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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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.
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)
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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