26 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM JANUARY 2009 VOL 5 NO 1 www.nature.com/clinicalpractice/endmet Endocrine manifestations of hepatitis C virus infection Alessandro Antonelli*, Clodoveo Ferri, Silvia Martina Ferrari, Michele Colaci, Domenico Sansonno and Poupak Fallahi INTRODUCTION Chronic infection with hepatitis C virus (HCV) can result in inflammation of the liver, which in turn can progress to cirrhosis, liver failure or cancer (Box 1). Extrahepatic manifestations can also develop as a consequence of chronic infec- tion. 1,2 HCV-related extrahepatic diseases include a number of organ-specific and organ-nonspecific immunological disorders and malignancies, such as mixed cryoglobulinemia, nephropathy and non-Hodgkin lymphoma. 1–2 In addition, some patients might develop ‘HCV syndrome’, a complex clinical condition that comprises vari- able combinations of both hepatic and extra- hepatic manifestations. Mixed cryoglobulinemia and lymphoproliferative disorders are probably the best-studied of the systemic, extrahepatic HCV-related diseases. The results of clinico- epidemiological, immunological, and virological studies have demonstrated great geographical heterogeneity in the prevalence of these disorders, which suggests that genetic and environmental cofactors have an important role. 1–2 In addition, an increased prevalence of endocrine disease has been observed in large series of patients infected with HCV. 1–4 The most frequently occurring— and clinically important—of these endocrine disorders are thyroid disease and type 2 diabetes mellitus (T2DM), although preliminary evidence suggests that gonadal dysfunction might also occur in patients with chronic HCV infection. HEPATITIS C VIRUS AND THYROID DISEASE Autoimmune thyroid disease Many studies have attempted to evaluate the preva- lence of autoimmune thyroid disease (AITD) in HCV-positive patients. Unfortunately, however, the results that have been reported to date have proven to conflict with one another, which could possibly be a consequence of poor internal con- trols. Nonetheless, a review of the literature identified 17 controlled studies, 5, 6 12 of which reported a positive association between HCV infection and AITD and/or thyroid dysfunction (reviewed elsewhere 6–8 ). The meta-analysis also SUMMARY Chronic infection with hepatitis C virus (HCV) can result in both hepatic and extrahepatic disease and endocrine dysfunction represents an important class of HCV-related extrahepatic disease. The most frequently occurring—and clinically important—of these endocrine disorders are thyroid disease and type 2 diabetes mellitus. In this Review, we evaluate the evidence in support of a link between HCV infection and endocrine-system dysfunction, and discuss potential pathophysiological mechanisms. A meta-analysis of the literature has revealed significant associations between chronic HCV infection, thyroid autoimmunity and hypothyroidism. Furthermore, a high prevalence of thyroid cancer has been reported in HCV-positive patients. Several clinicoepidemiological studies have demonstrated that chronic HCV infection could lead to the development of type 2 diabetes mellitus, possibly as a result of HCV-induced metabolic disturbances. Some researchers have postulated that a type 1 T-helper -cell mediated immune response underpins the association of chronic HCV infection with endocrine disease. Indeed, the available data suggest that a common immunological, type 1 T-helper cell pattern of cytokine expression and activation (via interferon-γ) could provide the pathophysiological basis for this association. Nonetheless, additional studies will be necessary to elucidate fully all the mechanisms involved in HCV-related endocrine dysfunction. KEYWORDS diabetes mellitus, hepatitis C virus, mixed cryoglobulinemia, thyroid autoimmunity, thyroid cancer A Antonelli is an Assistant Professor of Internal Medicine, SM Ferrari is a Research Fellow and P Fallahi is a Postdoctoral Researcher in the Department of Internal Medicine, University of Pisa; C Ferri is Full Professor of Rheumatology and M Colaci is a Researcher in the Department of Internal Medicine, University of Modena; D Sansonno is an Associate Professor of Internal Medicine in the Department of Internal Medicine and Clinical Oncology, University of Bari, Italy. Correspondence *Department of Internal Medicine, University of Pisa School of Medicine, Via Roma 67, I-56100 Pisa, Italy a.antonelli@med.unipi.it Received 10 July 2008 Accepted 17 October 2008 www.nature.com/clinicalpractice doi:10.1038/ncpendmet1027 REVIEW CRITERIA A search for English-language articles published between 1990 and 2008 was performed in MEDLINE and PubMed. The search terms included “hepatitis C”, “HCV”, “hepatitis C virus”, “anti-HCV antibodies”, “hepatitis C infection”, “thyroid, thyroid autoimmunity”, “anti-thyroid autoantibodies”, “thyroiditis”, “autoimmune thyroiditis”, “hypothyroidism”, “hyperthyroidism”, “Graves disease”, “thyroid nodules”, “goiter”, “thyroid cancer”, “diabetes mellitus (type 1, type 2, LADA)”, “insulin resistance”, “hepatosteatosis”, “islet cells”, “islet cell autoimmunity”, “gonadal dysfunction”, and “erectile dysfunction”. REVIEW