Lack of Anemia Despite Marked Elevation of Serum Methylmalonic Acid and Total Homocysteine in a Multiethnic Cohort.

It is controversial whether asymptomatic patients with metabolic evidence of cobalamin (Cbl) deficiency need vitamin treatment. Patients with clinical abnormalities due to Cbl deficiency which are proven to correct with treatment invariably have elevated serum methylmalonic acid(MMA) and total homocysteine(tHcy). However, many subjects with elevated MMA are found in screening studies of seniors and they often have no classical clinical abnormalities. We correlated hematologic and neurologic findings with elevated MMA and tHcy in subjects enrolled in the Northern Manhattan Study. Eligible subjects were over 40 yr, had not had a stroke and lived in Manhattan. Approximately 3000 subjects had serum MMA, tHcy and other relevant data available. The samples were collected from 1993 to 2001 thus spanning food folate fortification in the United States. We analyzed those in the top 1% MMA and/or tHcy since these subjects had values seen also in clinical Cbl deficiency. There were 30 subjects with MMA 975 to 179,900 nM (normal<271 nM), 15 female, age 56 to 90 yr, and 19% white, 15% black, 60% other including Hispanic. Only 7of 27 had mild anemia (lowest value, 33.6%) and 6 of 27 had elevated MCV>100fL. The male subject with the highest MCV (109.8 fL), had a hematocrit of 42.7 %, MMA 179,900 nM, tHcy 86.3 uM and Cbl 34 pg/mL with no neurologic findings. Neurologic abnormalities were present in 5 of 30. One subject had high grade spastic paraparesis, 3 had peripheral nervous system deficits, and one had central nervous system defects.Serum tHcy and MMA were not higher in those with neurologic abnormalities. The serum creatinine was < 1.3 mg/dL in the 27 with values thus the elevated MMA was not attributable to renal failure. The serum Cbl was < 200 pg/mL in only 6 of 22 and < 350 pg/mL in 16 of 22. The top 1% of tHcy value ranged from 24.9 to 102 uM (normal<14uM) and only 7 of 31 of these subjects had elevated tHcy without associated elevated MMA. Eight of those in the top 1 percentile for tHcy were also in the top 1 percentile for MMA. We conclude 1.Serum MMA is elevated > 975 nM in 1% of a randomly selected urban multiethnic cohort. 2. Hematologic abnormalities were absent or mild in this group with high MMA. 3. Neurologic abnormalities were found consistent with Cbl deficiency in 17 % of those with high MMA. 4. Both MMA and tHcy are usually elevated. 5. Even though the elevations of MMA and tHcy overlapped those found in clinical studies of Cbl deficiciency these randomly discovered subjects were generally asymptomatic, suggesting that the pathophysiology of megaloblastic anemia and combined systems disease still needs to be investigated.