PTH

**Synthesis/Regulation** - Secreted by chief cells of the parathyroid glands (derived from pharyngeal pouches III [inferior glands] and IV [superior glands]). - Stimulus for release: low ionized Ca2+ (sensed by the Ca2+-sensing receptor, CaSR, a GPCR). Also stimulated by high phosphate and low 1,25-(OH)2 D (calcitriol). Mild decrease in Mg2+ also stimulates PTH, but severe hypomagnesemia impairs PTH secretion and causes end-organ resistance (e.g., chronic alcohol use, PPIs, loop diuretics) and thus hypocalcemia that is refractory until Mg2+ is repleted. - Inhibited by high Ca2+, high 1,25-(OH)2 D (negative feedback).

**Mechanism of action** (PTH1 receptor, Gs → ↑cAMP) - Bone: Binds osteoblasts → ↑RANKL and ↓OPG → osteoclast activation → bone resorption → ↑Ca2+ and ↑phosphate. Note: intermittent (pulsatile) PTH is anabolic (teriparatide, an rhPTH 1-34 analog, treats osteoporosis); continuous PTH is catabolic. - Kidney: ↑Ca2+ reabsorption in the distal convoluted tubule; ↓phosphate reabsorption in the proximal tubule (phosphaturia); ↑1α-hydroxylase activity in the proximal tubule → ↑1,25-(OH)2 D (calcitriol) → ↑gut Ca2+ and phosphate absorption. - Net effect: ↑serum Ca2+, ↓serum phosphate, ↑urinary phosphate and cAMP, ↑1,25-(OH)2 D.

**Mnemonic**: PTH = "Phosphate Trashing Hormone"; PTH ↑ Ca2+ and ↓ PO4³⁻. Also, "PTH: stones, bones, groans, thrones, and psychiatric overtones" for hypercalcemia.

**Clinical correlates** - Primary hyperparathyroidism: parathyroid adenoma (most common, ~80-85%), hyperplasia, or carcinoma (rare). Labs: ↑Ca2+, ↓phosphate, ↑PTH, ↑urinary Ca2+, ↑ALP. Features: kidney stones, osteitis fibrosa cystica (brown tumors, subperiosteal resorption, "salt-and-pepper" skull), constipation/abdominal pain, depression. Associated with MEN1 (parathyroid, pituitary, pancreas) and MEN2A (medullary thyroid carcinoma, pheochromocytoma, parathyroid). Treatment: parathyroidectomy. - Secondary hyperparathyroidism: appropriate PTH elevation due to hypocalcemia, most commonly from CKD (↓1α-hydroxylase → ↓calcitriol, ↑phosphate retention) → ↓Ca2+ (or normal), ↑phosphate, ↑PTH → renal osteodystrophy. Treat with phosphate binders, vitamin D analogs, calcimimetics (cinacalcet). - Tertiary hyperparathyroidism: autonomous PTH secretion after long-standing secondary hyperparathyroidism (e.g., CKD) → ↑Ca2+, ↑PTH. - Hypoparathyroidism: low PTH from thyroid/parathyroid surgery (most common), autoimmune disease, DiGeorge syndrome (22q11 deletion, 3rd/4th pouch failure), or hypomagnesemia. Features: hypocalcemia (perioral numbness, paresthesias, tetany, carpopedal spasm, Chvostek and Trousseau signs, QT prolongation, seizures), ↑phosphate, ↓PTH. - Pseudohypoparathyroidism type 1A (Albright hereditary osteodystrophy): end-organ resistance due to GNAS1 (Gsα) mutation (maternal inheritance); ↑PTH, ↓Ca2+, ↑phosphate, short 4th/5th metacarpals, short stature, round face. Pseudopseudohypoparathyroidism has the same phenotype but normal labs (paternal inheritance of the mutation). - Humoral hypercalcemia of malignancy: PTHrP (e.g., from squamous cell carcinoma of the lung, breast, renal cell carcinoma) → ↑Ca2+ with ↓PTH. PTHrP binds the same receptor. - Familial hypocalciuric hypercalcemia (FHH): inactivating CaSR mutation → ↑Ca2+, ↑ or normal PTH, ↓urinary Ca2+ (Ca/Cr clearance ratio <0.01).

**Differential for hypercalcemia by PTH level** - ↑ or inappropriately normal PTH: primary or tertiary hyperparathyroidism, FHH, lithium use. - ↓ PTH: malignancy (PTHrP, osteolytic mets, myeloma), vitamin D toxicity, granulomatous disease (↑1α-hydroxylase from macrophages, e.g., sarcoidosis), milk-alkali syndrome, thiazides (↓urinary Ca2+ excretion), immobilization, hyperthyroidism.

**Drug associations** - Teriparatide / abaloparatide: PTH/PTHrP analogs for osteoporosis (intermittent dosing). Avoid in Paget disease, prior radiation, or open epiphyses due to osteosarcoma risk. - Cinacalcet / etelcalcetide: calcimimetics that increase CaSR sensitivity → ↓PTH (used in secondary hyperparathyroidism and parathyroid carcinoma). - Thiazides: ↑distal Ca2+ reabsorption (additive with PTH effect); loop diuretics: ↑Ca2+ excretion.

**Testing pearl**: Intact PTH is measured by immunoassay. Always interpret PTH together with serum Ca2+, phosphate, 25-OH vitamin D, creatinine, and Mg2+. Calcium and PTH should be inversely related; if both are high or PTH is "normal" in the setting of hypercalcemia, think primary hyperparathyroidism.