Vitamin B12 Assessment in Hypothyroidism
Screen all patients with autoimmune hypothyroidism for vitamin B12 deficiency at diagnosis and annually thereafter, as the prevalence ranges from 28-68% and is strongly associated with positive thyroid antibodies. 1, 2
Initial Screening Approach
Check serum B12 levels in all hypothyroid patients with positive anti-thyroid peroxidase (anti-TPO) or anti-thyroglobulin (anti-Tg) antibodies, as these patients have significantly higher rates of B12 deficiency (78.6% with positive anti-TPO and 78% with positive anti-Tg antibodies). 2 The correlation between thyroid antibodies and B12 deficiency is statistically significant (r = -0.302, p = 0.002 for anti-TPO; r = -0.253, p = 0.011 for anti-Tg). 2
Who to Screen
- All patients with autoimmune thyroid disease (Hashimoto's thyroiditis with positive TPO or Tg antibodies) should undergo B12 screening at diagnosis. 1, 3
- Patients with persistent symptoms despite adequate thyroid hormone replacement (fatigue, cognitive difficulties, memory problems, depression, numbness, decreased reflexes) warrant B12 testing regardless of antibody status. 4, 2
- Annual monitoring is recommended for patients with autoimmune thyroid disease due to the progressive nature of autoimmune gastritis. 1
Laboratory Testing Strategy
Order serum B12 as the initial test, with a deficiency threshold of <150 pmol/L (<203 pg/mL). 5 However, recognize that standard serum B12 testing misses functional deficiency in up to 50% of cases. 5
When serum B12 is borderline (150-258 pmol/L or 203-350 pg/mL) or symptoms persist despite "normal" B12, order:
- Methylmalonic acid (MMA) - elevated MMA confirms functional B12 deficiency even with normal serum B12. 5, 6
- Holotranscobalamin (active B12) - measures biologically active B12 and is more sensitive than total B12. 5, 6
- Homocysteine - elevated levels suggest functional deficiency. 5, 6
Complete blood count (CBC) should be checked, though anemia is absent in one-third of B12-deficient patients and mean corpuscular volume (MCV) may be normal. 5, 4
Evaluating Underlying Causes
In B12-deficient hypothyroid patients, test for pernicious anemia and celiac disease, as these autoimmune conditions frequently coexist:
- Intrinsic factor antibodies (IFAB) - positive in 7.5% of B12-deficient hypothyroid patients. 7
- Tissue transglutaminase (tTG) antibodies and total IgA - positive in 13.3% of B12-deficient hypothyroid patients. 1, 7
Review medications that interfere with B12 absorption: metformin (especially >4 months use), H2 receptor antagonists, proton pump inhibitors, phenobarbital, pregabalin, colchicine, anticonvulsants, sulfasalazine, and methotrexate. 5, 6
Treatment Recommendations
For confirmed B12 deficiency (<150 pmol/L or <203 pg/mL):
- Oral vitamin B12 1000-2000 μg daily is as effective as intramuscular administration for most patients and is the preferred initial approach. 5
- Intramuscular B12 injections monthly should be reserved for: severe neurologic manifestations, confirmed malabsorption (positive IFAB), or failure of oral therapy to normalize levels. 5, 4
- Continue treatment until levels normalize, then maintain therapy. For patients with positive intrinsic factor antibodies, lifelong treatment is necessary. 5
Clinical improvement occurs in 58.3% of B12-deficient hypothyroid patients within 6 months of replacement therapy. 4 Neurologic symptoms often present before hematologic changes and can become irreversible if untreated. 5
Monitoring and Follow-Up
Recheck B12 levels after 3-6 months of treatment to confirm normalization. 1 For patients with autoimmune thyroid disease, continue annual B12 screening even after initial treatment, as autoimmune gastritis is progressive. 1
Monitor thyroid function every 12 months including TSH, free T4, and TPO antibodies, as subclinical thyroid disease contributes to fatigue and may mask B12 deficiency symptoms. 1
Critical Clinical Pitfalls
Do not rely solely on serum B12 to rule out deficiency, especially in patients >60 years where metabolic deficiency is common despite normal serum levels. 5, 6 Up to 50% of patients with "normal" serum B12 have metabolic deficiency when measured by MMA. 5
Traditional symptoms (weakness, memory impairment, depression, numbness) are not reliable guides for determining B12 deficiency presence, as they overlap significantly with hypothyroid symptoms and may not achieve statistical significance between B12-deficient and B12-sufficient hypothyroid patients. 4
Do not assume negative thyroid antibodies exclude the need for B12 screening - prevalence of B12 deficiency does not differ significantly between antibody-positive (43.2%) and antibody-negative (38.9%) hypothyroid patients. 4
Borderline-to-low B12 levels (150-258 pmol/L) are significantly more prevalent in both overt hypothyroidism (68.9%) and subclinical hypothyroidism (85.4%) compared to controls (57.5%), warranting closer monitoring even when not frankly deficient. 7