MTHFR C677T polymorhism and hyperhomocysteinemia in patients with liver cirrhosis complicated by portal vein thrombosis and hepatocellular carcinoma

BACKGROUND: Mild hyperhomocysteinemia (HHcy) is an independent risk factor for deep vein thrombosis; the liver plays a key role in homocysteine (Hcy) metabolism, being the sole tissue provided with the whole enzymatic set of transsulfuration and remethylation pathways; the liver has also a key-role in storage and metabolism of vitamins needed as cofactor in sulphur aminocid metabolism. Among different determinants of HHcy, the methylen-tetrahydrofolate reductase (MTHFR) C677T polymorphism has an high prevalence in general population (the homozygous state (TT) have been estimated in about 18% of italians). MTHFR gene anomalies have been also involved in cancer development, through a mechanism involving the impairment of folate metabolism and hence inducing alterations in DNA repair and methylation. Liver cirrhosis (LC) is by far the most important risk factor of portal vein thrombosis (PVT) especially if complicated by hepatocellular carcinoma (HCC). AIM: Considering the complex interaction between HHcy, MTHFR status and liver function impairment , aim of our study was to investigate a possible relation between HHcy, MTHFR status, HCC and PVT in patients with liver cirrhosisMATERIALS and METHODS: To these purposes, we have studied 86 patients (35 f, mean age 65±10 years) affected by LC, 53 without portal thrombosis (LC group) and 33 with portal thrombosis (doppler ultrasonography, angio-CT or angiography dcumented) (PVT group) . Patients in the two groups were age- ,Child Pugh score- , etiology- and sex–matched. All patients were assessed for plasma homocysteine (HPLC) , MTHFR C677T and vitamin (reb blood cell folate, serum B12 and B6) status. RESULTS: The table resumes the results regarding HCC presence and homocysteine parameters in the two studied groups.PVT (n=33)LC (n=53)pOR (95% CI)HCC presence (y/n)21/12 (63.6 %)12/41 (22.6%).0073.26 (1.31÷8.12)Mean plasma Hcy16.4 ± 6.112.1 ± 6.1.0151.07 (1.01÷1.15)HHcy prevalence (y/n)§21/12 (63.6%)15/38 (28.3%).0023.08 (1.61÷7.41)MTHFR status (CC/CT/TT)8/12/1335/14/4.001* .013***TT prevalence; **CT plus TT status vs. CC prevalence; §= >15 nmol/mlNo significant differences in vitamin status (red blood cell folate, and serum B12 and B6) were observed between groups. Patients with HCC (n=33) showed significant higher levels of plasma Hcy (17.7±5.9 vs. 13.5±5.8, p.039) and significant higher prevalence of HHcy (19/33, 57.5% vs.17/53, 32.1%, p=.025, OR 1.79, 95% CI 1.12÷2.99) than patients without HCC(n=53). Patients with HCC had also a significant higher prevalence of MTHFR TT status (10/33, 30.3% vs. 7/53, 13.2 %, p=.044, OR 2.67, 95% CI 1.07÷6.67). Interestingly, all patients with MTHFR TT status had HHcy and all patients MTHFR TT and HCC had PVT.CONCLUSION: Mild HHcy associated to liver cirrhosis may play a possible role for PVT development. Even if confirmations by larger and prospective studies are needed, assessment of homocysteine (simple and cheap) may be suggested in patients with liver cirrhosis (especially in case of advanced liver disease or in the presence of HCC).Our data concerning the association between HCC and MTHFR TT status is intriguing, due the postulated role for this polymorphism in cancerogenesis: it may represent a further link between HCC and PVT