Autoimmune hepatitis: diagnostic criteria, subclassifications, and clinical features

Clin Liver Dis 6 (2002) 605 – 621

Autoimmune hepatitis: diagnostic criteria, subclassifications, and clinical features Ian G. McFarlane, PhD, DSc(Med), FRCPath Institute of Liver Studies, King’s College Hospital, Denmark Hill, London SE5 9RS, UK

Autoimmune hepatitis (AIH) is an a priori chronic liver disorder. It is defined as an unresolving, predominantly periportal hepatitis that is usually associated with hypergammaglobulinemia and tissue autoantibodies and that, in most cases, is responsive to immunosuppressive therapy [1]. The syndrome has been recognized in some form for more than 50 years and was previously termed ‘‘lupoid’’ or ‘‘autoimmune chronic active’’ hepatitis [2,3]. Although it is a relatively rare condition (see Chapter 3), it is being increasingly recognized. The worldwide prevalence remains unknown, however, because few reports have been discussed about AIH in populations other than those of mainly European caucasoid or Japanese extraction [4]. It is uncertain whether this reflects a much lower frequency in some countries (perhaps because of a lower genetic predisposition) or is the result of lack of awareness and underdiagnosis, particularly in regions where viral hepatitis is a more pressing hepatologic problem (vide infra). The patient conforming most closely to the early descriptions of lupoid hepatitis is a young woman who presents with either an acute hepatitis or a chronic illness characterized by lethargy, epigastric pain, arthralgia or myalgia, oligomenorrhea, fluctuating jaundice, and a cushingoid appearance with striae, hirsutism, and acne. It was considered to be a particularly aggressive disorder that rapidly progressed to cirrhosis and was associated with a high mortality rate in untreated patients [5 –8]. Clinical trials in the late 1960s and early 1970s [5,9 – 11] clearly demonstrated, however, that the disease can be effectively controlled with corticosteroids and that if azathioprine is added the steroid dose required to maintain remission can be substantially reduced (see Chapter 7). These observations, together with increasing awareness and understanding of the syndrome and the remarkable advances in clinical hepatology over the intervening years, have dramatically altered the ‘‘natural history’’ of AIH. Although females are predominately affected (approximately 4:1), AIH can also affect males and can present at any age [12]. A previous hypothesis that there

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are two peaks of onset (peripubertally and between the fourth and sixth decades of life) [13] appears to have been an artefact of the pattern of referrals to specialist centers because, despite suggestions that the condition may be underdiagnosed in the elderly [14,15], most patients presenting to general gastroenterology clinics are between 50 and 70 years of age (Fig.1). Within this broader spectrum of patients, signs and symptoms vary from the classic presentation described above to the completely asymptomatic patient whose disease may be revealed only incidentally during routine health screening. There is also variability in severity. Younger patients usually have more aggressive disease, which can be more difficult to control, and older patients tend to have a less severe form. Nonetheless, recent long-term follow-up studies indicate that, for most patients who are carefully managed, life expectancy today is probably not significantly different from that of the general population matched for age and gender, even if there is progression to cirrhosis [16 – 19]. Although the precise pathogenetic mechanisms involved in AIH are still unclear, considerable evidence exists to indicate that the disease has a basis in aberrant autoreactivity in genetically susceptible individuals (see discussion in Chapter 6). Like other autoimmune diseases, AIH in European caucasoids is associated with inheritance of the human leukocyte antigen (HLA) A1-B8-DR3 haplotype and particularly with the DR3 and (in DR3-negative patients) DR4 allotypes. In Japan, where DR3 is very rare in the general population, the primary association is with DR4 [20]. Different HLA associations may apply in other populations [21,22], whereas genotyping studies have identified HLA alleles and

Fig. 1. Distribution of age at onset in adults with autoimmune hepatitis presenting at gastroenterology clinics in Japan [20] and the UK [92]. (From: Kluwer Academic Publishers BV and Falk Foundation e.V. from McFarlane IG. Definition and classification of autoimmune hepatitis 1999 [on behalf of the International Autoimmune Hepatitis Group]. In: Manns MP, Paumgartner G, Leuschner U, editors. Immunology and liver. Boston: Kluwer; 2000. p. 57 – 68. Reproduced with kind permission.)

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polymorphisms in other immune response genes that seem to confer susceptibility or resistance to the disease (see discussion in Chapter 5).

Diagnosis Because no pathognomonic features exist for this syndrome [12,23], diagnosis requires the presence of a combination of suggestive clinical and laboratory abnormalities together with exclusion of other possible causes of liver disease (Table 1). In particular, viral hepatitis, Wilson’s disease, a1-antitrypsin deficiency, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) need to be excluded by appropriate investigations. Other etiologic factors that need to be carefully considered include alcohol and drugs (especially antibiotics such as minocycline and various anti-inflammatory, antiepileptic, and antihypertensive agents, which idiosyncratically produce syndromes that mimic AIH), and herbal remedies and environmental toxins. Clinical features Typical presentations The diagnosis is relatively straightforward in approximately 50% of patients. Although the patient may present with the features of classic lupoid hepatitis described above, more typically the onset is insidious with a prodromal phase of many weeks or months, not infrequently with a history of one or more episodes of an influenza-like illness. Lethargy (often profound fatigue) is a prominent feature and may be the dominant (occasionally the only) symptom. AIH should

Table 1 Typical clinical and laboratory features suggestive of autoimmune hepatitis Symptomsa Signsa Serum biochemistry

Immunologic parameters Viral markers Concurrent disorders Other etiologic factors Liver histology a

Fatigue, malaise, nausea, anorexia, arthralgia, myalgia, oligomenorrhea Jaundice, cutaneous stigmata, ascites, skin rash, hepatomegaly, splenomegaly, mild encephalopathy Elevated aminotransferase activity and bilirubin concentration with normal or, at most, moderately elevated alkaline phosphatase. Hypergammaglobulinemia with selective elevation of IgG. Normal copper, ceruloplasmin, and a1-antitrypsin. Seropositive for ANA or SMA or anti-LKM1 and/or other relevant autoantibodies (see text). Seronegative for AMA. Seronegative for markers of current hepatitis viral infections. Thyroiditis, rheumatoid arthitis, diabetes, or other immunologic disorders (see text) in the patient or family. No history of recent hepatotoxic drug use (including herbal remedies) or of excessive alcohol consumption. Interface hepatitis without any other prominent changes that are more usually associated with other liver disorders.

The patient may present with any one or more of these features, or none.

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therefore be considered in the differential diagnosis of chronic fatigue syndromes. Other common complaints include malaise, nausea, anorexia, upper abdominal discomfort and pain, arthralgia or myalgia, skin rashes, and oligomenorrhea in women. Patients may also complain of mild pruritus and may sometimes report persistent low-grade pyrexia. These symptoms may occur alone or in combination with any (or all) of the others. A history of other immunologic disorders (vide infra) in the patient or the family is suggestive. Signs of liver disease also vary widely. Importantly, although absence of jaundice does not exclude the diagnosis, approximately half of the patients with an insidious onset may be clinically jaundiced or may report prior icteric episodes. Cutaneous manifestations of chronic liver disease may be evident and about one third of patients will already have cirrhosis at accession, confirming the impression that the disease often has a protracted subclinical phase before it becomes clinically apparent. Ascites and peripheral edema may be present even in the absence of cirrhosis. Other physical findings may include hepatomegaly, splenomegaly and, occasionally, encephalopathy. Approximately 30% of patients (especially in the younger age groups) will have an acute presentation that mimics acute viral hepatitis clinically and biochemically. Although these patients may be deeply jaundiced and may report passing pale stools or dark urine, surprisingly, they often do not feel particularly unwell (in contrast to the typical patient with acute viral hepatitis). In terms of demographics, response to therapy, and frequency of cirrhosis, these patients are indistinguishable from those with an insidious onset [24]. Early recognition of the syndrome and prompt institution of therapy is critical, however, to avoid progression to subacute hepatic failure, which may require urgent liver transplantation. Asymptomatic patients The remaining 15% to 20% of patients in whom the disease does not have an insidious or acute onset have no obvious signs or symptoms suggestive of their underlying liver disorder, and the disease is detected incidentally as a result of the finding of elevated serum aminotransferase activities on biochemical screening [25]. Some patients are truly asymptomatic, and their AIH is found only during a routine health examination or during an investigation of another condition. Thus, it is common for AIH patients with amenorrhea or concurrent thyroid disease or diabetes to be seen first by endocrinologists, or those with concomitant rheumatoid arthritis by rheumatologists. On the other hand, some patients present with arthropathy or skin rashes as the first manifestation of AIH and may be referred initially to rheumatology or dermatology clinics. In most other respects, asymptomatic patients are indistinguishable from those with a symptomatic presentation; however, they do tend to have milder disease, which responds more promptly to therapy. Importantly, the frequency of cirrhosis in asymptomatic patients is very similar to that in symptomatic patients. Occasionally, these patients may present with a hematemesis or melena after rupture of gastric or esophageal varices as the first evidence of their liver disease [26]. Also, AIH may develop during pregnancy or postpartum in a previously asymptomatic patient

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[27]. For women presenting during pregnancy, prompt diagnosis and institution of therapy is essential to avoid risk to the fetus. Concurrent disorders Approximately 40% to 50% of AIH patients have at least one concurrent extrahepatic immunologic disorder. These disorders affect a wide variety of organ systems and, as noted above, their presence in the patient or family members adds weight to the diagnosis. Thyroid disease (Hashimoto’s thyroiditis or Graves’ disease) and rheumatoid arthritis are the most common conditions. Other disorders include diabetes, Sjo¨gren’s syndrome, polymyositis, IgA deficiency, idiopathic thrombocytopenia, urticaria, vitiligo, and Addison’s disease. Inflammatory bowel disease is also common, and screening for anti-endomysial antibodies is advisable to exclude celiac disease, which may be asymptomatic [28]. Associated ulcerative colitis must, however, raise suspicions about the diagnosis of AIH, and cholangiography is required in these cases to exclude PSC [29]. Children Although the features of AIH in children are discussed in detail in the next chapter, it is appropriate to briefly note here some important differences from adults with respect to presentation. Because of the rarity of the condition, experience in reasonably large series of pediatric patients has come almost entirely from tertiary referral centres and may not be typical of a wider population. Nonetheless, in children, AIH more frequently has an acute onset with a shorter prodrome and, somewhat paradoxically, a much higher incidence (60% to 80%) of cirrhosis at presentation than in adults [30,31]. On the other hand, no significant difference exists in the frequency or nature of concurrent immunologic disorders in children or their families compared with adults. It is noteworthy, however, that a high proportion of children initially diagnosed with AIH have been found (on the basis of cholangiographic evidence) to have what appears to be a pediatric form of PSC, which has been termed ‘‘autoimmune sclerosing cholangitis’’ [32]. Laboratory investigations Serum biochemistry Biochemical abnormalities include elevated serum aminotransferase activities and bilirubin concentrations with normal or only moderately elevated serum alkaline phosphatase, together with hypergammaglobulinemia. Although serum gammaglutamyl transferase (GGT) activities may be elevated (sometimes quite markedly), they are of uncertain clinical significance. It is now recognized, however, that aminotransferase and bilirubin levels vary widely among individuals (Fig. 2) and that, in keeping with the fluctuating nature of the condition, they may even normalize spontaneously for a time despite ongoing hepatic necroinflammation. The previous requirement for a more than threefold elevation in the

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Fig. 2. Biochemical liver test results at presentation in 140 consecutive adult patients with histologically severe definite type 1 AIH attending the Institute of Liver Studies, King’s College Hospital, London. AST = aspartate aminotransferase; ALP = alkaline phosphatase.

aminotransferase activity for diagnosis of AIH is therefore no longer considered applicable [12,23]. The hypergammaglobulinemia is characteristically caused by a disproportionate increase in the immunoglobulin G fraction, which may be raised even if total globulin concentrations are within the normal range. Although serum immunoglobulin M concentrations may sometimes be moderately elevated, they are rarely elevated to the same levels as in PBC, and they generally return to normal during treatment. Serum IgA is usually normal. Serum concentrations of copper, ceruloplasmin, and a1-antitrypsin are also usually normal. Importantly, interpretation of biochemical test results should not focus solely on the upper reference limits for the various parameters but rather should take account of what may be normal for the individual patient. By definition, half of the normal population will have values below the geometric means of the reference ranges and, for such individuals, a rise in a parameter to (or just above) the upper reference limit may represent a doubling of their normal value. Thus, a low aminotransferase or IgG level does not necessarily equate with mild or inactive disease nor does it exclude a diagnosis of AIH. Autoantibodies Approximately 70% to 80% of patients with AIH present with significant titers (1:40 or more when tested by immunofluorescence on rodent tissues) of antinuclear (ANA) or antismooth muscle (SMA) autoantibodies, or both. The ANA react mainly with histones and DNA and typically show a homogeneous immunofluorescent staining of nuclei similar to that seen with ANA in systemic lupus erythematosus. Other staining patterns, which reflect reactivities with a variety of nuclear antigens, are also frequently seen; however, the different patterns appear to have no practical clinical implications [33]. The SMA react

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with several cytoskeletal components, including F-actin. Although it has been suggested that high titer antiactin antibodies are specific for AIH, this suggestion is controversial [13]. Furthermore, antiactin occurs in only about 50% of AIH patients, and it has been noted that reliance on antiactin specificity of SMA might therefore cause missed diagnoses of AIH [34]. Although titers of ANA and SMA fluctuate during the course of the disease and may decline or become negative with response to treatment, they do not reliably reflect the severity of the disease [35]. A small proportion (3% to 4% overall) of patients with AIH (mainly children and young adults) present with so-called type 1 liver – kidney microsomal antibodies (anti-LKM1), usually without ANA or SMA. These antibodies are distinguishable from other microsomal autoantibodies by their specific reactivity with the cytochrome isoenzyme P450 2D6 [36,37]. Immunofluorescence of these antibodies shows a characteristic pattern of staining of proximal renal tubules and granular cytoplasmic staining of liver sections, which requires interpretation by an experienced observer because it can sometimes be confused with the staining pattern shown by antimitochondrial antibodies (AMA). Although there have been occasional reports of AMA positivity in apparently genuine cases of AIH [38], it seems that earlier reports of AMA occurring in up to 20% of AIH patients [39] may have been overestimated partly because of a misinterpretation of the anti-LKM1 staining pattern [40]. Anti-LKM1 can be quite easily distinguished from AMA, however, by testing on sections of other tissues, such as stomach, which are stained by AMA but not by anti-LKM1. Based on this finding and on the availability of more specific tests for AMA in PBC today, it has been recommended that AMA-positive patients should not usually be considered to have AIH [23]. Anti-LKM1-positive AIH seems to occur more frequently in southern Europe than elsewhere in the world but the true prevalence is unknown because the antibody is not routinely tested for in many countries. Nonetheless, testing for anti-LKM1 (and its distinction from AMA) is important to avoid the potentially serious consequences of missed diagnoses of AIH in this subset of patients [41]. In addition to ANA, SMA, and anti-LKM1, patients with AIH have a wide range of other serum autoantibodies. Perinuclear staining antineutrophil cytoplasmic antibodies (pANCA), which in the context of liver disease were previously thought to be particularly associated with PSC [42,43], have reportedly occurred in 60% to 90% of patients with AIH [44 – 48]. Thyroid microsomal and thyroglobulin autoantibodies can be found quite often, even in patients with normal thyroid function, whereas many patients are seropositive for rheumatoid factor (usually at low titer), without necessarily having clinically significant rheumatic disease. Several other antibodies, so-called ‘‘liver autoantibodies,’’ are of considerable potential importance in the diagnosis of AIH; however, routine tests are not yet available to detect them [23]. These include antibodies reacting with the hepatic asialoglycoprotein receptor (ASGPR) [49 –51], with a liverspecific cytosolic antigen (LC1) [52 – 54], with a soluble liver antigen (SLA), and with a liver-pancreas antigen (LP). Recent cloning of SLA [55,56] has revealed

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that it is identical with LP and the corresponding antibody is now designated antiSLA/LP (see discussion in Chapter 13). Liver histology It has been strongly recommended that the diagnosis be confirmed histologically (preferably in consultation with a specialist liver histopathologist [12,23] ) partly (1) because neither the magnitude of the biochemical abnormalities (Fig. 2) nor the titers of the autoantibodies [35] reliably reflect the severity of the disease and (2) to help exclude liver diseases of other etiologies, The histologic features of AIH are described in detail in Chapter 8. Briefly, although there are no pathognomonic morphologic features, the characteristic histologic picture in AIH is that of an interface (periportal or paraseptal) hepatitis with a predominantly lymphoplasmacytic necroinflammatory infiltrate. In severe cases, lobular (intra-acinar) involvement with portal – portal or central-portal bridging necrosis, liver cell rosettes, and nodular regeneration can often be seen. Patients with bile duct changes typical of PBC or PSC (i.e., cholangitis, severe concentric periductal fibrosis, marked ductopenia, and a substantial periportal ductular reaction with a cholangiolitis and copper/copper-associated protein deposition or with well-defined granulomas) should not be regarded as having AIH [23] but may be classified under an ‘‘overlap’’ or ‘‘variant’’ syndrome (see discussion in Chapters 4 and 8). Other features, such as steatosis, lymphoid aggregates, copper deposits, siderosis, and bile ductule proliferation, may be present to some degree and are considered to lack the required specificity to exclude AIH unless they are sufficiently prominent to question the diagnosis [23]. If there is doubt, and especially in children [32], cholangiography may be required to exclude PSC. Diagnostic conundrums ‘‘Autoantibody negative’’ patients At ascension, between 10% and 20% of patients with AIH are seronegative for the conventional autoantibodies (ANA, SMA, and anti-LKM1). These cases are often classified as ‘‘cryptogenic’’ chronic hepatitis [57 – 59]. In many cases, the autoantibodies will appear later in the course of the disease, often during response to immunosuppressive therapy. Although the reasons for this are unclear, it is possible in some patients with severe disease that massive release of tissue components from the damaged liver initially blocks the detection of autoantibodies by immunofluorescence through formation of immune complexes [30]. Nonetheless, AIH can still be diagnosed in these cases on the basis of the typical biochemical abnormalities, hypergammaglobulinemia, characteristic histology, and exclusion of other causes of liver disease. In addition, many cases will have one or more of the other autoantibodies discussed above. In particular, pANCA testing may be worthwhile. If the patient is HLA B8, DR3, or DR4 positive and has a concurrent immunologic disorder, this adds weight to the diagnosis. In terms of variability in severity of disease, response to treatment, and prognosis,

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these patients are indistinguishable from those who present with the conventional autoantibodies [57 – 59]. Cholestatic AIH Occasionally, patients who otherwise fulfil criteria for AIH present with markedly ( > fivefold) elevated serum alkaline phosphatase (ALP) activities. In almost all cases, the ALP will normalize with response to immunosuppressive therapy [60]. If the ALP remains elevated, however, the possibility of an overlapping syndrome of AIH with PBC or PSC should be considered (see discussion in chapters 4 and 8). Alcohol consumption Diagnosis of AIH against a background of excessive alcohol consumption can be difficult. On the other hand, in the patient with evidence of liver disease who freely admits to ‘‘social drinking,’’ it may be tempting to interpret what could be an honest and accurate admission of moderate alcohol intake as an indication of alcohol abuse and to look no further for the cause of their liver disorder. There are two possibilities: either the patient (1) does not have AIH and alcohol is the primary cause of their liver problem or (2) does have AIH and alcohol may or may not be a contributory factor. The serum biochemical abnormalities, in particular the GGT (which, as noted above, can often be elevated in AIH), are generally not helpful discriminants in this situation. Because interface hepatitis can be seen in some patients with alcoholic steatohepatitis [61], liver histology may be inconclusive. The immunologic parameters may, however, provide a clue. Although hypergammaglobulinemia is a feature of both conditions, in alcoholic liver disease there is typically an increase in the serum IgA concentration, which is usually normal in AIH. In addition, although 25% to 40% of patients with alcoholic liver disease are reportedly positive for ANA or SMA, titers are usually low, and anti-LKM1 and pANCA are rare in these cases [62]. Thus, the finding of an elevated serum IgG with normal IgA and high titer ANA or SMA, or antiLKM1 or pANCA, favors a diagnosis of AIH. Viral hepatitis Hypergammaglobulinemia and circulating autoantibodies (ANA, SMA, or anti-LKM1) occur with variable frequency and magnitude in acute and chronic viral hepatitis. In acute viral hepatitis, these abnormalities are usually transient and normalize during recovery; however, there are a few well-documented cases of hepatitis A virus infection apparently triggering AIH in susceptible individuals [63,64]. In chronic hepatitis B (HBV) or C (HCV) virus infections, however, approximately 20% to 40% of patients are persistently positive for various autoantibodies, albeit mostly at relatively low titers (1:40 to 1:80). This finding presents a dilemma for diagnosis and clinical management because interferon therapy for chronic viral hepatitis can exacerbate or unmask underlying autoimmune conditions [65], whereas glucocorticoid therapy for AIH enhances viral replication in patients with chronic HBV or HCV [66 –69]. Consequently, in

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recent years, there has been much controversy about the diagnosis and management of patients with chronic viral hepatitis who also have autoimmune markers. In particular, considerable attention has been devoted to the question of the significance of anti-LKM1 in chronic HCV, which seems to be most common in southern Europe [70]. The picture is now much clearer, and there seems to be agreement that interferon therapy is generally safe in cases of chronic viral hepatitis with autoantibodies [66 –68]. Caution is, however, advised because occasionally patients with AIH do have concomitant HBV or HCV infections, or vice versa. Also, depending on whether the viral infection is newly acquired or pre-existing, it may be a cause of relapse or treatment failure in AIH [71]. Current recommendations are that patients with chronic viral hepatitis be screened for autoantibodies before institution of interferon therapy and be monitored carefully thereafter [23]. Testing for pANCA may be useful in this situation because, in contrast to the high frequency of this antibody in AIH (see above), it seems to be rare in chronic viral hepatitis patients who are seropositive for ANA or SMA [48].

Classification From the preceding discussion, it is apparent that there is considerable variability between patients in mode of presentation, severity of disease, and in response to therapy (see discussion in Chapter 7). For this reason, attempts have been made over the years to classify AIH according to various parameters not only for diagnostic purposes but also for assisting in focusing investigations, for accurately defining prognosis, and for planning treatment strategies. Autoantibody profile-based classification The first formal proposals to classify AIH were promulgated in 1987. Homberg et al [72] noted that the large majority of patients with anti-LKM1 were young females with severe disease who were often seronegative for ANA and SMA, and in their series had a higher frequency of concurrent extrahepatic immunologic disorders than patients with ANA or SMA (particularly SMA with antiactin specificity). They suggested that the apparent mutual exclusivity of antiLKM1 and the other autoantibodies, together with differences in clinical profiles, justified subdividing AIH cases into type 1 (ANA/SMA positive) and type 2 (anti-LKM1 positive). Also in that year, Manns et al [73] reported the discovery of a new autoantibody, anti-SLA (now anti-SLA/LP, see above), which appeared to be specific for AIH. They noted that, although anti-SLA occurred in only about 30% of patients, it could be found in some who presented without the conventional autoantibodies, and they suggested that such cases should be classified as type 3 AIH. After the discovery of an association between anti-LKM1 positivity and HCV infection in southern Europe [70], Homberg et al proposed that type 2 AIH be

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subdivided into type 2a (HCV-negative young women with severe disease and high titers of anti-LKM1) and type 2b (HCV-positive, predominantly older males, with low anti-LKM1 titers) [74]. They further suggested that another autoantibody, anti-LC1, could be used to discriminate between these two subtypes [52]; however, this was later disputed [53,54]. It has since been shown that the association of anti-LKM1 with HCV infection is peculiar to southern Europe and is very rare elsewhere in the world [70,75 – 77], even in countries with a relatively high HCV prevalence [20,78]. Furthermore, advances in knowledge and improvements in diagnosis of HCV infection have rendered this subdivision largely unnecessary. During this period, there also were additional proposals for other classifications of AIH based on autoantibody profiles which, if all had been adopted, would have led to at least eight subtypes of the disease being recognized [13]. Although only the broad subdivision into type 1 and 2 has gained general acceptance [79], some authorities and several international working parties have found it difficult to endorse even this classification [1,12,23,80,81]. The controversy seems to relate mainly to the point from which the issue is viewed (i.e., pathogenetic or clinical). Evidence exists to suggest that types 1 and 2 may be two pathogenetically distinct subgroups of the disease [21,22,82] and, after the recent cloning of the SLA/LP antigen, it has been suggested that defining type 3 AIH on the basis of anti-SLA/LP positivity might also be justifiable on pathogenetic grounds [83]. Therefore, this type of classification may be useful for research. From the clinical standpoint, however, it seems to have little utility. Type 3 AIH is clinically indistinguishable from type 1 disease [57 – 59,84]; however, the main problem in making a clinical distinction between type 1 and type 2 AIH is that this classification is not exclusive. Age at presentation is an important factor. As noted above, younger patients (less than 30 years of age) usually have more severe disease, which can be difficult to control, whereas older patients generally tend to have a milder form, which responds more rapidly and satisfactorily to immunosuppressive therapy. Although type 2 patients are almost all young females with severe disease, they represent only a very small proportion of all cases of AIH, and the large majority of young women with severe disease are type 1. Although there are some differences in clinical, biochemical, and histologic features between type 1 and type 2, among young patients the two types are similar in respect to severity, overall response to treatment, and long-term outcome [30]. Immunogenetic classification HLA typing and testing for polymorphisms in other immune response genes is not usually part of the normal diagnostic workup for AIH, and there have been no formal proposals for a classification of the syndrome based on immunogenetic markers. The information derived from these investigations can be quite useful, however, as an adjunct to defining prognosis and formulating treatment strate-

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gies. The HLA class II allotypes DR3 and DR4 are independent risk factors for AIH and are associated with different clinical expressions of the disease [85]. Although almost all young patients have the DR3 allotype (whereas DR4 is mainly associated with an older age at presentation [13]), DR3-positive patients of any age usually have more active disease, enter treatment-induced remission less readily, relapse more frequently, and more commonly require liver transplantation for intractable disease [79,85]. A similar clinical profile is seen in patients with the HLA class I allotype B8, which is in strong linkage disequilibrium with DR3 [86]. In contrast, DR4-positive patients tend to have higher serum gammaglobulin concentrations, higher titers of autoantibodies, a greater frequency of concurrent immunologic disorders, but generally milder disease, and a more rapid and complete response to immunosuppressive therapy than those with DR3 [20,85,87]. Another genetic marker, which may be clinically useful as a determinant of disease severity, is found within the HLA class III complement genes. Persistently low levels of C4 are a common feature of both type 1 and type 2 AIH and are associated with inheritance of a null allele at the C4A locus [88 – 90]. The C4A null allele is in linkage disequilibrium with the A1-B8-DR3-DQ2 haplotype and was said to be associated with an earlier onset of AIH [89], although this was not confirmed in a later study [88]. It does, however, seem to be associated with a higher frequency of relapse and increased mortality [88].

Table 2 Outline of the International Autoimmune Hepatitis Group [36] scoring system for diagnosis of autoimmune hepatitis Positive weighting a

Negative weighting a

Female gender Low ALP:AST(or ALT) ratio Hypergammaglobulinaemia Autoantibody positive (ANA, SMA, Anti-LKM1, or other relevant) Negative viral serology Negative drug history Low alcohol consumption Liver histology: interface hepatitis Concurrent immunologic disorders (in patient or family) Positive for relevant HLA allotypes Positive treatment response

High ALP:AST(or ALT) ratio Antimitochondrial antibody positive Positive viral serology Positive drug history High alcohol consumption Liver histology: bile duct damage and/or other incompatible changes

Abbreviations: ANA, antinuclear auto-antibodies; SMA, anti-smooth muscle autoantibodies; LKM1, liver-kidney microsomal antibodies 1; HLA, human-leukocyte antigens; AIH, autoimmune hepatitis; AST, aspartate aminotransferase; ALT, alanine aminotransferase. a Features and parameters to which positive or negative weighting is assigned to achieve an aggregate score for classifying patients as ‘‘definite’’ or ‘‘probable’’ AIH. Data from International Autoimmune Hepatitis Group report. Review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31:929 – 38.

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‘‘Definite’’ and ‘‘probable’’ AIH Against the above background, an international panel has proposed that for most routine clinical purposes a simpler classification should suffice. The recommendation is that patients should be classified as having either ‘‘definite’’ or ‘‘probable’’ AIH according to how closely their presenting features conform to those of classic lupoid hepatitis [23]. Patients fulfilling criteria for either definite or probable AIH should initially receive standard immunosuppressive therapy (see discussion in Chapter 7). A satisfactory response to treatment can be considered to reinforce the diagnosis. The panel also devised a diagnostic scoring system in which positive or negative weighting is assigned to a large number of parameters that support or mitigate against the diagnosis, providing an aggregate score that can be used to classify patients as having either definite or probable AIH (Table 2). This schema has recently been validated [23,91] and appears to be fairly reliable. Although it was originally intended to facilitate selection of relatively homogeneous groups of patients for research purposes, it seems to have proved useful also in routine clinical practice, especially for difficult cases.

Summary The diagnosis of AIH depends on the finding of several suggestive features together with careful exclusion of liver diseases of other etiologies. Wherever possible, the diagnosis should be confirmed histologically by an experienced hepatopathologist. Seronegativity for the conventional autoantibodies at presentation does not exclude a diagnosis of AIH. It is important to test for antiLKM1 antibodies to avoid missing a diagnosis of type 2 AIH, with potentially serious consequences. Although the syndrome is associated with characteristic biochemical abnormalities, and biochemical parameters are commonly used for monitoring response to therapy, it should be borne in mind that neither these nor autoantibody titers are completely reliable indices of disease activity. Although the various systems that have been promulgated for classification of the disease may identify different groups of patients on pathogenetic or clinical criteria and are useful for research purposes, none is yet sufficiently exclusive in terms of defining prognosis or planning treatment strategies to be applicable to the individual patient seen in the clinic. Clinical management should therefore continue to be individually tailored.

References [1] Ludwig J, McFarlane IG, Rakela J. International Working Party Report: terminology of chronic hepatitis. Am J Gastroenterol 1995;90:181 – 9. [2] Mackay IR, Tait BD. The history of autoimmune hepatitis. In: Nishioka M, Toda G, Zeniya M, editors. Autoimmune hepatitis. Amsterdam: Elsevier; 1994. p. 3 – 23.

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