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

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Abstract

Background and Aim

Age at portal vein thrombosis (PVT) in liver cirrhosis (LC) carriers of the methylene tetrahydrofolate reductase (MTHFR) rs1801133 (C → T667 transition) polymorphism has never been addressed; we compared age at PVT in LC patients genotyped for the MTHFR and explored the interrelated clinical and laboratory factors predicting age at PVT.

Approach and Results

Retrospective cross-sectional cohort study. PVT participants: MTHFR CC n = 36, MTHFR CT n = 53, MTHFR TT n = 19; age, sex, age at PVT, Child–Pugh score, rs1799963 PT polymorphisms (G → A 20,210 transition), plasma HC and natural anticoagulants available for all participants. Age at PVT was lower in MTHFR TT than CT and CC (56 ± 13 vs. 57 ± 13 vs. 64 ± 9 years, p = 0.001); median (IQR) plasma HC was higher in MTHFR TT than in the other groups [(17 (9.4, 23.3) vs 13 (8,14.7) vs 11 (8.9, 12.7) μmol/l, p = 0.03)]. MTHFR TT, male gender and protein C predicted age at PVT (p = 0.02, p = 0.04 and p = 0.08); MTHFR TT and Child–Pugh score predicted plasma HC (p = 0.005 and p = 0.01) as well as low plasma protein C (p < 0.0001 and p = 0.0002). Plasma HC inversely related to protein C in the MTHFR TT group (p < 0.0001). Compound MTHFR TT with PT GA had lower age at PVT compared to MTHFR TT alone (49 ± 18 vs 58 ± 12 years).

Conclusions

MTHFR TT anticipates PVT associated with LC by an average of 8 years; MTHFR TT associates with severity of liver disease and to high plasma HC; the latter may contribute to the prematurity of PVT by interfering with the anticoagulant activity of protein C.

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Authors and Affiliations

  1. Immune Response & Vascular Disease Unit, Universidade NOVA de Lisboa, Lisbon, Portugal

    Paul R. J. Ames

  2. Dumfries & Galloway Royal Infirmary, Cargenbridge, DG2 8RX, Scotland, UK

    Paul R. J. Ames

  3. Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy

    Giovanna D’Andrea & Maurizio Maraglione

  4. Department of Medicine and Health Sciences ‘V. Tiberio’, University of Molise, Campobasso, Italy

    Alessia Arcaro & Fabrizio Gentile

  5. Multimedica Srl, Naples, Italy

    Vincenzo Marottoli & Luigi Iannaccone

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Contributions

All authors contributed to the study conception and design. PRJA, FG and VM designed the study; PRJA, LI and AA collected the data; PRJA and MM analyzed the data. The first draft of the manuscript was written by Paul RJ Ames, all authors provided comments on the first draft that was finalized by FG and MM. All authors read and approved the final manuscript.

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Correspondence to Paul R. J. Ames.

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None of the authors has any financial or non-financial competing interest to declare.

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At the time of their attendance for the thrombophilia screen patients gave informed and written consent to the use and storage of their genetic material and of their anonymized clinical information as per approval of the local Ethics Committee.

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Ames, P.R.J., D’Andrea, G., Arcaro, A. et al. Liver Cirrhosis Patients Homozygous for MTHFR C677T Develop Portal Vein Thrombosis 8 Years Earlier Than Wild Type. Dig Dis Sci 68, 1332–1338 (2023). https://doi.org/10.1007/s10620-022-07666-7

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