Laboratory Interpretation: Functional Vitamin B12 Deficiency Despite Normal Serum B12
These labs indicate functional vitamin B12 deficiency despite a normal serum B12 level of 413 pg/mL, as evidenced by the elevated methylmalonic acid (MMA) of 251 nmol/L, which is the most specific marker for B12 deficiency. The low folate (7.5 ng/mL) is contributing to the macrocytosis (MCV 104 fL), but the elevated MMA confirms that B12 metabolism is impaired at the cellular level 1.
Primary Diagnostic Findings
The elevated MMA (251 nmol/L, normal <271 nmol/L but functionally elevated above ~200 nmol/L) is the critical finding that reveals functional B12 deficiency. Serum B12 levels between 200-500 pg/mL are unreliable, as 5-10% of patients in this "low-normal" range have elevated metabolites indicating true deficiency 1. In one study, 44% of polyneuropathy patients with B12 deficiency were identified only through abnormal metabolites, not serum B12 levels 1.
MMA is more specific than homocysteine for B12 deficiency, with 98.4% sensitivity for B12 deficiency, while homocysteine is elevated in 91% of isolated folate deficiency cases 1. This specificity makes MMA the gold standard functional marker 1, 2.
Hematologic Status
The hemoglobin of 14.2 g/dL is normal, demonstrating a critical clinical principle: macrocytic anemia is often absent in B12 deficiency, occurring in only about two-thirds of cases 1. The absence of anemia does not exclude B12 deficiency and should never delay treatment 1, 3.
The MCV of 104 fL reflects macrocytosis from combined B12 and folate deficiency. The normal platelet count (276k) and adequate ferritin (137 ng/mL) exclude other causes of macrocytosis 4.
Folate Status
The folate level of 7.5 ng/mL (approximately 17 nmol/L) is borderline-low, falling in the 5-7 nmol/L range that warrants concern when accompanied by elevated functional markers 4. The slightly elevated total bilirubin (1.4 mg/dL) may reflect ineffective erythropoiesis from the combined vitamin deficiencies 5.
Importantly, folate deficiency can mask B12 deficiency by partially correcting the macrocytosis while allowing neurological damage to progress 6. This makes the elevated MMA finding even more critical, as it reveals the underlying B12 problem that might otherwise be obscured 7, 6.
Clinical Implications and Urgent Concerns
Neurological damage from B12 deficiency can occur without anemia and is often irreversible if not treated promptly 1. About 80% of patients with only neurological symptoms present between the fifth and seventh decades 1. The normal hemoglobin provides false reassurance—treatment must be based on the MMA elevation, not hematologic parameters 1.
The combination of elevated folate intake with low B12 is particularly dangerous, as it can correct megaloblastic changes while permitting neurological deterioration 7, 6. If this patient is taking folic acid supplements, they should be stopped immediately until B12 is repleted 6.
Management Algorithm
Immediate B12 replacement is required based on the elevated MMA, regardless of the normal serum B12 level 1, 6. The functional deficiency confirmed by MMA takes precedence over serum B12 measurements 2.
For folate repletion, address this after initiating B12 therapy to avoid masking B12 deficiency 7, 6. Target folate levels should reach approximately 330 μg DFE per day for adults 7.
Monitor response with repeat MMA levels, which should normalize with adequate B12 replacement 1, 2. Follow-up should occur at 3,6, and 12 months, then annually 1.
Key Clinical Pitfalls
Never rely on serum B12 alone when MCV is elevated or neurological symptoms are present 1. Up to 50% of metabolically B12-deficient patients have normal serum B12 levels 1.
Do not assume adequate B12 status based on normal hemoglobin—one-third of B12-deficient patients lack macrocytic anemia 1, 3.
Avoid folic acid supplementation before B12 repletion, as this can precipitate or worsen neurological complications 7, 6.