OJGas  Vol.4 No.2 , February 2014
Polymorphisms in methylenetetrahydrofolate reductase gene: Their impact on liver steatosis and fibrosis of chronic hepatitis c patients
ABSTRACT
Aim & Background: The mechanism of steatosis in Hepatitis C virus infection is multifactorial; therefore, it is complex and unclear. The aim of this study was to investigate the effects of methylentetrahydrofolate reductase (MTHFR) gene polymorphisms on the course of chronic hepatitis C virus infection and the development of steatosis due to hepatitis C virus. Methods: This study included 109 patients with chronic hepatitis C virus infection. Necroinflammatory activity, degrees of fibrosis and steatosis and MTHFR gene polymorphisms were investigated. Polymerase chain reaction-restriction fragment length polymorphism was used to determine MTHFR C677T and A1298C polymorphisms. Results: Fibrosis was correlated with age (r = 0.336, p = 0.002), platelet (r = ?0.448, p < 0.0001), ALT (r = 0.241, p = 0.026), AST (r = 0.361) and GGT (r = 0.224, p = 0.039). Steatosis was only correlated with fibrosis. MTHFR C677T and A1298C polymorphisms did not have a significant effect on the degree of steatosis (p = 0.857, p = 0.202 respectively). There was a relation between MTHFR C677T and the degree of fibrosis but not A1298C (p = 0.014, p = 0.187 respectively). Conclusion: We found that MTHFR C677T polymorphism contributed to the development of fibrosis in patients with chronic hepatitis C virus infection.

Cite this paper
Altintas, E. , Altintas, Z. , Sezgin, O. , Ucbilek, E. , Nayir, E. , Erdal, M. , Polat, A. and Orekeci, G. (2014) Polymorphisms in methylenetetrahydrofolate reductase gene: Their impact on liver steatosis and fibrosis of chronic hepatitis c patients. Open Journal of Gastroenterology, 4, 73-80. doi: 10.4236/ojgas.2014.42013.
References
[1]   Perz, J.F., Farrington, L.A., Pecoraro, C., Hutin, Y.J.F. and Armstrong, G.L. (2004) Estimated global prevalence of hepatitis C virus infection. 42nd Annual Meeting of the Infectious Diseases Society of America, Boston.
http://dx.doi.org/10.1056/NEJMra011775

[2]   Angulo, P. (2002) Nonalcoholic fatty liver disease. New England Journal of Medicine, 346, 1221-1231.

[3]   Ramesh, S. and Sanyal, A.J. (2004) Hepatitis C and non-alcoholic fatty liver disease. Seminars in Liver Disease, 24, 399-413.
http://dx.doi.org/10.1055/s-2004-860869

[4]   Lonardo, A., Adinolfi, L.E., Loria, P., Carulli, N., Ruggiero, G. and Day, C.P. (2004) Steatosis and hepatitis C virus: Mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology, 126, 586-597.
http://dx.doi.org/10.1053/j.gastro.2003.11.020

[5]   Charlton, M.R., Pockros, P.J. and Harrison, S.A. (2006) Impact of obesity on treatment of chronic hepatitis C. Hepatology, 43, 1177-1186.
http://dx.doi.org/10.1002/hep.21239

[6]   Asselah, T., Rubbia-Brandt, L., Marcellin, P. and Negro, F. (2006) Steatosis in chronic hepatitis C: Why does it really matter? Gut, 55, 123-130.
http://dx.doi.org/10.1136/gut.2005.069757

[7]   Lonardo, A., Loria, P., Adinolfi, L.E., Carulli, N. and Ruggiero, G. (2006) Hepatitis C and steatosis: A reappraisal. Journal of Viral Hepatitis, 13, 73-80.
http://dx.doi.org/10.1111/j.1365-2893.2005.00669.x

[8]   Leandro, G., Mangia, A., Hui, J., Fabris, P., Rubbia-Brandt, L., Colloredo, G., Adinolfi, L.E., et al. (2006) HCV Meta-Analysis (on) Individual Patients’ Data Study Group. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: A meta-analysis of individual patient data. Gastroenterology, 130, 1636-1642.
http://dx.doi.org/10.1053/j.gastro.2006.03.014

[9]   Adinolfi, L.E., Utili, R. and Ruggiero, G. (1999) Body composition and hepatic steatosis as precursors of fibrosis in chronic hepatitis C patients. Hepatology, 30, 1530-1531.
http://dx.doi.org/10.1002/hep.510300625

[10]   Fiore, G., Fera, G., Napoli, N., Vella, F. and Schiraldi, O. (1996) Liver steatosis and chronic hepatitis C: A spurious association? European Journal of Gastroenterology & Hepatology, 125-129.
http://dx.doi.org/10.1097/00042737-199602000-00006

[11]   Czaja, A.J., Carpenter, H.A., Santrach, P.J. and Moore, S.B. (1998) Host and disease-specific factors affecting steatosis in chronic hepatitis C. Journal of Hepatology, 29, 198-206.
http://dx.doi.org/10.1016/S0168-8278(98)80004-4

[12]   Hourigan, L.F., Macdonald, G.A., Purdie, D., Whitehall, V.H., Shorthouse, C., Clouston, A. and Powell, E.E. (1999) Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology, 29, 1215-1219.
http://dx.doi.org/10.1002/hep.510290401

[13]   Clouston, A.D., Jonsson, J.R., Purdie, D.M., Macdonald, G.A., Pandeya, N., Shorthouse, C. and Powell, E.E. (2001) Steatosis and chronic hepatitis C: Analysis of fibrosis and stellate cell activation. Journal of Hepatology, 34, 314-320.
http://dx.doi.org/10.1016/S0168-8278(00)00096-9

[14]   Hwang, S.J., Luo, J.C., Chu, C.W., Lai, C.R., Lu, C.L., Tsay, S.H., Wu, J.C., et al. (2001) Hepatic steatosis in chronic hepatitis C virus infection: Prevalence and clinical correlation. Journal of Gastroenterology and Hepatology, 16, 190-195.
http://dx.doi.org/10.1046/j.1440-1746.2001.02407.x

[15]   Adinolfi, L.E., Gambardella, M., Andreana, A., Tripodi, M.F., Utili, R. and Ruggiero, G. (2001) Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology, 33, 1358-1364.
http://dx.doi.org/10.1053/jhep.2001.24432

[16]   Petit, J.M., Benichou, M., Duvillard, L., Jooste, V., Bour, J.B., Minello, A., Verges, B., et al. (2003) Hepatitis C virus-associated hypobetalipoproteinemia is correlated with plasma viral load, steatosis, and liver fibrosis. The American Journal of Gastroenterology, 98, 1150-1154.

[17]   Monto, A., Alonzo, J., Watson, J.J., Grunfeld, C. and Wright, T.L. (2002) Steatosis in chronic hepatitis C: Relative contributions of obesity, diabetes mellitus, and alcohol. Hepathology, 36, 729-736.
http://dx.doi.org/10.1053/jhep.2002.35064

[18]   Poynard, T., Ratziu, V., McHutchison, J., Manns, M., Goodman, Z., Zeuzem, S., Younossi, Z., et al. (2003) Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology, 38, 75-85.
http://dx.doi.org/10.1053/jhep.2003.50267

[19]   Hu, K.Q., Kyulo, N.L., Esrailian, E., Thompson, K., Chase, R., Hillebrand, D.J. and Runyon, B.A. (2004) Overweight and obesity, hepatic steatosis, and progression of chronic hepatitis C: A retrospective study on a large cohort of patients in the United States. Journal of Hepatology, 40, 147-154.
http://dx.doi.org/10.1016/S0168-8278(03)00479-3

[20]   Rubbia-Brandt, L., Fabris, P., Paganin, S., Leandro, G., Male, P.J., Giostra, E., Carlotto, A., et al. (2004) Steatosis affects chronic hepatitis C progression in a genotype specific way. Gut, 53, 406-4012.
http://dx.doi.org/10.1136/gut.2003.018770

[21]   Patton, H.M., Patel, K., Behling, C., Bylund, D., Blatt, L.M., Vallee, M., Heaton, S., et al. (2004) The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. Journal of Hepatology, 40, 484-490.
http://dx.doi.org/10.1016/j.jhep.2003.11.004

[22]   Muzzi, A., Leandro, G., Rubbia-Brandt, L., James, R., Keiser, O., Malinverni, R., Dufour, J.F., et al. (2005) Insulin resistance is associated with liver fibrosis in non-diabetic chronic hepatitis C patients. Journal of Hepatology, 42, 41-46.
http://dx.doi.org/10.1016/j.jhep.2004.09.022

[23]   Petit, J.M., Minello, A., Jooste, V., Bour, J.B., Galland, F., Duvillard, L., Verges, B., et al. (2005) Decreased plasma adiponectin concentrations are closely related to steatosis in hepatitis C virus-infected patients. Journal of Clinical Endocrinology and Metabolism, 90, 2240-2243.
http://dx.doi.org/10.1210/jc.2004-1266

[24]   Ascencio, C., Torres, N., Isoard-Acosta, F., Gomez-Perez, F.J., Hernandez-Pando, R. and Tovar, A.R. (2004) Soy protein affects serum insulin and hepatic SREBP-1 mRNA and reduces fatty liver in rats. Journal of Nutrition, 134, 522-529.

[25]   Song, Z., Zhou, Z., Uriarte, S., Wang, L., Kang, Y.J., Chen, T., Barve, S., et al. (2004) S-adenosylhomocysteine sensitizes to TNF-alpha hepatotoxicity in mice and liver cells: A possible etiological factor in alcoholic liver disease. Hepatology, 40, 989-997.

[26]   Wang, G. and Siow, Y.L. (2000) Homocysteine stimulates nuclear factor kappaB activity and monocyte chemoattractant protein-1 expression in vascular smooth-muscle cells: A possible role for protein kinase C. Biochemical Journal, 352, 817-826.
http://dx.doi.org/10.1042/0264-6021:3520817

[27]   Adinolfi, L.E., Ingrosso, D., Cesaro, G., Cimmino, A., D’Anto, M., Capasso, R., Zappia, V., et al. (2005) Hyper-homocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C patients. Hepatology, 41, 995-1003.
http://dx.doi.org/10.1002/hep.20664

[28]   Finkelstein, J.D. (1990) Methionine metabolism in mammals. The Journal of Nutritional Biochemistry, 1, 228-236. http://dx.doi.org/10.1016/0955-2863(90)90070-2

[29]   Refsum, H., Ueland, P.M., Nygard, O. and Vollset, S.E. (1998) Homocysteine and cardiovascular disease. Annual Review of Medicine, 49, 31-62.
http://dx.doi.org/10.1146/annurev.med.49.1.31

[30]   Mato, J.M., Alvarez, L., Ortiz, P. and Pajares, M.A. (1997) S-Adenosylmethionine synthesis: Molecular mechanisms and clinical implications. Pharmacology & Therapeutics, 73, 265-280.
http://dx.doi.org/10.1016/S0163-7258(96)00197-0

[31]   Mayer, E.L., Jacobsen, D.W. and Robinson, K. (1996) Homocysteine and coronary atherosclerosis. Journal of the American College of Cardiology, 27, 517-527.
http://dx.doi.org/10.1016/0735-1097(95)00508-0

[32]   Miller, S.A., Dykes, D.D. and Polesky, H.F. (1988) A simple salting out procedure for extracing DNA from human nucleated cells. Nucleic Acids Research, 16, 1215.
http://dx.doi.org/10.1093/nar/16.3.1215

[33]   Kim, Y.L. (2000) Methylenetetrahydrofolate reductase polymorphisms, folate, and cancer risk: A paradigm of gene-nutrient interactions in carcinogenesis. Nutrition Reviews, 58, 205-217.
http://dx.doi.org/10.1111/j.1753-4887.2000.tb01863.x

[34]   Daly, S.F., Molloy, A.M., Mills, J.L., Less, Y.J., Conley, M., Kirke, P.N., Weir, D.G. and Scott, J.M. (1999) The influence of 5,10 methylenetetrahydrofolate reductase genotypes on enzyme activity in placental tissue. British Journal of Obstetrics & Gynaecology, 106, 1214-1218.
http://dx.doi.org/10.1111/j.1471-0528.1999.tb08151.x

[35]   Weisberg, I., Tran, P., Christensen, B., Sibani, S. and Rozen, R. (1998) A second genetic polymorphism in methylene-tetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Molecular Genetics and Metabolism, 64, 169-172.
http://dx.doi.org/10.1006/mgme.1998.2714

[36]   Knodell, R.G., Ishak, K.G., Black, W.C., Chen, T.S., Craig, R., Kaplowitz, N., Kiernan, T.W. and Wollman, J. (1981) Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology, 1, 431-435.
http://dx.doi.org/10.1002/hep.1840010511

[37]   Scheuer, P.J. (1991) Classification of chronic viral hepatitis: A need for reassessment. Journal of Hepatology, 13, 372-374.
http://dx.doi.org/10.1016/0168-8278(91)90084-O

[38]   Tevijano, E.R.G., Berasain, C., Rodríguez, J.A., Corrales, F.J., Arias, R., Martín-Duce, A., Caballería, J., Mato, J.M. Matías and Avila, A. (2001) Hyperhomocysteinemia in liver cirrhosis mechanisms and role in vascular and hepatic fibrosis. Hypertension, 38, 1217-1221.
http://dx.doi.org/10.1161/hy1101.099499

[39]   Toniutto, P., Fabris, C., Falleti, E., Cussigh, A., Fontanini, E., Bitetto, D., Fornasiere, E., Minisini, R., De Feo, T., Marangoni, F. and Pirisi, M. (2007) Methylenetetrahydrofolate reductase C677T polymorphism and liver fibrosis progression in patients with recurrent hepatitis C. Liver International, 28, 257-263.
http://dx.doi.org/10.1111/j.1478-3231.2007.01591.x

[40]   Zhou, X.M., Lin, J.S., Sun, X.M., Tang, W.X., Zhang, W.Y., Yuan, S.Y. and Ai, L. (2005) The relationship between the plasma homocysteine level and the polymorphism of MTHFR gene C667T in liver cirrhosis. Zhonghua Gan Zang Bing Za Zhi, 13, 908-910.

[41]   Ventura, P., Rosa, M.C., Abbati, G., Marchini, S., Grandone, E., Vergura, P., Tremosini, S. and Zeneroli, M.L. (2005) Hyperhomocysteinaemia in chronic liver diseases: Role of disease stage, vitamin status and methylenetetrahydrofolate reductase genetics. Liver International, 25, 49-56.
http://dx.doi.org/10.1111/j.1478-3231.2005.01042.x

[42]   Sazci, A., Ergul, E., Kaya, G. and Kara, I. (2005) Genotype and allele frequencies of the polymorphic methylenete-trahydrofolate reductase gene in Turkey. Cell Biochemistry and Function, 23, 51-54.
http://dx.doi.org/10.1002/cbf.1132

[43]   Watanabe, M., Osada, J., Aratani, Y., Kluckman, K., Reddick, R., Malinow, M.R. and Maeda, N. (1995) Mice deficient in cystathionine beta-synthase: Animal models for mild and severe homocysteinemia. Proceedings of the National Academy of Sciences of the United States of America, 92, 1585-1589.
http://dx.doi.org/10.1073/pnas.92.5.1585

[44]   Gulsen, M., Yesilova, Z., Bagci, S., Uygun, A., Ozcan, A. and Ercin, C.N. (2005) Elevated plasma homocysteine concentrations as a predictor of steatohepatitis in patients with non-alcoholic fatty liver disease. Journal of Gastroenterology and Hepatology, 20, 1448-1455.
http://dx.doi.org/10.1111/j.1440-1746.2005.03891.x

[45]   Werstuck, G.H., Lentz, S.R., Dayal, S., Hossain, G.S., Sood, S.K. and Shi, Y.Y. (2001) Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. Journal of Clinical Investigation, 107, 1263-1273.
http://dx.doi.org/10.1172/JCI11596

[46]   Golbahar, J., Aminzadeh, M.A., Kassab, S.E. and Omrani, G.R. (2007) Hyperhomocysteinemia induces insulin resistance in male Sprague-Dawley rats. Diabetes Research and Clinical Practice, 76, 1-5.
http://dx.doi.org/10.1016/j.diabres.2006.07.026

[47]   Altinova, A.E., Toruner, F., Bukan, N., Yasar, D.G., Akturk, M., Cakir, N. and Arslan, M. (2007) Decreased plasma adiponectin is associated with insulin resistance and HDL cholesterol in overweight subjects. Endocrine Journal, 54, 221-226.
http://dx.doi.org/10.1507/endocrj.K06-021

[48]   Meigs, J.B., Jacques, P.F., Selhub, J., Singer, D.E., Nathan, D.M., Rifai, N., D’Agostino, R.B. and Wilson, P.W.F. (2001) Framingham offspring study. Fasting plasma homocysteine levels in the insulin resistance syndrome: The Framingham offspring study. Diabetes Care, 24, 1403-1410.
http://dx.doi.org/10.2337/diacare.24.8.1403

[49]   Adinolfi, L.E., Gambardella, M., Andreana, A., Tripodi, M.F., Utili, R. and Ruggiero, G. (2001) Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology, 33, 1358-1364.
http://dx.doi.org/10.1053/jhep.2001.24432

[50]   Hui, J.M., Kench, J., Farrell, G.C., Lin, R., Samarasinghe, D., Liddle, C., Byth, K. and George, J. (2002) Genotype-specific mechanisms for hepatic steatosis in chronic hepatitis C infection. Journal of Gastroenterology and Hepatology, 17, 873-881.
http://dx.doi.org/10.1046/j.1440-1746.2002.02813.x

[51]   Castera, L., Hezode, C., Roudot-Thoraval, F., Roudot-Thoraval, F., Lonjon, I., Zafrani, E.S., Pawlotsky, J.M. and Dhumeaux, D. (2004) Effect of antiviral treatment on evolution of liver steatosis in patients with chronic hepatitis C: Indirect evidence of a role of hepatitis C virus genotype 3 in steatosis. Gut, 53, 420-424.
http://dx.doi.org/10.1136/gut.2002.009936

[52]   Torres, L., García-Trevijano, E.R., Rodríguez, J.A., Bustos, M., Fernández, E., Eguinoa, E., Mato, J.M. and Avila, M.A. (1999) Induction of TIMP-1 expression in rat hepatic stellate cells and hepatocytes: A new role for homocysteine in liver fibrosis. Biochimica et Biophysica Acta, 1455, 12-22.
http://dx.doi.org/10.1016/S0925-4439(99)00049-6

[53]   Duong, F.H., Filipowicz, M., Tripodi, M., La Monica, N. and Heim, M.H. (2004) Hepatitis C virus inhibits interferon signaling through up-regulation of protein phosphatase 2A. Gastroenterology, 126, 263-277.

[54]   Kharbanda, K.K. (2007) Role of transmethylation reactions in alcoholic liver disease. World Journal of Gastroenterology, 13, 4947-4954.

 
 
Top