Liver Cirrhosis Patients Homozygous for MTHFR C677T Develop Portal Vein Thrombosis 8 Years Earlier Than Wild Type

Homozygous MTHFR C677T carriers develop idiopathic portal vein thrombosis 20 years earlier than wild type

“…Reduced hepatic blood flow or local intravascular consumption may partly account for some of these lower PC values, as it is known that surgical correction of blood flow restored to normal the low concentration of natural anticoagulants [16]. Moreover, the higher concentration of homocysteine in our MTHFR TT patients may induce posttranslational modifications in protein C that becomes unable to digest factor Va and VIIIa in vivo, leading to thrombosis, and unable to digest its substrate in the chromogenic assay, leading to lower functional levels in vitro [17][18][19]; indeed, we found an inverse relation between plasma homocysteine and protein C in the MTHFR TT group, in close similarity to MTHFR TT carriers with PVT in liver cirrhosis [4].…”

“…Limitations of our survey are the lack of B12/folate measurement and of genotyping for other genes involved in homocysteine disposal, as also 50% of our MTHFR CC patients had a plasma homocysteine above the cut-off; and the retrospective cohort cross-sectional design; the latter, however, was offset by the stringent exclusion process that allowed us to evaluate the impact of MTHFR and plasma homocysteine with their attendant oxidative stress on age at PVT presentation once other disorders characterised by oxidative stress were removed from the cohort. The knowledge that idiopathic PVT thrombosis occurred with an anticipation of 20 years in MTHFR TT carriers may be of some relevance in families wherein a young first-degree relative had suffered any venous thromboembolism, provided the MTHFR was tested as part of a thrombophilia screen [32], a situation different from that of MTHFR TT patients who develop PVT in association with liver cirrhosis [4] in whom thromboprophylaxis should be offered to minimize the negative impact of PVT on liver transplant [33]. That said, idiopathic PVT carriers of MTHFR TT who do not show adequate recanalization after a fixed period of oral anticoagulation may be at risk of re-thrombosis with evolution to cavernoma and should be offered prolonged anticoagulation [34].…”

“…The knowledge that idiopathic PVT thrombosis occurred with an anticipation of 20 years in MTHFR TT carriers may be of some relevance in families wherein a young first-degree relative had suffered any venous thromboembolism, provided the MTHFR was tested as part of a thrombophilia screen [32], a situation different from that of MTHFR TT patients who develop PVT in association with liver cirrhosis [4] in whom thromboprophylaxis should be offered to minimize the negative impact of PVT on liver transplant [33]. That said, idiopathic PVT carriers of MTHFR TT who do not show adequate re-canalization after a fixed period of oral anticoagulation may be at risk of re-thrombosis with evolution to cavernoma and should be offered prolonged anticoagulation [34].…”

“…Almost 25% of the Italian population carries a homozygous polymorphism of the MTHFR gene (C !T nucleotide transition at position 677) (rs1801133) coding for an enzyme with 70% reduced activity [2]: this laboratory phenotype pushes the plasma homocysteine concentration into the mild-moderate atherothrombotic range that promotes venous thromboembolism in whites [2]. Two cohort studies have shown that carriership of the homozygous MTHFR TT genotype is associated with a 10-year earlier age of onset of first venous thromboembolism [3] and with an 8-year earlier age at onset of portal vein thrombosis (PVT) in liver cirrhosis [4] compared with carriership of the heterozygous or wild types, suggesting that an anticipated age at first thrombosis may represent the clinical phenotype of the MTHFR TT genotype.…”