Introduction: Hyperhomocysteinemia (HHcy) is a risk factor for venous thromboembolism, which in turn is a major cause of chronic venous insufficiency. HHcy may be more common in patients with chronic venous insufficiency, but the cause is unknown.
Methods: One hundred hospital outpatients (52 women; median age, 66.5 years [interquartile range, 53-77 years] with venous disease C(2-6) underwent assessment of serum vitamin B(12) and folate concentration, plasma Hcy concentration, and C677T methylene tetrahydrofolate reductase (MTHR) homozygosity with polymerase chain reaction. HHcy was defined as greater than 15 micromol/L, the 95th centile of the normal range.
Results: CEAP classification was C(2) in 39 patients, C(3) in 10 patients, C(4) in 13 patients, C(5) in 15 patients, and C(6) in 23 patients, with median Hcy concentration 11.6, 11.5, 12.5, 15.1, and 18.1 micromol/L, respectively (Kruskall-Wallis test, P <.001). Overall prevalence of HHcy was 39% (P <.001, binomial test vs normal population), and was significantly related (Pearson chi(2) for trend, 13.616; P <.009) to clinical grade: C(2), 23%; C(3), 20%; C(4), 39%; C(5), 53%; C(6), 65%. In a linear regression model, C(6) disease was a strong independent predictor (R(2) = 20.1%) for Hcy. Overall, 5 of 49 patients (10%, NS compared with normal population [5%]) with C(2-3) disease and 10 of 51 patients (20%) (P <.001, binomial test) with C(4-6) disease were homozygous for the C677T MTHFR polymorphism. Hcy levels and prevalence of HHcy were negatively correlated with vitamin B(12) levels (r = -0.248, P =.021, and r = -0.225;, P =.037, respectively). There was no significant relationship with folate. HHcy was present in 3 patients (all with C(5-6) disease) with either vitamin B(12) or folate deficiency, and in 8 of 15 patients homozygous for MTHFR C677T. No patient had HHcy, vitamin deficiency, and C677T mutation.
Conclusion: HHcy is common in patients with chronic venous insufficiency, especially those with ulceration. However, inasmuch as fewer than a third of patients with HHcy were C677T MTHFR homozygous or had vitamin B(12) or folate deficiency, other mechanisms must be responsible in the majority. Further work is required to determine the cause of HHcy in chronic venous insufficiency, whether HHcy is causally related to development and progression of the disease, and whether treatment would be beneficial.