Abstract
The hepatitis C virus (HCV) is a hepatotropic virus that causes liver cirrhosis and hepatocellular cancer, but it is now considered a systemic disease because of the additional HCV-associated extrahepatic manifestations (EHMs) that occur. HCV infection is a global health problem, with 150–170 million people being chronically infected. It is estimated that about 350,000 patients die from HCV-related complications. However, the risks of mortality and morbidity are underestimated because studies do not take into account extrahepatic outcomes of chronically infected HCV patients. Extrahepatic complications of HCV infection have been shown to be more prevalent in large cohort studies, where two thirds of patients chronically infected with HCV infection have experienced EHMs (Cacoub et al., Arthritis Rheum 42:2204–2212, 1999; El-Serag et al., Hepatology 36:1439–1445, 2002). Some of these EHMs are well documented and more common, while others are rare or their association with HCV is unproven. HCV-associated autoimmune or lymphoproliferative disorders, from benign mixed cryoglobulinemia to frank lymphomas, have been reported. More recently, many other extrahepatic HCV-related disorders have been reported, including cardiovascular, renal, metabolic, and central nervous system diseases. Viral eradication of HCV has significantly reduced the rates of hepatic and extrahepatic deaths (Cacoub et al., Arthritis Rheum 42:2204–2212, 1999; Adinolfi et al., World J Gastroenterol 20:3410–3417, 2014; Zignego et al., Dig Liver Dis 39:2–17, 2007; Lee et al., J Infect Dis 206:469–477, 2012; Omland et al., Clin Gastroenterol Hepatol 9:71–78, 2011; Uto et al., Hepatology 50:393–399, 2009; Hsu et al., Hepatology 59:1293–1302, 2014). The aim of this chapter is to give a brief objective approach to the epidemiology, pathogenesis, and treatment of HCV-associated EHMs.
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Abbreviations
- Anti-CCP:
-
Anti–cyclic citrullinated peptide
- DM:
-
Diabetes mellitus
- EHM:
-
Extrahepatic manifestation
- EMC:
-
Essential mixed cryoglobulinemia
- HCV:
-
Hepatitis C virus
- HFE:
-
Homeostatic iron regulator
- HLA:
-
Human leukocyte antigen
- HRQoL:
-
Health-related quality of life
- IR:
-
Insulin resistance
- KDIGO:
-
Kidney Disease Improving Global Outcomes
- LP:
-
Lichen planus
- NHL:
-
Non-Hodgkin lymphoma
- PCT:
-
Porphyria cutanea tarda
- RF:
-
Rheumatoid factor
- SVR:
-
Sustained virological response
- UROD:
-
Uroporphyrinogen decarboxylase
References
Cacoub P, et al. Extrahepatic manifestations of chronic hepatitis C. MULTIVIRC Group. Multidepartment virus C. Arthritis Rheum. 1999;42(10):2204–12.
El-Serag HB, et al. Extrahepatic manifestations of hepatitis C among United States male veterans. Hepatology. 2002;36(6):1439–45.
Adinolfi LE, et al. Chronic hepatitis C virus infection and atherosclerosis: clinical impact and mechanisms. World J Gastroenterol. 2014;20(13):3410–7.
Zignego AL, et al. Extrahepatic manifestations of hepatitis C virus infection: a general overview and guidelines for a clinical approach. Dig Liver Dis. 2007;39(1):2–17.
Lee MH, et al. Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study. J Infect Dis. 2012;206(4):469–77.
Omland LH, et al. Increased mortality among persons infected with hepatitis C virus. Clin Gastroenterol Hepatol. 2011;9(1):71–8.
Uto H, et al. Increased rate of death related to presence of viremia among hepatitis C virus antibody–positive subjects in a community-based cohort study. Hepatology. 2009;50(2):393–9.
Hsu YC, et al. Antiviral treatment for hepatitis C virus infection is associated with improved renal and cardiovascular outcomes in diabetic patients. Hepatology. 2014;59(4):1293–302.
Cacoub P, et al. Extrahepatic manifestations of chronic hepatitis C virus infection. Ther Adv Infect Dis. 2016;3(1):3–14.
Lunel F, et al. Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology. 1994;106(5):1291–300.
Terrier B, Cacoub P. Renal involvement in HCV-related vasculitis. Clin Res Hepatol Gastroenterol. 2013;37(4):334–9.
Cacoub P, et al. Extrahepatic manifestations of chronic hepatitis C virus infection. Dig Liver Dis. 2014;46(Suppl 5):S165–73.
Ferri C, et al. Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients. Semin Arthritis Rheum. 2004;33(6):355–74.
Cacoub P, et al. Rheumatologic manifestations of hepatitis C virus infection. Clin Liver Dis. 2017;21(3):455–64.
Sene D, et al. Longterm course of mixed cryoglobulinemia in patients infected with hepatitis C virus. J Rheumatol. 2004;31(11):2199–206.
Pietrogrande M, et al. Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus–infected patients. Autoimmun Rev. 2011;10(8):444–54.
Saadoun D, et al. Antiviral therapy for hepatitis C virus–associated mixed cryoglobulinemia vasculitis: a long-term followup study. Arthritis Rheum. 2006;54(11):3696–706.
Sise ME, et al. Treatment of hepatitis C virus–associated mixed cryoglobulinemia with direct-acting antiviral agents. Hepatology. 2016;63(2):408–17.
Emery JS, et al. Efficacy and safety of direct acting antivirals for the treatment of mixed cryoglobulinemia. Am J Gastroenterol. 2017;112(8):1298–308.
Giordano TP, et al. Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus. JAMA. 2007;297(18):2010–7.
Duberg AS, et al. Non-Hodgkin’s lymphoma and other nonhepatic malignancies in Swedish patients with hepatitis C virus infection. Hepatology. 2005;41(3):652–9.
Tursi A, et al. Detection of HCV RNA in gastric mucosa–associated lymphoid tissue by in situ hybridization: evidence of a new extrahepatic localization of HCV with increased risk of gastric malt lymphoma. Am J Gastroenterol. 2002;97(7):1802–6.
Gisbert JP, et al. Prevalence of hepatitis C virus infection in B-cell non-Hodgkin’s lymphoma: systematic review and meta-analysis. Gastroenterology. 2003;125(6):1723–32.
Hermine O, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med. 2002;347(2):89–94.
Silvestri F, et al. Hepatitis C virus infection among cryoglobulinemic and non-cryoglobulinemic B-cell non-Hodgkin’s lymphomas. Haematologica. 1997;82(3):314–7.
Kawamura Y, et al. Viral elimination reduces incidence of malignant lymphoma in patients with hepatitis C. Am J Med. 2007;120(12):1034–41.
Maciocia N, O’Brien A, Ardeshna K. Remission of follicular lymphoma after treatment for hepatitis C virus infection. N Engl J Med. 2016;375(17):1699–701.
Ennishi D, et al. Hepatic toxicity and prognosis in hepatitis C virus–infected patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy regimens: a Japanese multicenter analysis. Blood. 2010;116(24):5119–25.
Deybach JC, et al. European Porphyria Initiative (EPI): a platform to develop a common approach to the management of porphyrias and to promote research in the field. Physiol Res. 2006;55(Suppl 2):S67–73.
Alla V, Bonkovsky HL. Iron in nonhemochromatotic liver disorders. Semin Liver Dis. 2005;25(4):461–72.
Elder GH. Update on enzyme and molecular defects in porphyria. Photodermatol Photoimmunol Photomed. 1998;14(2):66–9.
Liu LU, Phillips J, Bonkovsky H. Familial porphyria cutanea tarda. In: Adam MP, et al., editors. GeneReviews®. Seattle: University of Washington; 1993.
Frank J, Poblete-Gutierrez P. Porphyria cutanea tarda—when skin meets liver. Best Pract Res Clin Gastroenterol. 2010;24(5):735–45.
Besur S, et al. Clinically important features of porphyrin and heme metabolism and the porphyrias. Meta. 2014;4(4):977–1006.
Bonkovsky HL, et al. Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America. Hepatology. 1998;27(6):1661–9.
Garcovich S, et al. Cutaneous manifestations of hepatitis C in the era of new antiviral agents. World J Hepatol. 2015;7(27):2740–8.
Nishina S, et al. Hepatitis C virus–induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology. 2008;134(1):226–38.
Gisbert JP, et al. Prevalence of hepatitis C virus infection in porphyria cutanea tarda: systematic review and meta-analysis. J Hepatol. 2003;39(4):620–7.
Sarkany RP. The management of porphyria cutanea tarda. Clin Exp Dermatol. 2001;26(3):225–32.
Puy H, Gouya L, Deybach JC. Porphyrias. Lancet. 2010;375(9718):924–37.
Schulenburg-Brand D, et al. The cutaneous porphyrias. Dermatol Clin. 2014;32(3):369–84, ix.
Linet MS, et al. Primary liver cancer, other malignancies, and mortality risks following porphyria: a cohort study in Denmark and Sweden. Am J Epidemiol. 1999;149(11):1010–5.
Sayiner M, et al. Dermatologic manifestations of chronic hepatitis C infection. Clin Liver Dis. 2017;21(3):555–64.
Szlendak U, Bykowska K, Lipniacka A. Clinical, biochemical and molecular characteristics of the main types of porphyria. Adv Clin Exp Med. 2016;25(2):361–8.
Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Hematol Am Soc Hematol Educ Program. 2012;2012:19–27.
Fernandez I, et al. Porphyria cutanea tarda as a predictor of poor response to interferon alfa therapy in chronic hepatitis C. Scand J Gastroenterol. 2003;38(3):314–9.
Azim J, McCurdy H, Moseley RH. Porphyria cutanea tarda as a complication of therapy for chronic hepatitis C. World J Gastroenterol. 2008;14(38):5913–5.
Desai TK, et al. Phlebotomy improves therapeutic response to interferon in patients with chronic hepatitis C: a meta-analysis of six prospective randomized controlled trials. Dig Dis Sci. 2008;53(3):815–22.
Aguilera P, Laguno M, To-Figueras J. Treatment of chronic hepatitis with boceprevir leads to remission of porphyria cutanea tarda. Br J Dermatol. 2014;171(6):1595–6.
Le Cleach L, Chosidow O. Clinical practice: lichen planus. N Engl J Med. 2012;366(8):723–32.
Gumber SC, Chopra S. Hepatitis C: a multifaceted disease. Review of extrahepatic manifestations. Ann Intern Med. 1995;123(8):615–20.
Shengyuan L, et al. Hepatitis C virus and lichen planus: a reciprocal association determined by a meta-analysis. Arch Dermatol. 2009;145(9):1040–7.
Nagao Y, et al. Genome-wide association study identifies risk variants for lichen planus in patients with hepatitis C virus infection. Clin Gastroenterol Hepatol. 2017;15(6):937–44. e5
Abdallah MA, et al. Necrolytic acral erythema: a cutaneous sign of hepatitis C virus infection. J Am Acad Dermatol. 2005;53(2):247–51.
Khanna VJ, et al. Necrolytic acral erythema associated with hepatitis C: effective treatment with interferon alfa and zinc. Arch Dermatol. 2000;136(6):755–7.
Hivnor CM, et al. Necrolytic acral erythema: response to combination therapy with interferon and ribavirin. J Am Acad Dermatol. 2004;50(5 Suppl):S121–4.
Tsai TF, et al. Epidemiology and comorbidities of psoriasis patients in a national database in Taiwan. J Dermatol Sci. 2011;63(1):40–6.
Imafuku S, Naito R, Nakayama J. Possible association of hepatitis C virus infection with late-onset psoriasis: a hospital-based observational study. J Dermatol. 2013;40(10):813–8.
Yang YW, Keller JJ, Lin HC. Medical comorbidity associated with psoriasis in adults: a population-based study. Br J Dermatol. 2011;165(5):1037–43.
Cohen AD, et al. Psoriasis associated with hepatitis C but not with hepatitis B. Dermatology. 2010;220(3):218–22.
Snast I, et al. Risk for hepatitis B and C virus reactivation in patients with psoriasis on biologic therapies: a retrospective cohort study and systematic review of the literature. J Am Acad Dermatol. 2017;77(1):88–97.e5.
Cacoub P, et al. Extrahepatic manifestations associated with hepatitis C virus infection: a prospective multicenter study of 321 patients. The GERMIVIC. Groupe d’Etude et de Recherche en Medecine Interne et Maladies Infectieuses sur le Virus de l’Hepatite C. Medicine (Baltimore). 2000;79(1):47–56.
Himoto T, Masaki T. Extrahepatic manifestations and autoantibodies in patients with hepatitis C virus infection. Clin Dev Immunol. 2012;2012:871401.
Hsieh MY, et al. Antinuclear antibody is associated with a more advanced fibrosis and lower RNA levels of hepatitis C virus in patients with chronic hepatitis C. J Clin Pathol. 2008;61(3):333–7.
Younossi Z, et al. Extrahepatic manifestations of hepatitis C: a meta-analysis of prevalence, quality of life, and economic burden. Gastroenterology. 2016;150(7):1599–608.
Antonelli A, et al. Thyroid disorders in chronic hepatitis C. Am J Med. 2004;117(1):10–3.
Prummel MF, Laurberg P. Interferon-alpha and autoimmune thyroid disease. Thyroid. 2003;13(6):547–51.
Mohammed RH, et al. Prevalence of rheumatologic manifestations of chronic hepatitis C virus infection among Egyptians. Clin Rheumatol. 2010;29(12):1373–80.
White DL, Ratziu V, El-Serag HB. Hepatitis C infection and risk of diabetes: a systematic review and meta-analysis. J Hepatol. 2008;49(5):831–44.
Petit JM, et al. Risk factors for diabetes mellitus and early insulin resistance in chronic hepatitis C. J Hepatol. 2001;35(2):279–83.
Bigam DL, et al. Hepatitis C–related cirrhosis: a predictor of diabetes after liver transplantation. Hepatology. 2000;32(1):87–90.
Moucari R, et al. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology. 2008;134(2):416–23.
Milner KL, et al. Chronic hepatitis C is associated with peripheral rather than hepatic insulin resistance. Gastroenterology. 2010;138(3):932–41.e1–3.
Romero-Gomez M, et al. Effect of sustained virological response to treatment on the incidence of abnormal glucose values in chronic hepatitis C. J Hepatol. 2008;48(5):721–7.
Arase Y, et al. Sustained virological response reduces incidence of onset of type 2 diabetes in chronic hepatitis C. Hepatology. 2009;49(3):739–44.
Conjeevaram HS, et al. Changes in insulin sensitivity and body weight during and after peginterferon and ribavirin therapy for hepatitis C. Gastroenterology. 2011;140(2):469–77.
Johnson RJ, et al. Hepatitis C virus–associated glomerulonephritis: effect of alpha-interferon therapy. Kidney Int. 1994;46(6):1700–4.
McGuire BM, et al. Brief communication: glomerulonephritis in patients with hepatitis C cirrhosis undergoing liver transplantation. Ann Intern Med. 2006;144(10):735–41.
Kidney Disease: Improving Global Outcomes. KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int Suppl. 2008;109:S1–99.
Morsica G, et al. Detection of hepatitis C virus genomic sequences in the cerebrospinal fluid of HIV-infected patients. J Med Virol. 1997;53(3):252–4.
Cozzi A, et al. Low serum tryptophan levels, reduced macrophage IDO activity and high frequency of psychopathology in HCV patients. J Viral Hepat. 2006;13(6):402–8.
Byrnes V, et al. Effects of anti-viral therapy and HCV clearance on cerebral metabolism and cognition. J Hepatol. 2012;56(3):549–56.
Thein HH, et al. Improved cognitive function as a consequence of hepatitis C virus treatment. HIV Med. 2007;8(8):520–8.
Kallman J, et al. Fatigue and health-related quality of life (HRQL) in chronic hepatitis C virus infection. Dig Dis Sci. 2007;52(10):2531–9.
Heeren M, et al. Active at night, sleepy all day—sleep disturbances in patients with hepatitis C virus infection. J Hepatol. 2014;60(4):732–40.
Bonkovsky HL, et al. Health-related quality of life in patients with chronic hepatitis C and advanced fibrosis. J Hepatol. 2007;46(3):420–31.
Marcellin P, et al. Adherence to treatment and quality of life during hepatitis C therapy: a prospective, real-life, observational study. Liver Int. 2011;31(4):516–24.
Younossi ZM, et al. Minimal impact of sofosbuvir and ribavirin on health related quality of life in chronic hepatitis C (CH-C). J Hepatol. 2014;60(4):741–7.
Fukui M, et al. Hepatitis C virus and atherosclerosis in patients with type 2 diabetes. JAMA. 2003;289(10):1245–6.
Domont F, Cacoub P. Chronic hepatitis C virus infection, a new cardiovascular risk factor? Liver Int. 2016;36(5):621–7.
Gill K, et al. Hepatitis C virus as a systemic disease: reaching beyond the liver. Hepatol Int. 2016;10(3):415–23.
Hsu YC, et al. Association between antiviral treatment and extrahepatic outcomes in patients with hepatitis C virus infection. Gut. 2015;64(3):495–503.
Wong RJ, et al. Hepatitis C virus infection and coronary artery disease risk: a systematic review of the literature. Dig Dis Sci. 2014;59(7):1586–93.
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Karaca, Ç. (2019). Extrahepatic Manifestations of Hepatitis C Virus Infection. In: Ozaras, R., Salmon-Ceron, D. (eds) Viral Hepatitis: Chronic Hepatitis C. Springer, Cham. https://doi.org/10.1007/978-3-030-03757-4_10
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