A 30-year-old woman has serum TSH < 0.01 mU/L, free T4 elevates, free T3 elevated, and a diffuse goitre. Thyroid-stimulating immunoglobulins (TSI) are positive. In Graves' disease, TSI mimics TSH by binding which receptor domain, and what is the intracellular consequence?

• A TSI binds the transmembrane domain of TSHR → Gq activation → IP3/DAG → Ca2+-mediated thyroid peroxidase activation
• B TSI binds leucine-rich repeat domain of TSHR → Gs activation → ↑cAMP → PKA-mediated thyroid hormone synthesis and cell growth ✓
• C TSI inhibits the TSH receptor, causing constitutive Gi activation → thyroid cell hyperplasia
• D TSI cross-reacts with thyroxine-binding globulin, saturating binding sites and raising free T4

Explanation

TSI (stimulating thyroid immunoglobulins) are IgG autoantibodies that bind the extracellular leucine-rich repeat domain of the TSH receptor (TSHR), which is a Gs-protein coupled receptor. Like TSH, binding activates Gs → adenylyl cyclase → ↑cAMP → PKA, which stimulates: iodide uptake (NIS), thyroid peroxidase activity (organification and coupling), thyroglobulin synthesis, and thyrocyte proliferation (goitre). Unlike TSH, TSI is not subject to pituitary negative feedback, causing unregulated hyperthyroidism.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.