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Induction of multiple autoantibodies to islet cell antigens during treatment with interferon alpha for chronic hepatitis C
  2. C STOLTE,
  3. A GEIER,
  1. Medical Department III
  2. Technical University of Aachen, Germany
  1. H E Wasmuth, Medical Department III, Technical University of Aachen, Pauwelsstraβe 30, D-52074 Aachen, Germany.hwasmuth{at}

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Editor,—Induction or augmentation of autoimmunity during the treatment of chronic hepatitis C with interferon alpha is a well known phenomenon and a matter of great concern to physicians involved in the field of viral hepatitis. In recent years there have been a number of reports suggesting a link between the antiviral therapy and the development of antibodies to multiple autoantigens. In a recent issue ofGut, Wesche et al(OpenUrlCrossRefPubMedWeb of Science) described the appearance of antibodies to 21-hydroxylase, an autoantigen of the adrenal cortex, and autoantibodies to glutamate decarboxylase 65 (GAD65) and the tyrosine phosphatase IA2 (IA2), both important autoantigens with respect to the pathogenesis of autoimmune (type 1) diabetes. Autoantibodies to GAD65 and IA2 appeared during or after therapy with alpha interferon for chronic hepatitis C in 5/62 and 1/62 patients, respectively. However, none of these patients was positive for both antibodies.

Type 1 diabetes is regarded as a chronic autoimmune disease caused by selective destruction of the insulin producing β cells. The disease is mediated by T cells but autoantibodies are well established markers for an ongoing autoimmune process within the islets.1 As these autoantibodies usually appear prior to the clinical onset of the disease, they may be used to predict type 1 diabetes in predisposed individuals. In recent studies it has been shown that only those individuals in whom more than one diabetes related autoantibody could be determined are at considerable risk of developing type 1 diabetes.2 Overall, the risk increases with the number of positive autoantibodies.3 Therefore, combined screening for diabetes related autoantibodies is suggested to increase the specificity and the positive predictive value of the autoantibody tests.

We studied 56 patients with chronic hepatitis C (defined by positive anti-HCV and positive HCV-RNA) for the appearance of diabetes related autoantibodies after interferon therapy. We first screened for islet cell antibodies (indirect immunofluorescene) and if positive additionally determined autoantibodies to GAD 65, IA2, and insulin (radioimmunoassay and ELISA, respectively). In case of positivity for any antibody we analysed a pretreatment serum sample to exclude the existence of any of these autoantibodies prior to interferon alpha therapy.

We identified four patients with diabetes related autoantibodies after cessation of therapy with interferon alpha (table 1). None of the patients had any of these antibodies prior to antiviral therapy nor had they a positive family history for autoimmune diabetes. Patient Nos 3 and 4 only developed insulin autoantibodies at a low titre. Induction of antibodies to insulin is a known phenomenon during therapy with interferon alpha and is described in a frequent number of cases.4 Overall, these patients seem to have a low risk of progressing to clinically overt diabetes. Patient No 1 was found to be positive for insulin and GAD65 autoantibodies. Based on prospective clinical studies, this patient has an intermediate risk of developing diabetes.5 We have now followed the patient for 16 months after interferon therapy and he has not developed an abnormal fasting glucose so far. The most striking example for induction of diabetes related autoantibodies was found in patient No 2. He developed three major autoantibodies during interferon therapy (GAD65, IA2, and ICA). Based on the predictive value of three positive autoantibody tests, this patient has a considerable risk of developing clinical overt diabetes over the next years. To date (follow up for 12 months) he has not developed an abnormal fasting glucose or an abnormal glucose tolerance test. The situation in this patient is further complicated as he did not respond to the antiviral therapy and another course of interferon might further increase his risk of developing autoimmune diabetes.

Table 1

Characteristics of patients with diabetes related autoantibodies after interferon alpha therapy for chronic hepatitis C infection

In summary, different diabetes related autoantibodies can be induced during interferon therapy for chronic HCV infection. However, we propose that only those patients with more than one autoantibody are at a considerable risk of progressing to clinically overt disease. Therefore, if one autoantibody appears during antiviral therapy, follow up should include screening for all other diabetes related autoantibodies. Furthermore, the question of whether patients with multiple autoantibodies should be retreated with interferon remains unsolved. Here the physician has to weigh possible progression of liver disease against the possibility of inducing autoimmune diabetes.


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