Residency · Residency · Endocrinology

Primary Hyperparathyroidism

Epidemiology and Etiology

Epidemiology

Primary hyperparathyroidism (PHPT) is one of the most common endocrine disorders, with an incidence of 1-3 per 1,000 population. Women are affected three times more frequently than men, with peak incidence occurring between 50 and 60 years of age, making postmenopausal women the most commonly affected demographic. The increasing detection of PHPT in recent decades is largely attributable to the widespread inclusion of serum calcium measurement on routine metabolic panels, leading to identification of patients with asymptomatic disease who would previously have gone undiagnosed.

Etiology

A single parathyroid adenoma is the underlying cause in 80-85% of cases, representing a monoclonal proliferation of parathyroid cells. Multi-gland hyperplasia accounts for 10-15% and involves all four parathyroid glands; this pattern is more common in familial and genetic forms of the disease. Double adenomas, with two enlarged glands and two normal glands, constitute 2-5% of cases. Parathyroid carcinoma is very rare, occurring in less than 1% of PHPT, and should be suspected when calcium exceeds 14 mg/dL, PTH is more than 5 times the upper limit of normal, a palpable neck mass is present, or recurrent laryngeal nerve palsy is identified. Ectopic parathyroid tissue, found in intrathymic (the most common ectopic location), retroesophageal, mediastinal, or intrathyroidal positions, occurs in 2-5% of patients and presents a particular surgical challenge.

Genetic Causes

Several genetic syndromes include PHPT as a major manifestation. MEN1, caused by mutations in the menin gene, produces PHPT in over 90% of carriers by age 50, characteristically as multigland hyperplasia associated with pituitary adenomas and pancreatic neuroendocrine tumors. MEN2A, caused by RET proto-oncogene mutations, includes PHPT in 20-30% of carriers, usually with mild disease, alongside medullary thyroid carcinoma and pheochromocytoma. MEN4, caused by CDKN1B/p27 mutations, produces a rare phenotype similar to MEN1. Familial isolated hyperparathyroidism (FIHP) may involve CASR, GCM2, or CDC73 mutations. Hyperparathyroidism-jaw tumor syndrome (HPT-JT), caused by CDC73 (HRPT2) gene mutations, carries a 15-20% risk of parathyroid carcinoma along with ossifying fibromas of the jaw and renal cysts or tumors. Familial hypocalciuric hypercalcemia (FHH), caused by inactivating CASR mutations, must be distinguished from PHPT, as discussed below. Neonatal severe hyperparathyroidism, caused by homozygous CASR mutations, produces life-threatening hypercalcemia requiring urgent parathyroidectomy.

Clinical Presentations

Asymptomatic PHPT (Most Common Presentation Currently)

The clinical landscape of PHPT has shifted dramatically over recent decades. Currently, 80% of newly diagnosed PHPT is asymptomatic, discovered incidentally through routine blood work revealing mild hypercalcemia, typically less than 1 mg/dL above the upper limit of normal, with mildly elevated PTH. Despite the absence of classic symptoms, subclinical end-organ effects may be present, including reduced bone mineral density, vertebral fractures that often go undiagnosed on clinical grounds, and renal calcification.

Symptomatic PHPT

The classic mnemonic "Stones, Bones, Groans, and Psychic Moans" captures the major organ system involvement. Renal manifestations include nephrolithiasis in 15-20% of patients, typically calcium oxalate or calcium phosphate stones, nephrocalcinosis, and hypercalciuria (24-hour urine calcium exceeding 400 mg/day). Skeletal involvement classically produces osteitis fibrosa cystica, though this is rare in the modern era; historical findings include "brown tumors" of bone, subperiosteal bone resorption on hand radiographs, and the "salt-and-pepper" skull appearance. DXA characteristically shows preferential cortical bone loss, most prominent at the distal one-third radius, along with vertebral fractures. Gastrointestinal symptoms include constipation, nausea, anorexia, peptic ulcer disease, and, uncommonly, pancreatitis. Neuropsychiatric manifestations encompass depression, cognitive dysfunction, fatigue, anxiety, insomnia, and decreased quality of life. Cardiovascular involvement includes hypertension in 40-60%, left ventricular hypertrophy, vascular calcification, and increased cardiovascular mortality, though the latter is more convincingly demonstrated with moderate-to-severe hypercalcemia.

Normocalcemic PHPT

Normocalcemic PHPT is defined by elevated PTH in the setting of consistently normal total and ionized calcium, after all secondary causes of elevated PTH have been excluded. Its true prevalence is unclear, but it may represent the earliest phase of PHPT. Secondary causes that must be excluded before making this diagnosis include vitamin D deficiency (25(OH)D below 30 ng/mL), chronic kidney disease (eGFR below 60), medications (thiazides, lithium), calcium malabsorption, and high urinary calcium excretion. Natural history data suggest that approximately 20% progress to hypercalcemic PHPT over 3-8 years, and subclinical skeletal and renal complications may be present. Management consists of observation with monitoring, and surgery is considered if complications develop.

<image>A clinical manifestation diagram of primary hyperparathyroidism organized by organ system. Central image: four parathyroid glands with one enlarged adenoma. Radiating outward to organ systems: (1) Kidney - show calcium oxalate kidney stones and nephrocalcinosis on CT, 24h urine calcium measurement. (2) Skeleton - show subperiosteal bone resorption on hand X-ray (radial side of middle phalanges), salt-and-pepper skull on lateral X-ray, brown tumor on long bone X-ray, and DXA showing preferential cortical bone loss at distal 1/3 radius. (3) GI tract - constipation, peptic ulcer. (4) Brain - depression, cognitive impairment. (5) Heart - LVH, vascular calcification. Include laboratory panel showing: elevated calcium, elevated PTH, low phosphate, elevated 1,25(OH)2D, elevated alkaline phosphatase, elevated urine calcium. Use medical illustration style with labeled radiographic images.</image>

Diagnosis

Biochemical Diagnosis

The diagnosis of PHPT rests on the finding of elevated calcium (total corrected or ionized) with an elevated or inappropriately normal PTH level. When PTH exceeds twice the upper limit of normal with calcium more than 1 mg/dL above normal, parathyroid carcinoma or FHH type 3 should be considered. Phosphate is typically low-normal or low, reflecting the phosphaturic effect of PTH. 25-hydroxyvitamin D should be checked to identify concomitant vitamin D deficiency, which is common in 40-80% of PHPT patients and should be repleted to at least 30 ng/mL before finalizing the diagnostic profile. 1,25-dihydroxyvitamin D is often elevated because PTH stimulates 1-alpha-hydroxylase, though it is not routinely needed for diagnosis.

The 24-hour urine calcium measurement is essential to exclude FHH. The calcium/creatinine clearance ratio (CCCR) is calculated as (urine calcium multiplied by serum creatinine) divided by (serum calcium multiplied by urine creatinine). A CCCR below 0.01 is highly suggestive of FHH rather than PHPT, and genetic testing for CASR mutations is recommended. A ratio between 0.01 and 0.02 is indeterminate and also warrants consideration of CASR genetic testing. A ratio above 0.02 is consistent with PHPT. Alkaline phosphatase is elevated in severe bone disease but may be normal in mild PHPT.

Familial Hypocalciuric Hypercalcemia (FHH) vs PHPT

The distinction between FHH and PHPT is critically important because FHH does not require parathyroidectomy -- surgery will not cure FHH. FHH results from autosomal dominant inactivating CaSR mutations that shift the calcium set-point upward, producing lifelong mild hypercalcemia with normal-to-high PTH and characteristically low urinary calcium excretion. Three subtypes exist: FHH1 (CASR mutations, the most common), FHH2 (GNA11 mutations), and FHH3 (AP2S1 mutations, which can cause significant hypercalcemia mimicking PHPT). Key differentiators include a CCCR below 0.01, a family history of hypercalcemia, and the presence of hypercalcemia since childhood.

Localization Studies (Pre-Surgical)

Localization studies are obtained for surgical planning and must never be used for diagnosis. The diagnosis is biochemical; negative imaging does not exclude PHPT or contraindicate surgery.

Sestamibi scan (99mTc-sestamibi) relies on delayed washout of radiotracer from parathyroid adenomas compared with thyroid tissue, with sensitivity of 60-90% for single adenomas but lower sensitivity for multigland disease and small adenomas. Sestamibi-SPECT/CT improves anatomic localization and can identify ectopic glands. Neck ultrasound has sensitivity of 70-80% for adenomas in typical positions but is operator-dependent and cannot detect ectopic glands; it also evaluates for coexisting thyroid nodules, which are common. Four-dimensional CT (4D-CT) of the parathyroids uses non-contrast, arterial, and venous phase imaging, achieving sensitivity of 85-94% for single adenomas with excellent detection of ectopic glands, and is increasingly used for reoperative cases. 18F-fluorocholine PET/CT is an emerging modality with superior sensitivity for multigland disease and small adenomas, though it is not yet widely available. Concordant imaging, in which two positive studies identify the same lesion, confers a high positive predictive value for successful focused surgery.

Management

Surgical Indications (2022 Fifth International Workshop Guidelines)

Surgery is recommended for all symptomatic patients with stones, fractures, or classic symptoms. For asymptomatic PHPT, surgery is recommended when any of the following criteria are met: serum calcium more than 1.0 mg/dL above the upper limit of normal; T-score of -2.5 or below at lumbar spine, total hip, femoral neck, or distal one-third radius on DXA; vertebral fracture on imaging (VFA or spine X-ray); eGFR below 60 mL/min/1.73m2; 24-hour urine calcium exceeding 400 mg/day with increased stone risk by biochemical stone profile; nephrolithiasis or nephrocalcinosis on imaging; or age under 50 years. Surgery is the only definitive cure for PHPT.

Surgical Approaches

Minimally invasive parathyroidectomy (MIP) is a focused approach used when concordant preoperative imaging localizes the adenoma. It employs a smaller incision and relies on intraoperative PTH monitoring using the Miami criterion: a PTH drop exceeding 50% from the highest pre-excision level at 10 minutes post-excision confirms successful adenoma removal. Cure rates exceed 95%. Bilateral neck exploration (BNE) is the traditional approach in which all four glands are visualized. It is preferred when multigland disease is suspected (as in MEN1), when imaging is negative or discordant, and achieves cure rates exceeding 95%. Intraoperative PTH monitoring using rapid PTH assays confirms successful adenoma removal; if PTH does not drop adequately, further exploration for multigland disease or a missed adenoma is warranted.

Post-Operative Management

Hungry bone syndrome is the most significant post-operative complication, characterized by a rapid and potentially severe drop in serum calcium due to unopposed bone mineralization following removal of the PTH-driven stimulus to bone resorption. Risk factors include high preoperative calcium, high PTH, high alkaline phosphatase, vitamin D deficiency, and a large adenoma. This can cause severe symptomatic hypocalcemia lasting days to weeks. Prevention involves repleting vitamin D preoperatively to a target of at least 30 ng/mL and starting calcium carbonate 1-2 g three times daily plus calcitriol 0.5-1 mcg twice daily immediately postoperatively in high-risk patients. Calcium and PTH should be monitored at 24 hours postoperatively and daily during hospitalization. Some patients require weeks to months of calcium and calcitriol supplementation.

Medical Management (When Surgery Declined/Contraindicated)

For patients who decline or have contraindications to surgery, monitoring consists of annual serum calcium and creatinine, DXA every 1-2 years, and 24-hour urine calcium if stones are a concern. Cinacalcet (Sensipar/Mimpara) is a calcimimetic that allosterically activates the CaSR, lowering serum calcium by 0.5-1.0 mg/dL. However, it does not improve BMD, does not reduce fractures, and does not lower PTH long-term; it is useful for calcium control in patients unfit for surgery. Bisphosphonates (alendronate) improve BMD at the lumbar spine and hip without significantly affecting calcium or PTH levels. Denosumab improves BMD more effectively than bisphosphonates in PHPT and also lowers calcium, though caution is required upon discontinuation due to the risk of rebound hypercalcemia and vertebral fractures. The combination of cinacalcet and alendronate addresses both calcium and bone density. General measures include adequate hydration (at least 2 liters daily), avoidance of thiazide diuretics (which reduce renal calcium excretion and worsen hypercalcemia), and vitamin D repletion, which is safe and important even in PHPT, targeting 25(OH)D of at least 30 ng/mL. Vitamin D repletion reduces PTH without significantly worsening hypercalcemia in most patients.

Hypercalcemic Crisis

Definition

Hypercalcemic crisis is defined by serum calcium exceeding 14 mg/dL (3.5 mmol/L) accompanied by severe symptoms including altered mental status, cardiac arrhythmias, and renal failure. This is a life-threatening emergency requiring immediate intervention.

Acute Management

The cornerstone of acute management is aggressive intravenous normal saline at 200-500 mL/hr initially, adjusted for cardiac and renal status. Calcitonin at 4 IU/kg intramuscularly or subcutaneously every 12 hours provides rapid onset of action within 4-6 hours but is limited by tachyphylaxis within 48 hours. Intravenous bisphosphonates provide more durable effect: zoledronic acid 4 mg IV over 15-30 minutes (onset 2-4 days, nadir 4-7 days, duration 2-4 weeks) or pamidronate 60-90 mg IV over 2-4 hours. Denosumab 120 mg subcutaneously is effective when bisphosphonates are refractory, with onset at 4-10 days. Loop diuretics such as furosemide should only be used after adequate volume resuscitation for their modest calciuric effect and should not be used routinely. Cinacalcet at 30-60 mg twice daily may help acutely in PHPT. Urgent parathyroidectomy is the definitive treatment for PHPT-related hypercalcemic crisis after medical stabilization.

<image>A management decision algorithm for primary hyperparathyroidism. Start with confirmed PHPT (elevated calcium + elevated/inappropriate PTH + CCCR >0.02). First decision: Symptomatic? If YES → parathyroidectomy. If NO → evaluate for surgical indications (list the 2022 Workshop criteria: calcium >1 above ULN, T-score ≤-2.5, vertebral fracture, eGFR <60, stones/nephrocalcinosis, urine Ca >400 with stone risk, age <50). If ANY criteria met → parathyroidectomy. If NO criteria met → observation with annual calcium/creatinine, DXA every 1-2 years. Include a pre-surgical pathway: localization (sestamibi + US; 4D-CT if discordant) → concordant = MIP with intraoperative PTH; discordant = bilateral exploration. Post-op box: monitor for hungry bone syndrome, check calcium at 24h. Medical management box for non-surgical candidates: cinacalcet ± bisphosphonate. Use flowchart with color-coded decision points.</image>

Key Clinical Pearls

• PHPT is diagnosed biochemically (elevated calcium with elevated/inappropriate PTH), NOT by imaging; localization studies are for surgical planning only; a negative sestamibi does not exclude PHPT
• Always calculate the calcium/creatinine clearance ratio (CCCR) to exclude FHH before proceeding to surgery; CCCR <0.01 strongly suggests FHH and surgery will not be curative
• Vitamin D deficiency is present in 40-80% of PHPT patients and should be corrected (to ≥30 ng/mL) before establishing the definitive biochemical profile; deficiency can mask the degree of hypercalcemia and elevate PTH further
• Hungry bone syndrome is the most common complication after parathyroidectomy for severe PHPT; preoperative vitamin D repletion and immediate postoperative calcium + calcitriol supplementation are essential in high-risk patients
• Parathyroid carcinoma should be suspected when calcium is markedly elevated (>14 mg/dL), PTH is >5x ULN, or there is a palpable neck mass or recurrent laryngeal nerve palsy; en bloc resection (not shelling out the adenoma) is required
• The 2022 Workshop guidelines expanded surgical indications to include vertebral fractures on imaging and refined renal criteria; more patients now qualify for surgery than under previous guidelines

References

1. Bilezikian JP, et al. "Evaluation and Management of Primary Hyperparathyroidism: Summary Statement and Guidelines from the Fifth International Workshop." J Bone Miner Res. 2022;37(11):2293-2314.
2. Wilhelm SM, et al. "The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism." JAMA Surg. 2016;151(10):959-968.
3. Khan AA, et al. "Primary Hyperparathyroidism: Review and Recommendations on Evaluation, Diagnosis, and Management." JAMA. 2023;330(12):1159-1170.
4. Silverberg SJ, et al. "Current Issues in the Presentation of Asymptomatic Primary Hyperparathyroidism." J Clin Endocrinol Metab. 2018;103(10):3585-3592.
5. Christensen SE, et al. "Familial Hypocalciuric Hypercalcaemia: A Review." Curr Opin Endocrinol Diabetes Obes. 2011;18(6):359-370.

Read this lecture as Markdown