What should be done for a relative with a family history of Vitamin B12 deficiency?

Family History of Vitamin B12 Deficiency: Screening and Management

For relatives with a family history of B12 deficiency, screen them now with serum B12 or active B12 testing, especially if they have autoimmune conditions, are over 60 years old, or take medications like metformin or PPIs for more than 4 months. 1, 2

Who Should Be Screened

Family members warrant immediate testing if they have:

• Autoimmune conditions (thyroid disease, type 1 diabetes, Sjögren syndrome) - these patients have a 28-68% prevalence of B12 deficiency and should be screened at diagnosis and annually thereafter 2, 3
• Age >75 years - 18.1% of those >80 years have metabolic B12 deficiency despite normal serum levels 2
• Metformin use >4 months or PPI/H2 blocker use >12 months 2, 3
• Gastrointestinal conditions including atrophic gastritis, celiac disease, or history of gastric/intestinal surgery 2, 3
• Vegetarian or vegan diet due to limited dietary B12 intake 2

Screening Algorithm

Initial Testing Approach

Start with serum total B12 (costs ~£2, rapid turnaround) or active B12 (holotranscobalamin) as the first-line test 1, 2:

• Total B12 <180 pg/mL (<133 pmol/L): Confirmed deficiency - initiate treatment immediately 2
• Total B12 180-350 pg/mL (133-258 pmol/L): Indeterminate - proceed to MMA testing 1, 2
• Total B12 >350 pg/mL (>258 pmol/L): Deficiency unlikely, but consider functional markers if high clinical suspicion 2

For active B12 interpretation 2:

• <25 pmol/L: Confirmed deficiency
• 25-70 pmol/L: Indeterminate - requires MMA testing

• 70 pmol/L: Deficiency unlikely

Confirmatory Testing for Indeterminate Results

Measure methylmalonic acid (MMA) when B12 results fall in the indeterminate range 1, 2:

• MMA >271 nmol/L confirms functional B12 deficiency with 98.4% sensitivity 2
• MMA detects an additional 5-10% of patients with functional deficiency who have low-normal B12 levels 2
• In polyneuropathy patients, 44% had B12 deficiency based solely on abnormal MMA when serum B12 was normal 2

Critical caveat: MMA can be falsely elevated in hypothyroidism, renal insufficiency, and hypovolemia - interpret cautiously in these conditions 2

Special Considerations for Family History

Genetic Testing Indications

Consider genetic testing for transcobalamin deficiency (TCN2 gene) and intracellular cobalamin metabolism defects (MMACHC, MMADHC, MTRR, MTR genes) if relatives have elevated MMA with normal serum B12, particularly with a strong family history 2

Autoimmune Clustering

If the family member with B12 deficiency has pernicious anemia, screen relatives for:

• Intrinsic factor antibodies
• Gastric parietal cell antibodies
• Thyroid antibodies (TPO)
• Celiac disease markers (tissue transglutaminase antibodies with total IgA) 2, 4

These autoimmune conditions frequently coexist, with 13.3% of B12-deficient hypothyroid patients having positive celiac markers 2

Endoscopy Considerations

For relatives found to have pernicious anemia, upper endoscopy should be considered for risk stratification and to evaluate for gastric neoplasia and neuroendocrine tumors 4. Topographical biopsies determine anatomic extent and histologic severity 4. Surveillance endoscopy every 3 years is recommended for advanced atrophic gastritis 4.

Monitoring Schedule

For relatives with autoimmune conditions: Annual B12 screening is recommended due to the progressive nature of autoimmune gastritis 2

For relatives without risk factors but with family history: Screen every 2-3 years, as this allows detection before irreversible neurological damage occurs 5

After initiating treatment: Recheck B12 levels at 3-6 months to confirm normalization, then continue annual screening 2

Common Pitfalls to Avoid

• Do not rely solely on serum B12 in elderly relatives (>60 years) - up to 50% with "normal" serum B12 have metabolic deficiency when measured by MMA 2, 6
• Never administer folic acid before treating B12 deficiency - it may mask anemia while allowing irreversible neurological damage to progress 2
• Do not overlook medication-induced deficiency - review use of metformin, PPIs, H2 blockers, colchicine, anticonvulsants 2, 4, 3
• Recognize that standard reference ranges may not be appropriate for all individuals, particularly those with autoimmune conditions 2