Parathyroid Disorders & Calcium Metabolism
A boards-focused walkthrough of calcium homeostasis and parathyroid disease: the PTH/vitamin D axis, the lab signatures that separate primary/secondary/tertiary hyperparathyroidism, FHH, hypoparathyroidism, and pseudohypoparathyroidism, plus the classic next-best-step decisions (check PTH first, urine calcium to exclude FHH, and when to operate).
The calcium axis: PTH, vitamin D, and their counterweights
Serum calcium is defended within a narrow range by three hormones acting on gut, bone, and kidney. PTH (from the four parathyroid glands) is the minute-to-minute regulator, released when the calcium-sensing receptor (CaSR) on chief cells detects low ionized Ca²⁺. PTH raises serum Ca²⁺ by (1) driving osteoclastic bone resorption (indirectly, via RANKL on osteoblasts), (2) increasing distal-tubule Ca²⁺ reabsorption, (3) causing phosphate wasting (blocks proximal Na–phosphate cotransport → phosphaturia), and (4) activating renal 1α-hydroxylase, converting 25-OH vitamin D to active 1,25-(OH)₂ D (calcitriol). Calcitriol then boosts intestinal absorption of both Ca²⁺ and phosphate. The net PTH signature is therefore ↑Ca²⁺ / ↓phosphate. Calcitonin (thyroid C cells) opposes osteoclasts but is physiologically minor in humans — mainly useful as a medullary thyroid carcinoma marker. FGF23 (from bone) is the phosphate-lowering counterweight, inhibiting 1α-hydroxylase and renal phosphate reabsorption.
- Best marker of vitamin D stores = 25-OH D (calcidiol); the active hormone is 1,25-(OH)₂ D (calcitriol).
- 1α-hydroxylase (proximal tubule) is turned up by PTH and low phosphate, down by FGF23 — the rate-limiting activation step.
- PTH = "Phosphate Trashing Hormone": raises Ca²⁺, lowers phosphate.
- Ionized (free) Ca²⁺ is the active fraction. Total Ca falls with hypoalbuminemia (ionized normal); alkalosis increases albumin binding → low ionized Ca → symptomatic hypocalcemia despite normal total Ca.
- Corrected Ca = measured Ca + 0.8 × (4 − albumin g/dL).
- First step in ANY hypercalcemia = measure PTH. High/inappropriately normal → parathyroid-driven (primary hyperPTH, FHH); low/suppressed → non-parathyroid (malignancy, vitamin D, granulomas).
- Malignancy = #1 cause of inpatient hypercalcemia; primary hyperparathyroidism = #1 outpatient.
Lab signatures — the one table to memorize
| Disorder | Ca²⁺ | Phosphate | PTH | 1,25-Vit D | Key clue |
|---|---|---|---|---|---|
| Primary hyperPTH | ↑ | ↓ | ↑ | ↑ | Adenoma; incidental ↑Ca |
| Secondary hyperPTH (CKD) | ↓/nl | ↑ | ↑ | ↓ | Renal failure |
| Tertiary hyperPTH | ↑ | ↑ | ↑↑↑ | ↓/nl | Autonomous after long CKD |
| Hypoparathyroidism | ↓ | ↑ | ↓ | ↓ | Post-thyroidectomy, DiGeorge |
| PseudohypoPTH (1A) | ↓ | ↑ | ↑ | ↓ | PTH resistance; AHO |
| FHH | ↑ | nl | nl/↑ | nl | ↓urine Ca; CaSR loss |
| Malignancy — PTHrP | ↑ | ↓ | ↓ | ↓ | Squamous/renal cell |
| Vitamin D excess / granuloma | ↑ | ↑ | ↓ | ↑ | Sarcoid, lymphoma |
Primary hyperparathyroidism: causes, presentation, management
Primary hyperparathyroidism = autonomous PTH secretion, usually a single benign adenoma (~85%); less often 4-gland hyperplasia (think MEN1 — 3 P's: parathyroid, pituitary, pancreas; and MEN2A — parathyroid + medullary thyroid CA + pheochromocytoma) or carcinoma (<1%, very high Ca). Most cases today are asymptomatic, caught as incidental hypercalcemia. Classic symptomatic disease = "stones, bones, groans, thrones, and psychiatric overtones": nephrolithiasis; bone pain / osteitis fibrosa cystica with brown tumors, subperiosteal resorption (radial phalanges), "salt-and-pepper" skull; abdominal pain, constipation, pancreatitis, PUD; polyuria; and fatigue/depression. Localize a suspected adenoma with Tc-99m sestamibi scan ± neck ultrasound before surgery — imaging never makes the diagnosis. Definitive treatment = parathyroidectomy. Operate even if asymptomatic when: age <50, Ca >1 mg/dL above ULN, T-score ≤ −2.5 or fragility/vertebral fracture, eGFR <60, nephrolithiasis/nephrocalcinosis, or 24-h urine Ca >400 mg with increased stone risk. Cinacalcet (calcimimetic) is the medical fallback when surgery isn't feasible.
Vignette: A 58-year-old woman has serum Ca²⁺ 11.4 mg/dL on routine labs. She feels well; a repeat confirms it, phosphate is low-normal, and albumin is normal.
Next best step → measure intact PTH.
- Result: PTH 88 pg/mL (elevated). High Ca + low phosphate + inappropriately high PTH = primary hyperparathyroidism.
- Before labeling her a surgical candidate, exclude the mimic: order a 24-hour urine calcium (with Ca/creatinine clearance ratio) to rule out FHH.
- Dx: primary hyperparathyroidism, likely solitary adenoma.
- Management: if she meets surgical criteria → parathyroidectomy after sestamibi localization; otherwise monitor with serial Ca, renal function, and DXA.
Board trap: do not order a parathyroid scan first — imaging localizes, it does not diagnose. The diagnosis is biochemical (Ca + PTH).
Vignette: A 24-year-old man has mild hypercalcemia (Ca 10.9) with PTH 62 pg/mL (upper-normal/mildly high). His asymptomatic father and sister also have high calcium. A prior parathyroidectomy failed to normalize his calcium.
Next best step → 24-hour urine calcium with the Ca/creatinine clearance ratio.
- Ca/Cr clearance ratio <0.01 (low urine Ca) → Familial Hypocalciuric Hypercalcemia (FHH).
- Cause: inactivating mutation of the calcium-sensing receptor (CaSR) → glands "sense" Ca as low (mild ↑Ca + normal/↑PTH), and the kidney over-reabsorbs Ca → hypocalciuria.
- Key contrast: primary hyperPTH spills calcium (urine Ca high); FHH retains it (urine Ca low).
- Management = reassurance, NO surgery — parathyroidectomy does not cure FHH. Family history + failed prior surgery are the tip-offs.
- Hypoparathyroidism labs: ↓Ca, ↑phosphate, ↓PTH, ↓calcitriol. #1 cause = iatrogenic (removal/devascularization during thyroidectomy).
- DiGeorge (22q11.2 deletion): failed 3rd/4th pharyngeal pouch development → absent parathyroids + thymic aplasia (hypocalcemia + T-cell immunodeficiency + conotruncal cardiac defects).
- Autoimmune (APS-1 / APECED, AIRE gene): hypoparathyroidism + chronic mucocutaneous candidiasis + adrenal insufficiency.
- Signs of hypocalcemia: perioral/acral paresthesias, Chvostek (facial-nerve tap → twitch), Trousseau (BP cuff → carpal spasm), tetany, prolonged QT, seizures.
- Pseudohypoparathyroidism 1A: end-organ PTH resistance from Gsα (GNAS) inactivation → ↓Ca, ↑PO₄, ↑PTH, plus Albright hereditary osteodystrophy (short stature, round face, short 4th/5th metacarpals). Occurs with maternal inheritance of the defect (imprinting).
- Pseudopseudohypoparathyroidism: same AHO habitus, paternal allele, but normal Ca/PTH.
- Hypercalcemia symptoms — "Stones, Bones, Groans, Thrones, and Psychiatric Overtones": kidney stones; bone pain; abdominal groans (constipation, PUD, pancreatitis); thrones (polyuria); depression/fatigue/confusion.
- "CHIMPANZEES" — causes of hypercalcemia: Calcium supplements, Hyperparathyroid/Hyperthyroid, Iatrogenic/Immobility, Milk-alkali/Myeloma, Paget disease, Addison/Acromegaly, Neoplasm, Zollinger-Ellison (MEN1), Excess vit D, Excess vit A, Sarcoidosis.
- PTH = "Phosphate Trashing Hormone" (raises Ca, dumps phosphate in urine).
- Chvostek = Cheek (facial tap); Trousseau = Tourniquet (BP cuff → carpal spasm) — both signal hypocalcemia.
- MEN1 = 3 P's (Parathyroid, Pituitary, Pancreas); MEN2A = Parathyroid + Medullary thyroid CA + Pheochromocytoma.
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