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BASICS

Description

  • Excess parathyroid hormone (PTH) production.
  • Primary HPT: Autonomous parathyroid hypersecretion unresponsive to hypercalcemia.
  • Secondary HPT: PTH increase in response to hypocalcemia/hyperphosphatemia due to vitamin D deficiency, kidney disease, or phosphate loading.
  • Tertiary HPT: Autonomous parathyroid activity after prolonged secondary HPT.

Epidemiology

  • Primary HPT prevalence: 1:500 to 1:1,000 in the U.S.
  • Accounts for 90% of hypercalcemia cases.
  • Predominantly affects postmenopausal women.

ETIOLOGY AND PATHOPHYSIOLOGY

  • Four parathyroid glands regulate calcium via PTH.
  • PTH increases serum calcium by:
  • Stimulating osteoclastic bone resorption.
  • Increasing distal tubular calcium reabsorption.
  • Enhancing phosphate excretion (decreased proximal tubular reabsorption).
  • Stimulating conversion of 25(OH)D to active 1,25(OH)2D (calcitriol), increasing GI absorption.

Primary HPT Causes

  • Solitary adenoma (80-85%)
  • Multigland hyperplasia (10-15%), sporadic or MEN association
  • Parathyroid carcinoma (<1%)

Secondary HPT Causes

  • Vitamin D deficiency, chronic kidney disease, decreased calcium intake or absorption.

Tertiary HPT

  • Autonomous hyperfunction after prolonged secondary stimulation.

Genetics

  • ~10% have identifiable genetic basis.
  • MEN-I gene mutation in multigland hyperplasia without renal disease.
  • Neonatal severe HPT: CaSR gene alleles deficiency.
  • Familial hypocalciuric hypercalcemia: heterozygous loss of CaSR.

RISK FACTORS

  • Chronic kidney disease
  • Advanced age
  • Poor nutrition
  • Radiation exposure
  • Family history

DIAGNOSIS

History

  • 80% asymptomatic.
  • Symptoms: kidney stones, bone disease (osteitis fibrosa cystica), neuropsychiatric symptoms, gastrointestinal complaints.
  • Associated conditions: MEN syndromes, nephrolithiasis, pancreatitis, hypertension, QT shortening, osteoporosis.

Physical Exam

  • Often no specific signs.
  • May find signs related to underlying etiology or complications.

Differential Diagnosis

  • Rule out familial hypocalciuric hypercalcemia (FHH) with 24-hour urine calcium:creatinine ratio.
  • Other causes of hypercalcemia: malignancy, granulomatous diseases, vitamin D intoxication, endocrine disorders.

Diagnostic Tests

  • Corrected serum calcium or ionized calcium.
  • Intact PTH level: elevated or inappropriately normal in primary HPT.
  • Serum phosphate: low in primary HPT; elevated in secondary.
  • 24-hour urine calcium:creatinine clearance ratio >0.02 suggests primary HPT; <0.01 suggests FHH.
  • 25(OH)D levels: assess vitamin D status; correct deficiency before management.
  • Imaging for surgical planning:
  • Tc-99m sestamibi scan ± SPECT (best for single adenoma)
  • Neck ultrasound (operator-dependent)
  • 4D-CT (superior localization)
  • PET (C-methionine) for ectopic glands
  • CT/MRI for mediastinal glands

TREATMENT

Medical Therapy

  • Primary HPT: Surgery is curative.
  • Bisphosphonates (alendronate) to reduce bone resorption (avoid in low GFR).
  • Calcimimetics (cinacalcet) to inhibit PTH secretion; FDA-approved for symptomatic non-surgical patients.
  • Selective estrogen receptor modulators (raloxifene) for bone density in postmenopausal women.
  • Avoid HRT as first line due to systemic risks.

Secondary HPT

  • Address underlying cause: calcium, vitamin D analogues, phosphate binders, calcimimetics.

Surgery

  • Parathyroidectomy indicated in symptomatic and certain asymptomatic primary HPT cases:
  • Symptomatic hypercalcemia
  • Kidney stones, fractures, osteitis fibrosa cystica
  • Serum calcium >1 mg/dL above normal
  • Age <50 years
  • Creatinine clearance <60 mL/min
  • Urine calcium >400 mg/day with stone risk

  • Bone density T-score < -2.5

  • Approaches:

  • Bilateral neck exploration

  • Minimally invasive parathyroidectomy (MIP) with localization and intraoperative PTH monitoring.

  • Postoperative care:

  • Monitor calcium, magnesium, phosphorus.
  • Watch for “hungry bone syndrome” requiring calcium and calcitriol supplementation.
  • Monitor for bleeding and airway compromise.

FOLLOW-UP

  • Asymptomatic primary HPT: annual serum calcium and creatinine, bone density every 1-2 years.
  • Dietary calcium maintenance (~1000 mg/day unless hypercalciuria).

PROGNOSIS

  • Excellent after surgery with symptom resolution.

COMPLICATIONS

  • From hypercalcemia and high PTH:
  • Kidney stones, nephrocalcinosis
  • Bone disease: fractures, cysts
  • Neuropsychiatric disturbances
  • Pancreatitis, hypertension
  • Cardiovascular effects (LV hypertrophy)

REFERENCES

  1. Bilezikian JP, et al. Guidelines for management of asymptomatic primary hyperparathyroidism. J Clin Endocrinol Metab. 2014;99(10):3561-3569.
  2. Cheung K, et al. Meta-analysis of preoperative localization for primary hyperparathyroidism. Ann Surg Oncol. 2012;19(2):577-583.
  3. Markowitz ME, Underland L, Gensure R. Parathyroid disorders. Pediatr Rev. 2016;37(12):524-535.
  4. Kunstman JW, et al. Parathyroid localization and clinical management. J Clin Endocrinol Metab. 2013;98(3):902-912.
  5. Kulkarni P, Tucker J. Symptomatic versus asymptomatic primary hyperparathyroidism: systematic review. J Clin Transl Endocrinol. 2023;32:100317.

Clinical Pearls

  • 80% of primary HPT patients are asymptomatic at diagnosis.
  • Classic symptoms: "stones, bones, moans, and groans."
  • Corrected calcium and intact PTH are essential for diagnosis.
  • Secondary HPT is a response to hypocalcemia; common in CKD and vitamin D deficiency.
  • Annual monitoring adequate for asymptomatic patients without surgical indications.