Publication Only: Enzymopathies, membranopathies and other anemias
Vitamin B12 (B12) deficiency causes hematological and non-hematological disorders. The latter include neurological syndromes such as polyneuropathies, subacute combined degeneration, basal ganglia lesions, dementia or ischemic stroke. These symptoms can be present even in the absence of anemia or macrocytosis, and the lack of these hematologic changes cannot exclude B12 deficiency as a cause of neurological symptoms.
There may be deficiency of B12 with normal or borderline serum levels, hence the relevance of assessing its metabolites homocysteine (HCY) and methylmalonic acid (MMA), that increase in case of B12 deficiency.
To determine the value of HCY and MMA in the diagnosis of B12 deficiency in patients with neurological symptoms.
A retrospective analysis of the cases in which evaluation of B12 and folic acid was requested from the Neurology department during a period of thirteen months was performed.
Analytical (complete blood count -CBC-, serum B12, serum folate, erythrocyte folate -when serum folate was low-, HCY, MMA, serum creatinine and estimated glomerular filtration rate -eGFR-) and demographic parameters were evaluated. B12 levels under 150 pg/L were considered low (LB12); between 150 and 200 pmol/L, borderline (BB12); and higher than 200 pmol/L, normal (NB12).
One thousand thirty nine (7.8%) of the 14644 requests came from the Neurology department. LB12 was found in 101 (9%) of these cases, BB12 in 177 (15.5%) and NB12 in 861 (75.6%). Folate deficiency was found in 11 (1%) patients.
Regarding to patients with LB12, 62% had no alterations in the CBC, 25% had non-macrocytic anemia and 8% had macrocytic anemia or macrocitosis. These results were similar in the group with BB12. Considering the patients with NB12, 72% of them had a normal CBC, 11,5% had non-macrocytic anemia, and macrocytic anemia or macrocytosis was observed in 6%. Hematological alterations in these three groups were mild or moderate in 90% of cases; in none was severe (considered if hemoglobin <7 gr/dL, platelets <50x10e9/L, neutrophils <0.5x10e9/L).
The metabolite levels were available in 162 cases of the NB12 group. In these patients, high HCY (>14.5 umol/L) was found in 18.8%. Folate levels were normal for all of them, although 32% had an abnormal eGFR that may contribute to the increase in HCY. Mutational status of the MTHFR gene is unknown in these patients. MMA was measured in 7.8% of the patients with NB12; increased levels (>0.4 umol/L) were found in 23.5%. In the NB12 group, 10 patients showed an increase in both metabolites (table 1), suggesting an actual B12 deficiency despite the normal B12 levels. Sensory polyneuropathy was the neurological finding in 9 of these patients and B12 deficiency was assumed the cause in 4 of them, who were given supplementary treatment.
The incidence of B12 deficiency in patients with neurological symptoms is high. Most of these B12-deficient patients did not show hematological changes or these were mild, and some of them presented with normal serum B12. Assessment of the metabolites is essential in these patients with normal serum B12 and neurological symptoms. This situation represents a true diagnostic and therapeutic challenge.
Therefore, in the context of a high clinical suspicion, a normal or borderline B12 does not rule out a functional deficiency and metabolites should be assessed.