Hyperhomoysteinemia as a risk factor for coronary heart diseases in chronic hepatitis C patients


Hepatitis C virus is one of the major health problems worldwide. It affects mainly the liver but several extrahepatic manifestations are also accounted. Chronic hepatitis C patients are at an increased risk of developing hepatic steatosis, which share many clinical features with the metabolic syndrome. Hepatic steatosis has also been associated with elevated levels of markers of inflammation such as homocysteine, identified as hyperhomocysteinemia (HHC). HHC due to Methylenetetrahydrofolate Reductase (MTHFR) gene, in particular the C677T polymorphism, was recently associated with coronary heart diseases (CHD) in chronic hepatitis C (CHC) patients. Homocysteine is an intermediate in methionine metabolism, which takes place mainly in the liver metabolism. Deficiencies of micronutrients (folate, vitamin B 6 and possibly vitamin B 12) along with mild hyperhomocysteinemia, perhaps, act synergistically with other classical risk factors to further increase the risk of CHD. Clinical data indicate that HHC is associated with an increased incidence of CHD as well as with the severity of the disease in CHC patients. In conclusion, HHC might be a potential aetiological factor of CHD in CHC patients. The aim of this review is to investigate the progression of coronary heart diseases in chronic hepatitis C patients and correlate with levels of homocysteine in concurrence to genetic defects and nutrient deficiencies. However, future studies need to clarify the mechanistic role of HHC in CHD and CHC as a useful paradigm with most interesting therapeutic implications.

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Kazmi, A. , Hanif, A. , Ismail, M. and Qazi, J. (2013) Hyperhomoysteinemia as a risk factor for coronary heart diseases in chronic hepatitis C patients. World Journal of Cardiovascular Diseases, 3, 499-505. doi: 10.4236/wjcd.2013.38079.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] National Institutes of Health Consensus Development Conference Panel statement Management of hepatitis C. (1997) Hepatology, 26, 2S-10S.
[2] Wilkins, T., Malcolm, J.K., Raina, D., Schade, R.R. Hepatitis, C: Diagnosis and treatment. (2010) American Family Physician, 81, 1351-1357.
[3] Choi, J., Ou, J.H.J. (2006) Mechanisms of liver injury. III. Oxidative stress in the pathogenesis of hepatitis C virus. American Journal of Physiology—Gastrointestinal & Liver Physiology, 290, G847-G851.
[4] Ghany, M.G., Strader, D.B., Thomas, D.L., Seeff, L.B. (2009) Diagnosis, management, and treatment of hepatitis C: An update. Hepatology, 49, 1335-1374.
[5] Ghany, M.G., Nelson, D.R., Strader, D.B., Thomas, D.L., Seeff, L.B. (2011) An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection: 2011 Practice Guideline by the American Association for the Study of Liver Diseases. Hepatology, 54, 1433-1444.
[6] Pearlman, B.L., Traub, N. (2011) Sustained virologic response to antiviral therapy for chronic hepatitis C virus infection: A cure and so much more. Clinical Infectious Diseases, 52, 889-900.
[7] Ko, W.S., Guo, C.H., Hsu, G.S.W., Chiou, Y.L., Yeh, M.S., Yaun, S.R. (2005) Effects of zinc supplementation on the treatment of chronic hepatitis C patients with interferon and ribavirin. Clinical Biochemistry, 38, 614-620. http://dx.doi.org/10.1016/j.clinbiochem.2005.04.003
[8] Anton, E., Becker, M.D., Becker A.E. et al. The atherosclerosis from Egyptian mummies to immune mediated intraplaque inflammation. Dialogue in Cardiovascular Medicine, 2006, 11, 116.
[9] Becker, A.E., Boer, O.J., Wal, A.C. The role of inflamemation and infections in coronary artery disease. Annual Review of Medicine, 2001, 52, 289-297.
[10] Libby, P., Hanssson, G.K. et al involvement of immune system in human atherogenesis, current knowledge and unanswered questions. Laboratory Investigation, 1991, 64, 52-50.
[11] Wal, A.C., Becker, A.E., Loos, C.M., et al. fibrous and lipid rich plaques. Plaques are part of interchangeable morphologies related inflammation a concept. Coronary Artery Disease, 1994, 5, 463-469.
[12] Wal, A.C., Becker A.E., Loos C.M., et al. Site of intimal rupture or erosion of thrombosed coronary atherosclerosis plaque is characterized by an inflammatory process irespective of the dominant plaque morphology. Circulation, 1994, 89, 36-44.
[13] Shah P.K. Link between infection and atherosclerosis. Who are the culprits: viruses, bacteria, both or neither? Circulation, 2001, 103, 5-6.
[14] Chiu, B., Viira, E., Tucker, W. and Fong I.W. (1997) Chalamydia pneumoniae, cytomegalo virus, and herpes simplex virus in atherosclerosis artery. Circulation, 96, 2144-2148. http://dx.doi.org/10.1161/01.CIR.96.7.2144
[15] Lin, C.C. and Yin, M.C. (2009) Vitamins B depletion, lower iron status and decreased antioxidative defense in patients with chronic hepatitis C treated by pegylated interferon alfa and ribavirin. Clinical Nutrition, 28, 34-38. http://dx.doi.org/10.1016/j.clnu.2008.09.003
[16] Roca, B., Bennasar, M., Ferrero, J.A., Monte, del M.C. and Resino, E. (2012) Hepatitis C virus co-infection and sexual risk behaviour are associated with a high homocysteine serum level in HIVinfected patients. Swiss Medical Weekly, 141, w13323.
[17] Borgia, G., Gentile, I., Fortunato, G., Borrelli, F., Borelli, S., Caterina, de M., et al. (2009) Homocysteine levels and sustained virological response to pegylated-interferon alpha2b plus ribavirin therapy for chronic hepatitis C: A prospective study. Liver International, 29, 248-452.
[18] Rosenberg, P. and Hagen, K. (2011) Serum B12 levels predict response to treatment with interferon and ribavirin in patients with chronic HCV infection. Journal of Viral Hepatitis, 18, 129-134.
[19] Danesh, J., Collins, R. and Peto, R. (1997) Chronic infections and coronary heart disease: Is there a link? Lancet, 350, 430-436.
[20] Sheehan, J., Kearney, P.M., Sullivan, S.O., Mongan, C., Kelly, E. and Perry, I.J. (2005) Acute coronary syndrome and chronic infection in the Cork coronary care casecontrol study. Heart, 91, 19-22.
[21] Fong, I.W. (2000) Emerging relations between infectious diseases and coronary artery disease and atherosclerosis. CMAJ, 163, 49-56.
[22] Arcari, C.M., Nelson, K.E., Netski, D.M., Nieto, F.J. and Gaydos, C.A. (2006) No association between hepatitis C virus seropositivity and acute myocardial infarction. Clinical Infectious Diseases, 43, e53-e56.
[23] Volzke, H., Schwahn, C., Wolff, B., et al. (2004) Hepatitis B and C virus infection and the risk of atherosclerosis in a general population. Atherosclerosis, 174, 99-103.
[24] Momiyama Y., Ohmori R., Kato R., Taniguchi H., Nakamura H. and Ohsuzu F. (2005) Lack of any association between persistent hepatitis B or C virus infection and coronary artery disease. Atherosclerosis, 181, 211-213.
[25] Tong, D.Y., Wang, X.H., Xu, C.F., Yang, Y.Z. and Xiong, S.D. (2005) Hepatitis B virus infection and coronary atherosclerosis: results from a population with relatively high prevalence of hepatitis B virus. World Journal of Gastroenterology, 11, 1292-1296.
[26] Vassalle, C., Masini, S., Bianchi, F. and Zucchelli, G.C. (2004) Evidence for association between hepatitis C virus seropositivity and coronary artery disease. Heart, 90, 565-566. http://dx.doi.org/10.1136/hrt.2003.018937
[27] Ishizaka, N., Ishizaka, Y., Takahashi, E., et al. (2002) Association between hepatitis C virus seropositivity, carotid-artery plaque, and intima-media thickening. Lancet, 359, 133-135.
[28] Sawayama, Y., Okada, K., Maeda, S., Ohnishi, H., Furusyo, N. and Hayashi, J. (2006) Both hepatitis C virus and Chlamydia pneumoniae infection are related to the progression of carotid atherosclerosis in patients undergoing lipid lowering therapy. Fukuoka Igaku Zasshi, 97, 245-255.
[29] Sanyal, A.J., Contos, M.J., Sterling, R.K., et al. (2003) Nonalcoholic fatty liver disease in patients with hepatitis C is associated with features of the metabolic syndrome. The American Journal of Gastroenterology, 98, 2064-2071.http://dx.doi.org/10.1111/j.1572-0241.2003.07640.x
[30] Sanyal, A.J. (2005) Review article: Non-alcoholic fatty liver disease and hepatitis C—risk factors and clinical implications. Alimentary Pharmacology & Therapeutics, 22, 48-51. http://dx.doi.org/10.1111/j.1365-2036.2005.02596.x
[31] Targher, G., Bertolini, L., Scala, L., Zoppini, G., Zenari, L. and Falezza, G. (2005) Nonalcoholic hepatic steatosis and its relation to increased plasma biomarkers of inflammation and endothelial dysfunction in non-diabetic men: Role of visceral adipose tissue. Diabetic Medicine, 22, 1354-1358.
[32] Butt, A.A., Xiaoqiang, W., Budoff, M., Leaf, D., Kuller, L.H. and Justice, A.C. (2009) Hepatitis C virus infection and the risk of coronary disease. Clinical Infectious Diseases, 49, 225-232.
[33] Refsun, H., Ueland, P., Nygard, O. and Vollset, S.E. (1998) Homocysteine and cardiovascular disease. Annual Review of Medicine, 49, 31-36.
[34] Bostom, A.G and Lathrop, L. (1997) Hyperhomocysteinemia in end-stage renal disease: Prevalence, etiology, and potential relationship to arteriosclerosis outcomes. Kidney International, 52, 10-20.
[35] Eskes, T.K.A.B. (1998) Open or closed? A word of differences: A history of homocysteine research. Nutrition Reviews, 56, 236-244.
[36] Ji, C. and Kaplowitz, N. (2003) Betaine decreases hyperyhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice. Gastroenterology, 124, 1488-1499.
[37] Miner, S.E., Evrovski, J. and Cole, D.E. (1997) Clinical chemistry and molecular biology of homocysteine metabolism: An update. Clinical Biochemistry, 30, 189-201.
[38] Taha, K., El-Shayeb, A., Shafeh, R., Deghady, A. and Eldin, S.Z. (2009) Clinical significance of plasma homocysteine concentration in chronic hepatitis C patients with liver cirrhosis. Alexandria Journal of Medicine, 45, 755-760.
[39] Roblin, X., Pofelski, J. and Zarski, J.P. (2007) Steatosis, chronic hepatitis virus C infection and homocysteine. Gastroentérologie Clinique et Biologique, 31, 415-720.
[40] García-Tevijano, E.R., Berasain, C., Rodríguez, J.A., Corrales, F.J., Arias, R., Martín-Duce, A., Caballería, J., Mato, J.M. and Avila, M.A. (2001) Hyperhomocysteinemia in liver cirrhosis: Mechanisms and role in vascular and hepatic fibrosis. Hypertension, 38, 1217-1221.
[41] Finkelstein, J.D. (2003) Methionine metabolism in liver diseases. The American Journal of Clinical Nutrition, 77, 1094-1095.
[42] Avila, M.A., Berasain, C. and Torres, L. (2000) Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. Journal of Hepatology, 33, 907-914.
[43] Lambert, D., Benhayoun, S., Adjalla, C., Gelot, M.M., Renkes, P., Gerard, P., Felden, F., Belleville, F., Gaucher, P., Guéant, J.L. and Nicolas, J.P. (1997) Alcoholic cirrhosis and cobalamin metabolism. Digestion, 58, 64-71.
[44] Halifeoglu, I., Gur, B. and Aydin, S. (2004) Plasma trace elements, vitamin B12, folate and homocysteine levels in cirrhotic patients compared to controls. Biochemistry, 69, 693-696.
[45] Gulsen, M., Yesilova, Z., Bagci, S., Uygun, A., Ozcan, A., Ercin, C.N., Erdil, A., Sanisoglu, S.Y., Cakir, E., Ates, Y., Erbil, M.K., Karaeren, N. and Dagalp, K. (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.
[46] Jaeckel, E., Cornberg, M., Wedemeyer, H., Santantonio, T., Mayer, J., Zankel, H., Dietrich, M., Trautwein, C. and Manns, M.P. (2001) Treatment of acute hepatitis C with interferon alfa-2b. The New England Journal of Medicine, 345, 1452-1457.
[47] Werstuck, G.H., Lentz, S.R. and Dayal, S. (2001) Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. The Journal of Clinical Investigation, 107, 1263-1267. http://dx.doi.org/10.1172/JCI11596
[48] Mudd, S.H., Levy, H.L. and Skovby, F. (1995) Disorders of transsulfuration. In: Scriver, C.R., Beaudet, A.L., Sly, W.S. and Valle, D., Eds., The metabolic and molecular bases of inherited disease, Vol. 1, McGraw-Hill, New York, 1279-1327.
[49] Carey, M.C., Donovan, D.E., FitzGerald, O. and McAuley, F.D. (1968) Homocystinuria: A clinical and pathological study of nine subjects in six families. The American Journal of Medicine, 45, 7-25.
[50] Mudd, S.H., Skovby, F., Levy, H.L., et al. (1985) The natural history of homocystinuria due to cystathionine b-synthase deficiency. The American Journal of Human Genetics, 37, 1-31.
[51] Malinow, M.R., Kang, S.S., Taylor, L.M., et al. (1989) Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. Circulation, 79, 1180-1188. http://dx.doi.org/10.1161/01.CIR.79.6.1180
[52] Coull, B.M., Malinow, M.R., Beamer, N., Sexton, G., Nordt, F. and de Garmo, P. (1990) Elevated plasma homocyst(e)ine concentration as a possible independent risk factor for stroke. Stroke, 21, 572-576.
[53] Malinow, M.R., Sexton, G., Averbuch, M., Grossman, M., Wilson, O. and Upson, B. (1990) Homocyst(e)ine in daily practice: Levels in coronary heart disease. Coronary Artery Disease, 2, 4-12.
[54] Mudd, S.H., Uhlendorf, B.W., Freeman, J.M., Finkelstein, J.D. and Shih, V.E. (1972) Homocystinuria associated with decreased methylenetetrahydrofolate reductase activity. Biochemical and Biophysical Research Communications, 46, 905-912.
[55] Erbe, R.W. (1986) Inborn errors of folate metabolism. In: Blakely, R.L. and Whitehead, V.M., Eds., Folate and pterins: Nutritional, pharmacological, and physiological aspects. Marcel Dekker, New York, 413-425.
[56] D’Angelo, A. and Selhub, J. (1997) Homocysteine and thrombotic disease. Blood, 90, 1-11.
[57] Kang, S.S., Zhou, J., Wong, P.W.K., Kowalisyn, J. and Strokosch, G. (1988) Intermediate homocysteinemia: A thermolabile variant of methylenetetrahydrofolate reducetase. The American Journal of Human Genetics, 43, 414-421.
[58] Frosst, P., Blom, H.J., Milos, R., et al. (1995) A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nature Genetics, 10, 111-113.
[59] Frosst, P., Blom, H.J., Milos, R., Goyette, P., Sheppard, C.A., Matthews, R.G., Boers, G.J., den Heijer, M., Kluijtmans, L.A., van den Heuvel, L.P. and Rozen, R. (1995) A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nature Genetics, 10, 111-113.
[60] Goyette, P., Sumner, J.S., Milos, R., Duncan, A.M., Rosenblatt, D.S., Matthews, R.G. and Rozen, R. (1994) Human methylenetetrahydro folate reductase: Isolation of cDNA, mapping and mutation identification. Nature Genetics, 7, 195-200. http://dx.doi.org/10.1038/ng0694-195
[61] Put van der, N.M.J., Gabreels, F., Stevens, E.M., Smeitink, J.A., Trijbels, F.J., Eskes, T.K., van den Heuvel, L.P. and Blom, H.J. (1998) A second common mutation in the methylenetetrahydrofolate reductase gene: An additional risk factor for neural-tube defects? The American Journal of Human Genetics, 62, 1044-1051.
[62] Andreassi, M.G., Botto, N., Battaglia, D., Antonioli, E., Masetti, S., Manfredi, S., Colombo, M.G., Biagini, A. and Clerico, A. (2003) Methylenetetrahydro folate reductase gene C677T polymorphism, homocysteine, vitamin B12, and DNA damage in coronary artery disease. Human Genetics, 112, 171-177.

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