Anti-Golgi complex antibodies during pegylated-interferon therapy for hepatitis C

Abstract

Abstract: Background/Aim: Pegylated interferon (Peg-IFN) plus ribavirin is the standard therapy for hepatitis C. Peg-IFN has several antiviral mechanisms, but its role in hepatitis C treatment seems to be related to its immunomodulatory effect. Ribavirin, an antiviral agent, potentiates IFN activity when added to it. Both drugs are associated with adverse reactions of different magnitudes. Autoimmune phenomena have been reported with this treatment. In this paper, we describe cases of ALT/GGT flares during Peg-IFN plus ribavirin treatment, which related to the appearance of anti-Golgi antibody and disease progress.

Methods: We investigated three patients with hepatitis C and severe ALT/GGT flares during Peg-IFN and ribavirin treatment coinciding with anti-Golgi complex antibody as the only marker of autoimmunity. We then reviewed the medical files and tested anti-Golgi antibody in stored sera from 25 patients treated with conventional IFN and in 14 patients treated with Peg-IFN.

Results: The three patients were male, over 45 years of age; all were relapsers and non-responders. Anti-Golgi antibody was positive during treatment coinciding with ALT/GGT flares but with hepatitis C virus (HCV)-RNA negativity, disappearing after stopping treatment, with normalization of ALT/AST levels. One patient had progression of fibrosis from F2 to F3 despite negativity of HCV-RNA. In the last group, only two patients treated with Peg-IFN experienced ALT/GGT flares but without anti-Golgi antibody

Conclusions: The presence of anti-Golgi complex antibody could be a marker of a temporary autoimmune phenomenon and progressive disease.

Infection with hepatitis C virus (HCV) is an important public health problem worldwide (1). About 55–86% of HCV patients develop chronic infection (2–4).

Chronic HCV is usually characterized by a lack of symptoms or only fatigue or abdominal pain. Extra hepatic manifestations are well known and primarily associated with autoimmune or lymphoproliferative states such as arthritis, autoimmune thyroiditis, diabetes mellitus, idiopathic thrombocytopenic purpura, myasthenia gravis, Sjogren syndrome, aplastic anemia, essential mixed (type II) cryoglobulinemia, monoclonal gammopathy and non-Hodking lymphoma. Dermatological manifestations include erythema multiforme, erythema nodosun, Lichen Planus, Porphyria cutanea tarda, psoriasis, pruritus and vasculitis. Idiopathic pulmonary fibrosis and membranoproliferative glomerulonephritis have also been reported (5).

Patients with chronic HCV infection do have a higher prevalence rate of autoantibodies in the serum (6). The determination of the antinuclear antibody has thus been recommended before starting HCV therapy (7).

Since 1999, interferon (IFN) plus ribavirin is considered as the standard of care for hepatitis C (8). IFN has several antiviral mechanisms, but its role in hepatitis C treatment seems to be related to its immunomodulatory effect (9). Despite its broad spectrum of antiviral activity, ribavirin has a negligible direct antiviral action against HCV replication when used in monotherapy. In contrast, it potentiates IFN activity when added to it, suggesting an additional immunomodulatory effect (10).

Both drugs are related to adverse reactions of different magnitudes. Among these side-effects, anemia, neutropenia, thrombopenia, depression and fatigue are the most common, but less frequent adverse reactions related to autoimmune phenomena have been frequently reported.

Therapy with IFN-α does also induce autoantibodies in more than half of the patients treated for chronic hepatitis C. Common antibodies are antithyroid, antinuclear antibodies and antibodies against insulin. In the majority of these patients, no evidence of autoimmune disease will develop. However, in susceptible patients, autoimmune features may occur (11, 12).

Another unusual side-effect is autoimmune hepatitis, which can prompt immediate discontinuation of the treatment (13). Antithyroid antibodies and autoimmune thyroiditis seem to be the most common side-effects attributable to the immunomodulatory role of IFN. Autoimmune hemolytic anemia and immune-mediated thrombocytopenia purpura were related to this therapy. Autoimmune arthritis including rheumatoid arthritis can emerge during IFN-α therapy as well as systemic lupus erythematosus-like syndrome. Diabetes mellitus may worsen or develop during this therapy (11–16).

More recently, Pegylated interferon (Peg-IFN) replaced the conventional one because of best results in terms of sustained virological response (17, 18). Although these newer agents are significantly more effective than earlier versions of standard IFN, the side-effect profile of IFN-based therapies has remained unchanged despite increased incidence of AES. Thus, influenza-like symptoms (fever, myalgia and rigor) and several gastrointestinal disturbances occur with increased frequency (P<0.05) in those treated with Peg-IFN combination therapy compared with standard IFN and ribavirine (19–21).

New side-effects of this therapy are reported continuously with the acknowledgment of the results of the different trials (22).

During Peg-IFN plus ribavirin treatment, some ALT and GGT elevations are observed, but its mechanism remains unknown (18). Such liver enzyme elevations do not seem to alter antiviral response and even mild to moderate flares are considered benign as they are not related to liver disease progression.

In this paper, we described cases of ALT/GGT flares during Peg-IFN plus ribavirin treatment, which were related to anti-Golgi antibody appearance and progressive liver disease. Interestingly, the Golgi apparatus may serve as the starting site of morphological changes associated with viral infection and replication leading to cell fusion and syncytia formation.