids and a randomized placebo-controlled trial using UCDA as adjunctive therapy after failure of conventional treatment [2 9 ] . The larger Japanese study described their experience over 18 years of 147 patients with AIH were treated with UDCA monotherapy (N = 25), UDCA plus prednisolone (N = 40), prednisolone monotherapy (N = 68), or other therapies (N = 14). The characteristics of the patients in each group prior to medication were dissimilar, however, the degree of histologic changes at baseline did not differ. UDCA monotherapy was used in patients who were elderly or had co-morbidities such as osteoporosis and diabetes. Of the 25 patients treated with UDCA alone, ten subsequently required prednisone because they did not achieve a biochemical response. Of the remaining 15, 11 achieved remission. Higher responses were noted in those receiving UDCA plus prednisolone group or prednisolone alone: both regimens had similar remission rates in terms of ALT normalization (94–95%) and similar relapse rates (57–58%). While biochemical remission was achieved with UDCA alone, it was slower than in the groups with corticosteroid use. Additionally, UDCA did not decrease relapse rates when combined with prednisolone [2 9 ] . No postdiagnosis biopsies were obtained to assess histologic improvement. In 1999, Czaja and colleagues evaluated UDCA as an adjunctive treatment in problematic type I AIH patients. A randomized placebo-controlled trial was per- formed with 37 patients who had multiple relapses, partial response, or treatment failure on conventional therapy. These patients were randomized to receive UDCA or placebo for 6 months in conjunction with their corticosteroid treatment. The trial unfortunately did not enroll enough patients to detect statistical differences in effi cacy between the two groups. The study reported a reduction in AST and alkaline phosphatase levels in the UDCA group compared to placebo, but this was not statis- tically signifi cant. During the 6 months that patients were on UDCA or placebo, UDCA did not allow for reduction in corticosteroid use nor did UDCA improve histological activity [3 0 ] . Thus while there are cases with improvement of biochem- ical markers of AIH with UDCA, there is not enough evidence to support routine use of UDCA in the treatment of AIH. Infl iximab A recent case report was published in 2009 of use of Infl iximab, a monoclonal antibody against TNF-alpha, for treatment of a particularly diffi cult case of autoimmune hepatitis who had failed prednisone, azathioprine, mycophenolate mofetil, and cyclophosphamide. Infl iximab was used only to induce remission and azathioprine and prednisone were used as

maintenance medications. Even with the evidence of cirrhosis on biopsy, the patient responded biochemically to Infl iximab. During her 156 E. Mileti and M. Peters treatment course, she had two relapses and Infl iximab was successful at inducing remission both times. However, infectious complications occurred during infl iximab treatment [3 1 ] . This agent remains experimental. Conclusion The current available evidence for second-line treatments of autoimmune hepatitis is based mostly on small retrospective case series. In patients who are not responding to therapy, it is imperative to ensure that these subjects are being compliant with their medications. In those who cannot tolerate the side effects or are true nonre- sponders, treatment with alternative medications should be considered. However, it is critical that both provider and patient understand the side effects of the medi- cation, which can be quite severe as noted in Table 8.2 . Education about these medications, their side effects, and the different treatment options available should be discussed with patients prior to initiating alternative therapy. While results of these studies are promising, with many agents inducing biochemical remission and allowing for weaning of steroids, they are diffi cult to interpret due to the lack of a common protocol for selection or management of these patients. Randomized control trials (RCT) are needed to compare these medications to the conventional therapy of prednisone and azathioprine. Only two randomized controlled trials have been performed: UDCA failed to show benefi t perhaps related to study size; but budesonide appears to have benefi t in patients without cirrhosis with similar effi cacy to standard therapy and likely fewer steroid-induced side effects. Only RCT can allow the development of a paradigm to determine which patients will benefi t from which alternative therapies. Chapter Summary 1. Second-line therapies for the autoimmune hepatitis should be reserved only for those individuals who are true nonresponders or are unable to tolerate the side effects of conventional therapy. 2. Current evidence surrounding effi cacy of second-line treatments results from mainly retrospective case series. The majority of empiric experi- ence has been with mycophenolate mofetil and cyclosporine. Only budesonide has shown benefi t in a randomized control trial. 3. It is critical when considering alternative medications for patients with treatment failure that both providers and patients understand the potential side effects, which can be quite severe. 8 Strategies for Treatment Nonresponders… 157 Useful Tips for Practitioners 1. Steroid and azathioprine dosing should be optimized to induce remission prior to using second-line therapies for AIH. 2. Budesonide is a benefi cial alternative and fi rst-line therapy in patients without cirrhosis who are unable to tolerate the side effects of corticosteroids. 3. Biochemical monitoring varies depending upon the side effect profi le of the second-line therapy being used. Common Pitfalls in Practice 1. Lack of adequate initial therapy may be misinterpreted as treatment failure. 2. Rapid weaning of steroids may result in loss of response which is not due to treatment failure. 3. Budesonide should only be used in patients without cirrhosis. References 1. Wolf D, Bojito L, Facciuto M, Lebovics E. Mycophenolate mofetil for autoimmune hepatitis. Dig Dis Sci. 2009;54:2519–22. 2. Inductivo-Yu I, Adams A, Gish R, Wakil A, Bzowej N, Frederick R, et al. A single center review of the use of mycophenolate mofetil in the treatment of autoimmune hepatitis. Clin Gastroenterol Hepatol. 2008;6:1036–40. 3. Richardson PD, James PD, Ryder SD. Mycophenolate mofetil for maintenance of remission in autoimmune hepatitis in patients resistant to or intolerant of azathioprine. J Hepatology. 2000;33:371–5. 4. Devlin S, Swain M, Urbanski S, Burak K. Mycophenolate mofetil for the treatment of autoim- mune hepatitis in patients refractory to standard therapy. Can J Gastroenterol. 2004;18(5):321–6. 5. Chatur N, Ramji A, Bain V, Ma M, Marotta P, Ghent C, et al. Transplant immunosuppressive agents in non-transplant chronic autoimmune hepatitis: the Canadian association for the study of liver (CASL) experience with mycophenolate mofetil and tacrolimus. Liver Int. 2005;25(4):723–7. 6. Hlivko J, Shiffman M, Stravitz R, Luketic V, Sanyal A, Fuchs M, et al. A single center review of the use of mycophenolate mofetil in the treatment of autoimmune hepatitis. Clin Gastroenterol Hepatol. 2008;6:1036–40. 7. Aw M, Dhawan A, Samyn M, Bargiota A, Mieli-Vergani G. Mycophenolate mofetil as rescue treat- ment for autoimmune liver disease in children: a 5-year follow-up. J Hepatol. 2009;51:156–60. 8. Czaja A, Carpenter H. Empiric therapy of autoimmune hepatitis with mycophenolate mofetil: comparison with conventional treatment for refractory. J Clin Gastroenterol. 2005;39(9):819–25. 9. Hennes E, Oo Y, Schramm C, Denzer U, Buggisch P, Wiegard C, et al. Mycophenolate mofetil as second line therapy in autoimmune hepatitis? Am J Gastroenterol. 2008;103:3063–70. 10. Pratt DS, Flavin DP, Kaplan MM. The successful treatment of autoimmune hepatitis with 6-mercaptopurine after failure with azathioprine. Gastroenterology. 1996;110:271–4. 158 E. Mileti and M. Peters 11. Kanzler S, Gerken C, Dienes H, et al. Cyclosphosphamide as alternative immunosuppression therapy for autoimmune hepatitis – report of three cases. Z Gastroenterol. 1997;35:571–8. 12. Pengelly CD, Jennings RC. Remission of active chronic hepatitis after treatment with cyclo- phosphamide and prednisolone. Report of four cases. Practitioner. 1975;214(1280):233–42. 13. Burak K, Urbanski S, Swain M. Successful treatment of refractory type 1 autoimmune hepati- tis with methotrexate. J Hepatol. 1998;29:990–3. 14. Venkataramani A, Jones MB, Sorrell MF. Methotrexate therapy for refractory chronic active autoimmune hepatitis. Am J Gastro. 2001;96(12):3432–4. 15. Danielsson A, Prytz H. Oral budesonide for treatment of autoimmune chronic active hepatitis. Aliment Pharmacol Ther. 1994;8(6):585–90. 16. Czaja A, Lindor K. Failure of budesonide in a pilot study of treatment-dependent autoimmune hepatitis. Gastroenterology. 2000;119(5):1312–6. 17. Manns MP, Woynarowski M, Kreisel W, Lurie Y, Rust C, et al. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology. 2010;139:1198–206. 18. Rebollo BJ, Cifuentes MC, Pinar MA, Caunedo AA, Salas HE, Jimenez-Saenz M, et al. Defl azacort for long-term maintenance of remission of type I autoimmune hepatitis. Rev Esp Enferm. 1999;91(9):630–8. 19. Van Thiel D, Wright H, Carroll P, Abu-Elmagd K, Rodriguez-Rilo H, McMichael J, et al. Tacrolimus: a potential new treatment for autoimmune chronic active hepatitis: results of an open-label preliminary trial. Am J Gastroenterol. 1995;90:771–6. 20. Aqel B, Machicao V, Rosser B, et al. Effi cacy of tacrolimus in the treatment of steroid refrac- tory autoimmune hepatitis. J Clin Gastroenterol. 2004;38(9):805–9. 21. Larsen FS, Vainer B, Eefsen M, Bjerring PN, Hansen BA. Low-dose tacrolimus ameliorates liver infl ammation and fi brosis in steroid refractory autoimmune hepatitis. World J Gastroenterol. 2007;13(23):3232–6. 22. Mistilis S, Vickers C, Darroch M, McCarthy S. Cyclosporin, a new treatment for autoimmune chronic active hepatitis. Med J Aust. 1985;143(10):463–5. 23. Sherman K, Narkewicz M, Pinto P. Cyclosporine in the management of corticosteroid-resistant type I autoimmune chronic active hepatitis. J Hepatol. 1994;21:1040–7. 24. Alvarez F, Ciocca M, Canero-Velasco C, Ramonet M, de Davila M, Cuarterolo M, et al. Short- term cyclosporine induces a remission of autoimmune hepatitis in children. J Hepatol. 1999;30(2):222–7. 25. Cuarterol M, Ciocca M, Canero-Velasco C, Ramonet M, Gonzalez T, Lopez S, et al. Follow-up of children with autoimmune hepatitis treated with cyclosporine. J Pediatr Gastroenterol Nutr. 2006;43:635–9. 26. Malekzadeh R, Nasseri-Moghaddam S, Kaviani MJ, Taheri H, Kamalian N, Sotoudeh M. Cyclosporin A is a promising alternative to corticosteroids in autoimmune hepatitis. Dig Dis Sci. 2001;46(6):1321–7. 27. Debray D, Maggiore G, Girardet J, Mallet E, Bernard O. Effi cacy of cyclosporin A in children with type 2 autoimmune hepatitis. J Pediatr. 1999;135(1):111–4. 28. Fernandes N, Redeker A, Vierling J, Fong T. Cyclosporine therapy in patients with steroid resistant autoimmune hepatitis. Am J Gastroenterol. 1999;94(10):241–8. 29. Miyake Y, Iwasaki Y, Kobashi H, Yasunaka T, Ikeda F, Takaki A, et al. Effi cacy of ursodeoxycholic acid for Japanses patients with autoimmune hepatitis. Hepatol Int. 2009;3:556–62. 30. Czaja A, Carpenter H, Lindor K. Ursodeoxycholic acid as adjunctive therapy for problematic type 1 autoimmune hepatitis: a randomized placebo-controlled treatment trial. Hepatology. 1999;30:1381–6. 31. Weiler-Normann C, Wiegard C, Schramm C, Lohse A. A case of diffi cult-to-treat autoimmune hepatitis successfully managed by TNF-alpha blockade. Am J Gastro. 2009;104:2878–9. Chapter 9 Liver Transplantation for Autoimmune Hepatitis James Neuberger Keywords Autoimmune hepatitis • Indications • Liver transplantation • Outcomes • Recurrent disease Abbreviations AIH Autoimmune hepatitis ANA Anti-nuclear antibodies ASM Anti-smooth muscle antibodies AST Aspartate aminotransferase CNI Calcineurin inhibitor GSTT1 Glutathione S-transferase T1 HCC Liver cell cancer(hepatocellular carcinoma) HCV Hepatitis C virus HLA Human leucocyte antigen IgG Immunoglobulin G INR International normalised ratio LKM Liver-kidney microsomal antibody MELD Model for end-stage liver disease MMF Mycophenolate mofetil OLT Orthotopic liver transplant PBC Primary biliary cirrhosis PEI Percutaneous ethanol injection J. Neuberger (*) Liver Unit, Queen Elizabeth Hospital , University Hospital Birmingham NHS Foundation Trust , Birmingham , B15 2TH, UK Directorate for Organ Donation and Transplantation , NHS Blood and Transplant , Fox Den Road , Bristol , UK e-mail: James.Neuberger@uhb.nhs.uk G.M. Hirschfi eld and E.J. Heathcote (eds.), Autoimmune Hepatitis: A Guide for Practicing 159 Clinicians, Clinical Gastroenterology, DOI 10.1007/978-1-60761-569-9_9, © Springer Science+Business Media, LLC 2012 160 J. Neuberger PT Prothrombin time PTLD Post-transplant lymphoproliferative disease rAIH Recurrent AIH RFA Radiofrequency ablation TACE Trans-arterial chemo-embolisation TIPS Transjugular intra-hepatic shunt TMPT Thiopurine methyl transferase UKELD United Kingdom model for end-stage liver disease Introduction Although immunosuppressive therapy is usually very effective in preventing progres- sion of autoimmune hepatitis (AIH), a small minority of patients may become transplant candidates. Some will have presented too late for treatment to prevent the onset of life-reducing complications (such as hepatocellular cancer), others will develop intractable symptoms such as hepatic encephalopathy and others may have failed to respond fully to treatment. A small proportion will have failed to comply with treat- ment and progress to end-stage disease. In such cases, liver replacement remains the only therapeutic option to increase the quantity or quality of life, or both. Indications for Liver Transplantation AIH account for just over 5% of liver transplants [ 1 ] . Of the various subtypes of AIH, those with type 2 (liver kidney microsomal antibody positive) and those with cholestatic hepatitis may have a more aggressive pattern and so come to transplant sooner than those with type 1. Chronic Liver Disease There is a signifi cant imbalance between the number of people who would benefi t from a liver transplant and the number of grafts available. The increasing use of organs from non-heart-beating donors (donation after circulatory death – DCD) and live donors has failed to bridge the gap. Thus, there is a need for rationing: this remains a controversial area where the often confl icting demands of justice, equity, utility, and benefi t have to be balanced. Selection (the process that determines who is placed on the transplant waiting list) is usually based on need and benefi t, whereas alloca- tion (deciding which recipient will be given a donated organ) is based on different criteria and considerations such as benefi t and utility are important. With mortality 9 Liver Transplantation for Autoimmune Hepatitis 161 of those on the waiting list between 10 and 15%, the role of transplantation for those with a relatively good liver prognosis but a poor quality of life because of the com- plications is more controversial. In some administrations, such as in North America, those with relatively good graft function but a very poor quality of life because of, for example, intractable encephalopathy, will be less likely to get a deceased-donor graft than those with end-stage disease. For those with chronic liver disease, the MELD (Model for end-stage liver disease) score has been validated and is utilised extensively [2 ] . Although MELD was originally developed to predict short-term survival following a transjugular intra-hepatic shunt (TIPS) [ 3 ] , it has been shown in many studies to be an effective predictive model for patients with a wide variety of chronic liver diseases. The MELD score is derived from the serum creatinine, bilirubin, and International Normalised Ratio (INR). There are some well-founded criticisms of the use of the MELD score: with time, it has been necessary to amend the coeffi cients of some of the variables; some of these variables can be affected by nonhepatic conditions (as, for example, the serum bilirubin can be elevated by hemolysis rather than liver disease) or serum creatinine can be “artifi cially” increased by over-use of diuretics. Furthermore, the creatinine value differs between the two genders (as the normal range is lower in

females than males, females may be disadvantaged by the use of the model) and different labora- tories may give different values for some analytes. In not all cases will the MELD score predict prognosis (as in the development of cancer, or the presence of ascites and hyponatremia). Thus, there are some indica- tions for which additional points can be given: these include hepatopulmonary syn- drome and porto-pulmonary hypertension. Liver cancer is discussed separately. Finally, it must be emphasised that these prognostic models, which have been well validated in many centres and countries, give useful information for a population and extrapolation to the individual must be done with caution. In the UK [ 4 ] , a similar approach was taken to develop a model to predict short- term survival in those with advanced liver disease; the model developed (UKELD – UK model for end-stage liver disease) included most of the variables included in the MELD model – serum sodium, creatinine, prothrombin time and bilirubin – but with different coeffi cients and, in a validation set, was better associated with out- come than MELD, suggesting that different countries may need to adapt MELD better to suit the local population. The introduction of the MELD system has been shown, in the United States, to be very effective in reducing the mortality of patients on the patient list without having a signifi cant deleterious impact on post-transplant outcomes however, resource utilisation may be increased. A MELD score of 16 or above is indicative of the need for transplant listing (for those without liver cell cancer) since at this level and above, the survival advantages of liver replacement exceeds the risk of dying without a transplant. In those systems where selection and allocation are not based solely on the risk of death without transplant, other indications for liver transplantation include an 162 J. Neuberger impaired quality of life due to intractable encephalopathy, those rare cases of refrac- tory ascites where the MELD is less than 15 and shunting is either ineffective, tech- nically not possible or otherwise contraindicated [4 ] . Other factors that suggest the need for transplantation include developing hepatopulmonary syndrome, porto- pulmonary hypertension, progressive muscle wasting, and progressive unresponsive hepatic osteodystrophy. There needs to be caution with children, where the course of AIH may be differ- ent to that seen in adults [ 5 ] : in particular, in some an initial syndrome, identical to classical AIH, may evolve into classical primary sclerosing cholangitis. Most patients transplanted for primary sclerosing cholangitis will have a Roux-en-y hepatic anastomosis because of the need to avoid doing a bile duct anastomosis with diseased tissue and the potential for development of cholangiocarcinoma in the native biliary tree, either before or after transplantation; hence it is important to determine the state of the biliary tree prior to transplant. Hepatocellular Carcinoma Patients with HCC pose additional challenges: the recipient has two life-threatening diseases (the parenchymal liver disease and the cancer). The MELD score will refl ect prognosis from the former but not the latter. An allocation system based on prognosis (as death on the list or progression of the cancer so a transplant becomes futile) must therefore refl ect these changes and balance the needs of these patients with those who have parenchymal disease. In recent years, the range of treatment options for those with liver cell cancer (HCC) has increased, with successful pharmacological therapy (such as sorafenib [6 ] ), loco-regional such as radiofrequency ablation (RFA) or percutaneous ethanol injection (PEI), trans-arterial chemo-embolisation (TACE) and resection being shown to be effective [7 ] . There remains no clear consensus as to the optimal treat- ment for the individual with HCC. One concern for those with HCC is the need to identify those in whom recur- rence of the cancer will preclude a successful long-term outcome. The impact of surgery and most immunosuppressive agents will enhance tumour growth. Thus, if there is tumour outside the liver, then transplantation may be futile. Clearly, detectable tumour extension beyond the liver will preclude transplantation. Several studies have suggested that tumour size and number may be a good surrogate for predicting the likelihood of tumour recurrence. However, it is likely that such a crude measure will be replaced in time by more sensitive predictive markers: the absolute level and rate of rise of a -fetoprotein, the rate of growth of tumour, and the molecular signature of the HCC may all prove to be superior but none yet has been robustly validated. The introduction of the Milan criteria, where the likelihood of recurrence was determined by the size and number of lesions, allowed greater use of transplantation for this indication [ 8 ] . However, it became clear that some patients with HCC that fell outside the Milan criteria would have an excellent prognosis after transplant 9 Liver Transplantation for Autoimmune Hepatitis 163 so these criteria were too restrictive and those with HCC were not treated equita- bly. Extension of the Milan criteria has been advocated by some and early out- comes are not dissimilar from those within the Milan criteria [9 ] . Revision (the Metro-ticket approach) has further refi ned selection of those who might benefi t from transplantation and justify the use of a scarce resource [1 0 ] . The extent to which the newer immunosuppressive agents, such as sirolimus [1 1 ] , may inhibit the recurrence rate is uncertain and is likely further to modify the role of trans- plantation in this group. A reasonable approach is, for those with good liver function is, to consider fi rst RFA or even resection and offer transplantation where this approach is not possi- ble or likely to be ineffective. Some centres use resection as a fi rst-line treatment where possible, and reserve salvage transplantation where recurrence or decom- pensation occurs. In the North American model, at present those with a documented HCC, greater than 2 cm in diameter, will be given additional MELD points to ensure that the revised MELD score refl ects survival to the stage where transplantation is futile from the cancer rather than the underlying liver disease. This has resulted in many more patients being grafted for HCC: whether this will adversely affect long-term outcomes is not clear but early data show little effect. Criteria for living donor liver transplantation: The shortage of livers has resulted in the development of new surgical techniques, including splitting livers, greater use of extended criteria donor livers living donation . For most centres, the indications for transplantation from living donors are similar to those from deceased and non- heart-beating donors. Fulminant AIH In those with fulminant liver failure due to AIH, the Kings College Hospital Criteria are widely utilised to identify those patients in whom the chance of survival with full medical support although these criteria were not developed for those with fulminant AIH , therefore may not be applicable in this situation [ 12 ] . As with patients with fulminant hepatic failure from other aetiologies, adverse serological happy, the development of cerebral oedema and cardiovascular instability should alert the clinician to the possible need for transplantation; contraindications include active sepsis, severe cardio-respiratory instability, and signifi cant extra-hepatic disease. The criteria used in the UK for consideration of liver transplantation in this situation include either prothrombin time >100 s o r INR >6.5, and any grade of encephalopathy or any grade of encephalopathy, a nd any three from the following: Age >40 years, jaundice to encephalopathy time >7 days, serum bilirubin >300 m mol/l, or prothrombin time >50 s or INR >3.5. Whether specifi c medical therapy with corticosteroids affects the natural history and reduces the need for liver transplantation remains controversial. A recent study, 164 J. Neuberger where corticosteroid therapy using prednisolone at a dose of 1 mg/kg/day in 12 patients with type 1 fulminant liver failure, showed that steroids did not obviate the need for liver replacement [1 3 ] but did highlight the risk of septic complications associated with high-dose steroids, with fi ve patients developing sepsis, which, in one case was fatal. The response to steroids varied from 36 to 100%, although the severity of the disease was not clearly defi ned [ 14– 20 ] . Villamil [2 0 ] identifi ed adverse prognostic criteria as: prothrombin time (PT) less than 20%, encephalopa- thy on admission, massive or sub-massive necrosis on histology, type II AIH, or 20% increase in PT at day 3 post-steroid therapy. Contraindications to Liver Transplantation There are relatively few contraindications for liver transplantation. These can be classifi ed as those factors that make the procedure not technically possible or too high risk factors that make the survival after transplantation limited. Technical factors that make transplantation futile include extensive vascular thrombosis, advanced pulmonary or cardiovascular disease that mean the patient would not survive the procedure. Previous upper abdominal surgery will add to the risks of the procedure but may not preclude it. The presence of active cancer and active bacterial and mycobacterial infection also contraindicate transplanta- tion. HIV infection may not be a contraindication for transplantation but many units consider active AIDS an absolute contraindication. Severe hyponatremia (<120 mmol/L) is associated with the risk of central pontine myelinolysis and so should be corrected prior to surgery. Renal impairment is not a contraindication to transplantation but is associated with increased post-transplant poor survival. A previous history of malignancy may contraindicate surgery: colorectal cancer, melanoma, thyroid carcinoma, oral squamous carcinoma, breast cancer, and vulvo- vaginal cancers are associated with more than 10% probability of tumour recurrence and so may contraindicate surgery but every case needs individual consideration. The presence of hepatopulmonary syndrome and porto-pulmonary hypertension may be contraindications for the procedure but, as indicated above and if not too advanced, may be indications. Porto-pulmonary hypertension is defi ned as a mean pulmonary artery pressure of more than 15 mm Hg (normal pulmonary artery occlu- sion pressure [<15 mm Hg]) and pulmonary vascular resistance of more than 250 dyn.s.cm− 5. However, a mean pulmonary artery pressure greater than 40 mm Hg classifi es those at high risk as does a pre-transplant partial pressure of oxygen of less than 50 mm Hg and a macroaggregated albumin lung scan showing more than 20% brain uptake in those with hepatopulmonary syndrome. Post-transplant, any factor that would prevent the recipient having a reasonable expectation of life or quality of life acceptable to the patient would also contraindi- cate the procedure. Alcohol abuse, illicit drug use, noncompliance with medications, and active smoking may be contraindications but will depend on the individual. The key question is whether the recipient will comply with the medication and need 9 Liver Transplantation for Autoimmune Hepatitis 165 for life-long follow-up and will not indulge in behaviour that will damage the graft. An agreed support package of care may be required before transplantation can be considered. Age itself is not an absolute contraindication: older patients do fare less well after transplantation than younger ones (as with any surgical procedure), but there is no absolute bar. Clearly, those aged over 60 years will require closer evaluation to look for cardiovascular and pulmonary disease and malignancy. Outcome of Patients Following Liver Transplantation for AIH Liver transplantation for AIH is associated with 5-year patient survival between 80 and 90% [2 1, 22] . The quality of life after transplantation is usually excellent, although only half are able to return to full-time employment. The optimal immunosuppression remains uncertain. As discussed below, patients grafted for AIH are at greater risk of developing acute cellular and possibly duc- topenic rejection. We found severe acute rejection occurred in 61% of those grafted for AIH compared with 42% for those grafted for alcohol-related liver disease [2 3 ] . Reasons for this increased susceptibility to rejection are not clear although it should be noted that those grafted for other indications with a presumed autoimmune aetiology (such as primary biliary cirrhosis and primary sclerosing cholangitis) have a rejection rate similar to that seen in AIH. The mainstay of immunosuppression includes a calcineurin inhibitor (usually tacrolimus), either alone of with an anti-metabolite (mycophenolate or azathio- prine). Whether corticosteroids should be used with other agents remains controver- sial. Our own practice is to use a calcineurin inhibitor in combination with low-dose steroids (such

as prednisolone 5–7.5 mg/day given with bone protection therapy) maintained long-term. Recurrent AIH (rAIH) Since the fi rst report in 1984 [ 24 ] , recurrent AIH is well recognised with [ 1, 22, 25– 34 ] recurrence rates of 20–30%. (Table 9 .1 ) However, serological and histologic features of AIH can also occur in those grafted for other conditions; this is termed “de novo AIH” or, more accurately, graft dysfunction mimicking autoimmune hepa- titis [ 35 ] . A more appropriate term, therefore, may be alloimmune hepatitis. Because of a lack of consensus about diagnostic criteria and diffi culties in inter- preting the nonspecifi c histological fi ndings, the diagnosis can be challenging. As protocol biopsies are not routinely done, the incidence of recurrent AIH may be under-reported. 166 J. Neuberger Table 9.1 Published series of recurrent autoimmune hepatitis No. of patients Autoantibodies transplanted for No. with Study AIH recurrence ANA ASMA LKM IgG Therapy at recurrence Outcome Wright, 1992 [ 65 ] 43 11 6 8 – Elevated C Birnbaum, 1997 [4 8 ] 6 5 4 4 – Elevated C (4), T(4) 2nd OLT (2), PTLD (1) Prados, 1998 [ 39 ] 27 9 17 11 7 n/a C (26), T(1) Resolution Ratzui, 1999 [ 31 ] 15 3 15 21 5 2.6 C, + prednisolone/ 2nd OLT (1), cirrhosis and death azathioprine (1), no change (1) Narumi, 1999 [ 66 ] 40 5 – – – n/a T or C. Prednisolone (1) No graft loss Milkiewicz, 1999 47 13 – – – 16.5 – 2nd OLT (3) [3 0 ] Reich, 2000 [4 9 ] 32 6 23 24 3 T 2nd OLT (3) Ayata, 2000 [2 5 ] 12 5 6 6 1 Elevated T (3), T & C (2), + Cirrhosis (2), Chronic rejection azathioprine/ (2) prednisolone Gonzalez-Koch, 41 7 – – – – T (4), C (3), + azathio- Lymphoma (2), 2nd OLT (1) 2001 [2 9 ] prine/prednisolone Molmenti, 2002 55 11 – – – – C (82% or T Lymphoma (1), no graft loss [2 2 ] (18%), + prednisolone Yusaff, 2002 [6 7 ] 12 2 – – – – Heffron, 2002 [4 2 ] 52 9 – – – – Prednisolone (6), no further data 9 Liver Transplantation for Autoimmune Hepatitis 167 Duclos-Vallee, 17 7 9 14 4 23.2 C, Prednisolone, 2nd OLT (2) 2003 [ 28 ] Azathioprine Vogel, 2004 [3 3 ] 28 9 24 14 16 6 T Renz, 2002 [ 32 ] 37 12 – – – – C Cirrhosis (1) Khalaf, 2007 [ 41 ] 16 3 – – – – Steroids Graft failure (1) Rowe, 2008 [1 ] 103 28% – – – – Steroids (last 5 years of 6.2% graft loss study) Campsen, 2008 66 23 – – – – C (26%), T (64%), No graft loss [2 7 ] prednisolone (50%), azathioprine/MMF (28%) Montanoi-Loza 46 11 [4 3 ] Key : T Tacrolimus, C Cyclosporine, A NA anti-nuclear antibodies, A SM anti-smooth muscle antibody, L KM liver kidney microsomal antibody, I gG immuno- globulin G, OLT orthotopic liver transplant, P TLD post-transplant lymphoproliferative disease, A IH autoimmune hepatitis 168 J. Neuberger Table 9.2 Criteria for the diagnosis of recurrent autoimmune hepatitis Liver transplant for AIH Autoantibodies in signifi cant titre (>1:40) Sustained rise in serum aminotransferase activity (> twice normal) Elevated serum immunoglobulins (especially IgG) Compatible liver histology, i.e. chronic infl ammatory cell infi ltrate consisting of • Plasma cells • Interface hepatitis (piece meal necrosis) • Bridging necrosis and fi brosis Corticosteroid dependency Exclusion of other causes of graft dysfunction (e.g. rejection, HCV infection) HCV Hepatitis C virus, A IH autoimmune hepatitis Diagnosis Criteria for the diagnosis of rAIH have been proposed (Table 9 .2 ) [ 36 ] . Diagnostic criteria for AIH in the native liver should not be directly applied to the liver allograft recipient: the liver recipient is usually taking immunosuppressive agents, there is usually a different HLA (human leukocyte antigen) and other antigenic environ- ment and there are many other causes of potential graft damage which, of course, may co-exist with rAIH. Organ nonspecifi c autoantibodies can be present in low titre post-transplant, and histological features of graft infl ammation do not always correlate with the presence of antibodies [ 37 ] . Histological abnormalities can precede changes in biochemical and immunological tests [2 8 ] . Raised transaminases do not correlate with chronic hepatitis in children following transplantation [3 8 ] ; biochemical improvement does not always correlate with histological remission [3 9 ] . Assessing response to treat- ment of recurrent disease is best served by liver biopsy, since liver tests do not cor- relate with liver histology and signifi cant histological infl ammation can be present with normal biochemistry. The use of routine protocol liver biopsies is controversial, and the risks of biopsy must be balanced with the potential benefi ts. While liver biopsy is associated with a small risk (and is very rarely fatal), over-immunosuppression is associated with an increased risk of sepsis, renal failure, and some malignancies. Interpretation of graft histology can be challenging due to the need to exclude rejection, although there are some typical features in both as detailed in Table 9 .3 [ 37 ] . One of the earliest fi nd- ings is that of lobular lymphoplasmacytic hepatitis with acidophil bodies [2 5 ] . Although it would seem likely that early diagnosis and modifi cation of immunosup- pression is desirable, this does not always prevent graft loss. Factors Associated with Recurrence Published series have resulted in confl icting conclusions as to the risk factors for rAIH: Factors associated with recurrence include the type of immunosuppression, 9 Liver Transplantation for Autoimmune Hepatitis 169 Table 9.3 Histological differences between recurrent AIH and rejection Recurrent AIH Rejection Portal and periportal changes Portal infl ammation Mononuclear cells (plasma Mixed infi ltrate (lymphocytes, cells ++) macrophages, blast cells, neutrophils, eosinophils) Interface hepatitis Variable (often prominent) Mild Bile duct infl ammation Mild (lymphocytes) Prominent (mixed infi ltrate) Bile duct loss Minimal/none Variable (may progress to chronic rejection) Venous endothelial None/mild Yes infl ammation Fibrosis Yes No Parenchymal changes Parenchymal infl ammation Variable Generally mild Composition Mononuclear Mixed (mainly lymphocytes) (mainly plasma cells) Pattern Spotty or confl uent Confl uent Distribution Random or zonal Zonal (acinar zone 3) Associated features Lobular disarray Hepatic vein endothelial infl ammation Cholestasis Rare Common HLA status of donor and/or recipient, severity and type of AIH in the recipient, and the length of follow-up. Weaning of corticosteroids may be associated with a high rate of recurrence [4 0 ] . One recent study reported that attempts at complete steroid withdrawal 1 year following live donor liver transplantation were unsuccessful [4 1 ] . Others have attempted alternative immunosuppression using mycophenolate [4 0 ] . However, data are confl icting [ 22, 29, 41, 42 ] and further prospective studies are needed. Greater necro-infl ammatory activity in the recipient liver prior to transplantation is associated with rAIH [2 5, 43 ] . These patients may also be less responsive to immunosuppression post-transplantation, although the fact that patients with a fulminant course can have very good outcomes may be evidence against this argument. Indeed, one small study suggested that recurrence is less likely in patients transplanted for fulminant AIH [4 1 ] . The length of follow-up is important in assessing the probability of rAIH. The rate of recurrence has been quoted at 8% at 1 year and up to 68% after 5 years [3 9 ] . Studies following up patients over a longer period have revealed that the risk of recurrent disease persists even over 10 years post-transplantation [2 8 ] . This late recurrence may be related to reduction in immunosuppression over time. Whether the use of current immunosuppression has an impact on long-term risk remains to be seen, although the evidence so far is that the choice of calcineurin inhibitor does not appear to be risk factor for recurrence [3 4 ] . There is confl icting evidence on the role of HLA phenotype on the risk of recurrence. Some studies have noted an association between HLA-DR3+ve recipient/HLA- DR3−ve graft and recurrent disease [4 1, 44 ] . Others have demonstrated a link between 170 J. Neuberger 0.20 AIH PBC 0.15 0.10 0.05 0.00 0 1000 2000 3000 4000 5000 Time to graft loss (days) Fig. 9.1 Proportion of patients transplanted for AIH and PBC in Birmingham UK who develop recurrent disease in the graft after OLT recipient HLA-DR3 positivity and recurrent disease, although HLA phenotype mismatch between donor and recipient was not confi rmed [2 9 ] . There are other studies which have failed to demonstrate a link with the HLA-DR3 phenotype [2 2, 45 ] . Management of Recurrent Disease and Outcomes Successful management relies on early detection, and, as mentioned above, there may be a role for protocol biopsies. In the majority of cases, increased immunosup- pression is successful in controlling progression, although early reports where over half of patients failed to respond to treatment [ 39 ] . Therapy usually involved increased doses of steroids and maintaining patients on steroids [1 , 25, 28– 30, 32, 41] , although in some cases azathioprine was introduced [2 2, 39 ] and patients were switched from cyclosporine to tacrolimus [2 2 ] . Tacrolimus has been used successfully as a salvage therapy for lack of response to steroids, azathioprine, and cyclosporine [4 6 ] . Others have used other agents such as cyclosphosphamide [2 5, 47 ] . The roles of rituximab, mycophenolate, and siroli- mus have not been well studied in this context [ 40, 47 ] , although anecdotal reports of benefi t have appeared. Additional immunosuppression has to be balanced against the risk of adverse events, which includes fatal post-transplant lymphoproliferative disorder [2 2, 29 ] . The outcome in patients with recurrent disease in terms of graft and patient sur- vival does not appear to be signifi cantly worse than patients without disease recur- rence, with 5-year survival is around 80% [2 2, 29, 33, 48, 49 ] . Comparison of outcomes of recurrent disease following transplantation for AIH with other indications [1 ] showed that when compared with recurrent primary biliary cirrhosis, there was a 4.1 times increased risk of graft loss (>90 days post-transplantation) (Fig. 9 .1 ). Cumulative proportion of grafts lost to recurrent disease 9 Liver Transplantation for Autoimmune Hepatitis 171 Recurrent disease can have an aggressive course unresponsive to immunosup- pression, resulting in the need for re-grafting or death [4 8, 49 ] and patients who develop signifi cant fi brosis may deteriorate despite immunosuppression [3 2 ] . This emphasises the need for early detection and treatment of these patients, and perhaps supports the argument for protocol biopsies. De Novo AIH The development of the clinical, serological, and histological features of autoimmune hepatitis in patients transplanted for other aetiologies was initially described in a paediatric population in 1998 [3 5 ] . There have been numerous reports since then with a predominance of paediatric patients, although adult patients also appear to be at risk [5 0, 51 ] . The condition usually presents between 2 and 10 years after trans- plant. The typical clinical, serological, and histological features of AIH are seen with elevated immunoglobulins, autoantibodies, and histological features of portal infl ammation and interface hepatitis. Some have reported cases presenting predomi- nantly with central peri-venulitis prior to the development of typical portal infl am- mation [5 2, 53 ] . There has also been a report of concurrent recurrent primary biliary cirrhosis (PBC) and de novo AIH [5 4 ] . The exact pathogenesis is not clear, and further work is necessary in this regard. It has been suggested that calcineurin inhibitors may interfere with the maturation of T cells and the function of regulatory T cells as has been demonstrated in animal studies [5 5 ] . The predominance of de novo AIH in children may be due to calcineu- rin inhibitors causing thymic dysfunction [5 6 ] . It is interesting that the calcineurin inhibitors, in particular tacrolimus, have been implicated in earlier and more aggres- sive recurrence of PBC, another disorder with a presumed autoimmune

basis [5 7 ] although this observation has not been supported by others [5 8 ] . De novo AIH may represent a form of late cellular rejection, since antibodies are directed against the graft and not self, i.e. alloimmune response. Some support for this theory comes from studies where an association between de novo AIH and previous episodes of acute cellular rejection was noted. Further evidence comes from studies where patients negative for glutathione-S-transferase T1 (GSST1) antibodies were transplanted grafts positive for GSST1 subsequently developed antibodies to GSST1 [ 50, 59 ] . This observation requires further validation. De novo AIH generally responds to modifi cation of immunosuppression, although there are studies reporting poor outcome in certain groups of patients. Gupta and colleagues described a series with an atypical histological feature of ductal proliferation [6 0 ] . Most of the patients developed progressive fi brosis. These patients may perhaps have a form of chronic rejection. In another series of patients who had live donor liver transplantation, cirrhosis was noted in half the cases with remission of interface hepatitis in only one patient [ 61 ] . It is noteworthy that aza- thioprine was not used. The combination of azathioprine and steroids appears to be the key to successful therapy. Azathioprine has also successfully treated patients 172 J. Neuberger who did not respond to high-dose steroids or changes in the dose of cyclosporin or tacrolimus therapy [6 2 ] . Similar fi ndings were noted by Andries and colleagues [ 63 ] , where one patient also responded to treatment with mycophenolate mofetil therapy after relapse following withdrawal of azathioprine. The lack of effect of calcineurin inhibitor was also demonstrated in a study where cyclosporine was withdrawn, and patients subsequently responded to azathioprine and steroid therapy [ 64 ] . The importance of maintenance therapy with steroid therapy was shown in a study comparing treatment with and without corticosteroids [5 2 ] . Patients on steroids did well, and all patients treated only with cyclosporine and azathioprine developed cirrhosis of the graft. Steroids were also effective in treating patients who relapsed. Conclusion Autoimmune hepatitis affects a diverse group of patients, and medical management is largely successful in controlling progression and prolonging survival. Alternative agents such as MMF have yet to gain universal acceptance. The indications for liver transplantation do not differ greatly from other aetiologies of chronic liver disease. The utility of MELD >16 as an indication for selection to the waiting list has been widely adopted. A further refi nement with the introduction of UKELD is likely to lead to improved patient selection. Special consideration is necessary for patients with other indications such as HCC, refractory ascites not amenable to nonsurgical therapies, and intractable hepatic encephalopathy. These conditions may merit list- ing despite not meeting MELD criteria. Fulminant hepatic failure associated with AIH can have a poor outcome despite aggressive immunosuppression, and an early decision for transplant listing is paramount. rAIH occurs in one-third of patients. There are no agreed diagnostic criteria, and differentiation with chronic rejection can be particularly challenging. Proposed risk factors for recurrence include level of immunosuppression HLA status, length of time following transplant, and severity of disease in the recipient explant. The lack of correlation between histology and biochemical abnormalities has led to some experts advocating routine protocol biopsies to aid early diagnosis and assessment of treatment response. Treatment involves increasing immunosuppression, and is largely successful. The outcome of rAIH is favourable, with most studies demon- strating no difference when compared with patients without rAIH. Optimisation of immunosuppression appears to have resulted in a trend toward a decline in graft loss over the years. While early detection and treatment are important, caution is necessary to minimise over-immunosuppression, which has been implicated in the develop- ment of fatal malignancies. De-novo AIH is a recent entity, where there are features of AIH in the graft of patients transplanted for other causes. CNIs may be involved in the pathogenesis, and optimal immunosuppression with steroids and anti-metabolites appears to be effective. 9 Liver Transplantation for Autoimmune Hepatitis 173 Chapter Summary 1. Liver transplantation is indicated in patients with AIH with end-stage disease (as evidenced by a MELD >16), liver cell cancer, intractable symptoms (such as encephalopathy), or variant syndromes such as hepatopulmonary syndrome. 2. Results after transplantation are usually excellent with 5-year survival over 70%. 3. Recurrent disease, which may develop in the presence of normal liver tests, may be present in 20–30% and may progress to end-stage graft failure, despite increased immunosuppression. 4. Long-term steroids should be considered as part of immunosuppressive regime as this may prevent recurrence and reduce the risk of graft loss. Useful Tips for Practitioners 1 . R eferral for transplantation should be considered when the MELD score approaches 15 or HCC is detected. 2. Time on the transplant list should be used to optimise the patient’s health, with special attention to nutrition, vaccination, and maintaining bone health. 3. Post-transplant, patients should remain under follow-up, with surveillance for recurrent disease; autoantibodies and immunoglobulins should be routinely measured as these may be abnormal while liver tests are normal. 4. Addition of long-term steroids to the immunosuppressive regime to reduce the risk and possibly the impact of recurrence. Common Pitfalls in Practice 1. It is still assumed, wrongly, that liver cell cancer does not occur in patients with AIH: those with cirrhosis should be in a surveillance programme and, if HCC is detected, transplantation considered. 2. In fulminant AIH, a trial of high-dose steroids should be used with caution as steroids are often ineffective in this situation, increase the risk of sepsis, and delay consideration of transplantation too long. 3. Mis-timing of referral to a transplant unit: referring too early does not harm the patient but referral too late may prejudice the outcome. 4. 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Heneghan Keywords Contraception • Fertility • Fetal health • Maternal health • Pregnancy Introduction Autoimmune hepatitis (AIH) is a condition that classically affects women of child- bearing age [1 , 2 ]. In such patients, the desire to have a family frequently raises questions around fertility and contraception in addition to the risks and outcomes of pregnancy. This chapter summarises the current literature regarding women’s health in AIH. Information regarding the complications, outcomes and best practice man- agement in AIH and pregnancy is sparse and evidence is delivered predominantly from reported case series. We discuss in detail the current evidence regarding best practice during pregnancy with an emphasis placed both on maternal and fetal health. Background AIH was fi rst described in 1950 by Waldenström, when he reported a chronic form of hepatitis which had a propensity to affect young women [3 ] . The classical phe- notype described was that of a young women with jaundice and extrahepatic mani- festations including arthralgia, endocrine abnormalities and amennorhoea [3 ] . R. H. Westbrook • M. A. Heneghan (*) Institute of Liver Studies , King’s College Hospital , NHS Foundation Trust Denmark Hill , London , SE5 9RS , UK e-mail: Michael.heneghan@kch.nhs.uk G.M. Hirschfi eld and E.J. Heathcote (eds.), Autoimmune Hepatitis: A Guide for Practicing 177 Clinicians, Clinical Gastroenterology, DOI 10.1007/978-1-60761-569-9_10, © Springer Science+Business Media, LLC 2012 178 R.H. Westbrook and M.A. Heneghan While reports regarding pregnancy in patients with AIH exist from as early as the 1970s, these outcomes were largely unfavourable with a high incidence of obstetric complications including early fetal loss, prematurity, low birth weight and a high rate of caesarean section [4 , 5 ] . Maternal complications included pre-eclampsia, fl ares in disease activity, hepatic decompensation and death [4 , 5 ] . These unfavour- able reports were published prior to the discovery of the hepatitis C virus. Thus, the sensitivity and specifi city of the diagnosis of AIH in these studies is likely to be poor. Furthermore, these studies also lacked pertinent information regarding the severity of the underlying liver disease, therapy during pregnancy and extent of disease control achieved prior to conception. Recent case series of AIH in preg- nancy report much more favourable outcomes (Table 1 0.1 ) [ 6– 9 ] . Impact of Pregnancy on Disease Activity Pregnancy impacts upon the activity of AIH. Flares in AIH activity during pregnancy and in the post-partum period have been described, in addition to index presenta- tions of disease. Remission of AIH in association with pregnancy has also been described [6 – 12 ] . Interestingly, of those patients that have a fl are associated with pregnancy the majority occur in the post-partum period with relatively few fl ares occurring during the pregnancy itself [6 – 9 ] . Understanding why some patients have an exacerbation during pregnancy whilst others maintain remission only to relapse post-partum remains unclear. The phenomenon of an improvement in disease activity during pregnancy, fol- lowed by a fl are in the post-partum period is not limited to AIH but has been reported in other autoimmune conditions. In patients with rheumatoid arthritis, pregnancy is associated with an improvement of symptoms in 75%, but relapses occur in up to 90% during the post-partum period [1 3 ] . The mechanism for this phenomenon in autoimmune conditions is incompletely understood. It is likely, in-part related to the fact that pregnancy induces the temporary development of immunological tolerance in order to allow the mother to tolerate the antigens expressed from the father by the foetus. Regulatory T-cells are required for the maternal immune system to tolerate the fetal allograft, and there is an increase in their circulating number during preg- nancy [1 4, 15 ] . The up-regulation of T-cells during pregnancy is thought to be hor- monally driven. Changes in the production of cortisol, estrogen and progesterone during pregnancy modulate cellular and humoral immune functions including the cytokine profi le [ 16] . High concentrations of estrogens are thought to inhibit immune activities whilst progesterone promotes T helper 2 cells and in itself has anti-infl am- matory properties [8 , 16 ] . Evidence published regarding the aetiopathogenisis of AIH has demonstrated that it is an impairment in regulatory T-cells that is key to the loss of immune tolerance in AIH and thus the emergence of uncontrolled effector autoimmune responses [ 17, 18 ] . Taking into account the above factors, it becomes clearer why patients with AIH, an indeed other autoimmune conditions, may induce remission during 10 Autoimmune Hepatitis and Pregnancy 179 Table 10.1 Potential complications encountered in pregnancy and AIH Maternal deaths Total number Incidence Flare during associated Hepatic of conceptions of post-partum fl ares gestational period with pregnancy decompensation Live birth rate Prematurity Heneghan et al. [ 6 ] 35 4/35 (11%) 4/35 (11%) 2 2 30 (86%) 2/30 (7%) Schramm et al. [7 ] 42 22/42 (52%) 9/42 (21%) 1 1 35 (83%) 7/35 (20%) Terrabuio et al. [ 9 ] 51 23/51 (45%) 4/51 (8%) 0 0 36 (71%) 6/36 (17%) Buchel et al. [8 ] 14 12/14 (86%) 1/14 (7%) 0 0 13 (93%) 1/14 (8%) 180 R.H. Westbrook and M.A. Heneghan pregnancy and then fl are in the post-partum period, such that when pregnancy ends, tolerance breaks down and fl ares in disease activity occur. Although this hypothesis has never been scientifi cally proven, it is attractive on many levels. Exacerbation of AIH in Pregnancy An exacerbation of AIH associated with pregnancy, as manifested by a rise in the aminotransferase activity, immunoglobulin level and/or the recurrence of symptoms is common. The four largest case series in the literature provide the most useful insight into incidence of disease fl ares associated with pregnancy along with infor- mation regarding their severity and impact on maternal health (Table 10.2 ) [ 6– 9 ] . Discrepancies exist between studies regarding what constituted a “fl are” in disease activity. Both Heneghan et al. and Schramm at al. defi ne a fl are as a twofold increase in serum aspartate aminotransferase (AST) activity above the upper limit of normal or a lesser increase in AST in conjunction with an increase in serum globulin level. Terrabuio et al. describe a fl are in AST activity of less than twice the upper limit of normal and a relapse as an elevation of AST above twice the upper limit of normal. Finally, Buchel et al. did not provide a standard defi nition but provided a descriptive report on each patient. Flares in AIH during pregnancy have been reported to occur in 7–21% of patients [ 6– 9 ] . In patients that do experience a fl are, AIH activity was easily controlled in the majority of cases with augmentation of baseline immunosuppression, usually in the form of prednisolone. Reported augmentation dosages to treat a fl are of AIH during pregnancy vary between 10 and 30 mg of prednisolone. The clinical signifi cance of disease fl ares appeared minor, with the majority of patients responding to medication Table 10.2 Maternal and fetal complication associated with pregnancy and AIH Non-cirrhotic Cirrhotic Maternal complications Disease fl ares Disease fl ares Decompensation Sepsis Transplantation if sub-acute Decompensation liver failure develops Variceal bleeding Death Encephalopathy Splenic artery aneurysm formation and rupture Bleeding during labour Transplantation Death Fetal complications Increased rate of spontaneous Increased rate of spontaneous pregnancy loss pregnancy loss Prematurity Prematurity Low birth weight Low birth weight Congenital malformations Congenital malformations 10 Autoimmune Hepatitis and Pregnancy 181 changes. However, in a small subset of patients, a fl are in AIH during pregnancy led to hepatic decompensation with the most serious consequence being death of the patient and/or foetus. Combining data from the largest four series published in the literature provides a total of 142 pregnancies in women with AIH [6 – 9 ] . Overall, a total of three maternal deaths were reported (2%), one of which was directly liver related to uncontrollable variceal haemorrhage in the post-partum period. The aeti- ology of the other two deaths were non-liver related and included a fatal pulmonary embolus and multi-organ failure following a septic abortion. Hepatic decompensa- tion following a fl are occurred in three additional patients, one of whom subse- quently required transplantation. Post-partum fl ares are common in AIH with reports of fl ares occurring in between 11 and 86% of patients [6 – 9 ] . Due to the relatively high post-partum fl are rates, some centres advocate for the routine use of steroid augmentation after delivery. This would typically involve the commencement or augmentation of prednisolone to 20 mg soon after delivery and tapering after 3 months [ 8 ] . Other centres under- take regular monitoring of the liver function tests during the post-partum period and only augment immunosupression in those that have a true fl are, thus not sub- jecting all patients to increased corticosteroids [6 ] . Terrabuio et al. routinely treated all patients with steroid augmentation post-partum. Despite this the post-partum fl are rate was still 45% [9 ] . Interestingly, this is not signifi cantly different to rates reported by Heneghan et

al. (18%) and Schramm et al. (55%), who did not rou- tinely augment immunosuppression post-partum. Moreover, in the study by Terrabuio et al. azathioprine dosing was reduced or discontinued in pregnancy and this in itself is likely to have contributed to the high post-partum fl are rate [9 ] . Thus, no convincing evidence exists to support the routine augmentation of immu- nosuppression medication in the post-partum period. Patients should be monitored closely and have prednisolone augmentation if a fl are in disease activity occurs (Fig. 10.1 ). Index Presentation of AIH in Pregnancy AIH can present as a new diagnosis in pregnancy or in the post-partum period [6 , 7, 11, 19, 20 ] . This is important to recognise as AIH must form part of the differ- ential diagnosis in any pregnant women who presents with jaundice or abnormal liver enzymes. The differential diagnosis includes viral infections (Hepatitis A, B, C and E viruses, Herpes simplex virus, Cytomegalovirus and Epstein Barr Virus), thrombotic complications such as Budd-Chiari Syndrome, drug reactions and liver diseases specifi c to the pregnant state including cholestasis of pregnancy, hyperten- sion-related disorders and acute fatty liver of pregnancy [2 1, 22 ] . In the literature, adverse outcomes have been reported with AIH arising de novo in pregnancy. This is in part due to the delay in diagnosis and subsequent delay in commencement of potentially life-saving treatment. Schramm et al. describe one woman whose fi rst 182 R.H. Westbrook and M.A. Heneghan Fig. 10.1 Algorithm for management of pregnancy in women with AIH without cirrhosis presentation was in the second trimester of her second pregnancy, but remained undiagnosed until she presented with fulminant hepatic failure in the second tri- mester of her third pregnancy. Emergency liver transplantation and hysterectomy was performed at 18 weeks gestation. The patient survived and remains well 6 years after transplantation [ 7 ] . Heneghan et al. described two women with index presentations of AIH during pregnancy [6 ] ; the fi rst presented with hepatic decom- pensation on a background of established cirrhosis at 24 weeks gestation. She was admitted to intensive care, and an emergency caesarean section was performed; however, the child has serious physical and mental developmental diffi culties since birth. The second patient presented with pre-eclampsia at 16 weeks gestation and was noted to have abnormal hepatic biochemistry. The diagnosis was made based on the serological tests, autoantibodies and liver biochemistry. She was commenced on immunosuppression and subsequently delivered a healthy infant at 37 weeks gestation. 10 Autoimmune Hepatitis and Pregnancy 183 Cirrhosis and Pregnancy in Patients AIH A subset of patients with AIH are cirrhotic at the time of conception. Pregnancy in patients with AIH and underlying cirrhosis, although rare, does occur and carries with it additional maternal risks and adverse fetal outcomes. It is recognised that women with cirrhosis who become pregnant are at risk of worsening liver synthetic function and hepatic decompensation including the development of ascites and encephalopathy [2 1, 23 ] . They also are at increased risk of developing varices as portal pressure rises in the second trimester of pregnancy due to a combination of the gravid uterus compressing the inferior vena cava and an increase in blood volume and fl ow [2 4, 25 ] . In previous small series, variceal haemorrhage has been reported to occur in 18–32% of pregnant women with cirrhosis and in up to 50% in those with pre-existing portal hypertension [2 5, 26 ] . Moreover, decompensation has been reported to affect up to 24% of pregnant women with cirrhosis and often follows an episode of variceal haemorrhage [2 4 ] . The optimal management of portal hypertension during pregnancy remains chal- lenging with the absolute need for variceal screening, primary prophylaxis against bleeding and the management of a variceal haemorrhage during pregnancy is largely undefi ned. Management is based on best guess experience extrapolated from the non-pregnant literature. Currently, it is recommended by experts that once pregnant, women with cirrhosis should have a screening endoscopy in the second trimester. Previous studies have reported the prevalence of varices in the second trimester to be in excess of 50% [2 7 ] . In a patient with “at risk” for bleeding oesophageal varices, endoscopic band ligation of varices, although not proven, is appropriate. Case reports describing this strategy in pregnancy have been published [2 8 ] , although no randomised trials have been carried out to prove effi cacy. The effi cacy of non- selective b (beta) blockers, such as propranolol, during pregnancy on portal pressure and variceal bleeding rates has never been investigated. Their use as a prophylactic agent against variceal bleeding in pregnancy has been extended from trials proving effi cacy in the non-pregnant literature [2 9, 30 ] . If a patient is established on b (beta) blockers prior to conception, continuation throughout pregnancy is appropriate. Case reports exist in the literature on the commencement of b (beta) blockers following the discovery of varices in the second trimester with no adverse outcomes reported [3 1 ] . The decision to commence an individual patient on b (beta) blockers needs to be made on a case-by-case basis. Their safety profi le is discussed below. If varices are confi rmed on screening endoscopy, delivery by caesarean section is often recommended. Although not proven, this strategy is thought to avoid the theoretical increased bleeding risk associated with an increase in portal pressure in the context of the valsalva manoeuvre during labour. The optimal timing of when to schedule caesarean section remains challenging and the risks between electively delivering a premature baby and the avoidance of a spontaneous labour must be balanced. In practice, patient management should be individualised and take into account local obstetric and hepatology expertise (Fig. 1 0.2 ). 184 R.H. Westbrook and M.A. Heneghan Fig. 10.2 Algorithm for management of pregnancy in women with AIH and underlying cirrhosis Overall, maternal mortality for pregnant women with cirrhosis was reported to be as high as 10.5% in the early 1980s [3 2 ] ; however, with advances in the manage- ment of liver disease and variceal haemorrhage, mortality is likely to have improved [ 33 ] . Despite this, maternal and fetal morbidity and mortality is thought to remain signifi cantly higher than the general population and women with cirrhosis need comprehensive pre-conception counselling if pregnancy is being considered. Pre- conception counselling is challenging since the underlying severity of cirrhosis can vary widely (Table 1 0.2 ). 10 Autoimmune Hepatitis and Pregnancy 185 Fetal Outcomes Fetal Loss The delivery of a healthy infant can be expected in the majority of patients with AIH that become pregnant, with live birth rates in case series reported to be between 71 and 86% [6 – 9 ] . These rates are comparable to live birth rates in patients with other autoimmune conditions, but lower than rates reported for the general population [3 4 ] . The cause for increased fetal loss in patients with AIH in unknown and most cases are labelled as spontaneous abortions. In the series by Terrabuio et al., no cause for pregnancy loss could be identifi ed in 87% of pregnancy losses [9 ] . Furthermore, no association between the activity of the underlying AIH, the maternal immunosu- pression or the presence of cirrhosis has been shown to be associated with an increased risk of pregnancy loss in patients with AIH. However, despite these spontaneous losses of pregnancy, other isolated pregnancy losses have been reported secondary to congenital abnormalities, maternal death or transplantation [6 , 7 ] . Affect of Maternal Antibody Profi le on Fetal Loss The effect of maternal antibody profi le on outcomes of pregnancy in AIH has been investigated [7 ] . Investigators reported 11 fetal losses in 42 pregnancies (26%), in whom seven had no identifi able medical cause [7 ] . Interestingly, they demonstrated that maternal antibodies to soluble liver antigen/liver-pancreas (SLA/LP) (p = 0.003) and Ro/SSA ( p = 0.01) were associated with an increased risk of fetal loss when compared to women without antibodies. It was postulated that a reason for this loss is the association between anti-Ro/SSA and adverse pregnancy outcomes in other autoimmune conditions, with the losses related to congenital heart conduction abnormalities. However, since pregnancy losses in this cohort all occurred early in the gestational period, heart conduction defects are unlikely in isolation, to explain these fetal losses. Prematurity, Birth Weight and Outcomes After Delivery Prematurity, defi ned as delivery of the foetus at less than 36 weeks gestation is asso- ciated with AIH and occurs in approximately 14% of live births [6 – 9 ] . Combining 114 live births from the largest reported case series, there were three neonatal deaths following delivery. These deaths occurred in babies that were born at 24, 26 and 32 weeks gestation and all deaths were directly related to prematurity. A further child has severe physical and mental handicap after an emergency caesarean delivery at 28 weeks following an index presentation of AIH during pregnancy. 186 R.H. Westbrook and M.A. Heneghan Fetal birth weights were normal in babies born at term, although low birth weight defi ned as a weight of less than 2,500 g can be expected in the majority of premature births [6 – 9 ] . Congenital abnormalities have been reported sporadically in infants delivered by patients with AIH. Cases vary from urethral stenosis to Edward’s syndrome, con- genital heart block and anencephaly [6 , 7 ] . The occurrence of a congenital anomaly appears sporadic and no evidence exists to suggest that the occurrence is related to either immunosupression or the underlying AIH. Finally, longer-term follow-up of infants born to mothers with AIH is reassuring with reports that children have nor- mal physical and mental development [6 ] . Drug Safety Data regarding the safety of medications commonly used in patients with AIH during pregnancy is scarce. Most of our information is obtained from its use in patients with other disease entities such as infl ammatory bowl disease or from post- transplant patients [3 5 ] . The common medications used in AIH are discussed with respect to their safety in pregnancy. Azathioprine In animal models, azathioprine has been associated with skeletal abnormalities, cleft palate, hydrops fetalis and hemopoetic abnormalities of the foetus [ 36, 37 ] . In humans, lymphopenia, hypogammaglobulinaemia and thymic hypoplasia have all been reported in children born to mothers on azathioprine. However, these latter changes seem to all be reversible after birth with no long-term effects on the child. Furthermore, azathioprine has been linked to pre-term deliveries [3 8 ] , and in light of the above reports, physicians historically recommended patients with AIH to discontinue azathioprine if they were trying to conceive. Azathioprine is classifi ed as a Food and Drug administration (FDA) category as class D, which states that positive evidence of risk to the fetus exists, but it is accepted that as in many medical conditions the potential benefi ts of its use throughout pregnancy may outweigh the risk (Table 1 0.3 ). Recently, experience with azathioprine in pregnancy has increased dramatically with information derived from other patient populations especially those with infl ammatory bowel disease, rheumatoid arthritis or patients following solid organ transplantation [3 5 ] . Following favourable reports in other pregnant populations, the number of reported cases in AIH and pregnancy is increasing. In 2001, our group addressed the risk–benefi t balance of azathioprine in AIH for the fi rst time [ 6] . A total of 35 pregnancies were reported, 18 of whom were taking azathioprine in isolation or in conjunction with prednisolone. Three patients had azathioprine withdrawn 10 Autoimmune Hepatitis and Pregnancy 187 Table 10.3 United States of America Food and Drug Administration categories of the safety of drugs in pregnancy Categories of drug safety in pregnancy A: Controlled studies show no risk Adequate, well-controlled studies in pregnant women have failed to demonstrate risk to the fetus B: No evidence of risk in humans Either animal fi ndings show risk (but human fi ndings do not) or, if no adequate human studies have been done, animal fi ndings are negative C: Risk cannot be ruled out Human studies are lacking and animal studies are either

positive for fetal risk or lacking as well. However, potential benefi ts may justify the potential risk D: Positive evidence of risk Investigational or post-marketing data show risk to fetus. Nevertheless, potential benefi ts may outweigh the risk X: Contraindicated in pregnancy Studies in animals or humans, or investigational or post-marketing reports have shown fetal risk which clearly outweighs any possible benefi t to the patient prior to or on discovery of conception. In this series, little was found to suggest that azathioprine or its metabolites were toxic in pregnancy. Indeed, the two congenital abnormalities reported in this series occurred in women not on azathioprine. It was concluded that for women with AIH that became pregnant on azathioprine, no evidence existed to support reduction or withdrawal of medication. This is especially pertinent in patients where azathioprine is critical for the maintenance of remission. Moreover, in a recent case series from Terrabuio et al., azathioprine was routinely stopped if the pregnancy was planned and withdrawn after conception if the preg- nancy was unplanned. Prematurity rates were no different in this study compared to ones where azathioprine was continued and interestingly the incidence of gesta- tional fl ares were similar to those reported by Heneghan et al. Indeed, rates of post- partum fl ares were much higher (11 versus 45%) [6 , 9 ] . In light of the above studies, it is generally recommended that azathioprine therapy should be continued during pregnancy, at the same dose used to control disease activity. At present, no evidence exists to suggest that discontinuing the azathioprine for the gestational period is benefi cial for the mother or fetal outcomes. Corticosteroids Prednisolone can cross the placenta, thus potentially exposing the fetus to adverse effects of the drug [ 39 ] . The major fetal risks regarding steroids are cleft palate (particularly with high dose exposure in the fi rst trimester), premature rupture of the membranes and intrauterine growth restriction (IUGR) [4 0, 41 ] . Reports of low birth weight and IUGR associated with steroid usage during pregnancy are con- founded by the severity of underlying disease necessitating corticosteroid therapy. 188 R.H. Westbrook and M.A. Heneghan In addition, fetal adrenal hypoplasia and suppression of the fetal pituitary have also been described, although both are uncommon due to the rapid maternal metabolism and placental breakdown of corticosteroids. Prednisolone is considered a class B drug in terms of its risk for pregnancy by the FDA. In the AIH literature, no adverse fetal outcomes have been thought to be directly related to prednisolone. An alternative to prednisolone is the synthetic corticosteroid budesonide. Budesonide has a high fi rst-pass metabolism and in comparison to prednisolone, it has been associated with fewer systemic side effects. In rats, budesonide is associ- ated with fetal loss, decreased birth weight and skeletal abnormalities. Currently there are no adequate studies in pregnant women and it is considered by the FDA as a class C drug. Overall, it is generally accepted amongst experts that control of the hepatic infl ammation is crucial and that risks associated with steroids are outweighed by the benefi t of good disease control. Thus, any maintenance prednisolone should be continued throughout pregnancy and fl ares occurring during pregnancy should be routinely treated with steroid augmentation. Tacrolimus In the last decade, tacrolimus has been used routinely in the post-transplant setting and consequently data regarding its safety in pregnancy is emerging. The neonatal malformation rate in reported series is approximately 4% [3 5, 42, 43 ] . Tacrolimus is considered a class C drug in terms of its risk in pregnancy by the FDA. No reports of its use or safety with regards to pregnancy, in women with AIH exist to date. Mycophenolate Mofetil Mycophenolate mofetil (MMF), an inhibitor of purine biosynthesis, has been shown to cause abnormal development of ova in animal models and therefore is potentially teratogenic [4 4 ] . A recent review of data of 119 human pregnancies with maternal exposure to MMF found outcome data for 65 and demonstrated a live birth rate of only 34% with miscarriage occurring in 31% and elective abortion in 20% [ 45 ] . The rate of congenital abnormalities, at 15%, was higher than that seen in the general population [ 46 ] . The most frequent congenital abnormalities reported included external ear and other facial malformations such as cleft lip and palate. Thus, when women of child-bearing age are commenced on MMF they should be counselled regarding its safety in pregnancy. If they wish to become pregnant, the drug must be discontinued with at least a 6-month wash out period before conception. MMF is considered by the FDA a class D drug in terms of the risks associated with its use in pregnancy. 10 Autoimmune Hepatitis and Pregnancy 189 b (Beta) Blockers The safety of profi le of the non-selective b (beta) blocker propranolol during pregnancy has been established from cohorts with indications other than portal hypertension, including maternal cardiac disease and hyperthyroidism. A number of fetal adverse events have been reported including neonatal hypoglycaemia brady- cardia and respiratory depression in addition to unproven concerns regarding intrauterine growth retardation and reduced placental weight. Doses greater than 160 mg/day are associated with the greatest risk. Propranolol is considered by the FDA a class C drug in terms of the risks associated in pregnancy. Breast Feeding Most physicians advise against breastfeeding due to concerns over the safety of neonatal exposure to immunosuppressants. Corticosteroids, azathioprine and tacrolimus are all known to be excreted in breast milk. Corticosteroids, however, are excreted in extremely low concentrations and are felt to be safe during breast- feeding [4 7 ] . Meanwhile, both azathioprine and tacrolimus levels are excreted in breast milk and in some cases levels are equivalent to, or even exceed that of maternal plasma and are therefore contraindicated [4 8 ] . Fertility Fertility in women with liver disease and AIH is variable. Historically, both Kunkel and Waldenström described a typical patient as being young, predominately female with chronic liver disease and associated hypergammaglobulinaemia [3 , 49 ] . In addition, they described common extra-hepatic features including arthralgia, rashes, fever and amennorhoea [ 3, 49 ] . More recent reports have estimated amennorhoea to affect approximately 20% of women of child-bearing age presenting with AIH [1 , 2, 50– 52 ] . The pathophysiology regarding amennorhoea and altered fertility in association with AIH is likely to be multifactorial. Firstly, AIH is associated with other endocrine abnormalities including hyperthyroidism, which in itself is widely acknowledged to affect fertility. Secondly, up to 40% of patients with AIH are cirrhotic at presentation [5 3 ] . In cirrhotic patients, disruption of the hypothalamic- pituitary axis in conjunction with disturbed estrogen metabolism occurs, leads to infertility [5 0 ] . Cundy et al. described two distinct hormonal profi les in women with cirrhosis and amennorhoea [5 0 ] . The fi rst suggests a hypothalamically driven process with low serum gonadotrophins, oestradiol and testosterone levels in asso- ciation with a low body mass index. This profi le mimics those seen in patients with 190 R.H. Westbrook and M.A. Heneghan secondary amennorhoea due to anorexia nervosa and suggests that chronic under-nutrition in patients with cirrhosis is likely to impact on fertility. The second is a cohort of patients with normal nutritional and gonadotrophin status. This group has higher oestradiol and testosterone levels mimicking profi les seen in patients with amennorhoea due to polycystic ovarian syndrome. Amennorhoea and infertil- ity driven by underlying cirrhosis is largely irreversible unless liver transplantation is performed. Following transplantation, however, menstruation can recover and several reports and case series of successful pregnancies exist [3 5, 54 ] . Finally, in patients with untreated AIH who do not have underlying cirrhosis or additional endocrine abnormalities, amennorhoea can still occur. Its occurrence is thought to be rare, but no population-based studies have reported its true incidence. The exact mechanism for the secondary amennorhoea is unknown. However, once disease control is achieved, menstruation can return allowing the potential for pregnancy to occur. Contraception Contraception should probably be discussed with all women with AIH of child- bearing age. The choice of contraception ultimately depends upon patient prefer- ence, requirement of reversibility and the nature and severity of the underlying liver disease. Barrier methods such as diaphragms and condoms are safe both with regard to liver function and drug interactions. Condoms also provide protection from potentially harmful infections. Barrier methods should be combined with a spermicide to increase the effi cacy, but despite this, failure rates when compared to other methods are reported to be between 15 and 32% [ 55] . Furthermore, barrier methods are frequently not the preferred choice of contraception for patients in long-term relationships. The combined oral contraceptive pill (COCP) is the most commonly used con- traceptive in many parts of the world. In patients with AIH the same contraindica- tions as in the general population apply. These include a personal history of myocardial infarction, stroke or deep vein thrombosis. Smokers over the age of 35, migraine with focal aura and uncontrolled hypertension should not have the drug [ 55 ] . The COCP has been linked with hepatic adenomas, cholestasis and hepatic vein thrombosis both in patients with and without underlying liver disease [5 6 ] . In addition, during an episode of acute hepatitis the COCP use can worsen the underly- ing infl ammation [ 56 ] . In chronic hepatitis the risk of the COCP is less clear, and evidence regarding its safety is lacking. An alternative hormonal contraception, especially for women with contraindica- tions for estrogens, is a progestin-only contraception method. They can be delivered orally, as an intramuscular injection or as an implantable device. Progesterone- based contraception appears to be safe in patients with liver disease. The liver has no progesterone receptors [5 7 ] ; however, some progesterones at high doses are metabolised to compounds that may have a small effect on liver function although 10 Autoimmune Hepatitis and Pregnancy 191 by a much lesser effect than estrogens [ 58 ] . The main drawback to this choice of contraception is that progesterone can cause salt and water retention and hence should be avoided in those patients with ascites. In view of the above comments the World Health Organisation recommend that in women with mild compensated cirrhosis or well-controlled hepatitis there is no restriction on the use of any hormonal contraceptive method. In women with severe decompensated cirrhosis, the benefi ts of progesterone only contraception may out- weigh the risks but all other methods of hormonal contraception pose an unaccept- able risk to health and should not be used. Finally, they recommend that in women who have a fl are of hepatitis or acute hepatitis, progestogen only contraception may be used without restriction but estrogen containing forms should be avoided. There are no reports on the use of intrauterine devices (IUD) in patients with AIH but they are generally regarded as safe and are used in the post-transplant setting. In Vitro Fertilisation Although patients with established cirrhosis have the potential to become pregnant, many women are unable to conceive naturally and the possibility and safety of in vitro fertilisation (IVF) is considered in such cases. Concern regarding hormonal changes associated with IVF which can potentially result in a fl are in disease activity may worsen underlying hepatic function and precipitate decompensation. This has led to a degree of reluctance in offering IVF. The largest experience is incorporated into a review from our group and describes three patients with AIH who conceived by IVF [ 6 ] . The outcomes reported were poor, with one fetal loss at 20 weeks gesta- tion, one severely handicapped child and only one healthy fetus. For the mothers, one patient had severe hepatic decompensation requiring premature delivery, one patient had a signifi cant post-partum fl are and although the fi nal patient had no adverse liver-related outcomes, she miscarried at 20 weeks as described above. Isolated case reports are more favourable with successful fetal and maternal outcomes reported even in women with underlying cirrhosis [5 9 ] . In light of the discrepancy regarding safety and outcomes in the literature, more information is needed regarding IVF in AIH before conclusions can be drawn. In

women with mild cirrhosis, or inactive AIH, IVF is a viable possibility providing women with a chance of pregnancy. Conclusion We have reviewed and appraised the available literature on AIH and pregnancy. Furthermore, we have highlighted the impact of AIH on fertility, discussed contra- ception options and the safety of common therapeutic regimes. We hope this chapter aids education and management of patients with AIH with regard to pregnancy. 192 R.H. Westbrook and M.A. Heneghan Chapter Summary 1. Patients with autoimmune hepatitis frequently wish to get pregnant, and their clinical outcomes are generally very good, so long as liver function is preserved. 2. For patients with cirrhosis attention to risk of variceal bleeding is important. 3. Most patients have normal pregnancies with only additional bloodwork, imaging and endoscopy. Useful Tips for Practitioners 1. Women with cirrhosis can conceive and therefore contraception and pre- conception counselling should be routine in women of child-bearing age. 2. Azathioprine is safe in pregnancy and should not be discontinued. 3. Patients are most likely to have a fl are in the post-partum period and require close monitoring. 4. All women with underlying cirrhosis should have a screening endoscopy in their second trimester and consider delivery by caesarean section if large varices present. Common Pitfalls in Practice 1. Failure to consider de novo AIH in pregnant women presenting with deranged LFT’s in pregnancy. 2. Azathioprine should not be reduced in women planning or reporting pregnancy. References 1. McFarlane IG. Autoimmune hepatitis: diagnostic criteria, subclassifi cations, and clinical fea- tures. Clin Liver Dis. 2002;6(3):605–21. 2. Lee WM. Pregnancy in patients with chronic liver disease. Gastroenterol Clin North Am. 1992;21(4):889–903. 3. Waldenström J. Leber, Blutproteine und Nahrungseiweib. Dtsch Z Verdau Stoffwechselkr. 1950;15:113–9. 4. Steven MM, Buckley JD, Mackay IR. Pregnancy in chronic active hepatitis. Q J Med. 1979;48(192):519–31. 5. Whelton MJ, Sherlock S. Pregnancy in patients with hepatic cirrhosis. Management and outcome. Lancet. 1968;2(7576):995–9. 10 Autoimmune Hepatitis and Pregnancy 193 6. Heneghan MA, Norris SM, O’Grady JG, Harrison PM, McFarlane IG. Management and outcome of pregnancy in autoimmune hepatitis. Gut. 2001;48(1):97–102. 7. Schramm C, Herkel J, Beuers U, Kanzler S, Galle PR, Lohse AW. Pregnancy in autoimmune hepatitis: outcome and risk factors. Am J Gastroenterol. 2006;101(3):556–60. 8. Buchel E, Van Steenbergen W, Nevens F, Fevery J. Improvement of autoimmune hepatitis during pregnancy followed by fl are-up after delivery. Am J Gastroenterol. 2002;97(12):3160–5. 9. Terrabuio DR, Abrantes-Lemos CP, Carrilho FJ, Cancado EL. Follow-up of pregnant women with autoimmune hepatitis: the disease behavior along with maternal and fetal outcomes. J Clin Gastroenterol. 2009;43(4):350–6. 10. Primo J, Ramos M, Julve R. The remission of autoimmune hepatitis during pregnancy. Gastroenterol Hepatol. 2000;23(1):24–5. 11. Riely CA. Meet Sarah–a vignette of autoimmune hepatitis and pregnancy. Am J Gastroenterol. 2002;97(12):2945. 12. Muratori P, Loffreda S, Muratori L, Ferrari R, Afandi K, Cassani F, et al. Spontaneous remis- sion of autoimmune hepatitis during pregnancy. Dig Liver Dis. 2002;34(8):608–9. 13. Golding A, Haque UJ, Giles JT. Rheumatoid arthritis and reproduction. Rheum Dis Clin North Am. 2007;33(2):319–43. 14. Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol. 2004;5(3):266–71. 15. Aluvihare VR, Kallikourdis M, Betz AG. Tolerance, suppression and the fetal allograft. J Mol Med. 2005;83(2):88–96. 16. Wilder RL. Hormones, pregnancy, and autoimmune diseases. Ann N Y Acad Sci. 1998;840:45–50. 17. Longhi MS, Ma Y, Mitry RR, Bogdanos DP, Heneghan M, Cheeseman P, et al. Effect of CD4+ CD25+ regulatory T-cells on CD8 T-cell function in patients with autoimmune hepatitis. J Autoimmun. 2005;25(1):63–71. 18. Longhi MS, Hussain MJ, Mitry RR, Arora SK, Mieli-Vergani G, Vergani D, et al. Functional study of CD4 + CD25+ regulatory T cells in health and autoimmune hepatitis. J Immunol. 2006;176(7):4484–91. 19. Izumi Y, Kaneko A, Oku K, Kimura M, Tanaka S, Tada H, et al. Development of liver dysfunc- tion after delivery is possibly due to postpartum autoimmune hepatitis. A report of three cases. J Intern Med. 2002;252(4):361–7. 20. Samuel D, Riordan S, Strasser S, Kurtovic J, Singh-Grewel I, Koorey D. Severe autoimmune hepatitis fi rst presenting in the early post partum period. Clin Gastroenterol Hepatol. 2004;2(7):622–4. 21. Hay JE. Liver disease in pregnancy. Hepatology. 2008;47(3):1067–76. 22. Joshi D, James A, Quaglia A, Westbrook RH, Heneghan MA. Liver disease in pregnancy. Lancet. 2010;375:594–605. 23. Tan J, Surti B, Saab S. Pregnancy and cirrhosis. Liver Transpl. 2008;14(8):1081–91. 24. Benjaminov FS, Heathcote J. Liver disease in pregnancy. Am J Surg. 2004;99:2479–88. 25. Britton RC. Pregnancy and esophageal varices. Am J Surg. 1982;143(4):421–5. 26. Pajor A, Lehoczky D. Pregnancy in liver cirrhosis. Assessment of maternal and fetal risks in eleven patients and review of the management. Gynecol Obstet Invest. 1994;38(1):45–50. 27. Russell MA, Craigo SD. Cirrhosis and portal hypertension in pregnancy. Semin Perinatol. 1998;22(2):156–65. 28. Zeeman GG, Moise Jr KJ. Prophylactic banding of severe oesophageal varices associated with liver cirrhosis in pregnancy. Obstet Gynecol. 1999;94(5 Pt 2):842. 29. Cheng JW, Zhu L, Gu MJ, Song ZM. Meta analysis of propranolol effects on gastrointestinal haemorrhage in cirrhotic patients. World J Gastroenterol. 2003;9(8):1836–9. 30. Hayes PC, Davis JM, Lewis JA, Bouchier IA. Meta-analysis of value of propranolol in preven- tion of variceal haemorrhage. Lancet. 1990;336(8708):153–6. 31. Subhan A, Abid S, Jafri W. Successful outcome of a pregnancy in a woman with advanced cirrhosis due to hepatitis B surface antigenemia, delta super-infection and hepatitis C co-infection: a case report. J Med Case Reports. 2007;1:96. 194 R.H. Westbrook and M.A. Heneghan 32. Steven MM. Pregnancy and liver disease. Gut. 1891;22:592–614. 33. Shaheen AA, Myers RP. The outcomes of pregnancy in patients with cirrhosis: a population- based study. Liver Int. 2010;30(2):275–83. 34. Penney GC, Mair G, Pearson DW. Outcomes of pregnancies in women with type 1 diabetes in Scotland: a national population-based study. BJOG. 2003;110(3):315–8. 35. Christopher V, Al-Chalabi T, Richardson PD, Muiesan P, Rela M, Heaton ND, et al. Pregnancy outcome after liver transplantation: a single-center experience of 71 pregnancies in 45 recipi- ents. Liver Transpl. 2006;12(7):1138–43. 36. Tuchmann-Duplessis H, Mercier-Parot L. Production in rabbits of malformations of the extremities by administration of azathioprine and 6-mercaptopurine. C R Seances Soc Biol Fil. 1966;160(3):501–6. 37. Rosenkrantz JG, Githens JH, Cox SM, Kellum DL. Azathioprine (Imuran) and pregnancy. Am J Obstet Gynecol. 1967;97(3):387–94. 38. Danesi R, Del Tacca M. Teratogenesis and immunosuppressive treatment. Transplant Proc. 2004;36(3):705–7. 39. Beitins IZ, Bayard F, Ances IG, Kowarski A, Migeon CJ. The transplacental passage of prednisone and prednisolone in pregnancy near term. J Pediatr. 1972;81(5):936–45. 40. Guller S, Kong L, Wozniak R, Lockwood CJ. Reduction of extracellular matrix protein expression in human amnion epithelial cells by glucocorticoids: a potential role in preterm rupture of the fetal membranes. J Clin Endocrinol Metab. 1995;80(7):2244–50. 41. Lockwood CJ, Radunovic N, Nastic D, Petkovic S, Aigner S, Berkowitz GS. Corticotropin- releasing hormone and related pituitary-adrenal axis hormones in fetal and maternal blood during the second half of pregnancy. J Perinat Med. 1996;24(3):243–51. 42. Bar Oz B, Hackman R, Einarson T, Koren G. Pregnancy outcome after cyclosporine therapy during pregnancy: a meta-analysis. Transplantation. 2001;71(8):1051–5. 43. Scantlebury V, Gordon R, Tzakis A, Koneru B, Bowman J, Mazzaferro V, et al. Childbearing after liver transplantation. Transplantation. 1990;49(2):317–21. 44. Downs SM. Induction of meiotic maturation in vivo in the mouse by IMP dehydrogenase inhibitors: effects on the developmental capacity of ova. Mol Reprod Dev. 1994;38(3):293–302. 45. Ostensen M, Khamashta M, Lockshin M, Parke A, Brucato A, Carp H, et al. Anti-infl ammatory and immunosuppressive drugs and reproduction. Arthritis Res Ther. 2006;8(3):209. 46. Nagy S, Bush MC, Berkowitz R, Fishbein TM, Gomez-Lobo V. Pregnancy outcome in liver transplant recipients. Obstet Gynecol. 2003;102(1):121–8. 47. Ito S. Drug therapy for breast-feeding women. N Engl J Med. 2000;343(2):118–26. 48. Flechner SM, Katz AR, Rogers AJ, Van Buren C, Kahan BD. The presence of cyclosporine in body tissues and fl uids during pregnancy. Am J Kidney Dis. 1985;5(1):60–3. 49. Kunkel HG, Ahrens EH, Eigenmenger WJ, Bongiovanni AM, Slater RJ. Extreme hypergam- maglobulinaemia in young women with liver disease of unknown etiology [abstract]. J Clin Invest. 1951;30:654. 50. Cundy TF, Butler J, Pope RM, Saggar-Malik AK, Wheeler MJ, Williams R. Amenorrhoea in women with non-alcoholic chronic liver disease. Gut. 1991;32(2):202–6. 51. Thiele DL. Autoimmune hepatitis. Clin Liver Dis. 2005;9(4):635–46. 52. Gruenberg JC, VanSlyck EJ, Abraham JP. Splenectomy in systemic lupus erythematosis. Am Surg. 1986;52(7):366–70. 53. Czaja AJ. Current concepts in autoimmune hepatitis. Ann Hepatol. 2005;4(1):6–24. 54. Cundy TF, O’Grady JG, Williams R. Recovery of menstruation and pregnancy after liver trans- plantation. Gut. 1990;31(3):337–8. 55. WHO medical eligibility for contraceptive use. 3 rd ed. Geneva, Switzerland, 2004. 56. Connolly TJ, Zuckerman AL. Contraception in the patient with liver disease. Semin Perinatol. 1998;22(2):178–82. 57. Lobo RA. Progestogen metabolism. J Reprod Med. 1999;44:148–52. 10 Autoimmune Hepatitis and Pregnancy 195 58. Chu MC, Zhang X, Gentzshein E, Stanczyk FZ, Lobo RA. Formation of ethynyl estradiol in women during treatment with norethindrone acetate. J Clin Endocrinol Metab. 2007;92:2205–7. 59. Powell EE, Molloy D. Successful in vitro fertilization and pregnancy in a patient with autoim- mune chronic active hepatitis and cirrhosis. J Gastroenterol Hepatol. 1995;10(2):233–5. Chapter 11 Treatment Side Effects and Associated Autoimmune Diseases Cynthia Levy Keywords Autoimmune hepatitis • Azathioprine • Combination therapy • Immunomodulators • Immunosuppressants • Prednisone Abbreviations 6-MMP 6-Methylmercaptopurine 6-MP 6-Mercaptopurine 6-TGN 6-Thioguanine nucleotides AIRE Autoimmune regulator APECED Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy APS Autoimmune polyglandular syndromes AZA Azathioprine CREST Subcutaneous calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly and telangectasias CTLA-4 Cytotoxic T lymphocyte antigen-4 HLA Histocompatibility leukocyte antigen IBD Infl ammatory bowel disease NRH Nodular regenerative hyperplasia PBC Primary biliary cirrhosis PSC Primary sclerosing cholangitis RA Rheumatoid arthritis SLE Systemic lupus erythematosus C. Levy (*) Division of Hepatology , University of Miami School of Medicine, 1500 NW 12th Avenue, Suite 1101 , Miami 33136 , FL , USA e-mail: clevy@med.miami.edu G.M. Hirschfi eld and E.J. Heathcote (eds.), Autoimmune Hepatitis: A Guide for Practicing 197 Clinicians, Clinical Gastroenterology, DOI 10.1007/978-1-60761-569-9_11, © Springer Science+Business Media, LLC 2012 198 C. Levy SS Systemic sclerosis TNF Tumor necrosis factor TPMT Thiopurine methyltransferase Introduction A wide variety of immunosuppressants and immunomodulators have been used to treat autoimmune hepatitis. As reviewed in Chaps. 6 and 7 , prednisone or prednisolone, alone or in combination with azathioprine is the treatment mainstay, limited mostly by the development of drug toxicity. In that regard, combination therapy is associ- ated with fewer side effects than prednisone monotherapy (10 versus 44%) [1 ] . In approximately 10% of the cases treatment with prednisone/azathioprine will fail and use of alternative therapy will be necessary. This chapter will review the most common side effects of these drugs used in the treatment of autoimmune hepatitis followed by a discussion regarding associated autoimmune diseases. Treatment Side Effects Prednisone/Prednisolone Glucocorticoids like prednisone or prednisolone are potent anti-infl ammatory agents which also have major metabolic effects. As such, steroids can cause a multitude of side effects which are usually related to both dosage and duration of therapy. Table 11.1 summarizes the most important side effects of steroids and other drugs used in the treatment of autoimmune hepatitis. Immunosuppression leads to decreased resistance to infections, especially, but not limited to, those bacterial in origin. In fact, it is recom- mended that a skin test for tuberculosis be considered prior to initiating long-term pred- nisone therapy. May be activate hepatitis B therefore head to be screened pre treatment. In endemic areas, consideration should be given to testing for Strongyloides infection as well and treating as appropriate prior to starting steroids. Hepatitis B reactivation should also be considered, and testing for prior exposure is recommended pre-treatment, with vaccination and/or subsequent monitoring on immunosuppression advisable. Due to the mineralocorticoid activity, fl uid retention and electrolyte imbalance can occur and induce or worsen hypertension. Patients receiving greater than 10 mg of prednisone daily are at risk for suppression of the hypothalamic–pituitary–adrenal axis leading to adrenal insuffi ciency. This manifests as anorexia, weight loss, leth- argy, fever, and postural hypotension. Despite this potentially serious threat, it is the endocrine derangements that most often lead to treatment discontinuation. Cushingoid habitus, obesity, acne and cosmetic changes can signifi cantly decrease compliance with therapy, and hyperglycemia may require the use of insulin [2 ] . Therefore, patients with brittle diabetes should be considered for combination therapy along with post-menopausal women, who are at signifi cant risk for osteopenia and compression fractures, and also patients with obesity or with labile hypertension. 11

Treatment Side Effects and Associated Autoimmune Diseases 199 Table 11.1 Main side effects of drugs used in the treatment of autoimmune hepatitis Drug Side effects Prednisone/Prednisolone Skin thinning, purpura Cushingoid appearance, weight gain Hypertension, fl uid retention, electrolyte imbalance Hyperglycemia Adrenal insuffi ciency Increased risk of infections Neutrophilia Myopathy Osteopenia/osteoporosis Cataracts formation Euphoria/psychosis other psychiatric symptoms Hepatitis B reactivation Azathioprine/6-Mercaptopurine GI intolerance Hypersensitivity Acute pancreatitis Hepatotoxicity Skin rash, fever Increased risk for infections Cytopenias Myalgias, arthralgias Lymphoma Cyclosporine A Renal insuffi ciency Hypertension Hyrsutism Gingival hyperplasia Hyperlipidemia Increased risk for infections Lymphoproliferative disorders Tacrolimus Hyperkalemia Renal insuffi ciency Tremors Hypertension, edema Paresthesias, neurotoxicity Headache Vivid dreams Mycophenolate mofetil Diarrhea Abdominal pain, nausea Cytopenias Alopecia Headache, dizziness Paresthesias Arthralgias Budesonide As prednisone, signifi cantly less pronounced Increased risk of portal vein thrombosis seen in cirrhotics Thioguanine nucleotides Hypersensitivity Nodular regenerative hyperplasia 200 C. Levy Other side effects of steroids include steroid myopathy, ischemic bone necrosis, increased intraocular pressure, formation of posterior subcapsular cataracts, pseudo- tumor cerebri, hyperlipidemia, and menstrual irregularities. Mental status changes can vary signifi cantly, from depression to euphoria, from mild anxiety and insomnia to full blown psychosis. Side effects are present in approximately 44% of patients on steroid monotherapy (20 mg/daily for maintenance), and can be minimized by dose reduction. Osteopenia and cataracts formation constitute an exception and can continue to progress despite minimal doses of steroids [2 ] . Thus, current guidelines recommend that patients at increased risk, usually those receiving ³ 7.5 mg/day, be started on regular weight- bearing exercises and supplementation with vitamin D and calcium as prophylaxis of bone disease [1 ] . Use of bisphosphonates or other anti-resorptive drugs should be individualized. In addition, these patients on chronic steroid therapy should be monitored for bone disease with baseline and annual bone densitometry tests. Likewise, eye exams for cataracts and glaucoma should be performed on a regular basis during chronic steroid therapy. Azathioprine/6-Mercaptopurine Azathioprine (AZA) and 6-mercaptopurine (6-MP) are frequently used in com- bination with prednisone in the treatment of autoimmune hepatitis. AZA is non- enzymatically converted to 6-MP, which is then either deactivated or metabolized to an active form through a complex web of reactions. Thiopurine methyltrans- ferase (TPMT) is the enzyme that methylates 6-MP and generates 6-methylmer- captopurine (6-MMP), an inactive metabolite. That enzyme activity is subject to signifi cant inter-individual genetic variability, thus affecting the drugs’ effi cacy and tolerability. According to different polymorphisms in the TPMT gene, patients can be slow, intermediate or fast methylators. The enzyme activity will determine the proportion of 6-MP shunted toward the active metabolites, 6-thioguanine nucleotides (6-TGN), versus that inactivated in the form of 6-MMP. Slow methylators will produce more 6-TGN, potent purine antagonists which have been associated with myelotoxicity [3 ] . At this time, it is unclear whether measuring TPMT activity and thiopurine metabolites levels is necessary prior to starting therapy, although it could be useful in patients who fail to respond to usual therapy [4 ] . Another potential use would be to identify slow methylators, a subgroup of patients at particularly higher risk for myelotoxicity, among cir- rhotics, who already have cytopenias at baseline. Adverse events are observed in less than 10% of patients with autoimmune hep- atitis taking AZA or 6-MP, and these adverse events can be divided into allergic and nonallergic reactions [5 , 6 ] . As such, allergic reactions include skin rash, fever, pancreatitis, hypersensitivity and hepatitis, and are not dose-dependent. These reactions tend to occur early after initiation of AZA/6-MP, and recur with re- challenging. The nonallergic reactions are dose-dependent and relate to the 11 Treatment Side Effects and Associated Autoimmune Diseases 201 concentration of active metabolites 6-thioguanine nucleotides in the blood. These include the cytopenias, increased risk of infections and GI intolerance with nausea, vomiting and abdominal pain. Some degree of cytopenia is expected and monthly CBCs are recommended for adequate monitoring during therapy. In case of GI intol- erance, dose reduction or switching from AZA to 6-MP or vice versa should be attempted prior to drug discontinuation. These GI symptoms will improve in up to 70% of patients [4 , 7, 8 ] . Other side effects include rare teratogenicity and a potential increase in the risk of developing lymphoma. Although there are no studies involving patients with autoimmune hepatitis, data derived from large populations with infl ammatory bowel disease and rheumatoid arthritis (RA) suggest a small increase in the relative risk of lymphoma [ 9, 10 ] . An association with the severity of disease as opposed to the use of AZA or 6-MP cannot be excluded [ 11, 12 ] . Finally, acute hypersensitivity can occur, albeit signifi cantly less often than in patients with infl ammatory bowel disease (2.5 vs. 19%) [1 3 ] . Cyclosporine A Cyclosporine A is a calcineurin inhibitor that impairs the transcription of interleu- kin-2 and its downstream activation, thereby preventing T-cell lymphocyte activa- tion. The use of cyclosporine has been mostly restricted to rescue therapy in adults with steroid-resistant disease or for induction of remission in children, in whom long-term use of steroids must be avoided [ 14, 15 ] . Reports in the pediatric popula- tion suggest that biochemical remission can be achieved in >90% of patients within the fi rst 6 months, when cyclosporine A (3.3–6.5 mg/kg/day) is used as fi rst-line therapy to induce remission in lieu of prednisone [ 16, 17 ] . Likewise, cyclosporine A (4.7–7.5 mg/kg/day) was successful in inducing remission in four pediatric patients who relapsed while on prednisone maintenance therapy and who had refused to resume high-dose steroids due to previous side effects, and in two patients who progressed to liver failure despite treatment with prednisone and aza- thioprine [ 17 ] . In these two patients with liver failure, cyclosporine was fi rst administered intravenously (1 mg/kg/day), and then converted to oral formulation once the liver function improved, with levels adjusted to maintain trough levels between 200 and 250 ng/mL. Importantly, patients with severe acute hepatitis who meet minimal listing criteria for liver transplantation (MELD ³ 15), as well as patients who show any signs of decompensation while on rescue therapy, should be referred for transplant evaluation. Despite its effi cacy in steroid-resistant patients, the benefi t of cyclosporine is signifi cantly limited by the toxicity profi le associated with its long-term use, including hypertension, renal impairment, tremors, headaches, hirsutism, gingival hyperplasia, severe infections, hyperlipidemia and even lymphoproliferative disorders. Other less toxic alternative therapies are increasingly available. 202 C. Levy Tacrolimus Tacrolimus is a calcineurin inhibitor 100 times more potent than cyclosporine A, but with a more favorable toxicity profi le. It has the ability to inhibit expression of the interleukin-2 receptor and impair cytotoxic T-cell proliferation. Formal experience in autoimmune hepatitis is restricted to a couple of clinical trials and a few case reports. Despite that, several hepatologists use tacrolimus in patients who fail ste- roids or who become steroid-dependent. Common side effects include hyperkalemia, renal insuffi ciency, tremors, hypertension, edema, paresthesias, vivid dreams, and headaches [1 8, 19 ] . These side effects can often be minimized by targeting a low serum level. Mycophenolate Mofetil Mycophenolate mofetil is an inhibitor of inosine monophosphate dehydrogenase which reduces proliferation of T-cell and B-cell lymphocytes by blocking de novo purine synthesis and impairing DNA synthesis. It represents a less toxic alternative for patients who are refractory to, or intolerant of, conventional therapy for autoim- mune hepatitis; reported side effects include diarrhea, abdominal pain, nausea, cytopenias, hair loss, headaches, dizziness, paresthesias, and arthralgias [2 0– 25 ] . When possible, dose reduction alleviates most of these side effects. Budesonide Budesonide is a potent synthetic glucocorticoid with high fi rst-pass metabolism by the liver, which reduces its systemic bioavailability to about 10%. With that, budes- onide is expected to be more effective and better tolerated than prednisone. Nevertheless, adverse events still occur, including leukocytosis, hypercholester- olemia, cushingoid habitus, acne, heartburn, weight gain and others [ 26, 27 ] . Importantly, steroid-induced diabetes [2 7 ] and bone demineralization [ 28 ] have been demonstrated even with budesonide. In a study comparing effi cacy and safety of budesonide/azathioprine to prednisone/azathioprine, steroid-induced side effects were noticed in 28% of patients on the budesonide group. The dose of budesonide was 3 mg three times daily until remission, and then it was decreased to 3 mg twice daily. The number of serious adverse events was similar in both groups [2 9 ] . Finally, budesonide should only be used in noncirrhotic patients. In patients with cirrhotic-stage primary biliary cirrhosis, use of budesonide led to marked elevation of serum levels and was associated with serious adverse events. Furthermore, two of the seven patients in that study developed portal vein thrombosis in close temporal relationship with drug administration [3 0 ] . It is unclear whether patients with cirrhosis due to other etiologies, such as autoimmune hepatitis, are at similar risk. 11 Treatment Side Effects and Associated Autoimmune Diseases 203 Tioguanine Nucleotides Active metabolites of AZA, tioguanine nucleotides (6-TG) have been advocated for use in patients with autoimmune hepatitis who were previously intolerant of AZA [3 1 ] . Prospective studies are not available and data derive from a single case series involving only three patients. Signifi cant side effects were not reported in that series. However, among patients with infl ammatory bowel disease who received 6-TG, up to 19% had an acute hypersensitive reaction and hepatic changes consistent with nodular regenerative hyperplasia were commonly described [3 2, 33 ] . Thus, 6-TG is not currently recommended for the treatment of autoimmune hepatitis outside the setting of a clinical trial. Others Use of other drugs including m ethotrexate and c yclophosphamide has been docu- mented only in small case reports and limited data are available but plenty of side effects documented in the general literature. R ituximab is a chimeric anti-CD20 monoclonal antibody which depletes B-cell lymphocytes by targeting their CD20 cell surface receptor. The rationale is scientifi cally sound and the drug has been successfully used in one case of autoimmune hepatitis [3 4 ] . However, the interest in treating this disease with monoclonal antibodies was dampened by fi ndings of possible induction of autoimmune hepatitis and liver failure by i nfl iximab , another chimeric monoclonal antibody which has the ability to block cytotoxic T-cell lymphocytes [3 5 ] . Associated Autoimmune Diseases Frequency Concurrent autoimmune diseases occur in approximately 18–46% of those with type 1 autoimmune hepatitis, and in 14–34% of those with type 2 autoimmune hep- atitis [3 6– 40 ] . Based on this increased frequency, the International Autoimmune Hepatitis Group (IAIG) included the presence of autoimmune diseases in either the patient or their fi rst-degree relatives as a diagnostic feature in their scoring system. Risk Factors It is well known that the histocompatibility leukocyte antigen (HLA) DR4 is associated with susceptibility to concurrent immune diseases in type 1 autoimmune hepatitis [4 1 ] , especially if the HLA-A11 is also present [ 40, 41 ] , and that women tend to have 204 C. Levy Table 11.2 Associated autoimmune diseases Endocrine Autoimmune thyroiditis Diabetes mellitus Autoimmune polyglandular syndromes Rheumatologic Synovitis Sjogren’s syndrome Rheumatoid arthritis, Felty’s syndrome Systemic sclerosis Systemic lupus erythematosus Polymyositis Juvenile arthritis Gastrointestinal/Hepatic Infl ammatory bowel disease ± PSC Celiac disease Primary biliary cirrhosis Primary sclerosing cholangitis Hematologic Idiopathic thrombocytopenic purpura Hemolytic anemia Pernicious anemia Neurologic Multiple sclerosis (? True association) Cutaneous Pemphigus vulgaris Morphea Lichen planus Pityriasis lichenoides chronic Discoid lupus Alopecia Nail dystrophy Vitiligo Renal Membranous nephropathy Cryoglobulinemic glomerulonephritis Focal glomerulonephritis Others Uveitis a higher frequency of such associated diseases [ 37 ] . Indeed, women have a higher frequency of HLA DR4 than men with type 1 autoimmune hepatitis. In addition, older patients also tend to have more concurrent autoimmune diseases, especially those rheumatic in nature [4 2 ] . Types Multiple extra-hepatic autoimmune diseases have been described in association with autoimmune hepatitis. The nature and frequency of each condition vary signifi - cantly according to the type of autoimmune hepatitis, genetic background, geo- graphic location, gender, and antibody profi le among other possible factors. Table 1 1.2 shows a list of autoimmune diseases commonly associated with 11 Treatment Side Effects and Associated Autoimmune Diseases 205 autoimmune hepatitis. In the United

States, thyroid disease and arthritis are the concurrent diseases most commonly associated with type 1 autoimmune hepatitis. In Brazil, on the other hand, seronegative arthritis and rheumatoid arthritis were more common. A brief discussion of extra-hepatic concurrent autoimmune dis- eases is provided below. Endocrine Diseases Autoimmune Thyroiditis Although a true association has not been clearly demonstrated between autoim- mune hepatitis and thyroiditis, this hypothesis is supported by the presence of a polymorphism in the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene in both groups of patients [4 3 ] . Thyroiditis can be seen both in type 1 and in type 2 auto- immune hepatitis and appears to be quite common in North American and Italian patients with type 1 autoimmune hepatitis [ 44, 45] as well as English and French patients with type 2 autoimmune hepatitis [3 6 ] . Not unexpectedly, patients with autoimmune hepatitis who are older than 65 years of age appear to be at a higher risk for autoimmune thyroiditis than younger counterparts (25 vs. 5%) [4 4 ] . More frequently, patients will complain of excessive fatigue despite good control of their AIH and laboratory testing will reveal abnormalities in the thyroid profi le. Both Hashimoto’s and Graves’ disease have been described in this scenario [ 46– 48 ] . Diabetes Mellitus The most common association is between type 1 diabetes mellitus and type 2 auto- immune hepatitis [4 9 ] . However, a case of latent autoimmune diabetes of adults has been reported [5 0 ] , as well as an association of Graves’ disease, type 1 diabetes mel- litus and autoimmune hepatitis [ 51 ] . As diabetes mellitus can be part of an autoim- mune polyglandular syndrome, these associations need to be evaluated. Autoimmune Polyglandular Syndromes Two types of Autoimmune Polyglandular Syndromes (APS) have been described. Type 1 is a rare autosomal-recessive disease, also known as autoimmune polyendo- crinopathy-candidiasis-ectodermal dystrophy (APECED), that affects juvenile patients. The gene responsible for this disease, the AIRE gene, is located on chro- mosome 21q22.3. APS-1 is characterized by the presence of two out of three of the 206 C. Levy following: hypoparathyroidism, adrenocortical failure, and chronic mucocutaneous candidiasis. Several other autoimmune manifestations may develop in APECED patients, with autoimmune hepatitis occurring in up to 20% of them [5 2 ] . Type 2 APS is autosomal-dominant, occurs more frequently than type 1 and affects predominantly adult women. Potential susceptibility genes include the CTLA-4 and cytokine-related genes TNF alpha and/or PTPN22. Several distinct disease combi- nations can be present in APS-2, with thyroid immune disease/type 1 diabetes mel- litus being the most common (41%), followed by Addison’s disease/thyroid disease (14.6%) [ 53 ] . Other disease presentations include vitiligo, alopecia, hypogonadism, and pernicious anemia. Genetic variants of both type 1 and type 2 APS have been described in children with autoimmune hepatitis. If suspected, genetic analysis of the AIRE gene may be useful to confi rm APS-1. Rheumatic Diseases Arthritis/Synovitis This was reported by 27% of White Argentinians with type 1 autoimmune hepatitis referred for a genetic study [4 0 ] . In the United States, seronegative arthritis is also commonly described, although an accurate incidence is not available. Most studies do not methodically exclude autoimmune rheumatic diseases. Sjogren’s Syndrome Sjogren’s is an autoimmune exocrinopathy that leads to destruction of the salivary and lacrimal glands by infi ltrating lymphocytes. As a result, patients develop dry eyes and dry mouth syndrome, and systemic symptoms such as fatigue and arthral- gias can occur. Up to 30% of patients with Sjogren’s syndrome eventually develop additional autoimmune syndromes; the liver is frequently involved [5 4, 55 ] . An earlier study from Denmark found that only 2 (6%) out of 16 patients with Sjogrens and abnormal liver tests had autoimmune hepatitis [5 6 ] . Subsequently, a smaller study from Japan, where 17 patients with Sjogrens and elevated liver tests under- went liver biopsy, eight patients (47%) were found to have autoimmune hepatitis [ 57 ] . More recently, a study from Mexico City, 44% of 95 patients with Sjogren’s syndrome had abnormal liver biochemistries, and 21 (22%) of those had a well- defi ned liver disease. Two of the 21 had autoimmune hepatitis (9.5%), fi ve had primary biliary cirrhosis, 11 had hepatitis C, one had hepatitis B and two had nonalcoholic fatty liver disease [5 5 ] . Thus, the reported incidence of autoimmune hepatitis in patients with Sjogren’s syndrome and elevated liver tests ranges from 6 to 47%, 11 Treatment Side Effects and Associated Autoimmune Diseases 207 depending possibly on the geographic location and genetic background. Conversely, Sjogren’s syndrome affects approximately 27% of patients with autoimmune hepatitis [5 8 ] . Rheumatoid Arthritis This chronic polyarthritis is often associated with liver test abnormalities, although a specifi c liver disease is infrequently found. When unselected liver biopsies were performed in 117 patients with RA, nonspecifi c changes were the most frequent fi nding (43%), followed by normal biopsy (35%) and fatty changes (22%). When liver biopsies of patients with RA and abnormal liver tests were examined, 74% of the specimens were nonspecifi c, 13% normal and 13% with a defi ned chronic liver disease, of which in only one case could autoimmune hepatitis be implicated [5 9 ] . In another study evaluating liver histology of 160 patients with multiple collagen diseases including RA, the investigators failed to identify a single case of autoim- mune hepatitis in association with RA [6 0 ] . Other liver diseases associated with RA are primary biliary cirrhosis (PBC), amyloidosis, and nodular regenerative hyper- plasia (NRH). Felty syndrome is a rare and severe presentation of RA characterized by splenomegaly and neutropenia. NRH has been reported in association with RA, especially in the setting of Felty’s syndrome. One case report of autoimmune hepa- titis associated with Felty syndrome has been published [6 1 ] . Systemic Sclerosis Systemic sclerosis (SS) is a chronic systemic disease characterized by tissue fi brosis, small blood vessel vasculopathy, and the presence of several types of auto-antibodies. Two forms are recognized: limited and diffuse cutaneous, and CREST (subcutane- ous calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly and telangectasias) syndrome is a form of limited scleroderma associated with produc- tion of anti-centromere antibodies [6 2 ] . Autoimmune hepatitis has been described in association with SS only in case reports [ 63, 64 ] . As is the case in RA, SS is more often associated with PBC and NRH. Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multiorgan involvement and the presence of specifi c auto-antibodies. Liver involvement is not a typical feature in SLE, and when present is usually due to steatosis [6 5 ] . Cases consistent with autoimmune hepatitis, however, have been described in 208 C. Levy up to 2.5–4.4% of patients [6 6 ] . Further, it is important to remember that in this scenario, autoimmune hepatitis can develop de novo or be triggered by medications. Findings of autoimmune hepatitis in a patient with SLE should be regarded as a second disease and treated as appropriate. Polymyositis This autoimmune infl ammatory muscle disease has been described in association with autoimmune hepatitis only in a couple of case reports [6 7, 68 ] . Elevation of serum transaminases is also a common feature of polymyositis and this can lead to signifi cant delay in diagnosis. The association with another autoimmune liver disease, PBC, is somewhat stronger. Elevation of serum alkaline phosphatase may be seen in polymyositis but should nevertheless trigger the clinician to investigate both diseases [6 6 ] . Gastrointestinal Diseases Infl ammatory Bowel Disease The liver disease most commonly associated with IBD is primary sclerosing cholan- gitis (PSC) [6 9– 71 ] . However, it is well documented that autoimmune hepatitis can also be associated with IBD. One study examined 105 patients with autoimmune hepatitis by proctoscopy and found that 17 (16%) had unsuspected fi ndings of chronic ulcerative colitis [7 2 ] . The course of autoimmune hepatitis among patients with coexisting IBD appears no different from that seen in patients without IBD. On further evaluation, 12 of these 17 patients underwent cholangiography and features of PSC were identifi ed in 5 (42%). Thus, in patients with autoimmune hepatitis and IBD, PSC must be thought of and appropriately excluded with magnetic resonance imaging. A series from the Mayo Clinic examined this issue from a different perspective: out of 32 patients with IBD and chronically elevated liver enzymes, only 2 (6.25%) had autoimmune hepatitis, whereas PSC was diagnosed in 25 (78%) [ 70 ] . Of note, both ulcerative colitis [7 3 ] and Crohn’s disease [7 4 ] have been described in conjunction with autoimmune hepatitis. Celiac Disease Also known as gluten-sensitive enteropathy, celiac disease is associated with many forms of liver disease, including autoimmune hepatitis, primary biliary cirrhosis, 11 Treatment Side Effects and Associated Autoimmune Diseases 209 PSC, viral hepatitis, and nonalcoholic liver disease [ 75 ] . The prevalence of celiac disease among patients with autoimmune hepatitis appears to be 4–6.4% [7 6, 77 ] , and both patients with type 1 and type 2 can be affected. The prevalence of celiac disease among pediatric patients with autoimmune hepatitis is higher, around 12.5–13.5% [7 8, 79 ] . As is frequently the case with other concurrent autoimmune diseases, celiac disease may be unmasked before or after autoimmune hepatitis is diagnosed. Liver Diseases PBC and PSC are chronic autoimmune liver diseases which can co-exist with autoimmune hepatitis in the so-called overlap syndromes – see Chapter 12 for details. Hematologic Diseases Idiopathic Thrombocytopenic Purpura This condition is characterized by an isolated thrombocytopenia, with a cut-off platelet count <50,000/ m L, in the absence of an implicated drug, condition or agent that is known to cause thrombocytopenia. There are several case reports describing an association with autoimmune hepatitis, particularly in conjunction with Sjogren’s syndrome [ 80, 81 ] . According to a nation-wide survey in Japan, idio- pathic thrombocytopenic purpura occurs in about 3% of patients with autoimmune hepatitis [8 0 ] . Autoimmune Hemolytic Anemia This entity is characterized by the production of IgG or IgM antibodies against red blood cell surface antigens. The red blood cells are then destroyed either by activa- tion of the complement system or by the reticuloendothelial system. The association between autoimmune hemolytic anemia and autoimmune hepatitis is rare but well documented [8 2, 83 ] . Pernicious Anemia This occurs as a result of Vitamin B12 (cobalamin) malabsorption caused by two main factors: (1) presence of anti-intrinsic factor antibodies causing destruction of gastric intrinsic factor needed for cobalamin absorption and (2) atrophic gastritis leading to a decreased production of intrinsic factor. Chronic atrophic gastritis may 210 C. Levy be associated with another condition called gastric carcinoid. Cases have been described of patients with autoimmune hepatitis, pernicious anemia, and atrophic gastritis with or without carcinoids [8 4, 85 ] . Of note, both pernicious anemia and autoimmune hepatitis are components of the APS-1 and thus this diagnosis should be excluded in the presence of both conditions. Neurologic Cases of untreated multiple sclerosis in association with autoimmune hepatitis as well as other autoimmune conditions have been reported [8 6– 88 ] . Whether this represents a true association versus chance association is unclear. In addition, treat- ment with interferon b can trigger development of autoimmune hepatitis. Cutaneous A number of skin manifestations have been reported in association with autoim- mune hepatitis, including pemphigus vulgaris, morphea, lichen planus, pityriasis lichenoides chronic, discoid lupus, alopecia, nail dystrophy and vitiligo [ 36, 89– 92 ] . Those are uncommon and may also be part of a polyglandular syndrome. Renal Cases of membranous nephropathy [6 7, 93 ] , cryoglobulinemic glomerulonephritis [ 94 ] , and focal glomerulonephritis [9 5 ] have been described and are extremely rare. Conclusion To appropriately manage patients with autoimmune hepatitis, the treating physician must understand the challenges consequent upon the chronic use of immunomodu- lators. As adherence is extremely important to treatment success, recognizing and managing side effects that may otherwise lead to medication intolerance is essen- tial. Likewise, a variety of concurrent autoimmune diseases can be seen in associa- tion with autoimmune hepatitis and a high index of suspicion

is needed. 11 Treatment Side Effects and Associated Autoimmune Diseases 211 Chapter Summary 1. Drug toxicity may lead to dose reduction or early discontinuation of therapy. Prednisone and azathioprine are currently the mainstay of treatment for autoimmune hepatitis, but a variety of drugs are available for use as alter- native therapies. This includes cyclosporine, tacrolimus, mycophenolate, and budesonide (latter only when cirrhosis about). 2. Many concurrent autoimmune conditions can be associated with autoim- mune hepatitis and can affect any organ system. 3. Associated autoimmune conditions are particularly common in females and elderly patients, with thyroid disease and arthritis being the two most common concurrent diseases. Useful Tips for Practitioners 1. Tailoring treatment according to individual patients’ conditions will help minimize development adverse events. For instance, patients with osteoporosis, brittle diabetes, acne, emotional instability, obesity, hypertension, postmeno- pausal or elderly are poor candidates for prednisone monotherapy and would benefi t from combination therapy with azathioprine. On the other hand, patients with cytopenias at baseline may not tolerate treatment with azathioprine at all. 2. Reviewing the side effects profi le of each drug with the patient prior to initiating treatment will increase compliance with therapy. 3. Clinicians must have a low threshold to investigate and diagnose associated autoimmune conditions. 4. Patients with autoimmune hepatitis and multiple endocrine syndromes should be evaluated for autoimmune polyglandular syndromes and testing for genetic mutations of the AIRE gene may be helpful in that scenario. 5. Patients with autoimmune hepatitis and concomitant infl ammatory bowel disease, especially in the pediatric population, should be evaluated for primary sclerosing cholangitis. Common Pitfalls in Practice 1. Not monitoring for signs of toxicity, which should be done with routine cell counts in the case of azathioprine, and periodic eye exams and annual bone densitometry tests for those on long-term steroid therapy. 2. Not supplementing patients on long-term steroid therapy with calcium and vitamin D. 3. Delaying referral for liver transplant evaluation due to experimenting with alternative therapies for too long while patients continue to deteriorate clinically. 4. Vaccinating for Hepatitis B prior to starting stands. 212 C. Levy References 1. Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010;51:2193–213. 2. Czaja AJ, Davis GL, Ludwig J, et al. Complete resolution of infl ammatory activity following corticosteroid treatment of HBsAg-negative chronic active hepatitis. Hepatology. 1984;4:622–7. 3. Sandborn W, Sutherland L, Pearson D, et al. Azathioprine or 6-mercaptopurine for inducing remission of Crohn’s disease. Cochrane Database Syst Rev 2000:CD000545 4. Hindorf U, Jahed K, Bergquist A, et al. Characterisation and utility of thiopurine methyltrans- ferase and thiopurine metabolite measurements in autoimmune hepatitis. J Hepatol. 2010;52:106–11. 5. Lamers CB, Griffi oen G, van Hogezand RA, et al. Azathioprine: an update on clinical effi cacy and safety in infl ammatory bowel disease. Scand J Gastroenterol Suppl. 1999;230:111–5. 6 . Obermayer-Straub P, Strassburg CP, Manns MP. Autoimmune hepatitis. J Hepatol. 2000;32:181–97. 7. Domenech E, Nos P, Papo M, et al. 6-mercaptopurine in patients with infl ammatory bowel disease and previous digestive intolerance of azathioprine. Scand J Gastroenterol. 2005;40:52–5. 8. Lees CW, Maan AK, Hansoti B, et al. Tolerability and safety of mercaptopurine in azathio- prine-intolerant patients with infl ammatory bowel disease. Aliment Pharmacol Ther. 2008;27:220–7. 9. 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J Gastroenterol Hepatol. 2001;16:356–9. 94. Evans JT, Shepard MM, Oates JC, et al. Rituximab-responsive cryoglobulinemic glomerulo- nephritis in a patient with autoimmune hepatitis. J Clin Gastroenterol. 2008;42:862–3. 95. Cuesta B, Fernandez J, Pardo J, et al. Evan’s syndrome, chronic active hepatitis and focal glomerulonephritis in IgA defi ciency. Acta Haematol. 1986;75:1–5. Chapter 12 Managing the Patient with Features of Overlapping Autoimmune Liver Disease Kirsten Muri Boberg Keywords Autoimmune hepatitis • Autoimmune liver diseases • Corticosteroids • Overlap syndromes • Primary biliary cirrhosis • Primary sclerosing cholangitis • Ursodeoxycholic acid Introduction For most patients within the spectrum of autoimmune liver diseases (i.e., autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC)), the classifi cation into one of the primary disorders is not diffi cult and patients can be treated accordingly. Patients with classical AIH should receive immunosuppres- sive therapy according to guidelines [1 , 2 ] . Ursodeoxycholic acid (UDCA) is recom- mended for patients with PBC [3 – 5 ] . In PSC, no effective medical therapy has been documented, but UDCA may also be used to some extent in this cholestatic condition [ 5 ] . Clinical experience indicates that some patients present with a combination of hepatitic and cholestatic features. These patients may be diffi cult to classify, or they fulfi ll the diagnostic criteria of one disorder but have additional features of another. Such conditions are commonly designated “overlap syndromes” [6 – 13 ] . Among these, PBC–AIH- and PSC–AIH “overlap syndromes” are most frequently described. There are no internationally agreed criteria for the diagnosis of “overlap syndromes,” and several defi nitions have been used in the various reports. Since there currently is no known etiopathogenetic basis for the distinction of overlaps from the classical disorders, it is questionable whether overlap conditions should be considered separate diagnostic entities [1 4 ] . Nevertheless, the management of patients with overlapping features of autoimmune liver disease may require special attention. Due to the lack of K. M. Boberg (*) Oslo University Hospital, Rikshospitalet, Box 4950 Nydalen, 0424 Oslo, Norway e-mail: kirsten.boberg@rikshospitalet.no G.M. Hirschfi eld and E.J. Heathcote (eds.), Autoimmune Hepatitis: A Guide for Practicing 217 Clinicians, Clinical Gastroenterology, DOI 10.1007/978-1-60761-569-9_12, © Springer Science+Business Media, LLC 2012 218 K.M. Boberg standardization of diagnostic criteria and the heterogeneity of patients as well as the low prevalence of these overlap conditions, randomized, controlled therapeutic trials have been impossible to perform. Treatment of PBC–AIH- and PSC–AIH overlap patients therefore is not evidence-based, but empirical and based (perhaps incorrectly) on experience in the primary conditions. Characteristics of PBC PBC is a chronic, cholestatic liver disease that is characterized by non-suppurative destruction of small intrahepatic bile ducts [3 , 4, 15, 16 ] . The disease process leads to progressive scarring and ductopenia and eventually to the development of cirrhosis. PBC is usually slowly progressive over decades, but the rate of progression varies con- siderably among patients [4 ] . Approximately 95% of patients are female, typically in the age range 30–65 years at presentation [1 5 ] . More than half are asymptomatic at diagno- sis of PBC. Fatigue and pruritus are the most frequently reported complaints in symp- tomatic cases. Biochemical tests typically reveal a cholestatic pattern with elevated serum alkaline phosphatase (ALP)- and gamma-glutamyl transpeptidase (GGT) levels [ 15 ] . Serum aminotransferase activities are normal or slightly elevated (<5× upper limit of normal (ULN)). Serum bilirubin concentration becomes elevated in later stages and is then a good marker of prognosis [3 ] . A positive antimitochondrial antibody (AMA) test is the serological hallmark of PBC and is found in 90–95% of patients [3 , 4, 16, 17 ] . AMA has a high specifi city (98%) for this disease. Antinuclear antibodies (ANA) and anti-smooth muscle antibodies (SMA) are present in nearly half of patients with PBC [1 6 ] . The ANAs anti-GP210 and anti-SP100 are highly specifi c for PBC [1 8 ] . Among immunoglobulins, in particular the IgM fraction is elevated [3 , 19 ] . The diagnosis of PBC can be made in a patient with otherwise unexplained biochemical evidence of cholestasis (mainly based on elevated ALP levels) in com- bination with the presence of AMA (³ 1:40) by immunofl uorescence and/or AMA type M2 [ 4, 5 ] . In this situation a liver biopsy is not required for the diagnosis, but it can add information on disease activity and stage [5 ] . In the absence of PBC- specifi c antibodies, a liver biopsy is necessary for the diagnosis. Characteristic fi nd- ings include non-suppurative destructive cholangitis and destruction of interlobular bile ducts [4 ] . A liver biopsy should also be considered in those patients with par- ticularly high serum levels of aminotransferases and/or serum IgG levels to assess potential histologic features of AIH that might have implications for therapy [ 5 ] . Lymphocytic hepatocellular piecemeal necrosis is seen in a proportion of patients with PBC [2 0– 22 ]. The 5–10% of PBC patients who are AMA-negative appear to have a disease that otherwise is identical to the AMA-positive cases [1 6 ] . Positive AMA titres, generally low and considered non-specifi c, have been reported in AIH patients [ 22, 23 ] . Even anti-M2 which is considered specifi c for PBC, has been detected in AIH [ 22] . Serum markers of cholestasis like elevated ALP levels, may also be present [2 4] . Some degree of biliary involvement may be part of the histological picture in AIH, but this is not associated with AMA [ 25 ] or other features of PBC [2 6] . AIH can be differentiated from PBC in the majority of cases. 12 Managing the Patient with Features of Overlapping Autoimmune Liver Disease 219 Characteristics of PSC PSC is a chronic, cholestatic liver disease with infl ammation and fi brosis affecting both intra- and extrahepatic bile ducts [2 7 ] . The disease process results in irregulari- ties and stricturing of the bile ducts. It is a disorder which progresses to cirrhosis and liver failure, although the clinical course varies considerably among patients. As opposed to AIH and PBC, there is a male preponderance in PSC with a male to female ratio of 2:1 in most populations. Patients are often young, with a median age at diagnosis between 30 and 40 years [2 8, 29 ] . Approximately half of the patients present with symptoms of the liver disease, most commonly fatigue, pruritus, jaun- dice, and right upper abdominal pain [2 8 ] . PSC patients characteristically have biochemical signs of cholestasis. ALP levels are typically at least three times ULN at diagnosis, but levels may fl uctuate and even be normal during the disease course. GGT levels are also regularly increased. Serum aminotransferase levels are often moderately elevated (typically two to three times ULN). Serum bilirubin concentra- tion is normal at diagnosis in up to 70% of patients [2 7, 28 ] , but usually increases or fl uctuates with disease progression. Both serum IgG- and IgM levels may be increased in PSC patients (in up to 61% and 45%, respectively) [2 7, 30 ] . Serum autoantibodies are also frequently detected, including ANA (8–77%), SMA (0–83%), and perinu- clear anti-neutrophil cytoplasmic antibodies (pANCA) (26–94%) [3 1 ] . Liver histo- logical changes in early-stage PSC may be very subtle, but typically consist of lymphocyte infi ltration in the portal tracts and biliary epithelium, along with ductu- lar proliferation. In later stages, bridging fi brous septa develop, while bile ducts degenerate and disappear [3 2 ] . Concentric periductal fi brosis is suggestive of PSC, but is not a regular fi nding. The histologic fi ndings in PSC are not pathognomonic and can only support the diagnosis. A variable degree of interface hepatitis may also be part of the picture and will sometimes make AIH an additional diagnostic possibility. The diagnosis of large duct PSC is confi rmed by MR cholangiography showing bile duct mural irregularities and diffusely distributed multiple strictures and dilata- tions [ 33 ] . Both intra- and extrahepatic bile ducts are affected in the majority of cases. Being non-invasive, magnetic resonance cholangiography (MRC) is recommended as the initial cholangiographic procedure [5 ] . Endoscopic retrograde cholangiography (ERC) may be necessary in equivocal cases or when therapeutic endoscopic proce- dures are anticipated. Small duct PSC (features of PSC confi ned to the small bile ducts) is diagnosed in patients who present with clinical, biochemical, and histologic features compatible with PSC, but who have a normal cholangiogram [ 34] . PSC is associated with infl ammatory bowel disease (IBD) in up to about 80% of cases. Overlapping Autoimmune Disorders Although AIH, PBC, and PSC all have some characteristic features, patients within each of these disorders can present with a spectrum of clinical, biochemical, sero- logical, and histological fi ndings. Practically all of these fi ndings may overlap with 220 K.M. Boberg those of one of the other disorders, and the boundaries between the

classical conditions are therefore not always distinct. Among 225 patients with autoimmune liver disease (162 type 1 AIH, 37 PBC, 26 PSC), variant forms were described in as many as 18% [3 5 ] . Overlapping features between two conditions most frequently present concomitantly, but sequential development of characteristics of two diseases has also been observed [3 6– 43 ] . There are several potential explanations for the concurrence of characteristics of two disorders: (1) Two independent diseases present in a susceptible individual, (2) “Overlap syndromes” represent distinct diagnostic entities, to be differentiated from classical AIH, PBC, or PSC, (3) There is a continuum of manifestations ranging from a “pure” hepatitic to a “pure” cholestatic disorder, with overlaps represented in the middle of the spectrum, (4) There is one primary disorder that due to heterogeneity also displays characteristics of another. The latter concept has gained most support [9 , 44, 45 ] . It is currently unknown whether there are genes or other shared pathogenetic factors that predispose to over- lapping features between AIH, PBC, and PSC [4 6 ] . In clinical practice, efforts should always be made to defi ne the primary disease and ensure that there are no external factors (e.g., medications) which may be responsible for the fi ndings suggestive of an “overlap syndrome.” Patient populations as well as criteria for classifi cation of subgroups of patients into overlap syndromes often differ among studies, resulting in variable fi ndings of prevalence and characteristics [2 2 ] . Patients with Overlapping Features Between PBC and AIH The largest series describing patients with overlapping features between AIH and PBC have used defi nitions essentially based on either (1) a combination of diagnos- tic criteria of each disease [3 7, 47, 48 ] or (2) the application of the International Autoimmune Hepatitis Group (IAIHG) scoring system for the diagnosis of AIH [ 49, 50 ] or modifi cations thereof to patients with a known diagnosis of PBC [1 4, 21, 35, 51– 54 ] . Yet, other variations of criteria have also been used [5 5– 58 ] . The rele- vance and utility of any of these criteria have been widely discussed [1 2, 44, 45, 59 ] . A major concern regarding the extensive use of the IAIHG scoring system to select cases of both PBC–AIH- and PSC–AIH overlap, is that this system was developed to have a high specifi city for the diagnosis of AIH rather than to look for similarities between conditions [5 9 ] . Chazouilleres et al. [3 7 ] defi ned PBC–AIH “overlap syndromes” strictly by the presence of at least two of three criteria of each disease (Table 1 2.1 ) and found that 12 (9.2%) among 130 PBC patients satisfi ed these criteria. Applying the same set of criteria to a group of 331 PBC patients included in a clinical trial, Joshi et al. [4 7 ] concluded that the prevalence of patients who also had features of AIH was 4.8%. Using a modifi ed original IAIHG scoring system [4 9 ] , Czaja et al. [3 5 ] found that 7 (19%) among 26 PBC patients also satisfi ed criteria of AIH. Corresponding results were reported by Talwalkar et al. [2 1 ] , with 26 (19%) among 137 PBC patients scoring as “probable” AIH according to the revised IAIHG scoring system [ 50 ] . 12 Managing the Patient with Features of Overlapping Autoimmune Liver Disease 221 Table 12.1 Diagnostic criteria of PBC–AIH “overlap syndrome” [3 7 ] PBC criteria • Serum ALP levels at least two times ULN or serum GGT levels at least fi ve times ULN • A positive test for AMA • A liver biopsy specimen showing fl orid bile duct lesions AIH criteria • Serum ALT levels at least fi ve times ULN • Serum IgG levels at least two times ULN or a positive test for SMA • A liver biopsy showing moderate or severe periportal or periseptal lymphocytic piecemeal necrosis PBC–AIH “overlap syndrome” is considered present when at least two of three criteria for both PBC and AIH are met, either simultaneously or consequtively. EASL guidelines in addition state that histologic evidence of moderate to severe lymphocytic piecemeal necrosis (interfase hepatitis) is mandatory for the diagnosis [5 ] . It should be noted that the relevance of using rather strict crite- ria can be discussed [5 9 ] Application of the revised scoring system to a group of 138 PBC patients from different geographical regions resulted in identifi cation of 7 (9%) overlap cases [1 4 ] . Even lower fi gures for the prevalence of PBC–AIH overlap by use of the revised scoring system have, however, also been reported [5 1, 53 ] . In an Italian group of patients with a diagnosis of PBC, the occurrence of PBC–AIH overlap was only 3 (2.1%) among 142 cases [5 3 ] . Among 800 Swedish PBC patients, 25 (3%) were classifi ed as overlaps [5 1 ] . Overall, the prevalence of PBC–AIH overlap con- ditions varies in part due to the criteria applied for features of AIH, and the number ranges from 2 to 19% of patients with an original diagnosis of PBC. The frequency of overlaps appears to be lower among patients with an original diagnosis of AIH [ 59 ] . Only 8 (5%) among 162 AIH type 1 patients in the study by Czaja et al. [ 35 ] could be classifi ed as an AIH–PBC variant. It should be noted that AMA positivity occasionally is observed in patients who otherwise fulfi ll the diagnostic criteria of AIH, but then usually in low titres and considered non-specifi c [ 22, 23 ] . Patients with Overlapping Features Between PSC and AIH A variable proportion of patients with cholangiographically confi rmed large duct PSC also have certain features which resemble AIH. They may have somewhat higher than expected levels of serum aminotransferases and/or immunoglobulins, positive autoantibody titres, and/or histological interface hepatitis. In most reports, PSC–AIH overlap has been defi ned according to the original or revised IAIHG scoring system for the diagnosis of AIH [1 4, 30, 35, 43, 53, 54, 60, 61 ] . By applying the original IAIHG scoring system, Boberg et al. [3 0 ] found that 2 (2%) of 114 PSC patients scored as “defi nite” AIH and 38 (33%) as “probable” AIH. By redefi ning patients according to the revised criteria, 2 (2%) still scored as “defi nite” AIH, whereas the number of “probable” AIH was reduced to 10 (9%) [5 0 ] . Kaya et al. 222 K.M. Boberg [6 0 ] reported similar results in a study of 211 PSC patients who according to the original scoring system scored as “defi nite” AIH in 2% of cases and “probable” in 19%, whereas the revised system reduced the proportion with scores in the probable range to 6%. These observations illustrate that the prevalence of overlap cases in any cohort of patients is highly sensitive to the criteria applied. Using the revised IAIHG scoring system, but requiring scores of “defi nite” AIH along with positive titres of autoantibodies and histological features of AIH, Floreani et al. [6 1 ] still found as many as 7 (17%) PSC–AIH overlaps among 41 PSC patients. In an inter- national panel of 221 patients with PSC, 32 (14%) scored as AIH (4 “defi nite” and 28 “probable” cases) [1 4 ] . Among the largest series of PSC patients, 7–14% of cases score for features of AIH. In a few cases considered PSC–AIH overlap, the diagnosis of AIH precedes that of PSC, often by several years [ 36, 43, 61 ] . The possibility of PSC must be consid- ered in patients classifi ed as AIH but presenting with one or more features typical of PSC, including cholestatic liver tests, histological evidence of bile duct injury, con- comitant IBD, and poor response to therapy. A sequential development of AIH in cases of PSC may also occur [4 1, 43 ] . Cases of overlapping AIH and small duct PSC have been described [6 2 ] . PSC in childhood is more commonly associated with features of AIH than is the case in adults [ 63– 66 ] . PSC was as prevalent as AIH in a study of 55 consecu- tive children presenting with evidence of liver disease and circulating autoanti- bodies [ 65 ] . Treatment of Patients with Overlap PBC–AIH Immunosuppression markedly improves prognosis in patients with classical AIH [1 , 2 ]. Patients who have the typical serum antibody markers and histological fi ndings of AIH, but in combination with a cholestatic biochemical pattern or positive AMA, should also be treated as AIH unless the liver biopsy suggests PBC [ 67 ] . UDCA is the treatment of choice in classical PBC [5 ] . There might be a benefi t of corticoster- oids in PBC [6 8– 70 ] , but there are considerable concerns regarding side effects [ 67 ] . Recommendations on treatment of patients with PBC–AIH overlap are based on the experience in treatment of the two primary disorders and on case reports and retrospective small patient series of PBC–AIH overlap conditions. Studies Indicating a Positive Response of PBC–AIH Overlap Conditions to a Combination of UDCA and Immunosuppressants Several studies support a combination of UDCA and immunosuppressants. Among 11 patients with PBC–AIH overlap defi ned by the presence of at least two of three biochemical, serological, and histological criteria of each disease (Table 1 2.1 ), fi ve 12 Managing the Patient with Features of Overlapping Autoimmune Liver Disease 223 patients were initially treated with UDCA alone (13–15 mg/kg/d) and six with prednisolone alone (0.5 mg/kg/d, tapered when remission was obtained with ALT levels below twice ULN) [3 7 ] . After UDCA therapy for median 23 months, levels of ALP and GGT, but not ALT and IgG, decreased signifi cantly. Two patients obtained normalization of ALP and ALT levels. Pruritus and jaundice disappeared in two of three patients who suffered from these symptoms. Liver fi brosis increased in three patients. Corticosteroid treatment with a duration of median 4 months resulted in a signifi cant decrease in ALP, ALT, and IgG levels, but without normal- ization in any patient. The only symptomatic patient became asymptomatic. The total of nine patients who had persistently abnormal biochemical tests after therapy with either UDCA or prednisolone, were subsequently treated with a combination of these drugs (additional azathioprine in 5) for median 18 months. All patients then became asymptomatic and obtained near normalization of biochemical parameters. The authors concluded that a combination of UDCA and corticosteroids is required in most cases of overlap PBC–AIH to obtain complete clinical and biochemical response. Corticosteroids could, however, be suspended in two patients, and it was emphasized that some patients may remain in remission with UDCA alone. In a subsequent report from these authors, they described the long-term follow-up (median 7.5 years) of 17 patients with PBC–UDCA overlap, identifi ed by the same criteria as in the previous study [7 1] . Eleven patients received initial therapy with UDCA alone, and six were given a combination of UDCA and immunosuppressants. Immunosuppressive therapy consisted of predniso(lo)ne 0.5 mg/kg/d, tapered when ALT levels were decreased by more than 50%, with addition of azathioprine or mycophenolate mofetil in most cases. Three of the UDCA-treated patients were con- sidered responders, with complete biochemical response in terms of AIH features (ALT <2 times ULN and IgG <16 g/l) and decreased or stable fi brosis. The remaining eight patients were non-responders with increased fi brosis in four. Seven UDCA non-responders were subsequently treated with a combination of UDCA and immu- nosuppressants. After follow-up for median 3 years, six among these obtained a com- plete biochemical response. Among those who underwent a liver biopsy, fi brosis was unchanged or decreased. Among the six patients receiving combined therapy from start, four achieved complete biochemical response, and fi brosis did not progress. Overall, fi brosis progression in non-cirrhotic patients occurred more frequently under UDCA monotherapy (4/8) than under combined therapy (0/6) (P = 0.04). Several important observations were thus made in this study: (1) Biochemical response occurred in only a minority of UDCA-treated patients, whereas

it was the rule in those receiving combined therapy, (2) Non-responders to UDCA monotherapy responded to combined therapy, and progression of liver fi brosis was signifi cantly more frequent in patients who received UDCA than in those given combined therapy, (3) Of note, there was a strong association between complete biochemical response of the AIH component and absence of progression of fi brosis. The authors concluded that a combination of UDCA and immunosuppressive therapy is able to induce bio- chemical response and to stop the progression of fi brosis in nearly all patients with strictly defi ned PBC–AIH “overlap syndrome” and that combined therapy appears to be superior to UDCA monotherapy [7 1 ] . 224 K.M. Boberg In another study, 9 (75%) among 12 patients with features of PBC and AIH entered remission on a conventional corticosteroid regimen, a response that was comparable to that in patients with defi nite AIH with a similar follow-up [3 5 ] . The PBC–AIH patients progressed to cirrhosis less frequently than the AIH cases. Response to corticosteroids was associated with serum ALP levels less than twice ULN before treatment start. It was concluded that corticosteroids can be effective therapy in patients with features of both PBC and AIH. In a study including 20 cases of a PBC–AIH overlap condition, 16 were treated with UDCA and steroids, and eight of these received additional azathioprine [5 5 ] . Transaminase levels fell below twice ULN in all 16 patients. In 14 among the 16 cases, both AST and ALT normalized. ALP levels normalized in the majority of patients and stayed above 1.5 times ULN in only three cases. The data supported the practice to treat PBC–AIH overlap patients with a combination of UDCA and immunosuppressants. It was underscored, however, that therapy should be individ- ualized with more hepatitic features being a stronger indication for additional immunosuppression. In a case report on PBC–AIH overlap, cirrhosis was appar- ently even reversed on a combined treatment of UDCA and prednisone [7 2 ] . Combined therapy with UDCA and steroids in 15 PBC–AIH overlap cases was also associated with biochemical response in 77% of cases in a recent report [7 3 ] . The term PBC–AIH “overlap syndrome” is most commonly used to denote patients with a simultaneous occurrence of features of PBC and AIH, but consecutive presentation of these disorders has also been observed. In a review of 282 PBC patients, 5 (1.8%) patients had an initial diagnosis of AIH and developed typical PBC during follow-up, and 12 (4.3%) typical PBC patients developed AIH while on UDCA therapy [4 2 ] . In the latter group, the diagnosis of AIH was made from 6 months to 13 years after diagnosis of PBC. Ten patients were initially treated with prednisone 0.5 mg/kg/d, with maintenance therapy consisting of prednisone 10–15 mg/d ± azathioprine 1.5 mg/kg/d. Sustained remission was obtained in eight patients, whereas two had multiple relapses following short-term remission and died 7 and 8 years after diagnosis of AIH. Two patients with remission under UDCA therapy did not receive steroids. Partial or complete remission of AIH during UDCA therapy has been observed by others [7 4, 75 ] and could be used as an argument to avoid corticosteroids in patients with PBC–AIH overlap. Based on their overall experience in the above study, however, the authors concluded that it seems justifi ed to give conventional AIH therapy to PBC patients with fl are-ups of aminotrans- ferase levels if they also fulfi ll the criteria of AIH [ 42 ] . Some data suggest that budesonide is a promising alternative to conventional immunosuppression to induce remission in AIH, and this drug has also been success- fully used in a few patients with PBC–AIH overlap [7 6 ] . On the other hand, the addition of budesonide to UDCA for 1 year in 22 PBC patients with an incomplete response to UDCA therapy did not result in any obvious benefi cial effect, but was associated with a signifi cant progression of osteoporosis [7 7 ] . PBC–AIH overlap patients without satisfactory response to UDCA and corticosteroids have in a few cases been treated with cyclosporine A and obtained a benefi cial effect [4 8, 78 ] . 12 Managing the Patient with Features of Overlapping Autoimmune Liver Disease 225 Studies Indicating that UDCA Alone is Suffi cient Therapy in PBC–AIH Overlap Conditions A few reports have indicated that response to UDCA therapy is similar in PBC patients with and without features of AIH. Biochemical response after 2 years of UDCA treatment and survival after 7 years of follow-up did not differ signifi cantly in a comparison of 12 patients with PBC–AIH overlap with 159 patients with PBC treated for the same period [ 47 ] . Comparable response to UDCA in PBC–AIH over- lap and PBC patients was also recorded in a study including 20 patients with PBC– AIH overlap (16 treated with UDCA and four with UDCA plus prednisolone) and 23 PBC patients (all treated with UDCA) [ 58 ] . It was suggested that UDCA is the fi rst-line treatment, but that non-responders to UDCA may benefi t from a combina- tion of UDCA with prednisolone. Impact of PBC–AIH Overlap on Prognosis In a comparison of the clinical course of 26 patients with features of PBC–AIH overlap with that of 109 patients with PBC alone during 5–6 years, an association of PBC–AIH overlap with a higher risk of portal hypertension and progression to death and/or liver transplantation was suggested [7 9 ] . Only a limited number of patients overall had received treatment with UDCA. Some patients in either group had also been treated with other drugs. The authors concluded that a worse progno- sis in PBC–AIH overlap could justify the risk of immunosuppressive therapy, but that a large, randomized study would be required to establish this strategy. In a study of liver biopsies from PBC patients before and after 4 years of treat- ment with UDCA, the severity of lymphocytic hepatocyte piecemeal necrosis and lobular infl ammation in the fi rst biopsy was signifi cantly associated with progression of fi brosis, giving support to the contention that features of AIH in PBC patients have a negative impact on prognosis [2 0 ] . The study further sug- gested that UDCA improves the bile duct destruction, but not the process leading to piecemeal necrosis and lobular infl ammation which thus may need additional therapy. The severity of lymphocytic piecemeal necrosis proved to be an inde- pendent predictor of prognosis in UDCA-treated PBC patients also in another report [8 0 ] . Among ten patients with PBC–AIH, eight were given immunosuppressive ther- apy and two were started on UDCA [ 57 ] . 3/8 in the fi rst group subsequently received additional UDCA and 1/2 on UDCA was given additional prednisolone. Compared with a group of 238 AIH patients, the overlap cases were signifi cantly less likely to obtain a complete response to conventional therapy and signifi cantly more likely to be classifi ed as non-responders (25 vs 0.8%; P < 0.05). However, this did not infl u- ence the outcome in terms of survival. 226 K.M. Boberg Recommendations for Therapy in Patients with PBC–AIH Overlap Conditions The lack of standardized diagnostic criteria as well as the absence of randomized, controlled data makes it diffi cult to provide fi rm guidelines for therapy in patients with overlapping features of PBC and AIH, and no clear consensus in optimal therapy for these patients exists [4 ] . It still seems reasonable to consider some patients within this spectrum of disease for a combined therapy with UDCA and corticoster- oids. The recent European Association for the Study of the Liver (EASL) guidelines for the management of cholestatic liver diseases suggest that the diagnostic criteria of PBC–AIH “overlap syndrome” previously proposed by Chazouillères et al. [3 7 ] provide a useful diagnostic template (Table 12.1 ) [ 5 ] . Of note, histologic evidence of moderate to severe lymphocytic piecemeal necrosis (interface hepatitis) is man- datory for the diagnosis [ 5 ] . According to the EASL guidelines, combined therapy with UDCA and corticosteroids should be the recommended therapeutic option in patients with PBC–AIH overlap features. An alternative is to start with UDCA only and add corticosteroids if an adequate biochemical response has not been reached within a reasonable time (3 months) [5 ] . The presence of a PBC–AIH overlap con- dition might be the cause of resistance to UDCA in patients with PBC [5 9 ] . As is the case in AIH, steroid sparing immunosuppressive agents (primarily azathioprine) should be considered in patients requiring long-term immunosuppression. Since corticosteroids are associated with potential deleterious side effects (in particular osteoporosis in cholestatic disorders), it is of paramount importance to be cautious and to treat patients on an individualized basis. It should also be kept in mind that the above criteria only are supplied as guidelines and that the relevance of using rather strict criteria can be discussed [5 9 ] . As previously pointed out, the premise “at least do no harm” should be kept in mind [ 7 ] . Steroid treatment should not be prolonged if a benefi cial effect cannot be documented. One option is to stop steroids after a while and observe the patient under continued therapy with UDCA only. In patients with predominant and pronounced hepatitic features, some clinicians will choose to make an initial therapeutic trial with corticosteroids alone. In end-stage liver disease, liver transplantation is the treatment of choice. Treatment of Patients with Overlap PSC–AIH Currently there is no effective medical therapy available in PSC. UDCA has been used in PSC patients to a certain extent, but a long-term survival benefi t has not been proven [ 81– 88] . Recently, even a higher risk for death or liver transplantation and serious adverse events in UDCA-treated patients compared with a placebo group was reported [ 89] . This study applied a higher UDCA-dose (28–30 mg/kg/d) than previously used, so a direct toxic effect of high-dose UDCA may be a possibility [8 9, 90] . This observation has led to a higher awareness about potential detrimental effects 12 Managing the Patient with Features of Overlapping Autoimmune Liver Disease 227 of UDCA in PSC and warnings against its use [9 1] . No studies have supported a defi nite role of various immunosuppressive agents in PSC [9 2 ] , although favorable effects in some patients have been suggested with [9 3 ] or without [9 4 ] combination with UDCA. Still, it is possible that such drugs can have a positive effect in the subgroup of PSC patients with concurrent features of AIH. As is the case in PBC–AIH overlap conditions, no randomized, controlled therapeutic trials have been performed in patients with overlapping features between PSC and AIH. Treatment therefore is not evidence-based, and therapeutic traditions may vary between centers. Studies of Immunosuppression ± UDCA in Patients with PSC–AIH Overlap Conditions There are several reports on patients with PSC–AIH overlap who have been treated with corticosteroids or a combination of corticosteroids and azathioprine. In an early case report in 1992, a combination of prednisone (40 mg/d, tapered to 10 mg/d) and azathioprine (50 mg/d, increased to 150 mg/d) resulted in signifi cant clinical improvement and near normalization of serum transaminase levels from an initial elevation of about ten times ULN [9 5 ] . In a small series of three patients, all appeared to benefi t from a combination of steroids, azathioprine, and UDCA [9 6 ] . The authors commented that it is important to distinguish PSC–AIH overlap patients from ordi- nary PSC, since immunosuppressive treatment can completely suppress the hepato- cellular infl ammatory component of this condition. A corresponding experience was reported in another fi ve patients who all demonstrated a marked clinical and biochemical response to prednisolone and azathioprine [9 7 ] . Four of these patients had relapses during subsequent reduction or withdrawal of therapy. Histological improvement was also noted in these four cases, except for progression of the biliary lesions. Normalization of biochemical parameters was noted in a case report of a patient with combined hepatitic and cholestatic features and cholangiographic fi ndings consistent with PSC [ 98

] . Among four PSC–AIH patients treated with steroids in another study, partial response was recorded in three cases and deterioration in one [ 60 ] . A positive biochemical response to cyclosporine in a patient with overlap- ping features between PSC and AIH has also been observed [9 9 ] . Impact of PSC–AIH on Prognosis In a study comparing the results of corticosteroid therapy in variant syndromes of autoimmune liver disease, remission was less common in patients with a PSC–AIH overlap condition than in patients with defi nite AIH or overlap PBC–AIH [3 5 ] . Among nine PSC–AIH patients, only two (22%) obtained remission. Overall, results in this subgroup were less favorable. The patients with PSC–AIH overlap died of liver failure or required liver transplantation signifi cantly more frequently than did patients with classical AIH. 228 K.M. Boberg Biochemical response to immunosuppressive therapy was obtained in all of nine patients with overlapping features of PSC and AIH in another study [ 43 ] . Three patients achieved long-term remission, but three needed liver transplantation after 4 months, and 7 and 9 years, respectively. A therapeutic effect of immunosuppres- sion in PSC–AIH overlap conditions inferior to that regularly obtained in classical AIH was supported, and the authors speculated that immunosuppressive treatment does not infl uence the PSC component of the overlap condition. During the course of their disease, six patients also received UDCA therapy with resulting slight bio- chemical improvement in some cases. In a prospective study of seven patients with AIH–PSC overlap syndrome treated with prednisolone (initial dose 0.5 mg/kg/d, tapered to 10–15 mg/d) and azathio- prine (initial dose of 2 mg/kg/d, maintenance dose of 50–75 mg/d) plus UDCA (15–20 mg/kg/d), a signifi cant reduction in serum AST levels was obtained over a 5-year course [6 1 ] . A reduction in ALT levels was also observed, but this was not signifi cant. Serum levels of ALP and GGT did not change signifi cantly. Among the 34 classical PSC patients receiving UDCA therapy only and followed in the same study, no signifi cant changes in biochemical parameters occurred. The Mayo score prognostic index did not change signifi cantly in the overlap cases, in contrast to a signifi cant increase (sign of disease progression) observed in the classical PSC group. Liver transplantation was carried out in 1/7 cases with overlap and 6/34 cases with classical PSC. Cholangiocarcinomas (fi ve cases) and deaths (nine cases) only occurred in the latter group. Notably, the survival among the PSC–AIH overlap cases appeared to be better than that in classical PSC patients. In a comparison of 16 patients with PSC–AIH overlap syndrome with ten PBC– AIH- and 238 AIH patients on similar immunosuppressive therapy, the PSC–AIH cases had a signifi cantly reduced survival (hazard ratio 2.08 and 2.14, respectively), despite the fact that the majority had a good initial response [5 7 ] . In a retrospective study of PSC patients treated with corticosteroids, it was con- cluded that a long-term benefi cial effect on disease progression may be obtained in a subgroup of patients [ 94 ] . The subgroup classifi ed as responders had features similar to patients otherwise denoted PSC–AIH overlap cases. The group was characterized by having signifi cantly higher serum levels of transaminases and bilirubin, but lower ALP levels, at treatment start than non-responders. They also tended to be younger. More patients among responders than non-responders had positive scores for histo- logical features of AIH, although the difference was not statistically signifi cant. Conclusion: Recommendations for Therapy in Patients with PSC–AIH Overlap Conditions Considerations regarding the managing of patients with overlapping features of PSC and AIH are in line with those in PBC–AIH overlap conditions outlined above, except that the role of UDCA is questionable. Recently both EASL [5 ] and American Association for the Study of Liver Diseases (AASLD) [9 1 ] guidelines recommended 12 Managing the Patient with Features of Overlapping Autoimmune Liver Disease 229 the use of immunosuppressive therapy in patients with a PSC–AIH overlap. In the EASL guidelines, UDCA is recommended along with immunosuppressive therapy, whereas the AASLD only recommends corticosteroids and other immunosuppres- sive agents. In our center, we select for such therapy PSC patients who present with markedly increased serum aminotransferase levels (usually at least fi ve times ULN) with or without elevated IgG concentration, in combination with a liver biopsy with clear features of AIH. We usually start with prednisolone 45 mg/d, tapering the dose like in AIH. Azathioprine is added as a steroid sparing agent according to guidelines for AIH. However, treatment is not evidence-based and as in PBC, there are con- cerns about side effects particular skeletal. If normalization of serum aminotrans- ferase levels is not easily obtained, we tend to accept higher levels during follow-up than in AIH. PSC–AIH patients are candidates for liver transplantation in end-stage liver disease. Chapter Summary 1. Randomized, controlled therapeutic trials in patients who present with overlapping features between the autoimmune liver diseases (i.e., PBC– AIH- and PSC–AIH “overlap” conditions) are impossible to conduct due to the lack of standardized diagnostic criteria, patient heterogeneity, and the low prevalence of such cases. Treatment recommendations therefore are not evidence-based. 2. Efforts should always be made to defi ne the primary disorder (PBC, PSC, or AIH), and appropriate treatment should be given accordingly. 3. Addition of immunosuppressive therapy (corticosteroids ± azathioprine) should be considered in patients with overlapping conditions between PBC- or PSC and AIH. Treatment must be individualized, with high atten- tion to potential side effects (in particular osteoporosis). Useful Tips for Practitioners 1. In patients with PBC or PSC and disproportionally elevated serum amin- otransferase activities and/or IgG concentration, a liver biopsy should be considered for assessment of histological features of AIH. 2. The possibility of PSC must be considered in patients classifi ed as AIH but presenting with one or more features typical of PSC (cholestatic liver tests, histological evidence of bile duct injury, concomitant infl ammatory bowel disease, poor response to immunosuppressive therapy). 3. Immunosuppressive therapy in patients with overlapping features between PBC or PSC and AIH should not be prolonged if a benefi cial effect cannot be documented. 4. Liver transplantation is the treatment of choice in patients with end-stage liver disease. 230 K.M. Boberg Common Pitfalls 1. Biopsy interpretation in the absence of clinical correlation can be misleading. 2. Cirrhosis can give changes to the biliary tree on imaging that mimics PSC. 3. 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Chapter 13 Autoimmune Hepatitis: A Look Toward the Future Gideon M. Hirschfi eld Over the last 50–60 years, autoimmune hepatitis as a complex disease has evolved in many ways, most notably for the now excellent outcomes for patients. When thinking about the future of any disease, and its management, it is sometimes help- ful to frame one’s thoughts about what patients are asking in clinic, in particular which questions you as the clinician fi nd hardest to answer. Patients ask many things, but frequent questions I am faced with which I fi nd variably hard to answer defi nitively include: (a) Why did I get this disease? (b) Will it recur if I stop treatment? (c) Why aren’t there more specifi c treatments with fewer side effects? (d) Will my family get this, or another associated autoimmune disease? (e) Are the long-term side effects of treatment worth the risk if I feel so well? (f) If I need a liver transplant will the disease come back? Although imperfect, the knowledge base we presently have does allow us to start to answer these questions. We hope that this textbook has gone some way to consoli- dating these, and other many day-to-day issues, faced by clinicians. We have attempted to cover the biology of the disease and its associated autoantibodies, as well as the clinical presentation in adults and children. Therapies for AIH, albeit apparently simple, require careful thought before initiation. Our authors describe the present varied treatment guidelines, including when to stop and when to con- sider more novel agents. Finally, we touch upon the contentious issue of overlap syndromes, which causes so much angst and confusion for clinicians and patients. G. M. Hirschfi eld (*) Department of Medicine , Toronto Western Hospital, University Health Network, University of Toronto, Ontario, Canada Centre for Liver Research, Institute of Biomedical Research, University of Birmingham, UK e-mail: gideon.hirschfi eld@uhn.on.ca G.M. Hirschfi eld and E.J. Heathcote (eds.), Autoimmune Hepatitis: A Guide for Practicing 235 Clinicians, Clinical Gastroenterology, DOI 10.1007/978-1-60761-569-9_13, © Springer Science+Business Media, LLC 2012 236 G.M. Hirschfi eld Overall, despite this concise but thorough look at this disease, it will be clear to the reader that regardless of our advances, AIH remains enigmatic and without a cure. Managing autoimmune liver disease, in particular AIH, will for the foresee- able future remain a traditional balance of science and art, until such time as we have truly representative descriptions of the disease and its triggers. Varied clinical, laboratory, histologic, and treatment responses suggest that while the disease carries one name, in reality it is likely a collection of many subtypes of disease. Looking to the future, accurate phenotyping of patients seems key to unlocking this substruc- ture, as that approach has the greatest potential to allow investigators to unscramble the triggering etiologies, alongside the individual predisposition and inherent responses to liver injury and its treatment. We will need to move beyond the tradi- tional type 1 and 2 descriptors and provide means of classifying patients with greater precision. Collaborative efforts are essential for such a process to be successful, given the relative rarity of the disease. The tools for such studies already exist and will need to harness both human and animal material. Genomics, whole genome sequencing, proteomics, and metabolomics are all hypothesis-free approaches that may come close to distinguishing the complex genetic, protein, and cellular changes in patients with AIH. Because it is nearly impossible to investigate patients before disease is clinically apparent or identifi ed, mouse models will remain an essential translational tool to test and develop disease hypotheses. Already there are exciting discoveries to suggest that regulation of T cell function may be amiss in AIH, and may be potentially a target for therapy. Alongside this idea are discoveries in the related autoimmune diseases, primary biliary cirrhosis, and primary sclerosing cho- langitis, which are defi ning the genetic architecture of disease predisposition. The goal of twenty-fi rst century medicine remains to provide personalized care that is disease-specifi c, and which maximizes treatment effi cacy while minimizing side effects. With this in mind hopefully this textbook will look very different if written again by the next generation of clinicians in 50 years. Index A oligoclonal T cells and liver-specifi c Adaptive immunity, 33–34 autoantigens, 20 Antiliver cytosol–1 (anti-LC1) antibody viral infections, 17 testing, 81 APS. See Autoimmune polyglandular Antiliver kidney microsomal (anti-LKM) syndromes

(APS) antibody testing Asialoglycoprotein receptor (ASGPR) antimitochondrial antibody (AMA), 79–80 antibody, 84 autoimmune polyendocrinopathy- Asymptomatic AIH, 51 candidiasisectodermal dystrophy Autoantibodies, serological testing, 68 (APECED), 79 antiliver cytosol–1 (anti-LC1) antibody ELISA, 81 testing, 81 microsomal fraction, 79 antiliver kidney microsomal (anti-LKM) target antigens, 80 antibody testing Antimetabolites antimitochondrial antibody (AMA), cyclophosphamide, 153 79–80 6-mercaptopurine, 153 autoimmune polyendocrinopathy- MMF, 152 candidiasisectodermal dystrophy Antimitochondrial antibody (AMA), 79–80 (APECED), 79 Antineutrophil cytoplasmic antibody (ANCA) ELISA, 81 testing, 82 microsomal fraction, 79 Antinuclear antibodies (ANA) testing target antigens, 80 anti-dsDNA antibodies, 76 antineutrophil cytoplasmic antibody autoimmune liver diseases, 74 (ANCA) testing, 82 clinical presentation, 62 antinuclear antibodies (ANA) testing ELISA, 76 anti-dsDNA antibodies, 76 homogenous nuclear pattern, 74, 75 autoimmune liver diseases, 74 Antismooth muscle antibody (anti-SMA) ELISA, 76 testing homogenous nuclear pattern, antiactin, 77 74, 75 ELISA, 78 anti-SLA antibodies, 70 vascular smooth muscle (VSM), 77 antismooth muscle antibody testing Antisoluble liver antigen antibody (anti-SLA) antiactin, 77 testing, 82–83 ELISA, 78 Apoptosis vascular smooth muscle (VSM), 77 class I HLA, 10 antisoluble liver antigen antibody Fas, 15 (anti-SLA) testing, 82–83 G.M. Hirschfi eld and E.J. Heathcote (eds.), Autoimmune Hepatitis: A Guide for Practicing 237 Clinicians, Clinical Gastroenterology, DOI 10.1007/978-1-60761-569-9, © Springer Science+Business Media, LLC 2012 238 Index Autoantibodies, serological testing (cont.) C asialoglycoprotein receptor (ASGPR) Calcineurin inhibitors, 140–141 antibody, 84 cyclosporine, 155–156 HEp–2 cells, 72 tacrolimus, 154–155 practical considerations, 71, 72 Celiac disease, 212–213 SMA testing, 77–78 Cellular immunity titers, 73 g (Gamma)/d (Delta)T cells, 21 Autoimmune diseases, associated immunoregulation, pivotal role, 21–22 cutaneous, 214 macrophages, 21 endocrine, 209–210 oligoclonal T cells and liver-specifi c frequency, 207 autoantigens, 19–21 gastrointestinal, 212–213 Treg defi ciencies, 22–23 hematologic, 213–214 Treg function restoration, 23 neurologic, 214 Chemoattractant cytokines, 33 renal, 214 Childhood AIH. See Pediatric treatment, AIH rheumatic, 210–212 Chronic AIH, 53–55 risk factors, 207–208 Chronic liver disease, 162–164 types, 208–209 Cirrhosis, 187–188 Autoimmune hemolytic anemia, 213 Clinical presentation, AIH Autoimmune liver diseases acute AIH, 52–53 characteristics age primary biliary cirrhosis (PBC), 222 ANA, 62 primary sclerosing cholangitis (PSC), 223 clinical and HLA fi ndings, 60, 61 overlapping autoimmune disorders, 223–224 gender, 63 overlapping features chronic AIH, 53–55 PBC vs. AIH, 223–224 diagnosis, 53 PSC vs. AIH, 225–226 ethnicity treatment, overlap PBC–AIH African Americans/Blacks, 58–59 prognosis, 229 North American indigenous peoples, 60 therapy recommendations, 230 South America, 59–60 UDCA alone, 229 South Asia, 60–61 UDCA and immunosuppressants, South East Asians, 61 226–228 fulminant AIH, 55–56 treatment, overlap PSC–AIH immunosuppressive therapy (IST), 51 prognosis, 231–232 overlap therapy recommendations, 232–233 primary biliary cirrhosis (PBC), 58 UDCA and immunosuppressants, 231 sclerosing cholangitis, 57 ursodeoxycholic acid (UDCA), 221 postliver transplantation, recurrence, 56–57 Autoimmune polyendocrinopathy- Corticosteroids, 191–192 candidiasisectodermal dystrophy Costimulation, 35 (APECED), 79 CTLA–4, 14–15 Autoimmune polyglandular syndromes (APS), Cutaneous diseases, 214 209–210 Cyclophosphamide, 153 Autoimmune sclerosing cholangitis. S ee Cyclosporine, 155–156 Sclerosing cholangitis Cytochrome P450 (CYP) Azathioprine (AZA) AIH, 95 pregnancy, 190–191 alcohol-induced liver disease, 101–102 side effects, 204–205 autoimmune polyendocrine syndrome type 1 (APECED), 97–98 cellular autoimmunity, 104 B drug-induced hepatitis, 99–100 b (beta) blockers, 193 exogenous and endogenous compounds, Breast feeding, 193 94–95 Budesonide, 128, 153–154, 206 hepatitis C virus infection, 98 Index 239 molecular mimicry, 102–103 South America, 59–60 nomenclature, 94 South Asia, 60–61 three-dimensional structure, 96 South East Asians, 61 UDP-Glucuronosyltransferases, 96 Cytokines, 15 Cytolysis, 29 F Cytomegalovirus (CMV), 17 Fas, 15 Cytotoxic T lymphocytes (CTLs), 36 Fetal health complication, 184 loss, 189 D maternal antibody profi le effects, 189 Damage-associated molecular patterns Fibrogenesis, 30 (DAMPs), 32 Fluorescent ANA (F-ANA). S ee Antinuclear Defl azacort, 154 antibodies (ANA) testing De novo AIH, liver transplantation, 173–174 Food and Drug administration (FDA) Drug induced and immune mediated liver categories, 190, 191 disease Fulminant AIH, 55–56 with autoantibodies, 106 liver transplantation, 165–166 Cytochrome P450 (CYP) treatment, 117–118 AIH, 95 alcohol-induced liver disease, 101–102 autoimmune polyendocrine syndrome G type 1 (APECED), 97–98 Gastrointestinal diseases cellular autoimmunity, 104 celiac disease, 212–213 drug-induced hepatitis, 99–100 IBD, 212 exogenous and endogenous Genetic susceptibility, 26 compounds, 94–95 Glucocorticoids, 202 hepatitis C virus infection, 98 Glutathione-S-transferase T1 (GSST1), 173 molecular mimicry, 102–103 nomenclature, 94 three-dimensional structure, 96 H UDP-Glucuronosyltransferases, 96 HCC. See Hepatocellular carcinoma (HCC) LKM–1 antibodies detection, 93, 94 Hematologic diseases uridine diphosphate autoimmune hemolytic anemia, 213 5’-glucuronosyltransferases idiopathic thrombocytopenic purpura, 213 AIH, 106 pernicious anemia, 213–214 hepatitis D virus infection, 105–106 Hepatitis mammalian UGT1 gene superfamily, 105 C virus infection, 98 Drug toxicity, 93. See also Drug induced and drug-induced, 99–100 immune mediated liver disease D virus infection, 105–106 Hepatocellular carcinoma (HCC), 164–165 Hepatocyte E autoantigens, 27 Ebstein Barr virus (EBV), 17 cytolysis regulation, 29 ELISA Hepatopulmonary syndrome, 166 ANA testing, 76 Hepatotropic viruses, 93. S ee also Drug induced anti-LKM antibody testing, 81 and immune mediated liver disease anti-SMA testing, 78 HEp–2 cells, 72 Endocrine diseases Herpes simplex virus (HSV), 17 autoimmune thyroiditis, 209 Histocompatibility leukocyte antigen (HLA) diabetes mellitus, 209–210 class I, 10 Ethnicity, AIH clinical presentation class II, 10–11 African Americans/Blacks, 58–59 class III, 14 North American indigenous peoples, 60 T cell receptors, 34 240 Index Humoral immunity antimetabolites, 153 autoantibodies Type I and Type 2 AIH, side effects, 204–205 24–25 MMF. S ee Mycophenolate mofetil (MMF) B cells and antibodies, 23–24 Model for end-stage liver disease (MELD), Hyperglobulinemia, 2 163–164 Hypothesis-free approaches, AIH, 240 Mumps virus, 17 Mycophenolate mofetil, 206 Mycophenolate mofetil (MMF), 127–128 I antimetabolites, 152 IBD. See Infl ammatory bowel disease (IBD) pregnancy, 192 Idiopathic thrombocytopenic purpura, 213 Immune-mediated liver disease, 1 Immunofl uorescence ANA (IF-ANA). S ee N Antinuclear antibodies (ANA) Natural killer (NK) cells, 33 testing Natural killer T (NKT) cells, 33 Immunosuppressants, 226–228 Necrosis, 27, 28 Immunosuppressive therapy (IST), 51 Neurologic diseases, 214 Infl ammatory bowel disease (IBD), 212 Non-HLA genes Infl iximab, 157–158 autoimmune regulator 1, 15–16 Innate immunity, 31 CTLA–4, 14–15 In vitro fertilisation (IVF), 195 cytokines, 15 Fas, 15 vitamin D receptor, 15 L Nonresponders treatment Liver failure, 1 alternative therapies Liver transplantation quality, 150 contraindications, 166–167 side effects, 150, 151 de novo AIH, 173–174 antimetabolites, 152–153 GSST1, 173 calcineurin inhibitors hepatopulmonary syndrome, 166 cyclosporine, 155–156 indications tacrolimus, 154–155 chronic liver disease, 162–164 immunosuppressive medications timeline, fulminant AIH, 165–166 149, 150 HCC, 164–165 infl iximab, 157–158 MELD, 163–164 side effects outcomes, 167 AZA/6-MP, 204–205 porto-pulmonary hypertension, 166 budesonide, 206 post-transplant, 166–167 cyclosporine A, 205 rAIH glucocorticoids, 202 diagnosis criteria, 170, 171 mycophenolate mofetil, 206 factors, 170–172 prednisone/prednisolone, 202–204 management and outcomes, 172–173 rituximab, 297 published series, 167–169 steroids, 202, 203 vs. rejection, 170, 171 tacrolimus, 206 treatment, 125 tioguanine nucleotides, 207 LKM–1 antibodies detection, 93, 94 steroid alternatives budesonide, 153–154 defl azacort, 154 M UDCA, 156–157 Macrophages, 21 Mammalian UGT1 gene superfamily, 105 MELD. See Model for end-stage liver disease O (MELD) Overlap syndromes. S ee Autoimmune liver 6-Mercaptopurine (6-MP), 128 diseases Index 241 P pattern recognition receptors (PRRs), 32 Pathogen associated molecular patterns proinfl ammatory and immunosuppressive (PAMPs), 32 cytokines, 32 Pathogenesis, AIH regulatory dendritic cells, 39 adaptive immunity, 33–34 T and B effector cell responses generation, 38 AIH vs. classical autoimmune diseases T cell receptors and HLA class I, II, and III vs. immunemediated infl ammatory molecules, 34 diseases, 4, 5 Th17 cells and immunoregulation, 39–40 alternatives, 41–42 T regulatory cells, 39 B cell activation and functions, 37–38 type 2, 13–14 CD8 T cells, 36–37 type I, 11–13 cellular immunity viral infections, 17–18 g (Gamma)/d (Delta)T cells, 21 working model immunoregulation, pivotal role, 21–22 autoantibodies production, 28 macrophages, 21 autoreactive t cells and b cells oligoclonal T cells and liver-specifi c activation, 28 autoantigens, 19–21 effector cells and cytokines evolution, Treg defi ciencies, 22–23 29–30 Treg function restoration, 23 environmental triggers and permissive class I HLA, 10 hepatic microenvironment, 27 class II HLA, 10–11 fi brogenesis, 30 class III HLA, 14 genetic susceptibility, 26 costimulation, 35 hepatocyte autoantigens/molecular damage-associated molecular patterns mimics, 27 (DAMPs), 32 hepatocyte cytolysis regulation, 29 drugs and xenobiotics as triggers, 18 immunopathology intensifi cation, 29 dynamic family, CD4 T cells, 35–36 immunoregulation failure, 28–29 environmental factors, 16 permissive immune repertoire g (Gamma)/d (Delta)T cells, 37 evolution, 26–27 gender, 16 Pattern recognition receptors (PRRs), 32 genetic factors, 8–9 Pediatric treatment, AIH hepatic fi brosis and cirrhosis, 25–26 future treatment options, 143 histopathology, 18–19 juvenile form, 137–138 humoral immunity liver transplantation, 142–143 autoantibodies Type I and Type 2 AIH, sclerosing cholangitis, 138 24–25 treatment B cells and antibodies, 23–24 autoimmune sclerosing cholangitis immune repertoire and natural T regulatory (ASC), 141–142 cells selection, 34–35 calcineurin inhibitors, 140–141 immune responses, 31 rapidity and response, 139 immunoregulation, immune responses, 38 refractory cases, 141 innate immunity, 31 remission and relapse, 139 interactive factors, 6 standard, 140 liver, organ of adaptive immunity, 40–41 treatment and prognosis, duration, 142 NK cells, 33 Pernicious anemia, 213–214 NKT cells, 33 Polymyositis, 211–212 non-HLA Genes Porto-pulmonary hypertension, 166 autoimmune regulator 1, 15–16 Postliver transplantation, recurrence, 56–57 CTLA–4, 14–15 Prednisolone, 202–204 cytokines, 15 Pregnancy Fas, 15 abnormalities, 190 vitamin D receptor, 15 AST activity, 184 pathogen associated molecular patterns birth weights, 190 (PAMPs), 32 breast feeding, 193 242 Index Pregnancy (cont.) published series, 167–169 cirrhosis, 187–188 vs. rejection, 170, 171 complications, 182, 183 Regulatory dendritic cells, 39 contraception, 194–195 Remission and relapse, AIH, 139 drug safety Rheumatic diseases azathioprine, 190–191 arthritis/synovitis, 210 b (beta) blockers, 193 polymyositis, 211–212 corticosteroids, 191–192 RA, 211 MMF, 192 Sjogren’s syndrome, 210–211 tacrolimus, 192 SLE, 211–212 exacerbation, AIH, 184–186 SS, 211 FDA categories, 190, 191 Rheumatoid arthritis (RA), 211 fertility, 193–194 Rituximab, 128–129 fetal outcomes Rubella virus, 17 complication, 184 loss, 189 maternal antibody profi le effects, 189 S fl ares, 184, 185 Sclerosing cholangitis impacts, 182, 184 overlap, AIH, 57 index presentation, 185–186 pediatric treatment, 138 IVF, 195 Serological testing, autoantibodies. S ee management algorithm Autoantibodies, serological testing AIH with cirrhosis, 187, 188 Sjogren’s syndrome, 210–211 AIH without cirrhosis, 185, 186 SLE. See Systemic lupus erythematosus (SLE) maternal complication, 184 SS. See Systemic sclerosis (SS) prematurity, 189 Systemic lupus erythematosus (SLE), Primary biliary cirrhosis (PBC), 2 211–212 vs. AIH, 223–224 Systemic sclerosis (SS), 211 characteristics, 222 overlap, AIH, 58 treatment, AIH overlap T prognosis, 229 Tacrolimus, 127, 154–155 therapy recommendations, 230 pregnancy, 192 UDCA alone, 229 side effects, 206 UDCA and immunosuppressants, 6-Thioguanine nucleotides, 128 226–228 Tioguanine nucleotides (6-TG), 207 Primary sclerosing cholangitis (PSC), 2, 212 Treatment, AIH vs. AIH, 225–226 absolute indications, 116 characteristics, 223 conventional treatment schedules, 118–119 treatment, AIH overlap drug therapies prognosis, 231–232 budesonide, 128 therapy recommendations, 232–233 cyclosporine A, 127 UDCA and immunosuppressants, 231 6-mercaptopurine (6-MP), 128 Proinfl ammatory and immunosuppressive mycophenolate mofetil (MMF), 127–128 cytokines, 32 rituximab, 128–129 tacrolimus, 127 6-thioguanine nucleotides, 128 R ursodeoxycholic acid, 129 RA. See Rheumatoid arthritis (RA) end points, 119–120 Reactive oxygen species, 25 fulminant AIH, 117–118 Recurrent AIH (rAIH) liver transplantation, 125 diagnosis criteria, 170, 171 no indication, 117 factors, 170–172 outcomes, 121 management and outcomes, 172–173 relapse after drug withdrawal, 123–124 Index 243 relative/uncertain indications, 116–117 hepatitis D virus infection, 105–106 screening, 124–125 mammalian UGT1 gene supserfamily, suboptimal responses, 121–123 105 symptoms, 117 Ursodeoxycholic acid (UDCA), 129, T regulatory cells (Treg), 39 156–157, 221 defi ciencies, 22–23 function restoration, 23 V Vitamin D receptor, 15 U Uridine diphosphate 5’-glucuronosyltransferases X AIH, 106 Xenobiotics, 18

Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocID=1&StartDoc=1&En. DELMAR'S PEDIATRIC NURSING CARE PLANS - 3rd Ed. (2005) FRONT MATTER TITLE PAGE DELMAR'S PEDIATRIC NURSING CARE PLANS THIRD EDITION KARLA L. LUXNER, RNC, ND Australia Canada Mexico Singapore Spain United Kingdom United States COPYRIGHT PAGE Delmar's Pediatric Nursing Care Plans, 3rd Edition by Karla L. Luxner Vice President, Health Care Business Unit: William Brottmiller Editorial Director: Cathy L. Esperti Acquisitions Editors: Matthew Filimonov, Melissa Martin Senior Developmental Editor: Elisabeth F. Williams Marketing Director: Jennifer McAvey Marketing Coordinator: Kip Summerlin Editorial Assistant: Patricia Osborn Technology Director: Laurie K. Davis Art and Design Coordinators: Connie Lundberg-Watkins, Alex Vasilakos Production Coordinator: Bridget Lulay 1 of 13 12/22/2006 7:13 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocID=1&StartDoc=1&En. Project Editor: Jennifer Luck COPYRIGHT © 2005 by Thomson Delmar Learning, a part of the Thomson Corporation. Thomson, the Star logo, and Delmar Learning are trademarks used herein under license. Printed in the United States of America 1 2 3 4 5 6 7 XXX 08 07 06 05 04 For more information, contact Thomson Delmar Learning, 5 Maxwell Drive, Clifton Park, NY 12065-2919 Or you can visit our Internet site at http://www.delmarlearning.com ALL RIGHTS RESERVED. No part of this work covered by the copyright hereon may be reproduced or used in any form or by any means—graphic, electronic, or mechanical, including photocopying, recording, taping, Web distribution or information storage and retrieval systems—without the written permission of the publisher. For permission to use material from this text or product, contact us by Tel (800) 730-2214 Fax (800) 730-2215 http://www.thomsonrights.com Library of Congress Cataloging-in- Publication Data Luxner, Karla L. Delmar's pediatric nursing care plans. — 3rd ed. / Karla L. Luxner p.; cm. Rev. ed. of: Pediatric nursing care plans / Marie Jaffe. 2nd ed. c1998. Includes bibliographical references and index. ISBN 0-7668-5994-0 (alk. paper) 1. Pediatric nursing. 2. Nursing care plans. [DNLM: 1. nursing diagnosis. 2. Patient Care Planning—Child. 3. Patient Care Planning—Infant. WY 100.4 L977d 2005] I. Title: Pediatric nursing care plans. II. Jaffe, Marie S. Pediatric nursing care plans. III. Title. RJ245.L89 2005 610.73´62—dc21 2003048936 Notice to the Reader Publisher does not warrant or guarantee any of the products described herein or perform any independent analysis in connection with any of the 2 of 13 12/22/2006 7:13 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocID=1&StartDoc=1&En. product information contained herein. Publisher does not assume, and expressly disclaims, any obligation to obtain and include information other than that provided to it by the manufacturer. The reader is expressly warned to consider and adopt all safety precautions that might be indicated by the activities described herein and to avoid all potential hazards. By following the instructions contained herein, the reader willingly assumes all risks in connection with such instructions. The publisher makes no representations or warranties of any kind, including but not limited to, the warranties of fitness for particular purpose or merchantability, nor are any such representations implied with respect to the material set forth herein, and the publisher takes no responsibility with respect to such material. The publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or part, from the readers' use of, or reliance upon, this material. CONTENTS PREFACE vii AN INTRODUCTION TO THE USE OF THE NURSING CARE PLANS ix UNIT 1 GROWTH AND DEVELOPMENT OF CHILDREN 1 1.0 Growth and Development 2 1.1 Basic Care Plan: Well Child 8 1.2 Hospitalized Child 12 1.3 Child Abuse 18 1.4 Dying Child 23 UNIT 2 CARDIOVASCULAR SYSTEM 29 2.0 Cardiovascular System: Basic Care Plan 30 2.1 Cardiac Catheterization 35 2.2 Congenital Heart Disease 39 2.3 Congestive Heart Failure 45 2.4 Cardiac Dysrhythmias 50 2.5 Hypertension 53 2.6 Kawasaki Disease 57 2.7 Acute Rheumatic Fever 61 UNIT 3 RESPIRATORY SYSTEM 65 3.0 Respiratory System: Basic Care Plan 66 3.1 Apnea 73 3.2 Asthma 77 3.3 Bronchiolitis 84 3.4 Bronchopulmonary Dysplasia 89 3.5 Cystic Fibrosis 95 3.6 Epiglottitis 103 3 of 13 12/22/2006 7:13 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocID=1&StartDoc=1&En. 3.7 Croup 107 3.8 Otitis Media 111 3.9 Pneumonia 115 3.10 Tonsillitis 119 3.11 Tracheostomy 123 3.12 Tuberculosis 129 3.13 Allergic Rhinitis 132 UNIT 4 GASTROINTESTINAL SYSTEM 135 4.0 Gastrointestinal System: Basic Care Plan 136 4.1 Appendicitis 145 4.2 Cleft Lip/Palate 150 4.3 Gastroenteritis 155 4.4 Gastroesophageal Reflux Disease (GERD) 158 4.5 Hepatitis 162 4.6 Hernia 166 4.7 Inflammatory Bowel Disease 170 4.8 Intussusception 175 4.9 Pyloric Stenosis 178 UNIT 5 GENITOURINARY SYSTEM 181 5.0 Genitourinary System: Basic Care Plan 182 5.1 Chronic Renal Failure 186 5.2 Glomerulonephritis 192 5.3 Hypospadius/Epispadias 197 5.4 Nephrotic Syndrome 202 5.5 Sexually Transmitted Diseases 207 5.6 Cryptorchidism 210 5.7 Urinary Tract Infection 213 5.8 Vesicoureteral Reflux 217 5.9 Wilms' Tumor 223 UNIT 6 MUSCULOSKELETAL SYSTEM 229 6.0 Musculoskeletal System: Basic Care Plan 230 6.1 Fractures 233 6.2 Congenital Hip Dysplasia 238 6.3 Lupus Erythematosus 242 6.4 Legg-Calve-Perthes Disease 248 6.5 Osteogenic Sarcoma 251 6.6 Osteomyelitis 256 6.7 Juvenile Rheumatoid Arthritis 262 6.8 Scoliosis 268 6.9 Talipes 272 4 of 13 12/22/2006 7:13 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocID=1&StartDoc=1&En. UNIT 7 NEUROLOGIC SYSTEM 275 7.0 Neurologic System: Basic Care Plan 276 7.1 Hydrocephalus 281 7.2 Brain Tumor 287 7.3 Guillain-Barre Syndrome 292 7.4 Meningitis 297 7.5 Sensory Deficits 302 7.6 Reye's Syndrome 307 7.7 Seizures 311 7.8 Spina Bifida 316 UNIT 8 HEMATOLOGIC SYSTEM 325 8.0 Hematologic Growth and Development 326 8.1 HIV/AIDS 327 8.2 Anemia 333 8.3 Hemophilia 340 8.4 ITP 345 8.5 Leukemia and Lymphoma 348 UNIT 9 ENDOCRINE SYSTEM 357 9.0 Endocrine Growth and Development 358 9.1 Insulin-Dependent Diabetes Mellitus 359 9.2 Hypothyroidism 365 UNIT 10 INTEGUMENTARY SYSTEM 369 10.0 Integumentary System: Basic Care Plan 370 10.1 Burns 373 10.2 Cellulitis 378 10.3 Dermatitis 380 BIBLIOGRAPHY 383 APPENDIX ABBREVIATIONS 396 PREFACE Health promotion, restoration, and disease prevention in children require the care and attention of parents and family as well as health care providers. Children are not simply small adults, but have their own unique physiologic, psychological, and cognitive processes at each stage of development. Pediatric nurses work with parents and families in the community as well as acute care settings to protect and enhance the well-being of infants and children so they may reach their full potential. Awareness and respect for cultural variation is essential to modern nursing as is sound 5 of 13 12/22/2006 7:13 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocID=1&StartDoc=1&En. scientific knowledge providing the framework for evidence-based practice. CONCEPTUAL APPROACH The nursing process serves as a learning tool for readers and as a practice and documentation format for clinicians. Based on a thorough assessment, the nurse formulates a specific care plan for each individual client. The care plans in this book are provided to facilitate that process for readers and practitioners. To that end, each care plan solicits specific client data and prompts the nurse to individualize the interventions, consider cultural relevance, and evaluate the client's individual response. The book provides basic nursing care plans for common diagnoses related to each body system followed by care plans and flow charts for specific illnesses commonly encountered in the pediatric population. ORGANIZATION Delmar's Pediatric Nursing Care Plans, 3rd edition, includes care plans that have been developed to reflect comprehensive pediatric nursing care based on the most common psychosocial and physiologic alterations. Because care is based on solid application of principles of growth and development, and respect and appreciation of the parents and family as partners in the care of their children, the book opens with an overview of growth and development of children. Subsequent chapters offer an overview of each body system, covering basic and diseasespecific care plans. The diagnoses are cross-referenced, and the practitioner is encouraged to add, subtract, delete, and otherwise adapt the diagnoses to provide individualized care for a specific client. Nursing care begins with a comprehensive review and assessment of each individual client. The data are then analyzed and a specific plan of care developed. Interventions for each diagnosis must again be individualized for each client. The format for each nursing care plan in this book is summarized below. • Nursing diagnoses as approved by the North American Nursing Diagnosis Association (NANDA) taxonomy (2003-2004). • Related factors (etiology) for each diagnosis are suggested and the user is prompted to choose the most appropriate for the specific client. • Defining characteristics for each actual diagnosis are listed with prompts to the user to include specific client data from the nursing assessment. • Goals are related to the nursing diagnosis and include a time frame for evaluation to be specified by the user. • Appropriate outcome criteria specific for the client are suggested. In keeping with current practice, this edition includes a Nursing Outcome Classification (NOC) label for each nursing diagnosis. • Nursing interventions and rationales are comprehensive. They include pertinent continuous assessments and observations. Common therapeutic actions originating from nursing and those resulting from collaboration with the primary caregiver are suggested with prompts for creativity and individualization. Client and family teaching and psychosocial support are provided with respect for cultural variation and individual needs. Consultation and referral to other caregivers is suggested when indicated. • Nursing Intervention Classification (NIC) labels are provided in this new edition for each nursing diagnosis. These are inserted after the interventions and rationales to assist the user in becoming familiar with this classification process for nursing interventions. • Evaluation of the client's goal and presentation of data related to the outcome criteria is followed by consideration of the next step for the client. A new, descriptive introductory chapter outlines how to customize care plans for an individual client based on the standardized care plans found in 6 of 13 12/22/2006 7:13 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocID=1&StartDoc=1&En. this book. ACKNOWLEDGMENTS I am grateful to editors for their encouragement and support, and to my students, nurse colleagues, and the many infants, children, and parents who have enriched my understanding of pediatrics. This book is dedicated to my own children: Sam, Julie, John, Mary, and Rebecca, who provided me with first-hand experience and many excellent stories about infants and children. Karla L. Luxner REVIEWERS Kathy Pearson, RN, BSN, MSN, CS Instructor of Nursing Temple College Temple, Texas Annette Gibson, BSN, MEd, MSN Instructor of Nursing Miami Dade Community College Miami, Florida Vera V. Cull, RN, DSN Assistant Professor University of Alabama at Birmingham School of Nursing Birmingham, Alabama AN INTRODUCTION TO THE USE OF THE NURSING CARE PLANS INTRODUCTION Excellent nursing practice reflects proficient use of the nursing process demonstrated by skillful assessment, diagnosis, planning, outcome identification, intervention, and evaluation. The nursing process provides the framework that directs nursing practice. Nursing care planning is the application of the nursing process to a specific client situation. Written nursing care plans are a means of communication among health care providers, clients, and families. They ensure that care is coordinated to achieve desired health care outcomes. A thorough assessment is the foundation of the nursing process. The assessment data are then reviewed and organized according to client needs. Nursing diagnoses, derived from the assessment, provide the basis for selection of interventions to achieve outcomes for which the nurse is accountable (NANDA, 2003). "Now, as never before, today's nurse must make more complex professional decisions, determine what things to do and what things not to do for which clients. Priorities are critical: often the nurse must make hard choices between what is essential and what is merely beneficial" (Barnum, 1999). The primary purpose of the nursing diagnostic processes applied by nurses is to design a plan of care for and in conjunction with the client that results in the prevention, reduction, or resolution of the client's health problem (Harkreader, 2004). In the current multidisciplinary health care environment, nurses are positioned for a high level of accountability. The nurse is required to make many independent decisions and to coordinate the various disciplines working together and sharing responsibility for client outcome achievement. This environment affords nursing an opportunity to define its boundaries and to use the nursing process to coordinate care across disciplines. Nurses need to develop strong assessment skills, organize the data obtained to prioritize client needs, predict achievable, measurable client outcomes,

and tailor interventions for the individual client. This text is designed to assist the user in that process. NURSING CARE PLANS AND INDIVIDUAL CLIENT CARE NEEDS This book is intended to facilitate the care planning process for nurses working with pediatric clients based on recognized nursing standards. Each of the nursing diagnoses is from NANDA's Taxonomy II (NANDA, 2003). The outcome criteria include the appropriate Nursing Outcome Classification 7 of 13 12/22/2006 7:13 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocID=1&StartDoc=1&En. (NOC) as well as prompts to assist the user in developing individualized outcomes. This text also contains suggested Nursing Intervention Classifications (NIC) for each nursing diagnosis in addition to suggested comprehensive and individualized interventions for each diagnosis. Each section begins with essential introductory information about the condition and the current medical management when appropriate. A thorough assessment of the client is essential to developing a plan of care. The user is prompted to insert specific client data into the care plan at strategic points in each diagnosis. The user is offered a variety of common and additional nursing diagnoses for each condition including: 1. The etiology (related to) for each diagnosis using specific client data obtained in the assessment. 2. Possible defining characteristics, with prompts for individualization, which support the diagnosis. 3. A client goal related to the nursing diagnosis with a prompt to identify an appropriate time frame for evaluation of the outcomes. 4. Measurable outcome criteria requiring the use of specific client data and individualized parameters. 5. Comprehensive and detailed nursing interventions with guidance to individualize care for the specific client. 6. Rationales for the nursing interventions to demonstrate evidence-based practice. 7. Evaluation based on individual client information. The user is prompted to evaluate goal achievement and present the specific client data called for in the outcome criteria. The nursing care plans provided in this text are intended to serve as a framework on which to design individualized client care reflecting current nursing standards of care. The user must first obtain comprehensive, reliable, and detailed assessment information for the particular client using all available sources. The initial assessment data should then be interpreted and organized into categories reflecting prioritized client needs. Frequently, after reflecting on the initial assessment, the nurse will find that additional focused assessment data must be obtained before care can be planned. Appropriate nursing diagnoses are then selected and prioritized. Individual client data are the defining characteristics that support the choice of nursing diagnosis. A specific goal and the necessary outcome criteria that will be used to identify when the goal has been met should be based on the defining characteristics. Outcome criteria reflect the individual client's capabilities and expectations. The nurse then selects a comprehensive array of interventions to provide current evidence-based client care directed toward the outcomes and resolution of the problem. Interventions should also be prioritized and may include additional ongoing assessments, therapeutic nursing activities, collaborative interventions, client and family teaching, and referrals. Current standards of care for pediatric nursing practice have been incorporated throughout the text. Every effort has been made to prompt the user to insert individual client data and to specify the parameters of care as the care plan is developed. Thoughtful use of this text will guide the user to develop comprehensive individualized care plans based on current scientific knowledge and evidence for best practices. The process for planning individualized care involves the same steps as the nursing process. 1. Collect assessment data from all available sources including the client, the family, other providers, and the chart. Chart data may include: nurse's notes or flow sheets; laboratory, diagnostic, or surgical reports; progress notes from dietary, rehab, or physical therapy; the physician's history and physical, and progress notes. Assess the client's current status through the interview, observation, and physical examination. After studying the health record and obtaining assessment data, organize the information into prioritized problem or client need categories. 2. Identify viable nursing diagnoses and potential client risks suggested by the categories of assessment data. Review the appropriate chapter in this text and review the nursing diagnoses provided for the condition. Choose the diagnoses that fit the specific client. The diagnostic process is individualized by identifying "related to" factors and "defining characteristics" that flow from the comprehensive client assessment. For example, 8 of 13 12/22/2006 7:13 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocID=1&StartDoc=1&En. "Acute pain related to surgical incision" is supported by the client data, "verbalizes pain at a 9 on a scale of 0-10." The client's own words and pain rating support the diagnosis and guide the nurse to choose an outcome criteria of "verbalizes pain as less than 9 on a scale of 1-10" and interventions that must include assessment of pain using a scale of 1-10. 3. Plan to identify and meet client goals using specific outcomes as evidence. The goal pertains to the diagnosis and moves the client toward resolution of the problem within a reasonable time frame. The outcome criteria included in the text indicate options to measure goal attainment and encourage specific qualifiers such as when, how much, and individual client variables to be added to individualize the plan. "Client will experience decreased pain within 24 hours" is a clear goal with an achievable target time. "Verbalizes pain as 5 or less on a scale of 1-10" would be a measurable outcome that, if based on the particular client situation and capabilities, individualizes the plan and indicates goal attainment. 4. Design interventions to meet the goal and resolve the nursing diagnosis. Choose interventions pertinent to the client that are consistent with the medical orders. Ongoing assessment of the client's pain perception, positioning, teaching the client to ask for medication before pain becomes severe, and the administration of pain medications, specifying the drug, dose, route, and times as ordered, are examples of both independent and collaborative nursing interventions, which would achieve the outcome, attain the goal, and resolve the "Acute Pain" diagnosis. 5. Evaluate the effectiveness of the plan. By setting a client goal and specific observable outcomes, the plan communicates the need for ongoing evaluation and updating. Evaluation of the outcome criteria at the specified time will either indicate resolution of the problem or the need to continue or revise the care plan. CRITICAL THINKING, THE NURSING PROCESS, AND CARE PLAN DEVELOPMENT Critical thinking and decision-making skills are used to identify nursing diagnoses. Critical thinking entails purposeful, goal-directed thinking and analysis of information. The nurse uses critical thinking to make clinical judgments based on evidence. The nurse synthesizes the information collected in the assessment and then makes judgments about how to put the information together to form nursing diagnoses. The format of this book encourages the nurse to review the client history and obtain thorough assessment data that are significant for a particular condition. The nurse is then prompted to insert relevant assessment findings as appropriate to formulate an individualized nursing care plan. The following case study illustrates how to apply individual client data to a care plan in this book. PEDIATRIC ASTHMA CASE STUDY A 14-year-old African-American female is brought to the pediatrician's office by her mother. She has just started running on her high school track team, but has been complaining to her mother that her running "feels different this year." When she ran in middle school she could race longer distances without becoming winded. She now says her "chest burns" and she is running fewer miles before she has to stop to catch her breath. Her girlfriend told her she could hear her wheezing and she should go to the nurse. The school nurse confirmed her wheezing and notified her mother to come pick her up from school. There is no history of asthma in the family but her parents both smoke cigarettes. The school nurse advised that cigarettes could be contributing to the child's respiratory complaints. At the pediatrician's office her peak flow is 380 L/min, which is within 5% of her predicted value for her height and weight. She does complain of coughing at night. Her lung sounds are now clear with no wheezing noted. Her ECG and heart sounds appear normal. She has no significant past medical history except for occasional ear infections. Immunizations are up-to-date, she is allergic to penicillin, and she denies smoking or drug use. The family nurse practitioner (FNP) discusses the possibility of exercise-induced asthma with the client and her mother. She directs the client to measure her peak flow before running and if she experiences symptoms to stop running and again measure her peak flow. She is to repeat these measurements five times, five minutes apart, and return to the office with her records. The FNP writes a note to the track coach and school nurse outlining the procedure. On one week follow-up peak flow pattern shows recovery after 30 minutes but her peak flow diminishes to 70% -85% of 9 of 13 12/22/2006 7:13 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocID=1&StartDoc=1&En. her estimated level. The FNP prescribes Albuterol, 2 puffs MDI, 15 minutes before exercise. The FNP reviews the peak flow guidelines with the mother and client and directs her to keep a daily record for two weeks and to return for reassessment. Three months later the client awoke in the middle of the night coughing and experiencing shortness of breath. She was suffering from a cold and her parents had a holiday party that evening with the house filled with cigarette smoke. She checked her peak flow and found she was in the yellow zone. She used her Albuterol inhaler and woke her mother. Her peak flow was repeated for her mother and was now in the red zone. She self-administered more Albuterol and her mother took her to the emergency room where she was given a nebulizer treatment, oxygen, and steroids. Her peak flow remained at 200 L/min and she was admitted to the pediatric unit with acute asthma. Her vital signs were: temperature 99°F, heart rate 124, respiratory rate 34 breaths per minute and shallow with expiratory wheezing. Her O2 saturation was 88%. She was placed on O2 at 4L/min. Upon admission the client's mother indicated awareness of the need for change by stating, "We have to do something to prevent this." NURSING DIAGNOSIS #1 Ineffective Airway Clearance Related to: Bronchospasm and increased pulmonary secretions. Defining Characteristics: Shallow respirations with expiratory wheeze, respiratory rate 34, SaO2 88%, peak flow 200L/min after medications. Goal: Client will maintain a clear airway throughout admission. Outcome Criteria: √ Respiratory rate less than 24, lungs clear to auscultation, SaO2 greater than 95%. NOC: Respiratory Status: Ventilation INTERVENTIONS Assess respirations for rate (count one full minute), pattern depth, and ease, auscultate lung sounds, and note use of accessory muscles and retractions q 4 h. Assess for cough, characteristics of cough and sputum q 4 h. Administer humidified oxygen at 4 L/min via nasal canula per physician's order. Monitor O2 saturation continuously reporting saturation that remains less than 93% to the physician. Assess skin for pallor or cyanosis every 4 hours, note distribution or duration of cyanosis (nail beds, skin, mucous membranes, circumoral). Position with head elevated at least 30° or seated upright with head on pillows; position on side if more comfortable; avoid tight clothing or bedding; use pillows and/or padding as needed to maintain positioning. Demonstrate and instruct to parents and child possible positions for comfort and ventilation during activities and sleep. Teach parents and child correct disposal of tissues; appropriate covering of mouth and nose when coughing to avoid respiratory infections. Pace activities and exercises and allow for rest periods and energy conservation. Instruct child in relaxation exercises, quiet play, and controlled 10 of 13 12/22/2006 7:13 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocID=1&StartDoc=1&En. breathing. Teach and demonstrate use of oxygen saturation monitor to parents (application, settings, alarm, electric source). NIC: Airway Management NURSING DIAGNOSIS #2 Health Seeking Behaviors: Prevention of Asthma Attack Related to: Expressed desire for information about preventive measures for child's asthma. Defining Characteristics: Mother states, "we have to do something to prevent this". Goal: Client and family will obtain information about asthma prevention during hospitalization. Outcome Criteria: √ Parents and child verbalize understanding of triggering agents and prevention measures for

asthma attacks. NOC: Health-Promoting Behavior INTERVENTIONS Assess for knowledge of factors related to attacks, past history of respiratory infections, and measures taken to maintain health of child. Assess health history of allergies in family members, what does or does not precipitate attack, and what behaviors result from the attack. Teach parents and child handwashing technique; allow for demonstration. Teach child to avoid contact with those who have respiratory infections, how to cover mouth and nose when coughing or sneezing, and to dispose of tissues properly. Discuss with parents/child about physiology and signs and symptoms of the disease and possible precipitating factors influencing an attack. Discuss with parents and child the signs and symptoms indicating the onset of an attack (change in respirations, wheezing, dyspnea). Teach parents of the effect of cigarette smoke and allergens, and how to avoid exposure to offending environmental factors (cold air, humidity, air pollution, sprays, plants). Assist parents to identify ways to change the home environment to reduce smoke, dust, exposure to pets, and indoor plants, changing of filters, avoidance of foods (yellow dye), and drugs (aspirin). Teach the child breathing exercises and controlled breathing and relaxation techniques. 11 of 13 12/22/2006 7:13 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocID=1&StartDoc=1&En. INTERVENTIONS Teach parent and child about medication administration as ordered at discharge (specify drug, dose route, and times to be given) and how to manage method of administration. Advise to avoid over-the-counter drugs without physician advice. Refer to community health department for additional information and adolescent asthma support group. NIC: Health Education CLINICAL PATHWAYS: A METHOD OF ACHIEVING OUTCOMES ACROSS THE CONTINUUM OF CARE Health care consumers expect affordable care and optimal outcomes. Third-party providers scrutinize client outcomes to validate the need for expensive health care services. Health care organizations report outcomes to state, federal, and independent agencies to verify practice standards and attract consumers and providers. The demand for the most effective and cost-efficient manner of restoring clients to health has led to collaborative responsibility for client care demonstrated by the clinical pathway. Clinical pathways, also known as "care maps," are care management tools that outline the expected clinical course and outcomes for a specific client type (Kelly-Heidenthal, 2003). The manner in which a pathway is constructed is usually agency-specific but typically it follows the client's length of stay on a day-by-day basis for the specific disease process or surgical intervention. Clinical pathways are a clinical tool that organizes, directs, and times the major care activities and interventions of the entire multidisciplinary team for a particular diagnosis or procedure. Their design is intended to minimize delays, maximize appropriate resource utilization, and promote high-quality care. "The clinical pathway describes a blended plan of care constructed by all providers, considering the subject together" (Barnum, 1999). Clinical pathways identify standard client outcomes against which the efficiency of care may be measured. The pathway guides the care team along a sequence of interdisciplinary interventions that incorporate standardized aspects such as client and family teaching, nutrition, medications, activities, diagnostic studies, and treatments. The tool is developed collaboratively by all health team members and includes predictable and established time frames, usually by delineating each hospital day as an event requiring new intervention along a continuum. A care map provides consistency of client care activities. Clinical pathways also, because of their standardization of practice, allow for measuring performance improvement within an agency and between similar agencies over time. Clinical pathways can only guide rather than dictate the course of care for an individual. They do not take into account additional client problems that may affect the client's recovery. Therefore, the process of incorporating clinical pathways is the same as in individualizing care plans. The nurse must include the individualized client needs in conjunction with the standard clinical pathway. When the client's needs vary from the expected outcome time frame, the nurse must reassess, report, and manage the variance to meet the client's needs. The manner of reporting variances is agency-specific. Not all clients' care can be organized into a clinical pathway model. For more complex client care situations an individualized care plan applying the various nursing diagnoses in this text, is more appropriate. Well-designed nursing care plans and/or care maps move the client from one level of care on the health continuum to another. These tools help the nurse to monitor and guide the progress of the client through a particular health condition including preventive and restorative phases and end-of-life care. Care planning organizes and coordinates client care according to relevant standards, promotes consistency and communication between caregivers, and incorporates the problem-solving process which integrates responsiveness to client needs and cost-efficiency. COPYRIGHT © 2005 by Thomson Delmar Learning. All Rights Reserved. Author: 12 of 13 12/22/2006 7:13 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocID=1&StartDoc=1&En. KARLA L. LUXNER, RNC, ND Copyright: COPYRIGHT © 2005 by Thomson Delmar Learning. All Rights Reserved. Database Title: STAT!Ref Online Electronic Medical Library ISBN: 0-7668-5994-0 Publication City: Clifton Park, NY Publication Year: 2005 Publisher: Thomson Delmar Learning Date Posted: 5/5/2006 6:51:38 AM PST (GMT -08:00) Book Title: Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) Date Accessed: 12/21/2006 5:35:57 PM PST (GMT -08:00) Electronic Address: http://online.statref.com/document.aspx?fxid=123&docid=1 Location In Book: DELMAR'S PEDIATRIC NURSING CARE PLANS - 3rd Ed. (2005) FRONT MATTER Send Feedback Teton Server (4.5.0) - ©2006 Teton Data Systems Title Updates Customer Service Send Us Your Comments User Responsibilities 800.901.5494 Training Center What's New 13 of 13 12/22/2006 7:13 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocId=2&FxId=123&Sessio. UNIT 1 - GROWTH AND DEVELOPMENT OF CHILDREN CHAPTER 1.0 - GROWTH AND DEVELOPMENT INTRODUCTION A solid understanding of growth and development is essential for planning and providing nursing care for infants and children. The child's ability to cope with stress, illness, hospitalization, or terminal illness is related to physical, cognitive, and psychosocial growth and development. Nursing care is designed to foster the individual child's growth and support his or her developmental needs. DEVELOPMENTAL THEORIES PSYCHOSOCIAL DEVELOPMENT (ERICKSON) • Trust Versus Mistrust, Infant (birth to 1 year): Characterized by taking in through all the senses; loving care of a mothering person is essential to develop trust; must have basic needs met; attachment to primary caretaker. The favorable outcome is faith and optimism. • Autonomy Versus Shame and Doubt, Toddler (1 to 3 years): Characterized by increasing ability to control bodies, themselves, and their environment; seek independence, negativism, threatened by changes in routine, curious explorer. The favorable outcome is self-control and will power. • Initiative Versus Guilt, Preschool (3 to 6 years): Characterized by enterprise and a strong imagination; develop conscience; feelings of being punished; egocentric, inquisitive, rich fantasy life, and magical thinking. The favorable outcome is direction and purpose. • Industry Versus Inferiority, School-Age (6 to 12 years): Active learners, well-developed language skills and concept of time, concerns about body image, understands concept of death. Enjoy sorting and ordering, making collections, and super heroes. Exhibit cognitive conceit. Can assist with own care and appreciates rewards. Physically graceful and skilled; sports and clubs of same-sex peers are important. The favorable outcome is competence. • Identity Versus Role Confusion, Adolescent (13 to 18 years): Characterized by ability to deal with reality and abstractions, mood swings, changing body image; preoccupied with the way they appear in the eyes of others as compared to their own self-concept. Peers of both same and opposite-sex are very important to identity formation. The favorable outcome is devotion and fidelity to others and to values and ideologists. PSYCHOSEXUAL DEVELOPMENT (FREUD) 1 of 8 12/22/2006 7:14 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocId=2&FxId=123&Sessio. • Oral Stage (birth to 1 year): Characterized by infant-seeking pleasure via oral activities such as biting, sucking, chewing, and vocalizing. • Anal Stage (1 to 3 years): Characterized by interest in the anal region and sphincter muscles (child is able to withhold or expel feces); toilet training is a major milestone (method of parent discipline, may have lasting effects on child's personality development). • Phallic State (3 to 6 years): Characterized by interest and recognition in differences between the sexes and becomes very curious about these differences; often described as interest by females as penis envy and by males as castration anxiety. • Latency period (6 to 12 years): Characterized by gaining increased skill on newly acquired traits and skills; interested in acquiring knowledge and vigorous play. Sexuality lies dormant while energy is focused elsewhere. • Genital stage (12 years and over): Characterized by maturation of the reproductive system and production of sex hormones; genital organs become a source of tension and pleasure; interested in forming friendships and preparation for marriage as an adult. INTERPERSONAL DEVELOPMENT (SULLIVAN) • Infant (0 to 1 year): Receive gratification and comfort from loving, tender care; develops trust and ability to count on others. • Childhood (2 to 5 years): Engage in peer, family, neighborhood activities; need adult participation; learn to delay gratification and accept interference with wishes: gradually seek attention and approval from peers. • Juvenile (5 to 12 years): Engage in socialization, competition, cooperation, and compromise; develop shared interests and genuine friendships with peers of same sex, and later with opposite sex; give more allegiance to peers than to family; promote personal identity COGNITIVE DEVELOPMENT (PIAGET) • Sensorimotor (birth to 2 years): Characterized by progression from reflex activity through simple repetitive behaviors to imitative behaviors; information is gained through the senses and developing motor abilities; develop a sense of "cause and effect"; problem-solving is by trial and error; high level of curiosity, experimentation, and enjoyment in novelty; begin to separate self from others; develop sense of "object permanence"; begin language development. • Preoperational (2 to 7 years): Characterized by egocentrism (inability to put oneself in the place of others); interpret objects and events in terms of their relationships or use of them; cannot see another's point of view; thinking is concrete, tangible; inability to make deductions or generalizations; display high level of imagination and questioning; reasoning is intuitive. • Concrete Operations (7 to 11 years): Characterized by thoughts; become increasingly logical and coherent; able to classify, sort, organize facts, and begin to problem-solve; develop conservation (realize volume, weight, and number remain the same even though outward appearances are changed); solve problems in a concrete, systematic fashion, based on visual perceptions. • Formal Operations (11 to 13 years): Characterized by thoughts which are adaptable and flexible; possess abstract thinking; able to make logical conclusions; able to make hypotheses and test them; can consider abstract, theoretical, philosophical issues. MORAL DEVELOPMENT (KOHLBERG) Based on cognitive development theory and consists of 3 major levels. 2 of 8 12/22/2006 7:14 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocId=2&FxId=123&Sessio. • Preconventional Level (2 to 7 years): Parallels Piaget's preoperational level of cognitive development and intuitive thinking. Characterized by development of: cultural values; sense of right and wrong; integrate things in terms of physical or pleasurable consequences of their actions. Initially, determines goodness or badness in terms of its consequences (attempt to avoid punishment). Later, determines right behavior consists of what satisfies own needs (and sometimes those of others). • Conventional Level (7 to 11 years): Parallels Piaget's stage of concrete operations of cognitive development. Characterized by a concern with conformity and loyalty; value a specific group (i.e., the family, group, or national expectations); behavior that conforms to specific group considered good and earns approval. Values such as fairness, give and take, and sharing interpreted in a practical manner without loyalty, gratitude, or justice. • Postconventional, Autonomous, or Principled Level (11 to 15 years): Parallels Piaget's stage of formal operations. Characterized by tendency/desire to display correct behavior in terms of individual rights and standards; begins to question possibility of changing existing laws/rules in terms of societal needs. SPIRITUAL DEVELOPMENT (FOWLER) Five stages of development of faith; four are closely associated with parallel cognitive (Piaget) and psychosocial (Erickson) development in childhood. • Stage 0, (Undifferentiated): Characterized by infant period of development, in which the infant is unable to determine concept of right or wrong. Development of basic trust lays the foundation for beginning faith. • Stage 1, (Intuitive-projectile): Characterized by toddler period of development, in which the primary behavior is referred to as imitating religious gestures and behaviors of others. Unable to comprehend meaning or

significance of religious practices; begin to assimilate religious values and beliefs held by parents; do not attempt to understand basic concepts of religion. • Stage 2, (Mythical-literal): Characterized by school-age period of development, in which the child's spiritual development parallels cognitive development. Belief that spiritual development is associated with previous experiences and societal interactions. Newly-acquired conscience influences actions (good vs. bad; bad actions create guilt); petitions to an omnipotent being important; able to articulate their faith. • Stage 3, (Synthetic-convention): Characterized by early phase of adolescent period of development, in which become aware of spiritual disappointments (i.e., prayers are not always answered); may begin to abandon or modify previous religious practices and those established by their parents. • Stage 4, (Individuating-reflexive): Characterized by middle phase of adolescent period of development, in which the adolescent may become skeptical and begin to compare religious standards of their parents and significant others. The adolescent will begin to compare religious beliefs with scientific facts, described as a period of searching for answers; and to be uncertain about their religious ideas. SELECTED MILESTONES GROSS MOTOR • 0 to 4 months: Lifts head if in prone position with head erect or bobbing and back rounded; raises chest with support of arms flexed limbs; 0 to 1 month, startle and rooting reflex are very strong, Moro reflex begins to fade at 2 months; 2 to 4 months, decrease in head lag when pulled up to sitting position. 3 of 8 12/22/2006 7:14 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocId=2&FxId=123&Sessio. • 4 to 8 months: Holds head up and erect without support; lifts head and shoulders to 90 degree angle and rolls from back to side; turns over both ways; supports weight on legs and may pull self into sitting position; beginning at 4 months, able to sit with support; head lag disappears; by 7 months, able to sit alone without support; likes to bounce on legs when held in standing position; Moro reflex has disappeared. • 8 to 12 months: Sits alone, creeps, crawls, cruises, sits from standing position without assistance, prefers being up instead of lying down; at 9 months, stands while holding onto furniture and able to pull self to standing position; at 11 months walks while holding onto furniture or with both hands held; at 12 months may be able to walk with one hand held. • 12 to 15 months: Walks alone with side-based gait, creeps up stairs, throws things. • 15 to 24 months: Walks alone with improvement, runs, pulls toys when walking, walks on toes, walks backwards, climbs up steps, climbs on furniture, sits on small chair, stands on one foot. • 2 years: Walks with steady gait, runs with few falls, walks on toes, stands on one foot, walks up and down stairs, jumps, kicks ball, rides tricycle, throws ball overhand. • 3 and 4 years: Pedals tricycle, climbs and jumps well, walks up and down stairs with alternating feet, gains increased coordination and balance, hops on one foot, throws ball overhand proficiently. • 5 and 6 years: Hops; skips well; jumps rope; has improved coordination and control of muscles; active; throws and catches ball; runs without difficulty, hits nail on head. • 7, 8, and 9 years: Repeats activities for mastery; active; rhythm, smoothness, and control of muscular movements increases; displays motor skills; strength and endurance increase. • 10, 11, and 12 years: Has control of timing, graceful high level of energy, explores environment, participates in team sports, builds or constructs things, interested in physical skills. FINE MOTOR • 0 to 4 months: Attempts to grab object but misses, brings object to mouth, holds hands in front and plays with hands and feet, grasps object with both hands; 1 month displays grasp reflex; 3 months, hands are usually open; 2 to 4 months, looks and plays with own fingers; 3 months, when object is placed in hands, will retain briefly; 4 months, reaches for objects and picks them up with a raking action of fingers. • 4 to 8 months: Grasps with thumb and fingers, explores objects, moves arms at sight of toy, reaches for object, picks up object with cupped hands, holds objects in both hands at same time, holds own bottle, puts nipple in mouth, feeds self a cookie; 5 months, able to voluntarily grasp an object; 6 to 7 months, able to transfer objects from one hand to another, enjoys banging objects together. • 8 to 12 months: Releases toy or object, locates hands for play, eats with fingers, uses spoon with assistance, drinks from cup with assistance, holds crayon and makes marks on paper; 10 months, pincer grasp is present, able to pick up small objects like a raisin; 11 months, able to put objects into a container and enjoys removing them; 12 months, displays interest in building a tower of two blocks, but it often falls down. • 12 to 15 months: Builds tower of 2 to 4 blocks, opens boxes, pokes finger in hole, turns pages of book, uses spoon with spilling. • 15 to 24 months: Drinks from cup with one hand, uses spoon without spilling, empties jar of contents, draws vertical line, scribbles, builds tower 4 of 8 12/22/2006 7:14 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocId=2&FxId=123&Sessio. of 4 blocks. • 2 years: Builds tower of 5 to 8 blocks, turns knob to open door, drinks from glass held in one hand, makes train of cubes by manipulating play materials. • 3 and 4 years: Strings beads, builds tower of blocks, learns to use and masters use of scissors, copies a circle-and-cross figures, holds crayon with fingers, unbuttons buttons on side or front, laces shoes, brushes teeth, cuts out simple pictures. • 5 and 6 years: Copies letters of alphabet and prints name, dresses self with assistance, uses hammer and nails, knows right from left hand, cuts and pastes well, may tie shoes, uses fork. • 7, 8, and 9 years: Hand-eye coordination improves; enjoys video games; writes rather than prints words; may play musical instruments, sew, build models, work jigsaw puzzles; adds details to drawings and uses perspective in drawing, uses both hands independently. • 10, 11, and 12 years: Uses increased detail in work, handwriting skill improves, more refinement to motor activities, gradual improvement to adult level. LANGUAGE • 0 to 4 months: Cries, whimpers; responds to sounds or activity; coos, gurgles, and babbles; smiles in response to adult sounds and makes sounds. • 4 to 8 months: Laughs out loud, vocalizes, uses two syllable sounds like da da without meaning, imitates expressions, cries if scolded. • 8 to 12 months: Responds to adult emotional tone, says one or two words, uses sounds to identify objects or persons, uses wide range of sounds, understands use of no, knows own name, communicates with others and self. • 12 to 14 months: Uses jargon, names for familiar pictures or objects; points to desired object or vocalizes wants, knows at least 10 words or more; uses short phrases; points to body parts. • 2 years: Uses about 300 words, uses pronouns, speaks 3 to 4 word sentences, enjoys stories, does not ask for help. • 3 and 4 years: Uses about 900 to 1500 words; talks in sentences; asks questions consistently; states own name; talks whether someone present or not; uses plural form of words; repeats words and sentences at will; may omit prepositions, adverbs, adjectives in speech; asks how and why; boasts and tattles; tells a story; counts to at least 3, understands simple questions. • 5 and 6 years: Identifies colors, uses 2,100 words, knows names of days of week, asks thoughtful questions, uses prepositions and conjunctions, uses complete sentences, shares experiences with others through language, expands vocabulary with exposure and stimulation, errors in sound disappear, begins to have a concept of abstract words. • 7, 8, and 9 years: Increases use of words to express self, increases use of words for exchange and communication, considers what others say, uses all parts of speech. • 10, 11, and 12 years: Uses 50,000 words, uses compound and complex sentences, understands abstract words. 5 of 8 12/22/2006 7:14 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocId=2&FxId=123&Sessio. PLAY AND SOCIALIZATION • 0 to 4 months: Stares at environment, smiles indiscriminately or responsively, enjoys having others around, recognizes familiar faces, determines that face is unfamiliar and freezes gaze, establishes cycle for sleep and awake periods; 0 to 1 month, prefers to look at faces, at black and white geometric designs, able to follow objects in line of vision; 2 to 4 months, follows objects 180°, turns head to look for voices and sounds. • 4 to 8 months: Self-centered, begins to be fearful of strangers; 4 to 6 months, watches the course of a falling object, responds readily to sounds, smiles at self in mirror, fascinated by own fingers and toes; 6 to 8 months, recognizes own name and responds by smiling when it is heard, seeks attention, imitates faces and sounds in play. • 8 to 12 months: Plays simple peek-a-boo, prefers mother, cries when upset, becomes anxious if separated, recognizes family members' requests if one at a time, displays various emotions. • 12 to 24 months: Plays pat-a-cake, is curious and gets into everything, has short attention span, enjoys solitary play or watching others play, has a favorite toy or object. • 2 years: Unable to distinguish right from wrong, imitates parents and others, enjoys parallel play, wants things own way, refuses to share, is possessive, sees self as a separate person, rituals important, benefits from transitional objects such as teddy bear. • 3 and 4 years: Able to share with peers and adults, interested in new activities and learning from them, may have an imaginary playmate, participates in imaginative play and imitation of adults. • 5 and 6 years: Likes achieving, wants to accept responsibilities, has strong feeling for family and home, identifies with parent of same sex, participates in fair play and cooperation, shows off. • 7, 8, and 9 years: Independently plays, able to reason and has a concept of right or wrong, likes rewards and praise, peer group gains in importance, short-lived interests, completes tasks. • 10, 11, and 12 years: Feels positive about self; is more tolerant; interested in rules and money; relates well with peers, friends, relatives; likes conversation, change, and variety in activities; avoids doing tasks; develops conscience. Enjoys sports, games. PLAY Play is described as the work of childhood. Children use play to learn about themselves and the world and also to cope with new or stressful events. Child development experts recognize play as a significant coping strategy for children. For example, children may use play as an outlet for self-expression, to manipulate experience, and to attempt to master the environment. Play provides the child with a measure of control over events and settings. Children's play also promotes social, cognitive, and physical development. Illness, treatment, and hospitalization create emotional stress for children. Reactions may include crying, clinging to parents, loss of sleep, and regression. Structured and/or medical play has been shown to be therapeutic in helping children preserve usual coping strategies and maintain emotional health. Therapeutic play has been identified as an effective intervention to help children prepare for, cope with, assimilate, and master painful procedures and the stress of hospitalization. A significant nursing intervention is to provide the child with a pleasurable play experience at the onset of hospitalization, that may ease the emotional distress associated with invasive procedures or with the hospitalization process itself. The nurse bases the choice of play activity offered on the child's developmental level, play preferences, and therapeutic goals. 6 of 8 12/22/2006 7:14 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocId=2&FxId=123&Sessio. FLOW CHART FOR PLAY COPYRIGHT © 2005 by Thomson Delmar Learning. All Rights Reserved. Author: KARLA L. LUXNER, RNC, ND Copyright: COPYRIGHT © 2005 by Thomson Delmar Learning. All Rights Reserved. Database Title: STAT!Ref Online Electronic Medical Library ISBN: 0-7668-5994-0 7 of 8 12/22/2006 7:14 AM Delmar's Pediatric Nursing Care Plans - 3rd Ed. (2005) http://online.statref.com/Document/DocumentBodyContent.aspx?DocId=2&FxId=123&Sessio. Publication City: Clifton Park, NY Publication Year: 2005 Publisher: Thomson Delmar Learning Date Posted: 5/5/2006 6:51:38 AM PST (GMT -08:00) Book Title: Delmar's Pediatric