Serum Total Homocysteine Concentrations in the Third National Health and Nutrition Examination Survey (1991–1994): Population Reference Ranges and Contribution of Vitamin Status to High Serum Concentrations

Background: The concentration of circulating total homocysteine is a sensitive marker of inadequate folate and vitamin B12 status. Elevated homocysteine concentrations are associated with an increased risk for vascular disease. Objective: To identify reference ranges for serum total homocysteine concentration in U.S. residents and quantify the contribution of circulating vitamin concentrations to high homocysteine concentrations. Design: Cross-sectional prevalence study. Setting: United States. Patients: A nationally representative sample of 3563 male participants and 4523 female participants 12 years of age or older who participated in the third National Health and Nutrition Examination Survey. Measurements: Reference ranges (5th and 95th percentiles) for the total homocysteine concentration were defined among participants who were folate- and vitamin B12-replete and had normal creatinine concentrations. A high total homocysteine concentration was defined as one that exceeded the sex-specific 95th percentile for the reference sample (participants 20 to 39 years of age). The population attributable risk percentage was calculated to determine the contribution of low folate (<11 nmol/L) and vitamin B12 (<185 pmol/L) concentrations to a high homocysteine concentration. Results: Reference ranges for serum total homocysteine concentration increased with age; these ranges were 4.3 to 9.9 µmol/L for male participants and 3.3 to 7.2 µmol/L for female participants 12 to 19 years of age and from 5.9 to 15.3 µmol/L for men and 4.9 to 11.6 µmol/L for women 60 years of age or older. A high homocysteine concentration was defined as at least 11.4 µmol/L for male participants and at least 10.4 µmol/L for female participants. Approximately two thirds of the cases of high homocysteine concentrations were associated with low vitamin concentrations. Conclusions: Upper reference limits for the serum total homocysteine concentration increased with age and were higher for male participants than for female participants at all ages. In most cases, high homocysteine concentrations were associated with low serum vitamin concentrations.