A 38-year-old woman on levothyroxine 75 mcg daily for Hashimoto thyroiditis presents for follow-up. She reports persistent fatigue and weight gain despite 8 weeks of therapy. Current TSH is 6.8 mIU/L (target 0.5–2.5) and free T4 is 1.0 ng/dL (normal 0.8–1.8). She denies malabsorption symptoms and takes her medication on an empty stomach in the morning. What is the most appropriate next step?

Explanation

## Clinical Scenario This patient on levothyroxine shows inadequate response: TSH remains elevated at 6.8 mIU/L despite 8 weeks of therapy. Before escalating the dose, it is critical to identify modifiable barriers to treatment efficacy. ## Differential Diagnosis of Poor Response | Cause | Frequency | Key Features | |-------|-----------|-------------| | **Poor adherence** | Most common | Intermittent dosing, forgetfulness | | **Drug interactions** | Common | Iron, calcium, PPIs, antacids | | **Malabsorption** | Less common | Celiac disease, H. pylori, pernicious anemia | | **Inadequate dose** | Possible | But must exclude above first | | **Persistent autoimmunity** | Rare | TSH receptor antibodies (Graves-like) | **Key Point:** The standard approach to inadequate TSH suppression is to first rule out adherence and absorption issues before increasing the dose. ## Rationale for Correct Answer Assessing adherence and drug interactions is the logical first step because: 1. **Adherence is the most common cause** of apparent levothyroxine resistance 2. **Drug interactions** (iron, calcium, PPIs, sucralfate) reduce levothyroxine absorption 3. **Malabsorption** (celiac disease, H. pylori, pernicious anemia) impairs thyroid hormone uptake 4. These are **reversible and must be excluded** before escalating therapy **Clinical Pearl:** Levothyroxine absorption is optimal on an empty stomach, 30–60 minutes before food or other medications. Even though the patient reports this practice, actual adherence should be verified. **High-Yield:** The "inadequate response" algorithm: 1. Confirm adherence (pill count, patient interview, pharmacy refill records) 2. Identify drug interactions (separate dosing by ≥4 hours) 3. Screen for malabsorption (celiac serology, H. pylori, B12/folate) 4. Only then increase the dose if the above are optimized ## Why Other Options Are Premature **Combination T4/T3 therapy:** No evidence supports T4/T3 combination over levothyroxine monotherapy in primary hypothyroidism. It is reserved for rare cases of persistent symptoms despite adequate TSH suppression and normal free T4/T3 levels—not for inadequate TSH suppression. **TSH receptor antibodies and ultrasound:** These tests are indicated if Graves disease (secondary hyperthyroidism) or thyroid cancer is suspected, not in a patient with elevated TSH on levothyroxine.