Determinants of changes in plasma homocysteine in hyperthyroidism and hypothyroidism

OBJECTIVE Hyperhomocysteinaemia is a risk factor for premature atherosclerotic vascular disease and venous thrombosis. The aim of the present study was to assess plasma total homocysteine (tHCys) concentrations in hypo- as well as hyperthyroid patients before and after treatment, and to evaluate the role of potential determinants of plasma tHCys levels in these patients. DESIGN Prospective follow up study. PATIENTS Fifty hypothyroid and 46 hyperthyroid patients were studied in the untreated state and again after restoration of euthyroidism. MEASUREMENTS Fasting plasma levels of tHCys and its putative determinants (plasma levels of free thyroxine (fT(4)), folate, vitamin B-12, renal function, sex, age, smoking status and the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene were measured before and after treatment. RESULTS Restoration of the euthyroid state decreased both tHCys (17.6 +/- 10.2-13.0 +/- 4.7 mu mol/l; P < 0.005) and creatinine (83.9 +/- 22.0-69.8 +/- 14.2 mu mol/l; P < 0.005) in hypothyroid patients and increased both tHCys (10.7 +/- 2.5-13.4 +/- 3.3 mu mol/l; P < 0.005) and creatinine (49.0 +/- 15.4-66.5 +/- 15.0 mu mol/l; P < 0.005) in hyperthyroid patients (values as mean +/- SD). Folate levels were lower in the hypothyroid group compared to the hyperthyroid group (11.7 +/- 6.4 and 15.1 +/- 7.6 nmol/l; P < 0.05). Pretreatment tHCys levels correlated with log fT(4) (r = - 0.47), folate (r = - 0.21), plasma creatinine (r = 0.45) and age (r = 0.35) but not with C677T genotype. Multivariate analysis indicated that pretreatment log(fT(4)) levels and age accounted for 28% the variability of pre-treatment tHCys (tHCys = 14.2-5.50 log(fT(4)) + 0.14 age). After treatment the logarithm of the change (Delta) in fT(4) (expressed as the post-treatment fT(4/)pre-treatment fT(4) ratio) accounted for 45% of the variability in change of tHCys ( tHCys = - 0.07-4.94 log ( fT(4))); there was no independent contribution of changes in creatinine which was, however, strongly related to changes in tHCys (r = 0.61). CONCLUSIONS Plasma tHCys concentrations increased in hypothyroidism and decreased in hyperthyroidism. Plasma fT(4) is an independent determinant of tHCys concentrations. Lower folate levels and a lower creatinine clearance in hypo-thyroidism, and a higher creatinine clearance in hyperthyroidism only partially explain the changes in tHCys.