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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Question 1EndocrineMedium
A 35-year-old woman is evaluated after passing a kidney stone and is found on bone densitometry to have osteoporosis. Laboratory studies show serum calcium 11.8 mg/dL, phosphorus 2.1 mg/dL, intact parathyroid hormone 145 pg/mL (elevated), and a 24-hour urine calcium of 320 mg. Which of the following is the most likely diagnosis?
AFamilial hypocalciuric hypercalcemia
BMalignancy-associated hypercalcemia
CSecondary hyperparathyroidism
DPrimary hyperparathyroidism
Reveal answer & full explanation
Correct answer: D — Primary hyperparathyroidism
AFamilial hypocalciuric hypercalcemia
BMalignancy-associated hypercalcemia
CSecondary hyperparathyroidism
DPrimary hyperparathyroidism✓
Why Primary hyperparathyroidism is correct
Hypercalcemia (11.8 mg/dL) with an inappropriately elevated PTH (145 pg/mL) defines PTH-dependent hypercalcemia, and a parathyroid adenoma is the cause in roughly 85% of cases.
Excess PTH drives renal phosphate wasting (hypophosphatemia 2.1 mg/dL), increased bone resorption (osteoporosis), and hypercalciuria (urine calcium 320 mg/24h), producing this patient's stone and bone disease.
Why the others are wrong
Familial hypocalciuric hypercalcemia — also shows hypercalcemia with non-suppressed PTH but is defined by LOW urine calcium (calcium-to-creatinine clearance ratio typically <0.01); the elevated 24-hour urine calcium refutes it, a confused-with trap on 'high calcium, normalish PTH.'
Malignancy-associated hypercalcemia — PTHrP-mediated hypercalcemia suppresses PTH, so an elevated PTH excludes it; it is the premature-closure pick for any hypercalcemia.
Secondary hyperparathyroidism — a compensatory PTH rise to chronic hypocalcemia (renal failure, vitamin D deficiency) that presents with low or normal calcium, not hypercalcemia; buzzword-matching on 'high PTH.'
Question 2EndocrineMedium
A 66-year-old woman presents with fatigue, constipation, and depression for 6 months. BP 142/86. Labs: Na 138, K 3.2, Ca 11.8 mg/dL, albumin 4.0, parathyroid hormone (PTH) 98 pg/mL (normal 10–65), creatinine 1.0. 24-hour urine calcium is elevated. DEXA shows T-score -2.3 at the lumbar spine. She is asymptomatic regarding renal symptoms. Which of the following is the most appropriate management?
ABisphosphonate therapy
BCinacalcet therapy
CParathyroidectomy
DAnnual monitoring with labs
Reveal answer & full explanation
Correct answer: C — Parathyroidectomy
ABisphosphonate therapy
BCinacalcet therapy
CParathyroidectomy✓
DAnnual monitoring with labs
Why Parathyroidectomy is correct
This is primary hyperparathyroidism: elevated calcium (11.8 mg/dL) with an inappropriately elevated parathyroid hormone (PTH) of 98 pg/mL (normal 10–65)
Surgical indications include: age <50, serum calcium >1 mg/dL above upper limit of normal, T-score ≤-2.5 (osteoporosis), 24-hour urine calcium >400 mg, glomerular filtration rate (GFR) <60, or nephrolithiasis
This patient has calcium 11.8 mg/dL (>1 above upper limit of normal of ~10.5) and elevated 24-hour urine calcium; the T-score of -2.3 does not quite meet the ≤-2.5 threshold, but the calcium criterion alone is sufficient — multiple criteria are met
Parathyroidectomy is indicated and is curative
Why the others are wrong
Annual monitoring with labs — observation is appropriate only when no surgical criteria are met; this patient meets multiple criteria
Bisphosphonate therapy — does not correct the underlying disease
Cinacalcet therapy — reserved for patients who are not surgical candidates
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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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