title: Hepatitis C virus as a systemic disease: reaching beyond the liver.
abstract: Chronic hepatitis C (CHC) is associated with multiple extrahepatic manifestations that may impact infected patients. The mechanisms through which these develop include those which are immunological, in which the chronic persistence of virus leads to the circulation of immune complexes (mixed cryoglobulinemia) and other autoimmune phenomena, and those which are virological and related to the extrahepatic tropism of the virus to other tissues. It is estimated that 40-74 % of patients with CHC may develop at least one extrahepatic manifestation during the course of the disease. Extrahepatic syndromes may represent the first signal of hepatitis C infection in some patients. CHC is associated with a four-fold increased risk of insulin resistance and type 2 diabetes mellitus; with cardiovascular disease in 17-37 % of patients; and with increased risk for cerebrovascular deaths, with a biological gradient of cerebrovascular mortality correlating with an increasing serum viral load. CHC is also associated with lymphoproliferative disorders, particularly non-Hodgkin B-cell lymphoma. The kidney is involved in 35-60 % of patients with CHC-associated mixed cryoglobulinemia. The prevalent type of glomerulonephritis associated with mixed cryoglobulinemia is membranoproliferative glomerulonephritis. In 30 % of cases, renal involvement begins with a nephritis syndrome and acute renal failure, while in 55 % there is only mild hematuria, microalbuminuria, proteinuria and renal insufficiency. CHC is also associated with cognitive impairment, especially in memory and concentration. Thus, extrahepatic CHC manifestations involve multiple organ systems outside the liver linked to a variety of comorbidities which may lead to significantly increased mortality from non-liver-related events.
authors.affiliation: Department of Internal Medicine, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
authors.forename: Kirat
authors.initials: K
authors.lastname: Gill
authors.affiliation: Hepatology Department, Nork-Marash Medical Center, 13 Armenak Armenakyan Street, 0047, Yerevan, Armenia.|Department of Infectious Disease, Nork-Marash Medical Center, 13 Armenak Armenakyan Street, 0047, Yerevan, Armenia.
authors.forename: Hasmik
authors.initials: H
authors.lastname: Ghazinian
authors.affiliation: Department of Internal Medicine, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Manch
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA. rgish@robertgish.com.|National Viral Hepatitis Roundtable, San Francisco, CA, USA. rgish@robertgish.com.
authors.forename: Robert
authors.initials: R
authors.lastname: Gish
mesh_terms: D002561:Cerebrovascular Disorders / Q000209:etiology; D003449:Cryoglobulinemia / Q000209:etiology; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology; D005921:Glomerulonephritis / Q000209:etiology; D016174:Hepacivirus; D006526:Hepatitis C / Q000150:complications* / Q000276:immunology; D006801:Humans; D007333:Insulin Resistance; D008232:Lymphoproliferative Disorders / Q000209:etiology
keywords: Chronic hepatitis C; Diabetes mellitus; Extrahepatic manifestations; HCV brain syndrome; Insulin resistance; Lymphoproliferative disorder; Mixed cryoglobulinemia; Renal failure