Manifestations of Chronic Hepatitis C Virus Infection Beyond the Liver Ira M. Jacobson, Patrice Cacoub, Luigino Dal Maso, Stephen A. Harrison, Zobair M. Younossi  Clinical Gastroenterology and Hepatology  Volume 8, Issue 12, Pages 1017-1029 (December 2010) DOI: 10.1016/j.cgh.2010.08.026 Copyright © 2010 AGA Institute Terms and Conditions

Figure 1 Possible mechanisms of mixed cryoglobulinemia vasculitis. HCV-mediated effects on lymphocytes may lead to antibody production and formation/deposition of immune complexes containing rheumatoid factor, resulting in tissue damage. IgG, immunoglobulin G. Clinical Gastroenterology and Hepatology 2010 8, 1017-1029DOI: (10.1016/j.cgh.2010.08.026) Copyright © 2010 AGA Institute Terms and Conditions

Figure 2 Differential diagnosis between mixed cryoglobulinemia and other autoimmune-lymphoproliferative disorders in the setting of HCV infection. MC syndrome, primary SS, and RA show a clinicopathological overlap, including the possible association with HCV infection. Adapted with permission (Ferri C, Mascia MT. Cryoglobulinemic vasculitis. Curr Opin Rheumatol 2006;18:54–63). The following parameters may be usefully employed for a correct differential classification/diagnosis: primary SS shows typical histopathological pattern of salivary gland involvement and specific autoantibodies (anti-RoSSA/LaSSB), which are rarely found in MC patients; conversely, cutaneous leukocytoclastic vasculitis, visceral organ involvement (glomerulonephritis, hepatitis), low C4, and HCV infection are typically found in MC. Moreover, erosive symmetrical polyarthritis and serum anti-CCP characterize classical RA. Finally, B-NHL may complicate these diseases, more frequently MC and SS. The appearance of B-NHL can be detected by timely and careful clinicoserological monitoring and diagnosed by bone marrow/lymph node biopsies and total body CT scan. Anti-CCP, anti-cyclic citrullinated peptide antibodies; B-NHL, B-cell NHL; RF, rheumatoid factor; SS, Sjögren's syndrome. Clinical Gastroenterology and Hepatology 2010 8, 1017-1029DOI: (10.1016/j.cgh.2010.08.026) Copyright © 2010 AGA Institute Terms and Conditions

Figure 3 Possible mechanisms of lymphoma development include growth stimulation via BLys ligand-receptor activity, progression from MC to lymphoma via an oncogenic event, and direct and indirect lymphocyte transformation. AID, activation-induced deaminase; BCR, B cell receptor; NOS, nitric oxide synthase. Clinical Gastroenterology and Hepatology 2010 8, 1017-1029DOI: (10.1016/j.cgh.2010.08.026) Copyright © 2010 AGA Institute Terms and Conditions

Figure 4 Possible mechanisms of insulin resistance include effects of HCV-induced fibrosis/cirrhosis, direct viral effects on insulin sensitivity via proinflammatory cytokines, and effects of obesity in the development of insulin signalling defects. Clinical Gastroenterology and Hepatology 2010 8, 1017-1029DOI: (10.1016/j.cgh.2010.08.026) Copyright © 2010 AGA Institute Terms and Conditions