Primary Hyperparathyroidism
Autonomous PTH oversecretion (most often a single adenoma) producing hypercalcemia.
Also known as: primary hyperparathyroidism, parathyroid adenoma, PHPT, hyperparathyroidism
Overview
Inappropriately elevated or non-suppressed PTH in the setting of hypercalcemia. Most commonly due to a solitary parathyroid adenoma (~85%); less often hyperplasia of all four glands (~10-15%), double adenoma (~4%), or parathyroid carcinoma (<1%).
Epidemiology
Most common cause of outpatient hypercalcemia. Prevalence ~1 in 1000; up to 1 in 500 women >50. Female-to-male ratio ~3:1. Peak incidence 50-60 years. Most cases now detected on routine chemistry panels (mild, asymptomatic).
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Risk factors
- Female sex, postmenopausal age
- Prior neck radiation
- Lithium therapy (alters set point)
- Familial syndromes: MEN1 (parathyroid + pituitary + pancreas), MEN2A (parathyroid + medullary thyroid + pheo), familial isolated hyperparathyroidism, HPT-jaw tumor syndrome (CDC73 mutation)
- Chronic vitamin D deficiency (can mask presentation)
Pathophysiology
Loss of calcium-sensing regulation in one or more parathyroid glands → autonomous PTH secretion despite normal or elevated serum calcium. PTH increases bone resorption (osteoclast activation), enhances renal calcium reabsorption and phosphate excretion, and stimulates 1-alpha-hydroxylation of vitamin D (boosting intestinal calcium absorption). Net effect: hypercalcemia, hypophosphatemia, and skeletal/renal pathology.
Clinical presentation
Symptoms
- 'Stones, bones, abdominal groans, psychic moans, fatigue overtones'
- Most are asymptomatic — discovered on routine calcium
- Renal: nephrolithiasis (calcium oxalate or phosphate), polyuria, polydipsia, nephrocalcinosis
- Skeletal: bone pain, pathologic fracture, osteoporosis
- GI: anorexia, nausea, constipation, peptic ulcer, pancreatitis
- Neuropsychiatric: depression, fatigue, memory loss, confusion
- Cardiovascular: hypertension, short QT, LVH
Signs / physical exam
- Often a normal exam
- Band keratopathy (rare), brown tumors (rare advanced disease)
- Hypertension, sometimes bradyarrhythmia
- DEXA: cortical bone loss (distal radius > spine), fractures
Classic findings
Postmenopausal woman with kidney stones, mild fatigue, osteoporosis, and incidentally elevated calcium on routine labs.
Differential diagnosis
- Secondary hyperparathyroidism — Compensatory PTH elevation from hypocalcemia or vitamin D deficiency; calcium normal/low, phosphate often elevated (CKD)
- Tertiary hyperparathyroidism — Autonomous PTH after prolonged secondary HPT (long-standing CKD); calcium elevated; usually requires parathyroidectomy
- Familial hypocalciuric hypercalcemia (FHH) — AD inactivating CaSR mutation; mild lifelong hypercalcemia with LOW urinary calcium (Ca/Cr clearance ratio <0.01); DO NOT operate
- Malignancy-associated hypercalcemia — PTH suppressed; PTHrP elevated (squamous cell, renal, breast) or osteolytic mets, or 1,25-OH vitamin D from lymphoma
- Vitamin D toxicity — Elevated 25-OH vitamin D, suppressed PTH
- Granulomatous disease (sarcoidosis, TB) — Elevated 1,25-OH vitamin D from macrophage activity, suppressed PTH
- Milk-alkali syndrome — Large calcium carbonate ingestion; suppressed PTH, alkalosis, AKI
- Hyperthyroidism, thiazides, lithium — Drug or hormonal causes; review medication list
Diagnostic workup
Diagnostic criteria
Hypercalcemia + inappropriately elevated or non-suppressed PTH + low urinary calcium excretion rules OUT FHH (urinary calcium high or normal in PHPT, low in FHH).
Labs
- Serum calcium (corrected for albumin) and ionized calcium — confirm hypercalcemia
- PTH (intact) — elevated or inappropriately normal
- Phosphate (low), magnesium, alkaline phosphatase (elevated in bone disease)
- 25-OH vitamin D (replace if deficient before final assessment), 1,25-OH vitamin D
- 24-hour urine calcium and creatinine — calculate calcium/creatinine clearance ratio to exclude FHH (<0.01 = FHH)
- BUN, creatinine, eGFR
- DEXA scan (lumbar spine, hip, AND distal third of radius)
- Consider genetic testing for MEN1/MEN2 if young, family history, or multigland disease
Imaging
- Renal ultrasound or CT (assess for stones, nephrocalcinosis)
- Pre-operative localization: Sestamibi (Tc-99m) scan ± SPECT/CT, neck ultrasound, 4D CT — identifies adenoma for minimally invasive parathyroidectomy
- Not all guidelines require localization — surgeon-dependent
Diagnostic algorithm
| Diagnosis | Ca | PTH | Phosphate | Urine Ca | Key feature |
|---|---|---|---|---|---|
| Primary HPT | High | High / inappropriate | Low | High / normal | Most often single adenoma |
| FHH | Mildly high | High / inappropriate | Normal | LOW (Ca/Cr <0.01) | AD, lifelong; do not operate |
| Secondary HPT (CKD) | Low / normal | High | High | Variable | Compensatory; treat underlying |
| Tertiary HPT | High | High | Variable | Variable | After long-standing 2°; parathyroidectomy |
| Malignancy (PTHrP) | High | LOW (suppressed) | Low | High | Squamous, renal, breast cancer |
| Vitamin D toxicity | High | Low | High | High | Elevated 25-OH vitamin D |
Complications
- Osteoporosis, fragility fracture, osteitis fibrosa cystica (advanced)
- Nephrolithiasis, nephrocalcinosis, CKD
- Hypercalcemic crisis, pancreatitis, peptic ulcer
- Surgical: recurrent laryngeal nerve injury, hypoparathyroidism (especially after subtotal/total parathyroidectomy)
- Hungry bone syndrome post-op: profound hypocalcemia and hypophosphatemia
- Persistent or recurrent hyperparathyroidism (missed gland, ectopic location)
PANCE pearls
- Always check a 24-h urinary calcium to exclude FHH before parathyroidectomy — operating on FHH does NOT cure hypercalcemia.
- Lithium and thiazide diuretics elevate calcium and PTH — stop if possible and re-test.
- Always measure DEXA at distal third of radius — primary HPT preferentially affects cortical bone.
- Intra-operative PTH should drop >50% within 10 min and to normal range — confirms removal of the offending gland.
- Post-parathyroidectomy 'hungry bone syndrome': skeleton avidly takes up Ca and PO4, producing severe hypocalcemia — pre-treat with vitamin D and calcium.
References
- Fourth International Workshop 2014 — Guidelines for the Management of Asymptomatic Primary Hyperparathyroidism (Bilezikian et al., J Clin Endocrinol Metab 2014)
- AAES 2016 — American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism (Wilhelm et al., JAMA Surg 2016)
- Endocrine Society 2011 — Evaluation and Treatment of Hypercalcemia of Malignancy (Stewart, NEJM 2005) and ES guideline on vitamin D
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