A 38-year-old woman with a history of Hashimoto thyroiditis is on levothyroxine replacement. She reports persistent fatigue and weight gain despite reported compliance. Her TSH is 2.5 mIU/L (normal: 0.4–4.0). Which investigation is most appropriate to evaluate the cause of her ongoing symptoms?

Explanation

## Evaluating Persistent Symptoms Despite Normal TSH **Key Point:** When TSH is normal but symptoms persist, measurement of Free T4 is essential to assess adequacy of thyroid hormone replacement and rule out central hypothyroidism or malabsorption. ### Clinical Context: TSH-Normal Hypothyroidism This patient presents a diagnostic dilemma: TSH is within the normal range, yet she has symptoms suggestive of hypothyroidism. This scenario requires assessment of the actual circulating thyroid hormone level (FT4) rather than relying on TSH alone. ### Why FT4 is the Next Best Investigation 1. **TSH may not reflect tissue thyroid hormone status** — TSH is a pituitary hormone; it does not directly measure circulating T4/T3 availability to peripheral tissues 2. **Malabsorption of levothyroxine** — GI conditions (celiac disease, pernicious anemia, H. pylori) can impair absorption despite normal TSH 3. **Inadequate replacement dose** — some patients require higher doses to achieve optimal FT4 despite normal TSH 4. **Central hypothyroidism** — TSH can be normal or low while FT4 is low (though less common in Hashimoto) 5. **Conversion deficiency** — impaired T4→T3 conversion (rare but possible with selenium deficiency, medications) ### Diagnostic Decision Tree ```mermaid flowchart TD A[Patient on levothyroxine with persistent symptoms]:::outcome --> B{TSH level?}:::decision B -->|Elevated| C[Increase levothyroxine dose]:::action B -->|Normal/Low| D[Measure Free T4]:::action D --> E{FT4 level?}:::decision E -->|Low| F[Increase dose or investigate malabsorption]:::action E -->|Normal/High| G[Symptoms likely non-thyroidal]:::outcome G --> H[Investigate alternative diagnoses]:::action ``` ### Interpretation Guide | TSH | FT4 | Clinical Interpretation | |-----|-----|------------------------| | Normal | Low | Inadequate replacement; malabsorption; central hypothyroidism | | Normal | Normal | Symptoms non-thyroidal; consider depression, anemia, sleep apnea | | Normal | High | Over-replacement (iatrogenic hyperthyroidism) | | Low | Low | Central hypothyroidism | **High-Yield:** The combination of normal TSH + persistent symptoms warrants FT4 measurement to determine if the patient is truly euthyroid or if the TSH is misleading (e.g., due to secondary hypothyroidism or malabsorption). **Clinical Pearl:** Patients with Hashimoto thyroiditis may have concurrent autoimmune conditions (celiac disease, pernicious anemia) that impair levothyroxine absorption — always consider this in treatment-resistant cases.