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Objectives: Patients with inflammatory bowel disease (IBD) have an increased risk of thrombotic complications. Moreover, a hypercoagulable state has been hypothesized as a contributing factor in the pathogenesis of IBD. Recently, a growing amount of interest has focused on mild-to-moderate hyperhomocysteinemia as a risk factor for thromboembolic disease. We aimed to evaluate the prevalence of hyperhomocysteinemia in patients with IBD and to investigate the contribution of genetic defects in the enzymes involved in homocysteine (Hcy) metabolism and vitamin status in determining increased levels of plasma total Hcy (tHcy)., Methods: The concentrations of tHcy, folate, and vitamin B12 as well as the prevalence of methylenetetrahydrofolate reductase (MTHFR) 677C to T mutation and the 68-bp insertion at exon 8 of cystathionine beta-synthase (CBS) were measured in patients with IBD and healthy controls., Results: In all, 17 out of 64 IBD patients (26.5%) and four out of 121 (3.3%) controls had hyperhomocysteinemia with a statistically significant difference (p < 0.0001). No significant difference was found between IBD patients and controls with regard to the prevalence of homozygotes for the C677T variant (TT) of MTHFR or the prevalence of heterozygotes for the CBS-gene mutation (IN). Among the IBD patients the only independent factor significantly associated with hyperhomocysteinemia was folate deficiency (p = 0.0002), regardless of the MTHFR or the CBS genotype., Conclusions: IBD patients have a higher prevalence of hyperhomocysteinemia than do healthy controls. Folate deficiency is the only independent risk factor in developing hyperhomocysteinemia.

Hyperhomocysteinemia is an established risk factor for deep vein thrombosis. Factor V Leiden has been reported to potentiate the thrombotic risk related with severe hyperhomocysteinemia, being more represented in thrombotic patients with homocystinuria as compared with patients without a history of thrombosis. The results concerning the interaction between moderate hyperhomocysteinemia and inherited thrombophilic factors such as Factor V Leiden or the prothrombin G20210A mutation are contradictory. The relative risk for venous thrombosis has been reported to be increased 10- to 50-fold in patients carrying both hyperhomocysteinemia and inherited thrombophilia in comparison with normal controls, suggesting a synergistic interaction, yet other studies failed to confirm such conclusion. The heterogeneity of these findings is in part due to the small number of individuals with double defects, leading to statistically unreliable results. Genotyping for mutations that are possible causes of moderate hyperhomocysteinemia, such as the thermolabile variant (C677T) of methylenetetrahydrofolate reductase (MTHFR), does not seem useful to identify individuals at higher risk for venous thromboembolism. In fact, in most of the studies the presence of the C677T MTHFR homozygous genotype does not increase the thrombotic risk associated with Factor V Leiden or the prothrombin mutation.

Mild hyperhomocysteinaemia is an established risk factor for deep vein thrombosis (DVT); few data concerning its potential interaction with thrombophilic genotypes are available at the present time. We investigated 121 thrombosis-free individuals and 111 patients with at least one objectively confirmed episode of DVT. A thrombophilic condition (deficiency in antithrombin, protein C and S, factor V Leiden, prothrombin G20210A) was detected in 25.2% of the patients; mutant factor V or prothrombin genotypes were present in 6.6% of the controls. Hyperhomocysteinaemia was found in 14.4% of patients and 3. 3% of the controls, with a 3.7-fold increase in risk for DVT (95% CI 1.1-12.3). Adoption of different cut-off levels for definition of hyperhomocysteinaemia did not substantially change the magnitude of the risk. Carriership of both hyperhomocysteinaemia and factor V Leiden or prothrombin G20210A was detected in 2.7% of patients for each combination and in none of the controls. An approximate estimate of 30-fold increased risk in carriers of both hyperhomocysteinaemia and factor V Leiden and 50-fold increased risk in carriers of both hyperhomocysteinaemia and prothrombin G20210A was calculated, suggesting a synergistic interaction between hyperhomocysteinaemia and such thrombophilic genotypes. Yet statistical analysis is highly unstable due to the small number of individuals with combined defects. Further investigations on large series of patients are needed.