Autoimmune Hepatitis: Making Sense of All Those Antibodies

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Autoimmune Hepatitis: Making Sense of All Those Antibodies By Bruce A. Luxon, MD, PhD

Introduction

Diagnostic Considerations

Traditional Autoantibodies

Subtypes of Autoimmune Hepatitis

Nontraditional Autoantibodies

Who Should Be Treated?

Medical Therapy

Evaluation of Treatment Response

Summary

Introduction

The following review of autoimmune hepatitis provides a wealth of information about this condition that includes the diagnostic criteria for autoimmune hepatitis, the use of serologic markers and other tests in diagnosis and treatment, and current recommendations for treatment and follow-up.

In many patients with chronic hepatitis, no obvious cause can be found. Some of these patients have an overactive immune system reaction that is responsible for the chronic inflammation. Diagnosis can be difficult because autoantibodies and other typical features of autoimmunity are not present in all cases. In this article, Dr Luxon provides a roadmap through the maze of antibodies that are involved in autoimmune hepatitis and discusses current treatment options and evaluation of response to medical therapy.

Autoimmune hepatitis is an idiopathic hepatitis characterized by histologic evidence of chronic liver inflammation, autoantibodies, and increased serum levels of gamma-globulins (1). The clinical manifestations of the disease have been well characterized since its initial description by Waldenström in 1950.

Surprisingly, the clinical presentation and understanding of this disease have remained essentially unchanged in the last 50 years. The purpose of this article is to provide a brief summary of the diagnostic criteria for autoimmune hepatitis, emphasizing new information about autoantibodies and autoantigens, and to provide an algorithmic approach to initial treatment.

Diagnostic Considerations

Like many other autoimmune diseases, autoimmune hepatitis has no pathognomonic feature. The diagnosis requires the presence of typical features and the exclusion of other conditions (table 1) (2). The clinical features may be suggestive of autoimmune hepatitis or of another condition that can cause hepatitis. The conditions that are most likely to confuse diagnosis are 's disease, chronic viral hepatitis (especially hepatitis C), and drug-induced hepatitis.

A scoring system for the quantitative diagnosis of autoimmune hepatitis has been proposed by the International Autoimmune Hepatitis Group (table 2) (3). In this system, a patient is evaluated on the basis of a number of biochemical, epidemiologic, and clinical markers before treatment, and a pretreatment score is calculated. The score can be modified by response to treatment and allows appropriate diagnosis in patients with discrepant features. High scores (>15) before corticosteroid treatment are consistent with a "definite" diagnosis of autoimmune hepatitis. A definite diagnosis after treatment requires a score higher than 17. Patients with a score of less than 10 are unlikely to have autoimmune hepatitis.

The scoring system was originally designed to aid in the selection of homogeneous groups of patients for research purposes. However, it has also proved valuable in routine clinical practice, especially for atypical or overlapping cases. The system has been validated in several large patient populations in the United States, Europe, and Asia. Its sensitivity for probable or definite autoimmune hepatitis ranges from 97% to 100%, and its specificity for excluding autoimmune hepatitis in patients with chronic hepatitis C is 66% to 92% (4).

However, the ability of the scoring system to differentiate autoimmune hepatitis from a variety of cholestatic syndromes is not nearly as good. In one study (5), patients with cholestatic features due to primary sclerosing cholangitis were especially likely to be erroneously categorized as having autoimmune hepatitis.

Liver biopsy remains essential to diagnosis and evaluation of disease severity in patients with autoimmune hepatitis. The degree of elevation of transaminase levels is not predictive of the histologic pattern of injury or the extent of fibrosis. Liver biopsy is also key in diagnosis and treatment of variant syndromes of autoimmune hepatitis and exclusion of concomitant liver diseases, such as nonalcoholic fatty liver disease, and drug toxicity.

A liver biopsy specimen showing the typical interface hepatitis is presented in figure 1. Interface hepatitis consists of a lymphoplasmacytic inflammatory infiltrate that may extend from the portal tract into the lobule. Plasma cells are classically thought to be a hallmark of the disease, although 34% of patients with autoimmune hepatitis have few or no plasma cells (6). A rosette of hepatocytes (figure 2) is a collection of swollen hepatocytes separated from other damaged hepatocytes by inflammation and collapsed stroma. These rosettes are often found in conjunction with portal plasma cell infiltration.

Traditional Autoantibodies

Autoimmune hepatitis is traditionally associated with three antibodies: antinuclear antibodies (ANA), anti-smooth-muscle antibodies (ASMA), and antibodies to liver-kidney microsomes (anti-LKM). These three antibodies are the main ones that define autoimmune hepatitis, and they also may serve as a means of serologic sub-classification of autoimmune hepatitis. The presence of these antibodies should be determined in all patients in whom autoimmune hepatitis is suspected.

Antinuclear AntibodiesANA are common markers of immune-mediated disease in humans and are the traditional markers of autoimmune hepatitis. They are present in two thirds of patients with the disease. Most commonly, the determination of ANA is performed by indirect immunofluorescence. A homogeneous or speckled immunofluorescence pattern is typical. Despite intensive research, the particular nuclear targets of ANA in autoimmune hepatitis remain uncertain. Proposed targets include the centromere, ribonuclear proteins, and ribonucleoprotein complexes. None of these antigens are associated with a specific pattern on immunofluorescence.

In diagnosis of autoimmune hepatitis, the specific molecular targeting of the antibody does not connote additional information to increase diagnostic precision. ANA occur in high titers, usually exceeding 1:160. However, the titer does not correlate with disease stage, activity, or prognosis (7). These antibodies can also be found in other hepatitic and cholestatic liver diseases, including primary biliary cirrhosis, primary sclerosing cholangitis, chronic viral hepatitis, drug-induced hepatitis, nonalcoholic steatohepatitis, and alcoholic liver disease.

Anti-Smooth-muscle AntibodiesThese antibodies are traditionally found in autoimmune hepatitis and are directed against cytoskeletal proteins, including actin, troponin, tubulin, vimentin, desmin, and skeletin. ASMA are present in 87% of patients with the disease and are accompanied by ANA in 54% of patients (7). They are not specific for autoimmune hepatitis; rather, they occur in other liver diseases as well as various infectious and rheumatologic disorders. ASMA are detected with immunofluorescence using murine stomach and kidney. Antibody titer does not correlate with disease course or prognosis, and titers can change dramatically over time in individual patients (7).

Microsomal AntibodiesAutoantibodies directed against the cytochrome enzymes are found in patients who typically do not have antibodies against smooth-muscle or nuclear antigens. These antibodies to liver-kidney microsomes (anti-LKM) are directed against specific members of the cytochrome P-450 system, including 2D6, 2C9, 2A6, and 1A2 (8).

Anti-LKM are rare in the United States and are found in less than 1 in 25 adults with autoimmune hepatitis. In Europe, they are found in pediatric patients as well as in up to 20% of affected adults. Although the cause of these geographic differences is unknown, genetic differences in the immune response to a particular target antigen have been suggested (9).

Anti-LKM also occur in patients who have drug-induced hepatitis. In such patients, drug-metabolizing enzymes may create reactive metabolites, which cause the immune system to form autoantibodies. Responsible agents include halothane (Fluothane), dihydralazine, and anticonvulsive agents.

Subtypes of Autoimmune Hepatitis

Different forms of autoimmune hepatitis are defined on the basis of the presence of specific antibodies. Type 1 (classic) autoimmune hepatitis is the most common and the predominant form in the United States. Patients with type 1 autoimmune hepatitis have either ANA or ASMA. The age distribution is bimodal: teenagers and adults aged 50 to 70 years are most commonly affected. In contrast, type 2 autoimmune hepatitis is rare in the United States and primarily affects young children.

Patients with type 2 autoimmune hepatitis have anti-LKM; by definition, ANA and ASMA are absent. Type 3 autoimmune hepatitis is characterized by antibodies to soluble liver antigen (discussed later) or liver-pancreas antigen and has a bimodal age distribution similar to that of type 1 disease.

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