What lab tests should be checked in a patient with normal iron levels and persistent feelings of cold intolerance, potentially indicating hypothyroidism or vitamin B12 deficiency?

Evaluation of Cold Intolerance with Normal Iron Levels

Check thyroid function tests (TSH and free T4) first, followed by vitamin B12 levels, as these are the two most common causes of persistent cold intolerance when iron studies are normal. 1

Primary Laboratory Evaluation

Thyroid Function Testing

• Order TSH and free T4 as the initial screening tests for patients presenting with cold intolerance, unexplained fatigue, weight gain, hair loss, constipation, or depression 1
• Cold intolerance is a classic symptom of hypothyroidism and warrants immediate thyroid evaluation 1
• Free T4 is preferred over total T4 because it provides a more accurate assessment of thyroid status, unaffected by thyroid hormone-binding protein variations 2
• In primary hypothyroidism, expect elevated TSH with low free T4 1
• If hypothyroidism is confirmed, check thyroid peroxidase (TPO) antibodies to identify autoimmune etiology 1

Vitamin B12 Assessment

• Measure serum vitamin B12 levels in all patients with persistent cold intolerance and normal iron studies, particularly those with hypothyroidism 1, 3
• Vitamin B12 deficiency occurs in approximately 40% of hypothyroid patients and can cause symptoms that overlap with hypothyroidism, including fatigue, cold intolerance, and weakness 4
• Consider checking B12 even if thyroid function is normal, as deficiency can occur independently 1
• In autoimmune hypothyroidism, there is a negative correlation between vitamin B12 levels and anti-TPO antibodies, suggesting shared autoimmune mechanisms 5

Additional Considerations

Complete Blood Count

• Obtain a CBC to evaluate for macrocytic anemia, which may indicate B12 or folate deficiency despite normal iron studies 1
• Low mean corpuscular volume (MCV) suggests iron, folate, or B12 deficiency, while normal MCV with anemia in the context of chronic disease is common 1

Vitamin D Levels

• Consider checking 25-hydroxyvitamin D levels, as vitamin D deficiency is associated with autoimmune hypothyroidism and correlates negatively with anti-TPO antibodies 5

Common Diagnostic Pitfalls

Critical caveat: Normal TSH alone does not exclude thyroid dysfunction in all cases. In secondary or tertiary hypothyroidism (pituitary or hypothalamic dysfunction), TSH may be low or inappropriately normal despite low free T4 1. In these cases, monitor free T4 levels and maintain them in the upper half of the normal range 1.

Important note: Patients may have subclinical hypothyroidism (elevated TSH with normal free T4) that still causes symptoms including cold intolerance 6. The presence of positive anti-TPO antibodies in subclinical hypothyroidism increases the likelihood of progression to overt hypothyroidism 6.

Clinical Algorithm

1. First-line testing: TSH and free T4 1
2. If TSH elevated: Add TPO antibodies to confirm autoimmune etiology 1
3. Regardless of thyroid results: Check vitamin B12 levels 1, 4
4. If B12 deficient in hypothyroid patients: Screen for pernicious anemia, particularly in those with positive thyroid antibodies 1, 3
5. Consider: CBC, vitamin D, and assessment for other autoimmune conditions if initial workup suggests autoimmune thyroid disease 1, 5

Management priority: If both hypothyroidism and B12 deficiency are present, replacement of B12 leads to improvement in symptoms in approximately 58% of patients, and thyroid hormone replacement should be initiated concurrently 4.