Clinical spectrum and diagnosis of cobalamin deficiency

Abstract

To better estimate how frequently patients with low serum cobalamin (CbI) levels in current clinical practice are truly deficient in CbI and to determine the incidence of atypical or nonclassic presentations of CbI deficiency, we prospectively studied 300 unselected consecutive patients with serum CbI concentrations less than 200 pg/mL seen at two medical centers over a 2-year period. Baseline hematologic, neuropsychiatric, and biochemical measurements were obtained, followed by a course of parenteral CbI therapy and reassessment. A response to CbI therapy was defined as one or more of the following: (1) an increase in hematocrit of 0.05 or more; (2) a decrease in mean cell volume of 5 fL or more; (3) a clearing of hypersegmented neutrophils and macroovalocytes from the peripheral blood smear; and (4) an unequivocal and prompt improvement of neuropsychiatric abnormalities. Of the 300 patients with serum CbI levels less than 200 pg/mL, 86 had one or more responses to CbI therapy and 59 had no response. In 155, insufficient data was available. In the CbI-responsive patients, normal values were found for the following tests: hematocrit, 44%; mean cell volume ≤100 fL, 36%; white blood cell count, 84%; platelet count, 79%; serum lactic dehydrogenase, 43%; and serum bilirubin, 83%. Peripheral blood smears were nondiagnostic in 6% when reviewed by the investigators, but 33% as reported by routine laboratories. Serum CbI levels in the 100 to 199 pg/mL range were present in 38%. Neuropsychiatric abnormalities were noted in 28%, often in the absence of anemia, macrocytosis, or both. Serum levels of methylmalonic acid and/or total homocysteine were elevated greater than 3 SDs above the mean for normal subjects in 94% of the CbI-responsive patients. We conclude that CbI deficiency should be considered and investigated in patients with unexplained hematologic or neuropsychiatric abnormalities of the kind seen in CbI deficiency, even if anemia, an elevated mean cell volume, a marked depression of the serum CbI, or other classic hematologic or biochemical abnormalities are lacking. Levels of serum methylmalonic acid and total homocysteine are useful as ancillary diagnostic tests in the diagnosis of CbI deficiency. © 1990 by The American Society of Hematology.