Virus C Genotype Predisposes To Primary Hypothyroidism During Interferon-α Treatment For Chronic Hepatitis C

Objective: The treatment of the chronic hepatitis C (HCV) with α-interferon is associated with thyroid dysfunction (TD). The aim of this study was to evaluate thyroid function outcome among patients with chronic HCV under treatment with conventional interferon (IFN) or peguilated interferon (PEG-IFN) in association with ribavirin. Patients and Methods: We studied 293 patients with chronic HCV, submitted to drug therapy for 24 or 48 weeks. Initially, we evaluated FT4, TSH, TPOAb, TgAb, and continued to monitor FT4 and TSH every three months during therapy and six months thereafter. Results: At baseline, TD prevalence was 6.82% (n = 20); 6.14% hypothyroidism; 0.68% hyperthyroidism. TPOAb was present in 5.46% of euthyroid patients. Out of 273 euthyroid patients at baseline, 19% developed TD: 17.2% hypothyroidism; 1.8% hyperthyroidism; 5.1% destructive thyroiditis (DT). 90% of TPOAb-positive patients at baseline developed hypothyroidism vs 14.5% of TPOAb-negative patients (p < 0.001). On average, TD occurred after 25.8 ± 15.5 weeks of treatment 87.2% of patients who developed hypothyroidism did so during the first therapeutic cycle (p = 0.004; OR = 3.52; 95% CI = 1.36-9.65). Patients infected with genotype 1 virus were 2.13 times more likely to develop hypothyroidism (p = 0.036; 95% CI = 1.04-4.38). Hypothyroid and DT patients presented higher TSH levels before-treatment than patients who had remained euthyroid (p < 0.001; p = 0.002, respectively). DT patients presented lower qALT (p = 0.012) than euthyroid patients. Conclusion: Hypothyroidism was the most frequent TD, especially during the first cycle of α-interferon. Genotype 1 virus was associated with a risk two times higher for developing the illness. There was no need to interrupt or to change HCV treatment. Therefore, approximately 34% of TD was transient. © 2011 Elsevier Editora Ltda.155449456Bellentani, S., Tiribelli, C., The spectrum of liver disease in the general population: lessons from the Dionysos study (2001) J Hepatol, 35, pp. 531-537Poynard, T., Marcellin, P., Lee, S.S., Randomized trial of interferon a2b plus ribavirin for 48 weeks or for 24 weeks versus interferon a2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus (1998) Lancet, 352, pp. 1426-1432Tam, R.C., Pai, B., Bard, J., Ribavirin polarizes human T cell responses toward a type 1 cytokine profile (1999) J Hepatol, 30, pp. 376-382Koh, L.K.H., Greenspan, F.S., Yeo, P.P.B., Interferon-α induced thyroid dysfunction: three clinical presentations and review of the literature (1997) Thyroid, 7, pp. 891-896Dalgard, O., Bjoro, K., Hellum, K., Thyroid dysfunction during treatment of chronic hepatitis C with interferon-α: no association with either interferon dosage or efficacy of therapy (2002) J Int Med, 251, pp. 400-406Carella, C., Mazziotti, G., Amato, G., Interferon-α related thyroid disease: pathophysiological, epidemiological, and clinical aspects (2004) J Clin Endocrinol Metab, 89, pp. 3656-3661Prummel, M.F., Lauberg, P., Interferon-α and autoimmune thyroid disease (2003) Thyroid, 13, pp. 547-551Tomer, Y., Blackard, J.T., Akeno, N., Interferon alpha treatment and thyroid dysfunction (2007) Endocrinol Metab Clin N Am, 36, pp. 1051-1066Blackard, J.T., Kemmer, N., Sherman, K.E., Extrahepatic replication of HCV: insights into clinical manifestations and biological consequences (2006) Hepatology, 44, pp. 15-22Fried, M.W., Side effects of therapy of hepatitis C and their management (2002) Hepatology, 36, pp. 237-244Evon, D.M., Verma, A., Simpson, K., Psychiatric symptoms during interferon treatment for hepatitis C: experiences from a tertiary care hepatology centre (2008) Aliment Pharmacol Ther, 27, pp. 1071-1080Fentiman, I.S., Thomas, B.S., Balkwill, F.R., Primary hypothyroidism associated with interferon therapy of breast cancer (1985) Lancet, 8438, p. 1166Sachithanandan, S., Clarke, G., Crowe, J., Interferon-associated thyroid dysfunction in anti-D-related chronic hepatitis C (1997) J Interf Cytok Res, 17, pp. 409-411Pateron, D., Hartmann, D.J., Duclos-Vallee, J.C., Latent autoimmune thyroid disease in patients with chronic HCV hepatitis (1992) J Hepatol, 16, pp. 244-245Antonelli, A., Ferri, C., Fallahi, P., Thyroid disorders in chronic hepatitis C virus infection (2006) Thyroid, 16, pp. 563-572Tran, A., Quaranta, J.F., Benzaken, S., High prevalence of thyroid autoantibodies in a prospective series of patients with chronic hepatitis C before interferon therapy (1993) Hepatol, 18, pp. 253-257Preziati, D., La Rosa, L., Covini, G., Autoimmunity and thyroid function in patients with chronic active hepatitis treated with recombinant interferon alpha-2a (1995) Eur J Endocrinol, 132, pp. 587-593Fernandez-Soto, L., Gonzalez, A., Escobar-Jimenez, F., Increased risk of autoimmune thyroid disease in hepatitis C vs hepatitis B before, during, and after discontinuing interferon therapy (1998) Arch Int Med, 158, pp. 1445-1448Antonelli, A., Ferri, C., Pampana, A., Thyroid disorders in chronic hepatitis C (2004) Am J Med, 117, pp. 10-13Muratori, L., Bogdanos, D.P., Muratori, P., Susceptibility to thyroid disorders in hepatitis C (2005) Clin Gastroenterol Hepatol, 3, pp. 595-603Stefanova-Petrova, D.V., Tzvetanska, A.H., Naumova, E.J., Chronic hepatitis C virus infection: prevalence of extrahepatic manifestations and association with cryoglobulinemia in Bulgarian patients (2007) World J Gastroenterol, 13, pp. 6518-6528Matsuda, J., Saitoh, N., Gotoh, M., High prevalence of antiphospholipid antibodies and anti-thyroglobulin antibody in patients with hepatitis C virus infection treated with interferon-alpha (1995) Am J Gastroenterol, 90, pp. 1138-1141Custro, N., Montalto, G., Scafidi, V., Prospective study on thyroid autoimmunity and dysfunction related to chronic hepatitis C and interferon therapy (1997) J Endocrinol Invest, 20, pp. 374-380Boadas, J., Rodríguez-Espinosa, J., Enríquez, J., Prevalence of thyroid autoantibodies is not increased in blood donors with hepatitis C virus infection (1995) J Hepatol, 22, pp. 611-615Prentice, L.M., Phillips, D.I., Sarsero, D., Geographical distribution of subclinical autoimmune thyroid disease in Britain: a study using highly sensitive direct assays for autoantibodies to thyroglobulin and thyroid peroxidase (1990) Acta Endocrinol, 123, pp. 493-498Minelli, R., Braverman, L.E., Giuberti, T., Effects of excess iodine administration on thyroid function in euthyroid patients with a previous episode of thyroid dysfunction induced by interferon-alpha treatment (1997) Clil Endocrinol, 47, pp. 357-361Moncoucy, X., Leymarie, F., Delemer, B., Risk factors and long-term course of thyroid dysfunction during antiviral treatments in 221 patients with chronic hepatitis C (2005) Gastroenterol Clin Biolog, 29, pp. 339-345Hsieh, M.C., Yu, M.L., Chuang, W.L., Virologic factors related to interferon-alpha-induced thyroid dysfunction in patients with chronic hepatitis C (2000) Eur J Endocrinol, 142, pp. 431-437Lisker-Melman, M., Di Bisceglie, A.M., Usala, S.J., Development of thyroid disease during therapy of chronic viral hepatitis with interferon alfa (1992) Gastroenterol, 102, pp. 2155-2160Primo, J., Hinojosu, J., Molés, J.R., Development of thyroid dysfunction after alpha-interferon treatment of chronic hepatitis C (1993) Am J Gastroenterol, 88, pp. 1976-1977Reid, I., Sharpe, I., McDevitt, J., Thyroid dysfunction can predict response to immunotherapy with interleukin-2 and interferon-2 alpha (1991) Brit J Cancer, 64, pp. 915-918Watanabe, U., Hashimoto, E., Hisamitsu, T., The risk factor for development of thyroid disease during interferon-alpha therapy for chronic hepatitis C (1994) Am J Gastroenterol, 89, pp. 399-403Vanderpump, M.P., Tunbridge, W.M., French, J.M., The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey (1995) Clin Endocrinol, 43, pp. 55-68Huang, J.F., Chuang, W.L., Dai, C.Y., The role of thyroid autoantibodies in the development of thyroid dysfunction in Taiwanese chronic hepatitis C patients with interferon-alpha and ribavirin combination therapy (2006) J Vir Hepat, 13, pp. 396-401Grossman, C.J., Roselle, G.A., Mendenhall, C.L., Sex steroid regulation of autoimmunity (1991) J Ster Biochem Mol Biol, 40, pp. 649-659Tomer, Y., Davies, T.F., Searching for the autoimmune thyroid disease susceptibility genes: from gene mapping to gene function (2003) Endocr Rev, 24, pp. 694-717Carella, C., Amato, G., Biondi, B., Longitudinal study of antibodies against thyroid in patients undergoing interferon-alpha therapy for HCV chronic hepatitis (1995) Horm Res, 44, pp. 110-114Katabami, S., Kamijo, K., Kodama, T., An episode of silent thyroiditis in a patient with chronic thyroiditis and papillary adenocarcinoma following alpha interferon treatment for hepatitis C (1993) Endocr J, 40, pp. 311-316Simmonds, P., Genetic diversity and evolution of hepatitis C virus - 15 years on (2004) J Gen Virol, 85, pp. 3173-3188Gisslinger, H., Gilly, B., Woloszczuk, W., Thyroid autoimmunity and hypothyroidism during long-term treatment with recombinant interferon-alpha (1992) Clil Exp Immunol, 90, pp. 363-367Nagayama, Y., Ohta, K., Tsuruta, M., Exacerbation of thyroid autoimmunity by interferon alpha treatment in patients with chronic viral hepatitis: our studies and review of the literature (1994) Endocr J, 41, pp. 565-572Chung, Y.H., Shong, Y.K., Development of thyroid autoimmunity after administration of recombinant human interferonalpha 2b for chronic viral hepatitis (1993) Am J Gastroenterol, 88, pp. 244-247Yamazaki, K., Kanaji, Y., Shizume, K., Reversible inhibition by interferons alpha and beta of 125I incorporation and thyroid hormone release by human thyroid follicles in vitro (1993) J Clin Endocrinol Metab, 77, pp. 1439-1441Hollowell, J.G., Staehling, N.W., Flanders, W.D., Serum TSHm T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III) (2002) J Clin Endocrinol Metab, 87, pp. 489-499Weetman, A.P., Smallridge, R.C., Nutman, T.B., Persistent thyroid autoimmunity after subacute thyroiditis (1987) J Clin Lab Immunol, 23, pp. 1-6Paraná, R., Cruz, M., Lyra, L., Cruz, T., Subacute thyroiditis during treatment with combination therapy (interferon plus ribavirin) for hepatitis C virus (2000) J Vir Hepat, 7, pp. 393-39

The Influence Of Occult Infection With Hepatitis B Virus On Liver Histology And Response To Interferon Treatment In Chronic Hepatitis C Patients.

Occult hepatitis B virus (HBV) infections have been identified in patients with chronic hepatitis C virus (HCV) infection, although the clinical relevance of occult HBV infection remains controversial. We searched for serum HBV DNA in 106 HBsAg negative/anti-HBc positive patients with chronic HCV infection and in 150 blood donors HBsAg negative/anti-HBc positive/anti-HCV negative (control group) by nested-PCR. HCV genotyping was done in 98 patients and percutaneous needle liver biopsies were performed in 59 patients. Fifty-two patients were treated for HCV infection with interferon alone (n=4) or combined with ribavirin (n=48) during one year. At the end and 24 weeks after stopping therapy, they were tested for HCV-RNA to evaluate the sustained virological response (SVR). Among the 106 HCV-positive patients, 15 (14%) were HBV-DNA positive and among the 150 HCV-negative blood donors, 6 (4%) were HBV-DNA positive. Liver biopsy gave a diagnosis of liver cirrhosis in 2/10 (20%) of the HBV-DNA positive patients and in 6/49 (12%) of the HBV-DNA negative patients. The degree of liver fibrosis and portal inflammation was similar in HCV-infected patients HBV-DNA, irrespective of HBV-DNA status. SVR was obtained in 37.5% of the HBV-DNA positive patients and in 20.5% of the HBV-DNA negative patients; this difference was not significant. In conclusion, these data suggested that occult HBV infection, which occurs at a relatively high frequency among Brazilian HCV-infected patients, was not associated with more severe grades of inflammation, liver fibrosis or cirrhosis development and did not affect the SVR rates when the patients were treated with interferon or with interferon plus ribavirin.8643143

Viral Hepatitis In Patients Infected With Human Immunodeficiency Virus.

From 1992 to 1995 we studied 232 (69% male, 87% Caucasian) anti-human immunodeficiency virus (anti-HIV) positive Brazilian patients, through a questionnaire; HIV had been acquired sexually by 50%, from blood by 32%, sexually and/or from blood by 16.4% and by an unknown route by 1.7%. Intravenous drug use was reported by 29%; it was the most important risk factor for HIV transmission. The alanine aminotransferase quotient (qALT) was >1 for 40% of the patients, 93.6% had anti-hepatitis A virus antibody, 5.3% presented hepatitis B surface antigen, 44% were anti-hepatitis B core antigen positive and 53.8% were anti-hepatitis C virus (anti-HCV) positive. The anti-HCV test showed a significant association with qALT>1. Patients for whom the probable HIV transmission route was blood had a 10.8 times greater risk of being anti-HCV positive than patients infected by other routes. Among 30 patients submitted to liver biopsy, 18 presented chronic hepatitis.7425326

Comparative Study Of Patients With Chronic Hepatitis C Virus Infection Due To Genotypes 1 And 3 Referred For Treatment In Southeast Brazil

Background: The progression of liver disease in patients with chronic hepatitis C virus (HCV) infection is influenced by host and viral factors. Distinct clinical outcomes in patients infected with different HCV genotypes have been described in the literatute. However, the association between specific HCV genotype and clinical outcome remains unclear. We set out to study the natural history of HCV genotype 1 and 3 infections in Campinas, São Paulo state, Brazil, focusing on epidemiological, clinical, biochemical, and histological characteristics. Methods: Patients with HCV infection referred for treatment between January 2003 and December 2006 were included in this study. We collected epidemiological, clinical, and laboratorial data using standard forms. Results: A total of 283 patients were included; genotype 1 was idenfied in 163 (57.6%) patients, genotype 3 in 112 (39.6%), genotype 2 in 7 (2.5%), and genotype 4 in 1 (0.35%). Patients with genotype 2 and 4 were excluded from analysis. Multivariate analysis showed that intravenous energetic drug, positive cryoglobulin, and cirrhosis were independently and significantly associated with HCV genotype 3 (p < 0.05). Conclusion: Genotype 3 currently seems to be associated with intravenous energetic drug, high frequency of cryoglobulinemia, and advanced liver disease in our region. Understanding the distribution of the different HCV genotypes can elucidate transmission of HCV and support optimal prevention strategies. © 2008 Vigani et al; licensee BioMed Central Ltd.8Armstrong, G.L., Alter, M.J., McQuillan, G.M., The past incidence of hepatitis C virus infection: Implications for the future burden of chronic liver disease in the United States (2000) Hepatology, 31, pp. 777-782. , 10.1002/hep.510310332 10706572Consensus Statement (1999) J Hepatol, 30, pp. 956-961. , EASL International Consensus Conference on Hepatitis C 10.1016/ S0168-8278(99)80154-8 10365827Treatment of hepatitis C. Guidelines (2002) Gastroenterol Clin Biol, 26, pp. B312-B320. , Consensus ConferenceCodes, L., Freitas, L.A.R., Santos-Jesus, R., Comparative study of Hepatitis C virus genotypes 1 and 3 in Salvador, Bahia (2003) Braz J Infect Dis, 7, pp. 409-417. , 10.1590/S1413-86702003000600009 14636481Silva, G.F., Nishimura, N.F., Coelho, K.I.R., Soares, E.C., Grading and staging chronic hepatitis C and its relation to genotypes and epidemiological factors in Brazilian blood donors (2005) Braz J Infect Dis, 9, pp. 142-149. , 16127590Alberti, A., Chemello, L., Bevebnú, L., Natural history of hepatitis C (1999) J Hepatol, 31, pp. 17-24. , 10.1016/S0168-8278(99)80369-9 10622555Poynard, T., Bedossa, P., Opolon, P., Natural history of liver fibrosis progression in patients with chronic hepatitis C (1997) The Lancet, 349, pp. 825-832. , 10.1016/S0140-6736(96)07642-8Simmonds, P., Viral heterogeneity of the hepatitis C virus (1999) J Hepatol, 31 (SUPPL. 1), pp. 54-60. , 10.1016/S0168-8278(99)80375-4 10622561Zein, N.N., Rakela, J., Krawitt, E.L., Hepatitis C virus genotypes in the United States: Epidemiology, pathogenicity, and response to interferon therapy (1996) Ann Intern Med, 125, pp. 634-639. , 8849147McOmish, F., Yap, P.L., Dow, B.C., Geographical distribution of hepatitis C virus genotypes in blood donors: An international collaborative survey (1994) J Clin Microbiol, 32, pp. 884-892. , 263157 7913097Zein, N.N., Clinical significance of hepatitis C genotypes (2000) Clin Microbiol Rev, 13, pp. 223-235. , 100152 10755999 10.1128/CMR.13.2.223-235.2000Bedossa, P., Poynard, T., An algorithm for the grading of activity in chronic hepatitis C (1996) Hepatology, 24, pp. 289-293. , The METAVIR cooperative study group 10.1002/hep.510240201 8690394Simmonds, P., Genetic diversity and evolution of hepatitis C virus - 15 years on (2004) J Gen Virol, 85, pp. 3173-3188. , 10.1099/vir.0.80401-0 15483230Campiotto, S., Pinho, J.R.R., Carrilho, F.L., Geographic distribution of hepatitis C virus genotypes in Brazil (2005) Braz J Med Biol Res, 38, pp. 41-49. , 10.1590/S0100-879X2005000100007 15665987Pawlotsky, J.M., Tsakiris, L., Roudot-Thoraval, E., Relationship between hepatitis C virus genotypes and sources of infection in patients with chronic hepatitis C (1995) J Infect Dis, 171, pp. 1607-1610. , 7769300Liakina, V., Speiciene, D., Irnius, A., Prevalence of cryoglobulinemia in patients with chronic HCV infection (2002) Med Sci Monit, 8 (1), pp. CR31-CR36. , 11782678Frangeul, L., Musset, L., Cresta, P., Hepatitis C virus genotypes and subtypes in patients with hepatitis C, with and without cryoglobulinemia (1996) J Hepatol, 25, pp. 427-432. , 10.1016/S0168-8278(96)80200-5 8912140Willems, M., Sheng, L., Roskams, T., Hepatitis C virus and its genotypes in patients suffering from chronic hepatitis C with or without a cryoglobulinemia-related syndrome (1994) J Med Virol, 44, pp. 266-271. , 10.1002/jmv.1890440310 7531756Zehender, G., De Maddalena, C., Bernini, F., Compartmentalization of hepatitis C virus quasispecies in blood mononuclear cells of patients with mixed cryoglobulinemic syndrome (2005) J Virol, 79, pp. 9145-9156. , 1168762 15994809 10.1128/JVI.79.14.9145-9156.2005Parise, E.R., de Oliveira, A.C., Ferraz, M.L., Cryoglobulinemia in chronic hepatitis C: Clinical aspects and response to treatment with interferon alpha and ribavirin (2007) Rev Inst Med Trop S Paulo, 49, pp. 67-72. , 10.1590/S0036-46652007000200001 17505661Silini, E., Bottelli, R., Hepatitis C virus genotypes and risk of hepatocellular carcinoma in cirrhosis: A case control study (1996) Gastroenterology, 111 (1), pp. 1999-2005. , 10.1053/gast.1996.v111.pm8698200Zeuzem, S., Franke, A., Lee, J.H., Phylogenetic analysis of hepatitis C virus isolates and their correlation to viremia, liver function tests, and histology (1996) Hepatology, 24, pp. 1003-1009. , 10.1002/hep.510240505 8903367Manns, M.P., McHutchison, J.G., Gordon, S.C., Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial (2001) Lancet, 358, pp. 958-965. , 10.1016/S0140-6736(01)06102-5 11583749Fried, M.W., Shiffman, M.L., Reddy, K.R., Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection (2002) N Engl J Med, 26 (347), pp. 975-982. , 10.1056/NEJMoa02004