What is the next step in evaluating and managing a 65-year-old woman with numbness and tingling in the balls of her feet and a borderline low serum vitamin B12 level of 245 pg/mL?

Evaluation and Management of Peripheral Neuropathy with Borderline B12 Level

Measure methylmalonic acid (MMA) immediately to confirm functional B12 deficiency, as a serum B12 of 245 pg/mL falls in the indeterminate range (180–350 pg/mL) where up to 50% of patients have metabolic deficiency despite "normal" serum levels. 1

Why MMA Testing is Essential in This Case

Your patient's B12 level of 245 pg/mL sits squarely in the diagnostic gray zone. While not definitively low, this level cannot exclude functional B12 deficiency—the Framingham Study demonstrated that 50% of patients with "normal" serum B12 actually had elevated MMA indicating true metabolic deficiency. 1 Given her neurological symptoms (numbness and tingling), waiting or dismissing this level would risk irreversible nerve damage.

MMA >271 nmol/L confirms functional B12 deficiency with 98.4% sensitivity, making it the gold standard for clarifying indeterminate B12 results. 1 This test costs £11–80 but is cost-effective at £3,946 per quality-adjusted life year when used appropriately after indeterminate B12 results. 1

Concurrent Diagnostic Workup

While awaiting MMA results, evaluate for other causes of peripheral neuropathy:

Screen for Diabetes

• All patients with peripheral neuropathy should be screened for diabetes starting at diagnosis of type 2 diabetes, as diabetic peripheral neuropathy is the most common cause of neuropathy in this age group. 2
• Check fasting glucose and HbA1c immediately. 2

Assess for Medication-Induced Deficiency

• Review her medication list for drugs that impair B12 absorption: metformin (if used >4 months), proton pump inhibitors or H2 blockers (if used >12 months), colchicine, phenobarbital, or pregabalin. 1, 3
• These medications can cause functional B12 deficiency even with borderline serum levels. 1

Check for Autoimmune Conditions

• Patients with autoimmune conditions (thyroid disease, type 1 diabetes) have 28–68% prevalence of B12 deficiency and should undergo screening. 1
• Order TSH and consider anti-intrinsic factor antibodies if MMA is elevated. 1

Rule Out Other Nutritional Deficiencies

• Check folate, iron studies (ferritin, transferrin saturation), vitamin D, and copper levels concurrently, as these deficiencies often coexist and can cause similar neurological symptoms. 1, 3
• In inflammatory conditions, ferritin up to 100 μg/L may still indicate iron deficiency. 1

Interpretation Algorithm for MMA Results

If MMA >271 nmol/L (Confirms B12 Deficiency)

Begin treatment immediately without waiting for additional tests. 1

For neurological involvement (which your patient has):

• Hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement, then maintenance of 1 mg IM every 2 months for life. 3
• Intramuscular administration is superior to oral therapy when neurological symptoms are present, as it ensures rapid correction and prevents irreversible damage. 3, 4

Critical pitfall to avoid: Never administer folic acid before treating B12 deficiency, as it may mask anemia while allowing irreversible neurological damage to progress. 1, 3

If MMA ≤271 nmol/L (Rules Out B12 Deficiency)

Focus diagnostic efforts on other causes:

• Diabetic neuropathy remains the leading consideration—ensure comprehensive diabetes screening with 10-g monofilament testing, vibration sense with 128-Hz tuning fork, and assessment of ankle reflexes. 2
• Consider referral to neurology if the clinical picture remains atypical or diagnosis unclear. 2

Monitoring After Treatment Initiation

If B12 deficiency is confirmed and treated:

• Recheck B12 and MMA at 3–6 months to confirm normalization, targeting MMA <271 nmol/L and homocysteine <10 μmol/L for optimal outcomes. 1
• Monitor complete blood count at 5–10 days post-treatment—absence of reticulocytosis should prompt hematology referral for alternative diagnoses. 3
• Continue annual B12 monitoring even after initial treatment, as the underlying cause (often malabsorption) typically persists. 1

Age-Specific Considerations

At 65 years old, your patient faces elevated risk:

• 18.1% of adults >60 years have metabolic B12 deficiency, and 25% of those ≥85 years have B12 <170 pmol/L. 1
• Atrophic gastritis affects up to 20% of older adults, causing food-bound B12 malabsorption while crystalline B12 absorption remains intact—this is why supplementation works even in malabsorption states. 1, 5

Why This Approach Prioritizes Outcomes

Neurological symptoms from B12 deficiency can become irreversible if left untreated, with subacute combined degeneration of the spinal cord occurring even before anemia develops. 3 The 2024 NICE guideline emphasizes that MMA testing in the indeterminate range detects an additional 5–10% of patients with functional deficiency who would otherwise be missed. 1 Given the safety of B12 treatment and the catastrophic consequences of missed diagnosis, aggressive evaluation is warranted.

The single most important next step is MMA measurement—do not delay this test or dismiss the borderline B12 level in a patient with active neurological symptoms. 1, 4