Diagnostic uncertainty is probably the main reason so few trials of thetreatment of autoimmune hepatitis have been performed. The earlier studies probably included some patients with hepatitis C who had autoimmune markers, since tests for hepatitis C virus were not available. With a better understanding of the pathophysiology of autoimmune hepatitis, a better definition of its target autoantigens, data on its immunoregulatory control, the availability of experimental models, and more accurate international diagnostic criteria, there are now firmer grounds for complementary studies of the natural history and treatment of autoimmune hepatitis.

The short- and long-term efficacy of immunosuppression in patients with autoimmune hepatitis has been demonstrated unequivocally. In many cases, however, patients are not treated or treatment is begun too late because the diagnosis is missed. Autoimmune hepatitis has been considered a disease occurring predominantly in young women, but up to one third of the patients are men, and the disease can develop in all age groups. Although the clinical findings can vary substantially, a chronic fluctuating course is most common. Up to 40 percent of patients present with acute hepatitis, but either a fulminant presentation or a long subclinical course with only minimal elevations of liver enzymes may be seen. Almost all patients have autoantibodies, but only about two thirds have one of the classic autoimmune markers: antinuclear or anti-smooth-muscle antibodies. Tests for autoantibodies to soluble liver antigen, liver cytosol antigen, and the asialoglycoprotein receptor can help identify most cases.

Hypergammaglobulinemia with a selective increase in serum IgG concentrations is a characteristic laboratory finding. In addition, HLA typing should be performed, since most patients are positive for HLA-B8, DR3, or DR4. If the findings are suggestive but not definitive, a prompt and complete response to immunosuppressive therapy may confirm the diagnosis. It is estimated that in Western countries 20 percent of patients with chronic hepatitis have autoimmune hepatitis, but many cases remain undiagnosed and thus untreated. Considerable progress in therapy could be made by considering the diagnosis earlier and more often.

Initial therapy usually includes corticosteroids. Unless the disease is very mild, therapy should be started at about 1 mg of prednisone per kilogram of body weight daily. When serum aminotranferasc concentrations start to fall, the dose of prednisone should be tapered (at a rate of 10 mg per week, down to a dose of 30 mg per day, and then at a rate of 5 mg per week, down to a dose of 10 to 15 mg per day). Adding azathioprine can help keep the required dose of corticosteroids low. Azathioprine takes several weeks to work and should therefore be initiated as soon as the diagnosis is certain. Reports from King College Hospital in London, in particular the report by Johns on et al. [October 1995] Journal, have helped define the role of azathioprine in the treatment of autoimmune hepatitis. The superiority of azathioprine over corticosteroids in maintaining remission and its efficacy as long-term maintenance therapy have been clearly shown by these studies.

The rate of steroid withdrawal and the increased risk of cancer with long-term and high-dose azathioprine therapy in the study by Johnson et al. merit discussion. The researchers used 1 mg of azathioprine per kilogram together with prednisolone to induce remission and maintain it for one year. The dose of azathioprine was then doubled, and the prednisolone was withdrawn fairly rapidly in decrements of 2.5 mg per day every two weeks. Why was the dose of azathioprine doubled, and why was the prednisolone withdrawn over such a short time? More than half the patients in the study by Johnson et al. has arthralgias - presumably a symptom of corticosteroid withdrawal - which required the use of analgesic agents in about 40 percent of the patients. In our experience, withdrawal symptoms can generally be averted by tapering the prednisolone much more slowly (usually, 2.5 mg per day every three months).

The relatively high dose of azathioprine was probably chosen because of concern about frequent relapses after the withdrawal of corticosteroids. After remission, the goal of therapy is to prevent relapses, with minimal side effects. The risks of osteoporosis and obesity, the most serious dose-dependent adverse effects of corticosteroids, have to be weighed against the risk of cancer due to relatively high doses of azathioprine. Many patients remain in remission with a dose of 50 mg of azathioprine per day. If this dose is insufficient, it may be safer to add 5 to 7.5 mg of prednisone per day than to increase the dose of azathioprine to 2 mg per kilogram per day. Of the 72 patients described by Johnson et al., 5, including 4 who died, had tumors. The risk of cancer is of particular concern in treating young patients, most of whom require lifelong immunosuppression.

Other questions remain. First, can this experience in treating patients with the classic type of autoimmune hepatitis be extended to patients with autoantibodies to soluble liver antigen or liver-kidney-microsomal antigen or to the few patients with autoantibody-negative disease? We believe the answer is yes. Second, which drugs should be given to the minority of patients who cannot tolerate azathioprine or who do not have a complete remission? We have had favorable results with cyclophosphamide. Cyclosporine has been used successfully by other investigators. Third, should the goal always be complete biochemical remission, and should mild disease be treated? We believe the answer in both cases is yes, because fibrosis can develop rapidly, even serum aminotransferase concentrations are not very high. In the early clinical experience with this disease, many patients already had cirrhosis at the time of diagnosis. This is still true today.

Finally, how long should patients be treated? Most patients with autoimmune hepatitis have to be treated throughout their lives, but 10 to 30 percent remain in remission without medications after a minimum of four years of maintenance therapy. Before immunosuppressive therapy is stopped, a liver biopsy should be performed to confirm that there is no inflammatory activity. After therapy has been stopped, patients should be monitored closely. Relapses usually occur during the first year but are still possible after many years.

Source: Karl-Hermann Meyer, ZUM; Buschenfelde, M.D., Ph.D. Ansgar W. Lohse, M.D.