SENSITIVITY OF SERUM METHYLMALONIC ACID AND TOTAL HOMOCYSTEINE DETERMINATIONS FOR DIAGNOSING COBALAMIN AND FOLATE DEFICIENCIES

PURPOSE: Patients with cobalamin (vitamin B12) deficiency usually lack many of the classic features of severe megaloblastic anemia; because of the low diagnostic specificity of decreased serum cobalamin levels, demonstrating the deficiency unequivocally is often difficult. We exa mined the sensitivity of measuring serum concentrations of methylmalon ic acid and total homocysteine for diagnosing patients with clear-cut cobalamin deficiency and compared the results with those of patients w ith clear-cut folate deficiency. PATIENTS AND METHODS: Serum metabolit es were measured for all patients seen from 1982 to 1989 at two univer sity hospitals who met the criteria for cobalamin and folate deficienc y states and for such patients seen from 1968 to 1981 from whom stored sera were available. In all, 406 patients had 434 episodes of cobalam in deficiency and 119 patients had 123 episodes of folate deficiency. Criteria for deficiency states included serum vitamin levels, hematolo gic and neurologic findings, and responses to therapy. Responses were documented in 97% of cobalamin-deficient patients and 76% of folate-de ficient patients. Metabolite levels were measured by modified techniqu es using capillary-gas chromatography and mass spectrometry. RESULTS: Most of the cobalamin-deficient patients had underlying pernicious ane mia; two thirds were blacks or Latinos. Hematocrits were normal in 28% and mean cell volumes in 17%. Of the 434 episodes of cobalamin defici ency, 98.4% of serum methylmalonic acid levels and 95.9% of serum homo cysteine levels were elevated (greater than 3 standard deviations abov e the mean in normal subjects). Only one patient had normal levels of both metabolites. Serum homocysteine levels were increased in 91% of t he 123 episodes of folate deficiency. Methylmalonic acid was elevated in 12.2% of the folate-deficient patients; in all but one, the elevati on was attributable to renal insufficiency or hypovolemia. CONCLUSIONS : For the cobalamin-deficient patients, measuring serum metabolite con centrations proved to be a highly sensitive test of deficiency. We con clude that normal levels of both methylmalonic acid and total homocyst eine rule out clinically significant cobalamin deficiency with virtual certainty.