Ian G. McFarlane

Azathioprine for Long-Term Maintenance of Remission in Autoimmune Hepatitis

BACKGROUND In most patients with autoimmune hepatitis, remission can be maintained with prednisolone, usually in combination with azathioprine, but the majority of patients have a relapse when treatment is stopped and therefore require long-term therapy. Because prolonged corticosteroid therapy may have serious toxic effects, in 1984 we undertook a controlled trial of maintenance therapy with azathioprine alone. None of the 25 patients in that trial had relapses during the follow-up period of one year. We have now followed these 25 patients for 10 years and have treated an additional 47 patients in a similar manner. METHODS The 72 patients (median age, 47 years; range, 14 to 71) had been in complete remission for at least one year with 5 to 15 mg of prednisolone per day and 1 mg of azathioprine per kilogram per day. The dose of azathioprine was increased to 2 mg per kilogram per day, and the prednisolone was gradually withdrawn. Remission was defined as the absence of symptoms suggestive of a relapse and serum globulin and aspartate aminotransferase concentrations within the normal range, with or without a liver biopsy showing only minimal inflammation. RESULTS Sixty patients (83 percent) remained in remission while receiving azathioprine alone for a median of 67 months (range, 12 to 128). Of 48 follow-up liver biopsies in 42 patients, 45 showed inactive or minimal disease, and 3 showed moderate disease (2 after one year of therapy and 1 after eight years). After the prednisolone had been withdrawn, 26 patients lost their cushingoid facies, and 32 patients lost weight (median loss, 6.4 kg; range, 1.5 to 22.3). The most common adverse effect was arthralgia (in 38 patients). With the higher dose of azathioprine, four patients had myelosuppression, defined as a decrease in the leukocyte and platelet counts to less than 4000 and 150,000 per cubic millimeter, respectively. Two of these patients (both with pancytopenia) relapsed when the azathioprine was withdrawn; in the other two, remission was maintained with the resumption of prednisolone. Lymphopenia developed in 32 of 56 patients treated with 2 mg of azathioprine per kilogram per day for more than two years. During follow-up, nine patients died: one of liver failure and eight of causes not directly related to their liver disease. CONCLUSIONS Many patients with autoimmune hepatitis who have been in complete remission for at least one year with prednisolone and azathioprine can remain in remission with a higher dose of azathioprine alone.

Detection of Antibodies Directed against a Liver-Specific Membrane Lipoprotein in Patients with Acute and Chronic Active Hepatitis

A specific and sensitive radioimmunoassay was used to measure the levels of antibody to a liver-specific membrane lipoprotein in patients with acute and chronic liver disease. Antibody was detected in 29 of 30 patients with chronic active hepatitis (all of 15 HBsAg-negative and 14 of 15 HBsAg-positive cases), and in 10 of 17 patients with chronic persistent hepatitis but at significantly lower titer. The titer of antibody to the lipoprotein showed a significant correlation with activity of disease as judged histologically and biochemically. Transiently elevated levels were found in 20 of 21 patients with acute viral hepatitis, but there was no correlation with the degree of liver damage. Antibody to liver-specific membrane protein may be part of the final common pathway of liver-cell damage in both HBsAg-positive and HBsAg-negative chronic activite hepatitis, whereas other immune mechanisms determine the liver-cell injury in acute viral hepatitis.

Cell-mediated immunity and suppressor-T-cell defects to liver-derived antigens in families of patients with autoimmune chronic active hepatitis.

By means of an indirect T-lymphocyte migration inhibitory factor assay, T-cell sensitisation to the asialoglycoprotein receptor, a liver-specific protein on the surface of hepatocytes, was found in patients with autoimmune chronic active hepatitis (CAH) but not in healthy relatives or spouses. Cellular immunity to a liver-derived lipoprotein complex (LSP) which also contains the asialoglycoprotein receptor, and to which immune reactions have been previously demonstrated in patients with CAH, was also examined. In contrast to the findings with the purified asialoglycoprotein receptor, cell-mediated sensitisation to LSP was detected in all the patients and also in 24% of first-degree relatives and 27% of spouses, suggesting an environmental influence. There was a functional defect in suppressor T lymphocytes specific for liver-derived antigens in 50% of first-degree relatives and 43% of second-degree relatives, but in only 9% of spouses. This abnormality of immunoregulation may be genetically determined and crucial to the development of the disease.

Autoimmune Hepatitis: Clinical Manifestations and Diagnostic Criteria

In 1998, the International Autoimmune Hepatitis Group--a panel of 40 hepatologists and hepatopathologists from 17 countries who have a particular interest in autoimmune hepatitis (AIH)--undertook a review, in light of subsequent experience, of the descriptive criteria and diagnostic scoring system that it had proposed in 1993 for the diagnosis of AIH. This review (published in 1999) noted that the original descriptive criteria appeared to be quite robust and required only relatively minor modifications to bring them up to date with developments and experience in diagnostic modalities for liver disease in general. Analysis of published data on the application of the original criteria in nearly 1000 patients revealed that the diagnostic scoring system had an overall diagnostic accuracy of 89.8%, with a sensitivity of 98.0%. Specificity for excluding definite AIH in patients with chronic viral hepatitis and circulating autoantibodies or patients with overlapping cholestatic syndromes was 98% to 100%, but specificity for excluding probable AIH in these disorders ranged from only 60% to 80%. Modifications, including adjustments to the weightings against biochemical and histological cholestatic features, have been made to the scoring system to improve its specificity.

Serial study of liver-directed autoantibodies and autoreactive T-lymphocytes in acute viral hepatitis B

To explore the mechanisms underlying liver-directed autoimmune reactions in acute Hepatitis B Virus (HBV) infection, we followed five subjects who were identified in the early incubation phase (30-70 days before the first elevation of transaminases). We assessed serially cellular (using a T-lymphocyte migration inhibitory factor assay) and humoral (RIA) immunity to LSP (a macromolecular, liver-derived lipoprotein complex) and hepatic lectin (HL), the liver-specific receptor for desialylated glycoproteins, which appears to be a major target antigen for autoreactions in autoimmune chronic active hepatitis. Anti-LSP and anti-HL autoantibodies were found, at some stage during acute HBV infection, in 4/5 subjects, whereas cellular immunity to the same antigens was detected in only two patients. Sustained production of anti-HL antibodies was noted only in patients showing cellular immunity to this antigen and was apparently secondary to liver damage, whereas anti-LSP antibodies were first detected at the onset of liver injury when there was no evidence of T-cell immunity to the same antigenic complex. One explanation for this apparent dichotomy between cellular and humoral responses to LSP is that a helper T-cell response to the major envelope component of HBV, HBsAg, which precedes by 10-20 days the development of anti-LSP antibodies, promotes a humoral reaction to autoantigens contained in the LSP preparation, coexpressed with HBsAg, on the surface of infected hepatocytes.