The Emerging Extrahepatic Manifestations of Hepatitis C Virus Infection in Chronic Hepatitis and Mixed Cryoglobulinemia

Hepatitis C virus (HCV) is known to be responsible for both hepatic and extrahepatic diseases. Mixed cryoglobulinemia, Sjögren syndrome, and chronic polyarthritis are the most documented rheumatologic extrahepatic manifestations of HCV infection. The most frequent and clinically important extrahepatic endocrine manifestations of chronic HCV infection are thyroid disorders and type 2 diabetes mellitus. From a meta-analysis of the literature, a significant association between HCV infection and thyroid autoimmunity and/or hypothyroidism as well as a high prevalence of thyroid cancer have been reported. The pattern of thyroid disorders observed in HCV infected patients is characterized by the presence of elevated circulating anti-thyroid peroxidase antibodies with increased risk of hypothyroidism. Several clinical epidemiologic studies have reported that HCV infection is a risk factor for type 2 diabetes. The type of diabetes manifested by subjects with chronic HCV infection is not of the classical type 2 diabetes; in fact, HCV-related diabetic patients are leaner than the classical diabetic patients, and have a significantly lower LDL-cholesterol, and both systolic and diastolic blood pressure. Furthermore, patients with mixed cryoglobulinemia (mixed cryoglobulinemia) and chronic HCV infection with type 2 diabetes have more frequently non-organ-specific-autoantibodies than non-diabetic patients with mixed cryoglobulinemia and those with chronic HCV infection. Based on the above-mentioned findings, it has been hypothesized that diabetes in HCV infection may have an immune-mediated pathogenesis. In patients with chronic HCV infection, we found an increased risk of carotid artery plaque and carotid intima-media thickening. These findings suggested a possible role for chronic hepatitis C in the pathogenesis of carotid artery remodelling. Recently, high prevalence rates of anti-HCV antibodies were shown in patients with hypertrophic cardiomyopathy or dilatated cardiomyopathy; association with myocarditis has also been suggested. Many studies have linked the Th1 immune response with HCV infection, autoimmune thyroid disorders and diabetes. These findings suggest that a possible common immunological Th1 pattern could be the pathophysiological basis of the association.