@article{e715f5a1a3de4678a11126e31b60f7ef,
title = "Extrahepatic Morbidity and Mortality of Chronic Hepatitis C",
abstract = "Chronic hepatitis C virus (HCV) infection is associated with several extrahepatic manifestations. Patients with HCV may develop mixed cryoglobulinemia and its sequelae, ranging from cutaneous and visceral vasculitis to glomerulonephritis and B-cell non-Hodgkin lymphoma. HCV-infected patients have increased rates of insulin resistance, diabetes, and atherosclerosis, which may lead to increased cardiovascular morbidity and mortality. Neurological manifestations of HCV infection include fatigue and cognitive impairment. The mechanisms causing the extrahepatic effects of HCV infection are likely multifactorial and may include endocrine effects, HCV replication in extrahepatic cells, or a heightened immune reaction with systemic effects. Successful eradication of HCV with interferon alfa and ribavirin was shown to improve some of these extrahepatic effects; sustained virological response is associated with resolution of complications of cryoglobulinemia, reduced levels of insulin resistance, reduced incidence of diabetes and stroke, and improved fatigue and cognitive functioning. The availability of new interferon-free, well-tolerated anti-HCV treatment regimens is broadening the spectrum of patients available for therapy, including those in whom interferon was contraindicated, and will likely result in greater improvements in the extrahepatic manifestations of HCV. If these regimens are shown to confer significant benefit in the metabolic, cardiovascular, or neuropsychiatric conditions associated with HCV infection, extrahepatic manifestations of HCV may become a major indication for treatment even in the absence of liver disease.",
keywords = "Cardiovascular Risk, Cryoglobulins, Fatigue, Health-Related Quality of Life, Insulin Resistance",
author = "Francesco Negro and Daniel Forton and Antonio Crax{\`i} and Sulkowski, {Mark S.} and Feld, {Jordan J.} and Manns, {Michael P.}",
note = "Funding Information: Although there is accumulating evidence that HCV is able to infect and replicate in B cells, it is not clear that lymphocyte infection is required for MC to develop. 113 Clonal expansion of B cells in response to viral antigens leads to production of rheumatoid factor–containing immune complexes, which cause symptomatic disease due to a complement C1q-mediated vasculitis on deposition in small vessels of different organs ( Figure 1 B ). 17 Demonstration that the cryoprecipitate contains viral antigens, particularly the core protein, along with the expected monoclonal IgM, polyclonal IgG, and complement proteins, furthered the evidence supporting a direct link between HCV and MC. 17 HCV may stimulate B-cell proliferation through direct interaction of the HCV E2 glycoprotein with CD81 on the surface of B cells or may directly bind to and activate HCV-specific B-cell receptors. 114 B cells in patients with MC show a restricted Ig heavy chain use, with V H 1-69 and V K 3-20 highly overrepresented. 10 Notably, these same clonal populations are found in patients with HCV-associated non-Hodgkin lymphoma (NHL), suggesting a strong link between these 2 lymphoproliferative conditions. 11 However, even among patients with MC, NHL is rare, occurring at a rate of 6.6 per 1000 person-years or less; this suggests that NHL requires a second event beyond clonal B-cell expansion. 115 This is supported by careful evaluation of the B-cell populations. Patients with MC show expansion of peripheral IgM + κ + CD27 + B cells, characteristic of memory B cells. 10 Phylogenetic analysis suggests antigen-driven affinity maturation, supporting the concept that these cells are responding to viral antigens. 17 However, transcriptional analysis has shown that many of the B cells in patients with MC display an anergic and proapoptotic phenotype, suggesting a loss of antigen-driven proliferation, possibly as a feedback mechanism to prevent autoreactive B-cell responses and explaining the relatively low frequency of clinical manifestations in patients. 116 Loss of the proapoptotic phenotype through specific gene translocations, stimulation by B-cell activating factor, and other mechanisms may lead MC to give rise to low-grade NHL. 112 HCV is also associated with aggressive diffuse large B-cell NHL; however, the pathogenesis may differ with less evidence of antigen-driven proliferation and a greater association with direct viral infection of B cells. 109,110 Funding Information: Medical writing assistance, funded by Boehringer Ingelheim Pharma GmbH Co KG, was provided by Jennifer Tobin of Choice Healthcare Solutions.",
year = "2015",
month = nov,
doi = "10.1053/j.gastro.2015.08.035",
language = "English (US)",
volume = "149",
pages = "1345--1360",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "6",
}