A 27-year-old man establishes care for evaluation of resting tachycardia and occasional palpitations. He feels otherwise well and has no weight changes, heat intolerance, or visual disturbances. His pulse is 108/min and blood pressure is 138/82 mmHg. Physical examination reveals a normal-sized, non-tender thyroid gland and a fine resting tremor. There is no proptosis or pretibial myxedema. Laboratory studies show:
| Laboratory Test | Result | Reference Range |
|---|---|---|
| Thyroid-stimulating hormone (TSH) | 4.5 mIU/L | 0.5 - 5.0 mIU/L |
| Free Thyroxine (T4) | 3.2 ng/dL | 0.9 - 2.4 ng/dL |
| Free Triiodothyronine (T3) | 5.8 pg/mL | 2.3 - 4.2 pg/mL |
| TSH receptor antibodies | Undetectable | - |
A recent magnetic resonance imaging (MRI) of the brain, ordered by his previous provider, showed a normal pituitary gland and sella turcica. Serum alpha-subunit levels are within normal limits. Which of the following describes the fundamental molecular mechanism underlying this patient's laboratory abnormalities?
- AStimulatory autoantibody binding to a G-protein coupled transmembrane receptor
- BAutonomous hypersecretion of a heterodimeric glycoprotein by anterior pituitary cells
- Impaired ligand binding to an intracellular nuclear transcription factorAnswer
- DPharmacologic inhibition of peripheral 5'-deiodinase activity
- EReduced hepatic synthesis of a hormone-transporting carrier protein
Answer
Impaired ligand binding to an intracellular nuclear transcription factor
The correct answer identifies impaired ligand binding to an intracellular nuclear transcription factor. This patient's laboratory profile shows elevated free T4 and free T3 with an inappropriately normal TSH, indicating a state of central resistance to thyroid hormone negative feedback. The normal pituitary MRI and normal alpha-subunit levels effectively rule out a TSH-secreting pituitary adenoma. This leaves Resistance to Thyroid Hormone (RTH), which is most commonly caused by an autosomal dominant mutation in the THRB gene. This gene encodes the thyroid hormone receptor beta (TR-beta), which functions physiologically as an intracellular nuclear transcription factor. The mutated receptor has decreased affinity for T3, preventing appropriate suppression of TSH in the anterior pituitary gland. Meanwhile, the unmutated TR-alpha receptors in the heart remain highly responsive to the elevated circulating levels of thyroid hormone, leading to the patient's presenting tachycardia.
Step-by-Step Solution
Key Concept
Resistance to thyroid hormone (RTH) presents with elevated free T4 and T3 alongside unsuppressed TSH due to defective negative feedback. It is most commonly caused by mutations in the intracellular nuclear thyroid hormone receptor beta (TR-beta).