MKSAP 19 "Quiz Me!" Question: Answer and Critique


A: Free thyroxine measurement

Educational Objective

Diagnose primary hypothyroidism.


The most appropriate diagnostic test to perform next is free thyroxine (T4) measurement (Option A). This patient presented with classic symptoms of hypothyroidism: fatigue, cold intolerance, constipation, and dry skin and hair. Her physical examination is notable for bradycardia and a goiter. The thyroid-stimulating hormone (TSH) level is elevated, suggestive of primary hypothyroidism. The diagnosis of primary hypothyroidism is made by measuring serum TSH, and if elevated, measuring free T4. Serum TSH is elevated in both overt and subclinical hypothyroidism, but free T4 is normal in subclinical hypothyroidism and low in hypothyroidism. The free T4 result will confirm hypothyroidism and the need for thyroid hormone replacement.

Although triiodothyronine (T3) is the active hormone producing thyroid action in the body, free T3 measurement (Option B) is unnecessary for diagnosing hypothyroidism. Free T3 levels are variable and the product of deiodination of T4; their levels may be misleading because many drugs (e.g., amiodarone) and physiologic states (fasting and illness) may cause free T3 to be low in conditions of normal thyroid function. Measurement of T3 is recommended in three settings: (1) in the evaluation of thyrotoxicosis to identify isolated T3 toxicosis; (2) to assess the severity of hyperthyroidism and response to therapy; and (3) to potentially differentiate hyperthyroidism from destructive thyroiditis. In T3 toxicosis, the T3-to-T4 ratio is often greater than 20 because of preferential secretion of T3.

A thyroid peroxidase (TPO) antibody titer (Option C) is unnecessary unless the diagnosis of hypothyroidism is unclear. The most common cause of primary hypothyroidism is Hashimoto thyroiditis, which is an autoimmune thyroid disorder characterized by diffuse infiltration of the thyroid gland by lymphocytes and plasma cells with subsequent follicular atrophy and scarring. It is more common in patients with other autoimmune disorders or a family history of thyroid autoimmunity. Diffuse goiter is most common in younger patients. Most patients (90%) have TPO antibodies, and the risk for developing hypothyroidism is four times higher in euthyroid patients with TPO antibodies.

Thyroid ultrasonography (Option D) is useful in evaluating goiters associated with normal TSH levels. It is also recommended for patients with Graves disease or Hashimoto thyroiditis in cases of thyroid gland asymmetry or nodules on examination. Because this patient has neither thyroid gland asymmetry nor nodules, ultrasonography is not indicated.

Key Points

The diagnosis of primary hypothyroidism is made by measuring serum thyroid-stimulating hormone and free thyroxine.

A thyroid peroxidase antibody titer is unnecessary in the evaluation of hypothyroidism.


McDermott MT. Hypothyroidism. Ann Intern Med. 2020;173:ITC1-ITC16. PMID: 32628881

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