Section 2 -

Autoimmune Hepatitis Kay Washington Vanderbilt University Medical Center Nashville, Tennessee

Definition Recognized as a clinical entity for over 50 years, autoimmune hepatitis (AIH) is generally characterized as an unresolving hepatitis usually associated with hypergammaglobulinemia and tissue-directed autoantibodies and responding in most cases to immunosuppressive therapy. The pathogenesis appears to be aberrant autoreactivity in genetically susceptible individuals [1]. Epidemiology and Demographic Features The worldwide prevalence of autoimmune hepatitis is unknown; most reported cases are in patients of European Caucasian or Japanese extraction. In North American populations, the prevalence is estimated as ~ 1 per 100,000 population [2] . In Western Europe and North America , where viral hepatitis prevalence rates are relatively low, AIH accounts for roughly 20% of chronic hepatitis in the white populations. In patients of European descent, AIH is associated with the HLA A1-B8-DR3 haplotype and particularly with DR3. In Japan, it appears to be primarily associated with the DR4 haplotype [3] ; this form of the disease occurs in elderly patients who exhibit mild necroinflammatory activity and a good response to immunosuppressive therapy. Clinical Features AIH, like most autoimmune disorders, is more common in female patients, with a male: female ratio of roughly 1:4. It can present at any age, but younger patients appear to have a more severe form of the disease. Presentation varies widely, ranging from asymptomatic elevations of serum liver enzymes, to massive hepatic necrosis resulting in fulminant hepatic failure. Most patients present with a prodrome phase characterized by a flu-like illness and lethargy; indeed, the latter may be the only symptom. About one-third of patients are cirrhotic at presentation, confirming the impression that AIH often has a prolonged subclinical phase. Approximately 30% of patients, usually younger patients, will have an acute presentation mimicking acute viral hepatitis. The response to therapy and prevalence of cirrhosis at presentation in this group are the same as in patients who present with more insidious onset. Roughly 20% of patients will be asymptomatic, with elevated transaminases identified on screening examination or during evaluation for amenorrhea, thyroid disease, arthralgia, or diabetes mellitus. Frequency of cirrhosis in this group at presentation is similar to that for symptomatic patients. In children, acute presentation is common, and the patients are more likely to be cirrhotic (60-80%) [4] . About 50% of patients with AIH will have concurrent autoimmune disorders, most commonly thyroid disease or rheumatoid arthritis. The presence of ulcerative colitis, however, should raise questions about the diagnosis of AIH; such patients are more likely to have PSC. Diagnosis AIH is diagnosed by consideration of the combination of clinical and laboratory features with exclusion of other causes of liver disease such as viral hepatitis, Wilson's disease, alpha-1-antitrypsin deficiency, PBC, PSC, alcohol abuse, and drug reaction. Diagnosis is straightforward in 50% and is aided by serum studies and the scoring system developed by the International Autoimmune Hepatitis Working Group [5, 6] . Serum studies Characteristic biochemical abnormalities include elevated transaminase levels, often accompanied by hyperbilirubinemia, hypergammaglobulinemia with a disproportionate increase in serum IgG, and normal or only slightly elevated alkaline phosphatase. Aminotransferases and bilirubin levels may vary widely, however, and may even normalize spontaneously for a period of time, and thus no threshold level for aminotransferases for diagnosis of AIH is specified. Bilirubin and transaminase levels do not reliably reflect disease severity. Total globulins may be in the normal range, and IgM levels are not as elevated as in PBC. 70-80% of patients with AIH have antinuclear (ANA) or smooth muscle (SMA) antibodies or both (>1:40). Because the ANA react mainly with histones and DNA, the pattern is homogeneous, similar to that seen in lupus; other patterns also occur, with no apparent clinical significance [7] . The autoantibody titer does not reliably reflect disease severity. The SMA reacts with several cytoskeletal components, including F-actin. 3-4% of overall patients (usually children) present with anti-liver kidney microsomal (LKM1) antibodies, without ANA or SMA. This serologic marker is more common in southern Europe but the true prevalence is not known. The antibody is directed against P450(CYP)2D6 and is associated with DRB1*0701 allele [4] . Antibodies against the soluble liver antigen/liver pancreas antigen (SLA/LP) are found in 10-30% with AIH; while testing for this autoantibody is not routine, but it appears to have a global distribution. pANCA, while not specific, is present in 60-90% [4] . Histopathology Key histologic features of AIH are a chronic hepatitis pattern of injury, with portal and periportal lymphoplasmacytic infiltrates and interface hepatitis. Plasma cells are often but not always prominent, and are sometimes seen singly and in clusters in the lobule. The severity of necroinflammatory activity is quite variable, ranging from mildly active hepatitis to bridging necrosis to massive hepatic necrosis. Hepatocyte regeneration may be prominent, with regenerating rosette-like structures. Ballooning degeneration, spotty hepatocyte necrosis, and apoptotic bodies are common but not specific. Syncytial multinucleated hepatocyte giant cells are seen in some cases and many cases of so-called giant cell hepatitis probably represent a variant of AIH [8] . As the disease progresses, periportal fibrosis with formation of portal-portal and portal-central bridges and nodular regeneration results in cirrhosis, often with severe necroinflammatory activity. In most cases the necroinflammatory process responds promptly to immunosuppressive therapy, although relapses with withdrawal of therapy are common and the disease can recur following liver transplantation. Portal plasma cell infiltrates while on immunosuppressant therapy are associated with relapse upon drug cessation [9, 10] . Centrilobular injury with prominent hepatocellular necrosis and mononuclear inflammation occurs in some cases of AIH, either as an isolated finding (rare) or in conjunction with periportal activity and interface hepatitis. Because the centrilobular pattern of injury can evolve over time to a more typical portal-based chronic hepatitis pattern of injury, it has been postulated that this may represent an early stage of the disease [11, 12] . However, this centrilobular necroinflammatory injury pattern is not specific for AIH, and may be seen in particular in drug reactions [13] . Bile duct destruction is generally not prominent in AIH, but up to 12% of biopsies may show duct destruction, and an additional 12% show lymphocytic infiltration of bile duct epithelium without ductopenia [14, 15] . The histologic pattern of injury may be indistinguishable from primary biliary cirrhosis [16] . Scoring system A working classification useful in diagnosis and research has been developed by the International Autoimmune Hepatitis Group and modified in 1999 [5, 6] . This system classifies cases as definite or probable autoimmune hepatitis, based upon weighted parameters. In multiple reports, this system has a high degree of sensitivity (97-100%) for diagnosis of AIH. The system also effectively excludes AIH in patients with PSC and biliary disorders (96-100% accuracy for exclusion of definite AIH). However, if cases considered probable AIH are included, the overall specificity is reduced. The overall diagnostic accuracy of the scoring system is roughly 90%. Table 1: Outline of the International Autoimmune Hepatitis Group Modified Scoring System [5] Positive Weighting Negative Weighting Female sex High ALP: AST (or ALT) ratio Low ALP:AST (or ALT) ratio AMA + Hypergammaglobulinemia Positive viral serology Autoantibody + Positive drug history Negative viral serology High alcohol consumption Negative drug history Bile duct damage on biopsy, other incompatible changes Low alcohol consumption Interface hepatitis on biopsy Concurrent immunologic disorders, patient or family Positive for relevant HLA haplotypes Positive treatment response Classification AIH may be subclassified based upon the autoantibody profile; such subclassification may be useful for research purposes and may define pathogenetically distinct groups, but has little application in clinical practice at the present time. Type I AIH is defined as ANA and/or SMA positive and has a bimodal age distribution with peaks between 10 and 20 and 45-70 years of age. Type 2 AIH is characterized by the presence of anti-LKM1 antibodies; the majority of these patients are young women with severe disease. However, because Type 1 AIH is much more common than Type 2, most young women with severe disease will actually represent type 1 AIH. Patients with Type 2 AIH present between ages 2 and 4 years, and may have ectodermal dysplasia, mucocutaneous candidiasis, and endocrinopathies suggesting autoimmune polyglandular syndrome Type 1 [17]. Type 3 AIH is characterized by positivity for SLA/LP antibodies and is clinically indistinguishable from Type 1. Diagnostic Difficulties Autoantibody negative patients Approximately 10-20% of AIH patients are initially seronegative for the conventionally autoantibodies, which may appear after immunosuppressive therapy is begun. pANCA testing may be helpful in this subgroup of patients, and viral hepatitis B and C should be excluded prior to initiation of treatment. Viral hepatitis 20-40% of patients with chronic HBV of HCV are persistently positive for various autoantibodies, usually at low titers (~1:20 or 1:40) [4] . Conversely, patients with AIH sometimes have a false positive test for anti-HCV antibodies but will have undetectable HCV-RNA. Three categories of patients with potential concurrent AIH/hepatitis C may be identified: patients with true AIH and false positive anti-HCV antibodies (undetectable HCV-RNA) Patients with true HCV and autoantibodies at low titers, but no other signs of AIH Patients with true HCV and features of AIH including young age, female gender, high autoantibody titers (> 1:320), hypergammaglobulinemia, and history of extrahepatic autoimmune disorders Distinction of chronic viral hepatitis from AIH is important, because interferon therapy can exacerbate autoimmune conditions, and corticosteroids can enhance viral replication. There has been considerable controversy about the diagnosis and management of chronic hepatitis patients with autoimmune markers, particularly regarding the presence of anti-LKM antibodies in HCV patients in southern Europe . It has recently been shown that anti-LKM1 antibodies directed against CYP2D6 can cross-react with HCV proteins, perhaps as a result of molecular mimicry at the B cell level [18] . The current general consensus is that interferon therapy is usually safe in HCV patients with anti-LKM1 autoantibodies. Patients with chronic viral hepatitis should be screened for autoantibodies before starting interferon therapy and monitored carefully. pANCA testing may be useful, as this autoantibody is rare in chronic hepatitis patients but relatively common in AIH. Overlap with Other Autoimmune Liver Diseases AIH-PBC overlap Although it may be difficult to distinguish AIH from PBC on histologic grounds, accurate diagnosis is important because treatment for autoimmune hepatitis differs from that for primary biliary cirrhosis. Up to 10% of AIH or PBC patient may belong in this overlap category. Difficulties arise because the portal inflammatory infiltrate of PBC often contains numerous plasma cells, and infiltration of bile duct epithelium by lymphocytes is not uncommon in autoimmune hepatitis, if looked for, and some degree of bile duct injury is often present. Although non-destructive bile duct lesions are quite common in autoimmune hepatitis, duct loss is relatively uncommon, and granulomatous bile duct destruction is not seen. Serum alkaline phosphatase, cholesterol, and IgM levels are elevated to higher levels in PBC. To add to the problem, some patients with clinical and histologic features of autoimmune hepatitis will have serum anti-mitochondrial antibodies. In some cases this is caused by misreading of immunofluorescence-type tests (confusing anti-LKM antibodies with antimitochondrial antibodies). In other patients, however, the AMA is truly positive, but usually in low titer. Serologic markers may not be definitive in such cases, as patients with PBC may have a positive ANA and patients with autoimmune hepatitis may have a low titer AMA. Liver biopsies in such cases show features of both PBC (granulomatous inflammation and bile duct lesions) and autoimmune hepatitis (piecemeal necrosis and spotty hepatocyte necrosis) [19] . In addition to these cases with "overlapping" simultaneous features of both diseases, rare patients who switch from one disease to another over time are reported [20] . AIH-PSC overlap is not uncommon in young patients with autoimmune liver disease , and may comprise 6% of patients with AIH [21] and 8% of PSC patients [22] . In one 16 year prospective study [17] in which 55 children with AIH were followed, 27 developed cholangiographic findings typical of PSC. The term "autoimmune sclerosing cholangitis" has been proposed for this AIH-PSC overlap syndrome. References Krawitt EL. Autoimmune hepatitis. N Engl J Med 2006;354:54-66. Boberg KM. Prevalence and epidemiology of autoimmune hepatitis. Clinics in Liver Disease 2002;6:347-359. Toda G, Zeniya M, Watanabe F, Imawari M, Kiyosawa K, Nishioka M, et al. Present status of autoimmune hepatitis in Japan - correlating the characteristics with international criteria in an area with a high rate of HCV infection. Journal of Hepatology 1997;26(6):1207-1212. McFarlane IG. Autoimmune hepatitis: diagnostic criteria, subclassifications, and clinical features. Clinics in Liver Disease 2002;6(3):317-33. 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