What is the diagnosis for a patient with anemia, hypersegmented neutrophils, normal vitamin B12 (Vit B12) level, slightly low folate level, and elevated methylmalonic acid level?

Diagnosis: Functional Vitamin B12 Deficiency (Pernicious Anemia)

This patient has functional vitamin B12 deficiency despite a "normal" serum B12 level of 210 pg/mL, confirmed by the markedly elevated methylmalonic acid (MMA) of 580 nmol/L (normal <271 nmol/L), anemia with hypersegmented neutrophils, and borderline low folate. 1, 2

Diagnostic Interpretation

Why This is B12 Deficiency Despite "Normal" B12 Level

• Serum B12 of 210 pg/mL falls in the indeterminate range (180-350 pg/mL) where functional deficiency commonly occurs 1, 2
• The elevated MMA of 580 nmol/L (>271 nmol/L) confirms functional B12 deficiency with 98.4% sensitivity, indicating inadequate cellular B12 availability despite measurable serum levels 1, 2
• Standard serum B12 testing misses functional deficiency in up to 50% of cases, as serum B12 measures total B12, not the biologically active form (holotranscobalamin) available for cellular use 1
• Hypersegmented neutrophils are pathognomonic for megaloblastic anemia, strongly supporting B12 deficiency as the primary diagnosis 2, 3, 4

Supporting Laboratory Findings

• Hemoglobin 10.2 g/dL represents moderate anemia requiring treatment 2
• Ferritin 220 ng/mL is elevated and excludes absolute iron deficiency, though in inflammatory conditions ferritin up to 100 μg/L may still mask iron deficiency 2
• Folate 12 ng/mL is borderline low (normal >3.4 ng/mL, but optimal >10 nmol/L), which may contribute to the anemia but is secondary to the B12 deficiency 5, 2

Critical Treatment Algorithm

Step 1: Immediate B12 Replacement (NEVER Give Folate First)

Never initiate folate supplementation before treating B12 deficiency, as this can precipitate subacute combined degeneration of the spinal cord—an irreversible neurological complication 2, 6

• For patients without neurological symptoms: Cyanocobalamin 1000 mcg intramuscular three times weekly for 2 weeks, then 1000 mcg every 2-3 months for life 2, 6
• For patients with neurological symptoms (numbness, tingling, cognitive changes, gait disturbance): Hydroxocobalamin 1000 mcg intramuscular on alternate days until no further improvement, then 1000 mcg every 2 months 2

Step 2: Investigate Underlying Cause

• Check anti-intrinsic factor antibodies and anti-parietal cell antibodies to diagnose pernicious anemia, the most common cause of B12 deficiency 3, 4
• Measure gastrin levels if pernicious anemia suspected, with markedly elevated levels (>1000 pg/mL) confirming the diagnosis 1
• Review medications: metformin >4 months, PPIs >12 months, H2 blockers, colchicine, and anticonvulsants all impair B12 absorption 1

Step 3: Address Folate Deficiency (Only After B12 Treatment Initiated)

• After B12 treatment is initiated, give folic acid 5 mg orally daily for minimum 4 months 2, 6
• Folate deficiency can cause identical hematologic findings but does not elevate MMA (MMA is specific for B12 deficiency) 1

Step 4: Monitor Treatment Response

• Repeat complete blood count in 4 weeks to confirm response, expecting hemoglobin increase of at least 2 g/dL 2
• Hypersegmented neutrophils should disappear within 2 weeks of B12 therapy 4
• Recheck MMA in 3-6 months to confirm normalization (target <271 nmol/L) 1

Common Pitfalls to Avoid

Relying Solely on Serum B12 Levels

• Up to 50% of patients with metabolic B12 deficiency have "normal" serum B12 levels, particularly in elderly patients (>60 years) where 18.1% have metabolic deficiency despite normal serum levels 1
• MMA testing detects an additional 5-10% of patients with functional B12 deficiency who have low-normal B12 levels 1

Giving Folate Before B12

• Folic acid may mask anemia while allowing irreversible neurological damage to progress, a critical and preventable complication 1, 2, 6

Missing Pernicious Anemia

• This patient's presentation (anemia, hypersegmented neutrophils, elevated MMA, borderline B12) is classic for pernicious anemia, which requires lifelong B12 replacement 3, 4
• Positive intrinsic factor blocking antibodies are 100% specific for pernicious anemia 3, 4

Overlooking Iron Deficiency in Inflammatory States

• While ferritin 220 ng/mL appears normal, in inflammatory conditions ferritin may be falsely elevated despite true iron deficiency 2
• Check transferrin saturation (TSAT) and consider functional iron deficiency if TSAT 20-50% with ferritin 30-800 ng/mL 5

Alternative Diagnoses to Exclude

Myelodysplastic Syndrome (MDS)

• MDS can present with cytopenias, macrocytic anemia, and hypersegmented neutrophils 5, 6
• However, the elevated MMA confirms functional B12 deficiency as the primary cause 1, 2
• If anemia persists after 4 weeks of B12/folate treatment, bone marrow examination is indicated to exclude MDS 6

Copper Deficiency

• Copper deficiency can mimic MDS with vacuolation of myeloid/erythroid precursors and hypersegmented neutrophils 5
• Consider checking copper and ceruloplasmin levels if patient has history of gastrointestinal surgery or zinc supplementation 5