TBG

**Basics** - Glycoprotein made by the liver. It has high affinity but low capacity and binds ~70% of T4 and T3. The rest is bound to transthyretin (TTR, ~10-15%) and albumin (~15%). Only ~0.03% of T4 and ~0.3% of T3 is free (the active, regulated fraction). - T4 binds more tightly than T3, so T4 has a longer half-life (~7 days vs ~1 day for T3).

**Physiology** - The hypothalamic-pituitary-thyroid axis regulates FREE hormone. When TBG changes, total T4 shifts, free T4 transiently changes, and TSH-driven feedback restores free T4 to normal. The result is altered total T4/T3 with normal free T4, normal TSH, and a euthyroid patient.

**Increased TBG (↑ total T4/T3, normal free T4/TSH)** - Pregnancy (estrogen increases TBG synthesis and decreases its clearance via sialylation) - Estrogen-containing OCPs and HRT, tamoxifen, raloxifene - Hepatitis (acute/early) and other causes of liver hormone release - Hereditary TBG excess (X-linked) - Others: HIV, methadone/heroin, porphyria, 5-fluorouracil, mitotane - Clinical clue: an asymptomatic woman on OCPs or pregnant with a high total T4. Do not treat. Check TSH and free T4. - Also ↑ resin T3 uptake is LOW (more unoccupied binding sites on TBG take up less labeled T3 by the resin). The T3 resin uptake test is inversely related to TBG binding capacity.

**Decreased TBG (↓ total T4/T3, normal free T4/TSH)** - Androgens/anabolic steroids, danazol - Glucocorticoids (high-dose) - Nephrotic syndrome (urinary loss), protein-losing enteropathy - Cirrhosis/severe liver disease (↓ synthesis), malnutrition, critical illness - Hereditary TBG deficiency (X-linked) - Acromegaly, nicotinic acid - Resin T3 uptake is HIGH.

**Drugs displacing T4 from TBG** (salicylates, furosemide, heparin via free fatty acids, phenytoin, carbamazepine) transiently raise free T4, then total T4 falls to a new steady state with normal free T4.

**Clinical/test tips** - Hyperthyroidism: ↑ total T4, ↑ resin T3 uptake (fewer free binding sites). Pregnancy or TBG excess: ↑ total T4, ↓ resin T3 uptake. The direction of resin T3 uptake helps tell the two apart. - Always interpret total T4 in the context of binding proteins. Free T4 (and TSH) are the best tests. - Levothyroxine dose requirements increase in pregnancy (~25-50%) because of ↑ TBG and ↑ hCG/deiodinase effects. Check TSH once pregnancy is confirmed. - Thyroid hormone is carried on TBG; TBG is NOT the same as thyroglobulin (Tg), which is the thyroid follicular colloid protein used as a tumor marker for differentiated thyroid cancer after thyroidectomy.

**Mnemonic**: Estrogen = TBG up ("Pregnant women have more TBG"); Androgens, glucocorticoids, nephrotic syndrome, cirrhosis = TBG down.