The Variant Forms of Autoimmune Hepatitis

Autoimmune hepatitis has been recognized since the 1950s [1, 2], but its diagnostic criteria have only recently been codified [3]. The ability to exclude viral infection by using sensitive and specific diagnostic assays and the ability to confirm immunoreactivity through the use of batteries of diagnostically relevant immunoserologic markers have validated the existence of autoimmune hepatitis and justified the standardization of its diagnosis [4]. However, not all patients who have features associated with autoimmune hepatitis have the classic condition, and the improved standards of diagnosis have made it difficult to accommodate patients with variant findings [4]. Persons with atypical manifestations currently lack an established identity for their condition, an official designation, and a treatment strategy that can be applied with confidence [4]. In this report, the nature and importance of the variant forms of autoimmune hepatitis are discussed, and treatment options for these conditions are reviewed. Patients with variant disease are a consequence of progress in the classification of chronic liver diseases, and their number is destined to burgeon as the use of screening at the time of presentation is expanded and diagnostic criteria are rigidly applied. Methods All English-language articles published between 1990 and 1995 that addressed the diagnosis of autoimmune hepatitis, atypical manifestations of the disease, and variations in response to conventional corticosteroid therapy were identified by a search of the MEDLINE database. Search terms included autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune cholangitis, chronic hepatitis B and C with autoimmune features, cryptogenic chronic hepatitis, and overlap syndromes. Each identified title and abstract were reviewed by the author. Articles that focused on diagnostic criteria for autoimmune hepatitis and those that discussed atypical presentations, mixed features, concurrent diseases, and overlap syndromes were scrutinized further. Complete copies of each of these articles were obtained and read by the author. Additional articles of potential relevance were identified from the bibliographies of the pertinent articles. Articles that reported substantial clinical experience or provided novel insights were abstracted and recorded in a computer database. An extensive personal library of journals and reprints, maintained since 1975 and dedicated to the study of autoimmune liver diseases, was also searched. Pertinent articles found in this library were abstracted and entered in the database. A total of 548 articles were selected. Autoimmune Hepatitis Autoimmune hepatitis is an unresolving inflammation of the liver of unknown cause. It is characterized by the presence of hepatitis (piecemeal necrosis or interface hepatitis) that is periportal or more widespread on histologic examination, hypergammaglobulinemia, and autoantibodies in serum [5, 6] (Figure 1). The panels of the International Autoimmune Hepatitis Group, the World Congresses of Gastroenterology, and the International Association for the Study of the Liver have together standardized the definition of the disease [7-9], and the International Autoimmune Hepatitis Group [3] has promulgated criteria for definite and probable diagnosis. Figure 1. Histologic features of autoimmune hepatitis. arrow The definite diagnosis of autoimmune hepatitis requires the presence of compatible laboratory and histologic findings (Table 1), the absence of viral markers, denial of excessive alcohol consumption, lack of exposure to blood products and hepatotoxic medications, and the presence of hypergammaglobulinemia ( globulin level > 1.5 times the upper limit of normal) (Table 1) [3]. Lobular hepatitis is part of the histologic spectrum of autoimmune hepatitis if it is present in conjunction with periportal hepatitis (Figure 1), but biliary lesions, copper deposits, and other changes suggestive of another cause of lobular hepatitis preclude the diagnosis of autoimmune hepatitis [3]. Antinuclear antibodies, smooth-muscle antibodies, or antibodies to liver/kidney microsome type 1 are required for the diagnosis and must be present in titers of at least 1:80 in adults and 1:20 in children (Table 1) [3]. The definite diagnosis of autoimmune hepatitis requires satisfaction of all criteria shown in Table 1. Table 1. Criteria of the International Autoimmune Hepatitis Group for the Diagnosis of Autoimmune Hepatitis Findings that are compatible with autoimmune hepatitis but insufficient for a definite diagnosis of this condition justify the designation probable autoimmune hepatitis (Table 1) [3]. Patients who receive this designation typically have histories of alcohol consumption or exposure to hepatotoxic drugs or have serum levels of globulin or autoantibody titers (or both) that are lower than those required for a definite diagnosis. Patients who are seronegative for antinuclear antibodies, smooth-muscle antibodies, and antibodies to liver/kidney microsome type 1 are also considered to have probable autoimmune hepatitis if they have other liver-associated autoantibodies of a less conventional nature, such as antibodies to asialoglycoprotein receptor, soluble liver antigen, liver-pancreas, or liver cytosol type 1 [3]. Patients with probable diagnoses must satisfy histologic criteria that are as rigid as those for patients with definite diagnoses (Table 1); (Figure 1). In this context, predominant bile duct lesions and cholestatic features preclude the diagnosis [3]. Patients who are deficient in one or more of the criteria for a definite diagnosis must be assigned a probable diagnosis (Table 1). A scoring system has also been proposed by the International Autoimmune Hepatitis Group [3] for the definite and probable diagnoses of autoimmune hepatitis (Table 2). This system promises to provide a template for the systematic assessment of autoimmune hepatitis and its variants. Each manifestation of the disease is graded in accordance with its presumed importance in establishing the diagnosis, and a composite score before and after corticosteroid therapy is calculated [3]. The final score reflects the diagnostic effect of consistent and inconsistent features and the net strength of the diagnosis. By grading the manifestations of each variant condition, the similarity of the variant to autoimmune hepatitis can be determined and the degrees of difference between variants can be evaluated. In this way, the variant can acquire a clinical identity that can affect disease management, facilitate classification schemes, and promote investigative studies and treatment trials. The scoring system requires validation in a prospective trial before it can be applied with confidence in clinical settings [10]. Table 2. Scoring System for Diagnosis of Autoimmune Hepatitis as Proposed by International Autoimmune Hepatitis Group* Autoimmune Variants Patients with variant forms of autoimmune hepatitis have autoimmune features but do not satisfy the criteria for a definite or probable diagnosis of autoimmune hepatitis. In addition, they cannot be placed in another diagnostic category. Such patients have features associated with both autoimmune hepatitis and another type of chronic liver disease (overlap syndromes) or have findings that are incompatible with the diagnosis of autoimmune hepatitis according to the criteria codified by the international panels (outlier syndromes) (Table 3). Table 3. Variant Forms of Autoimmune Hepatitis Implicit in the diagnosis of variant disease is a resemblance of the condition to autoimmune hepatitis [4, 5]. The variant condition is typically indolent and characterized by nonspecific systemic symptoms, including fatigue, arthralgias, and myalgias. A hepatitic biochemical profile coexists with or predominates over cholestatic laboratory changes, and extreme pruritus, xanthelasma, and hyperpigmentation are unusual. Patients may be of either sex and of any age, but they are commonly women 40 years of age or younger. Histologic findings are consistent with the diagnosis of autoimmune hepatitis, featuring periportal hepatitis with or without lobular hepatitis, but unusual morphologic features are often seen, including bile duct injury, steatosis, and portal lymphoid aggregates [4]. The results of liver biopsy are not diagnostic of an autoimmune variant, and they usually show only atypicalities that must be placed in the proper clinical context. Patients with autoimmune variants are either the result of overly precise diagnostic criteria, examples of the blurring of diagnostic distinctions at the fringes of disease categories, or reflections of concurrent disorders in an unfortunate host. As yet, no variant form of autoimmune hepatitis has been established as a separate entity. In the experience at the Mayo Clinic, at least 30% of adult patients in whom features of autoimmune hepatitis predominate have mixed or inconsistent findings that justify the designation of their conditions as variant forms (Figure 2). Figure 2. Frequency of features shared by autoimmune hepatitis and other chronic liver diseases. Overlap Syndromes Concurrent Features of Primary Biliary Cirrhosis Autoimmune hepatitis can be distinguished from primary biliary cirrhosis with confidence in 92% of cases [11, 12]. The two disorders have distinctly different patterns of necroinflammation that are associated with characteristic laboratory and immunoserologic profiles. In 8% of patients, however, the patterns of hepatitis and cholestasis are not discriminating characteristics, and the disease of these few patients constitutes a variant syndrome. The most common findings in these patients are mitochondrial antibodies and histologic features of cholangitis (Table 3). Mitochondrial antibodies are found by indirect immunofluorescence in 20% of patients with autoimmune hepatitis [11]. Titers of these autoantibodies characteri