In a 40‑year‑old woman with fatigue, irregular menstrual cycles, BMI 27 kg/m², hemoglobin 11.6 g/dL and macrocytic anemia, should the next test be serum vitamin B12 level or thyroid‑stimulating hormone (TSH) measurement?

TSH Testing Should Be Performed First

In a 40-year-old woman presenting with fatigue, irregular periods, BMI 27, and macrocytic anemia (hemoglobin 11.6 g/dL, MCV >100 fL), thyroid-stimulating hormone (TSH) should be measured before vitamin B12 testing. This prioritization is based on the high prevalence of thyroid dysfunction in women of this age presenting with these symptoms, the reversibility of thyroid-related anemia, and the fact that hypothyroidism itself can cause macrocytic anemia independent of B12 deficiency 1, 2.

Rationale for Prioritizing TSH

Thyroid Dysfunction as a Common Cause

• Hypothyroidism is diagnosed in 20-60% of patients presenting with anemia and commonly manifests with fatigue and menstrual irregularities in reproductive-age women 2.
• Macrocytosis occurs in up to 55% of hypothyroid patients and may result from thyroid hormone deficiency itself, without any nutritional deficit 2, 3.
• Anemia is often the first presenting sign of hypothyroidism, and the diagnosis should be considered in every case of anemia with uncertain etiology 2.

Clinical Presentation Alignment

• The combination of fatigue, irregular periods, and mild obesity (BMI 27) strongly suggests thyroid dysfunction as the unifying diagnosis 4, 5.
• Menstrual irregularities warrant TSH measurement as part of the initial hormonal assessment, with thyroid dysfunction being a reversible cause of oligomenorrhea 4, 5.
• Hypothyroidism can cause macrocytic anemia that is unresponsive to B12 and folate supplementation until thyroid hormone replacement is initiated 3.

Why B12 Testing Can Wait

Macrocytosis Has Multiple Etiologies

• The morphologic approach to macrocytic anemia (MCV >100 fL) includes vitamin B12 deficiency, folate deficiency, hypothyroidism, alcoholism, liver disease, and myelodysplastic syndrome 6, 7.
• A carefully obtained history with evaluation of peripheral blood smear and reticulocyte count should guide the sequence of testing, with serum thyroid studies frequently required to confirm diagnosis 7.

Autoimmune Overlap Considerations

• Pernicious anemia occurs 20 times more frequently in patients with hypothyroidism than in the general population, suggesting that if hypothyroidism is present, B12 screening will be indicated regardless 2.
• Patients with autoimmune hypothyroidism should undergo B12 screening at diagnosis and annually thereafter, as the prevalence of B12 deficiency ranges from 28-68% in this population 1.

Functional Testing May Be Needed Anyway

• Standard serum B12 testing misses functional deficiency in up to 50% of cases, and methylmalonic acid (MMA) testing is required when B12 results are indeterminate (180-350 pg/mL) 1.
• If B12 testing is performed and returns in the indeterminate range, MMA testing will be necessary, adding cost and delay 1.

Practical Diagnostic Algorithm

Step 1: Measure TSH First

• Order TSH as the initial test, which costs approximately £2 with rapid turnaround 1.
• If TSH is elevated, diagnose hypothyroidism and initiate levothyroxine therapy 3.
• Correction of hematologic abnormalities typically occurs over a four-month period with thyroid hormone replacement 3.

Step 2: Evaluate Response to Thyroid Treatment

• Recheck complete blood count after 3-4 months of thyroid hormone replacement to assess whether macrocytic anemia resolves 3.
• If anemia persists despite normalized TSH, then proceed with B12 and folate testing 7, 3.

Step 3: Screen for B12 Deficiency in Confirmed Hypothyroidism

• Once hypothyroidism is diagnosed, measure serum B12 as part of the standard workup for autoimmune thyroid disease 1.
• If total B12 <180 pg/mL, diagnose deficiency and initiate treatment immediately 1.
• If total B12 is 180-350 pg/mL, measure MMA to confirm functional deficiency 1.

Common Pitfalls to Avoid

Do Not Assume B12 Deficiency Based on Macrocytosis Alone

• Macrocytosis in the setting of fatigue and menstrual irregularities may be entirely due to hypothyroidism, and treating with B12 without addressing thyroid dysfunction will not resolve symptoms 2, 3.
• Hypothyroidism can cause macrocytic anemia unresponsive to B12 and folate supplementation until thyroid hormone is replaced 3.

Do Not Overlook Menstrual History

• Irregular periods in a 40-year-old woman with fatigue warrant TSH measurement as part of the initial hormonal assessment 4, 5.
• Thyroid dysfunction is a reversible cause of oligomenorrhea and should be identified before pursuing more extensive reproductive endocrine workup 4.

Do Not Delay Treatment of Hypothyroidism

• If TSH is elevated, initiate levothyroxine therapy without waiting for B12 results, as thyroid hormone replacement is the primary treatment 3.
• Anemia of hypothyroidism is considered an adaptation to decreased basal metabolism and will improve with thyroid hormone replacement 2.

Additional Considerations

Iron Studies Are Already Available

• The patient's ferritin is 95 ng/mL and LDL is 125 mg/dL, which rules out iron deficiency as the cause of anemia 6.
• In the absence of inflammation, ferritin <30 µg/L indicates iron deficiency; this patient's ferritin is well above that threshold 6.

Reticulocyte Count Would Be Informative

• A low reticulocyte index indicates decreased RBC production, suggesting iron deficiency, vitamin B12/folate deficiency, or bone marrow dysfunction 6.
• Hypothyroidism typically presents with normocytic anemia characterized by reticulopenia and hypoplasia of erythroid lineage 2.

Consider Folate Testing Concurrently with B12

• When B12 testing is eventually performed, folate levels should be checked concurrently, as deficiencies often coexist 1.
• Folic acid should never be administered before treating B12 deficiency, as it may mask anemia while allowing irreversible neurological damage to progress 1.