Hyperhomocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C patients†‡

Abstract

The factors and mechanisms implicated in the development of hepatitis C virus (HCV)-related steatosis are unknown. Hyperhomocysteinemia causes steatosis, and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism induces hyperhomocysteinemia. We investigated the role of these factors in the development of HCV-related steatosis and in the progression of chronic hepatitis C (CHC). One hundred sixteen CHC patients were evaluated for HAI, fibrosis and steatosis grades, body mass index, HCV genotypes, HCV RNA levels, homocysteinemia, and the MTHFR C677T polymorphism. Hyperhomocysteinemia was associated with the TT genotype of MTHFR (r ‫؍‬ 0.367; P ‫؍‬ .001). Median values of homocysteine in the CC, CT, and TT genotypes of the MTHFR gene were 9.3, 12.2, and 18.6 mol/L, respectively (P ‫؍‬ .006). Steatosis correlated with the MTHFR polymorphism, homocysteinemia, HAI and fibrosis. Steatosis above 20% was significantly associated with fibrosis. Prevalence and high grade (>20%) of steatosis were 41% and 11% in CC, 61% and 49% in CT, and 79% and 64% in TT, respectively (P ‫؍‬ .01). Relative risk of developing high levels of steatosis was 20 times higher for TT genotypes than CC genotypes. According to multivariate analysis, steatosis was independently associated with hyperhomocysteinemia (OR ‫؍‬ 7.1), HAI (OR ‫؍‬ 3.8), liver fibrosis (OR ‫؍‬ 4.0), and HCV genotype 3 (OR ‫؍‬ 4.6). On univariate analysis, fibrosis was associated with age, steatosis, MTHFR, homocysteinemia and HAI; however, on multivariate analysis, liver fibrosis was independently associated with age (P ‫؍‬ .03), HAI (P ‫؍‬ .0001), and steatosis (P ‫؍‬ .007). In conclusion, a genetic background such as the MTHFR C677T polymorphism responsible for hyperhomocysteinemia plays a role in the development of higher degree of steatosis, which in turn accelerates the progression of liver fibrosis in CHC. ( H epatic steatosis frequently occurs in hepatitis C virus (HCV) infection, more so than in subjects with hepatitis B virus. 1 The prevalence of fatty infiltration in the livers of chronic hepatitis C (CHC) has been reported to average around 50%, with a range of 30% to 70%. 2-4 For HCV genotype 3 infection, it has been suggested that the virus exerts a direct steatogenic effect, supported by correlation of steatosis with the levels of HCV RNA, and by the reversal of steatosis as the result of antiviral therapy. [5][6][7][8] Moreover, the degree of steatosis has been related to the extent of hepatic fibrosis in CHC. 5,[9][10][11][12] The mechanisms involved in HCV-associated steatosis are unknown. Several host (body mass index [BMI], insulin resistance, hypertrigliceridemia) and viral factors may be implicated. Among viral factors, at least two HCV proteins-core and NS5A-have been credited with the ability to alter lipid metabolism in infected cells, thus causing hepatic steatosis in the absence of immune response. 13,14 In the transgenic mouse model, it has also been shown that the HCV core protein induces steatosis. 15 Transgenic mice expressing HCV co...

Genetic polymorphisms in the methylenetetrahydrofolate reductase and thymidylate synthase genes and risk of hepatocellular carcinoma

“…This is based on the recent report that the MTHFR C677T polymorphism is associated with steatosis and fibrosis in chronic hepatitis C patients. 51 Reduced MTHFR activity can reduce the SAMe pool (especially if folate is deficient), and we have accumulating evidence especially in animal models that chronic hepatic SAMe deficiency can predispose to HCC. 22 Reduced SAMe availability can lead to global DNA hypomethylation, which occurs in HCC.…”

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and the risk of primary Hepatocellular Carcinoma (HCC) in a Chinese population

“…Thirdly, MTHFR C667T has also been associated in several reports with an increased risk of invasive cervical cancer and premalignant lesions [21], which also indicate a possible role of MTHFR in viral infection associated cancers. Further, MTHFR C677T polymorphism is associated with hype-rhomocysteinemia among patients with chronic hepatitis C infection [22], which may accelerate the progression of liver fibrosis in CHC and possibly lead to liver cancer. It would be interesting to evaluate the potential interaction between MTHFR and HCV infection.…”

Review article: hepatitis C virus‐associated steatosis – pathogenic mechanisms and clinical implications

“…We found that the C677T polymorphism of the MTHFR gene was associated with both hyperhomocysteinaemia and a greater degree of steatosis in CHC patients. 16 Our data show that also adiponectin may be implicated in the pathogenesis of CHC-related steatosis. Adiponectin is secreted by adipocytes and has antilipogenic effects that may protect non-adipocyte tissues, such as the liver, from fat accumulation.…”