A 34-year-old woman presents with fatigue, weight gain, and cold intolerance for 3 months. On examination, she has a diffuse goiter and delayed relaxation of deep tendon reflexes. TSH is elevated at 8.2 mIU/L (normal: 0.4–4.0). What is the most appropriate next investigation to confirm the diagnosis and determine the etiology?

## Diagnostic Approach to Hypothyroidism **Key Point:** In a patient with elevated TSH and clinical features of hypothyroidism, measurement of **Free T4 (FT4)** is the most appropriate next investigation — it simultaneously **confirms the diagnosis** of primary hypothyroidism (low FT4 + high TSH) **and** provides the biochemical basis for determining etiology and guiding treatment. ### Why FT4 is the Correct Answer The stem asks for the investigation that **both confirms the diagnosis AND helps determine etiology**. FT4 fulfills the first criterion definitively: 1. **TSH elevated (8.2 mIU/L)** → suggests primary hypothyroidism, but TSH alone cannot confirm it (TSH can be transiently elevated in sick euthyroid syndrome, recovery phase, or subclinical disease) 2. **FT4 low + TSH high** = biochemically confirmed **primary hypothyroidism** — this is the gold standard pair per Harrison's Principles of Internal Medicine (21e, Ch. 405) 3. Once biochemical hypothyroidism is confirmed, the **etiology** (autoimmune vs. iodine deficiency vs. other) is pursued with TPO antibodies or imaging **Why not TPO antibodies (Option D)?** TPO antibodies identify the etiology (Hashimoto's thyroiditis) but do **not confirm hypothyroidism** — a patient can be TPO-positive and euthyroid. The question asks for the investigation that confirms the diagnosis *and* determines etiology; FT4 is the necessary first step before etiology workup. TPO antibodies are ordered *after* biochemical confirmation. ### Investigation Hierarchy | Investigation | Role | Timing | |---|---|---| | **TSH** | Screening test | First-line | | **FT4** | Confirms hypothyroidism; assesses severity | If TSH abnormal ← **This step** | | **TPO antibodies** | Determines autoimmune etiology | After biochemical confirmation | | **Thyroid ultrasound** | Structural/nodule assessment | If clinically indicated | | **Technetium-99m scan** | Functional assessment (Graves' vs. thyroiditis) | Rarely needed in hypothyroidism workup | **Clinical Pearl:** The TSH–FT4 pair is the cornerstone of thyroid function assessment. In this 34-year-old woman with goiter, delayed DTR relaxation, and elevated TSH, FT4 will confirm primary hypothyroidism and quantify the hormone deficit — directly guiding levothyroxine dosing. TPO antibodies are a logical *subsequent* test, not the immediate next step. **High-Yield Mnemonic: "Confirm Before Cause"** — Always confirm biochemical hypothyroidism with FT4 before ordering etiology-specific tests (TPO antibodies, ultrasound). [cite: Harrison's Principles of Internal Medicine, 21e, Ch. 405; Williams Textbook of Endocrinology, 14e]