Primary Hyperparathyroidism

Background

• Primary hyperparathyroidism is an endocrine disorder caused by autonomous overproduction of parathyroid hormone (PTH) by abnormal parathyroid glands and characterized by hypercalcemia without appropriate suppression of plasma parathyroid hormone levels; it is the most common cause of hyperparathyroidism and of hypercalcemia.
• It is most common in adults > 50 years old and 3-4 times more common in females compared to males. Possible risk factors include exposure to ionizing radiation, long-term lithium therapy, hereditary endocrine syndromes such as multiple endocrine neoplasia, reduced physical activity, and low calcium intake.

Evaluation

• Most patients (about 80%) are asymptomatic, and the disease is detected by an incidental finding of hypercalcemia on a laboratory test.
• Symptomatic patients present with findings related to chronic hypercalcemia, including renal findings (nephrolithiasis, hypercalciuria, and nephrocalcinosis), skeletal findings (osteitis fibrosa cystica, bone pain, fragility fractures, and osteoporosis), neuromuscular findings (proximal muscle weakness and muscular atrophy), neuropsychiatric symptoms (anxiety, depression, sleep disturbances, dementia, confusion, and stupor), cardiovascular findings (hypertension, left ventricular hypertrophy, impaired diastolic filling, and myocardial calcification), and acute pancreatitis.
• Measure serum levels of total or ionized calcium, albumin, PTH, creatinine, and 25-hydroxyvitamin D.
• Perform 24-hour measurement of urinary calcium and creatinine excretion to distinguish from hypocalciuric hypercalcemia (Strong recommendation).
• Measure bone mineral density at lumbar spine, hip, and distal radius, preferably using dual-energy x-ray absorptiometry (Strong recommendation).
• Diagnose primary hyperparathyroidism in patients with elevated or inappropriately normal PTH (typically > 28 pg/mL or 3 pmol/L) despite persistent hypercalcemia.
• Consider abdominal imaging in patients with asymptomatic primary hyperparathyroidism to detect nephrocalcinosis or nephrolithiasis (Weak recommendation).
• Provide genetic counseling for patients < 40 years old with primary hyperparathyroidism and multigland disease; also consider genetic counseling for patients with family history or syndromic manifestations (Strong recommendation).
• Consider parathyroid cancer, which requires en-block resection, in patients with primary hyperparathyroidism with significantly elevated PTH levels and severe hypercalcemia (Strong recommendation).

Management

• Patients presenting with hypercalcemic crisis (rapid-onset albumin-corrected serum calcium > 14 mg/dL and signs or symptoms of multiorgan dysfunction) require immediate management (Strong recommendation).
  • Provide IV rehydration with normal saline. Volume replacement is guided by the presence of underlying cardiac or renal disease as well as the degree of dehydration present. Following normalization of volume status loop, diuretics such as furosemide can be given to enhance renal calcium excretion and avoid volume overload.
  • Consider calcitonin 4 units/kg subcutaneously or intramuscularly every 12 hours for rapid action and pain relief prior to bisphosphonates taking effect (48 hours).
  • Consider bisphosphonates, such as pamidronate 60-90 mg IV over 4 hours, zoledronic acid 4 mg IV over 15 minutes, or consider denosumab 120 mg subcutaneously. bisphosphonates should be avoided if parathyroidectomy planned within a few days to avoid potential hypocalcemia after surgery.
  • Consider cinacalcet (initial dose 30 orally twice daily) to decrease albumin-adjusted calcium for primary hyperparathyroidism (in a patient who is not a surgical candidate) or parathyroid carcinoma.
  • Perform parathyroidectomy after medical management has resolved the hypercalcemic crisis, if the patient is a surgical candidate.
• Management of hyperparathyroidism in patients not in hypercalcemic crisis:
  • Start or maintain calcium intake of 1,000-1,200 mg/day of elemental calcium orally (Strong recommendation).
  • Consider vitamin D supplementation in patients who are vitamin D deficient before parathyroidectomy (Weak recommendation).
  • Consider parathyroidectomy for most patients, especially those:
    • with symptomatic primary hyperparathyroidism (Strong recommendation)
    • ≤ 50 years old at diagnosis (Strong recommendation)
    • with clinical or biochemical evidence consistent with parathyroid cancer (Strong recommendation)
    • with asymptomatic primary hyperparathyroidism and sustained hypercalcemia > 1 mg/dL (0.25 mmol/L) above the upper limit of normal (Strong recommendation), osteoporosis or evidence of fracture (Strong recommendation), or renal involvement (for example, glomerular filtration rate < 60 mL/minute, nephrolithiasis on imaging, nephrocalcinosis, or hypercalciuria) (Weak recommendation)
  • Consider medical management for asymptomatic patients unwilling or unable to have surgery, including maintaining hydration, antiresorptive therapy (alendronate or raloxifene), and/or cinacalcet to maintain normal serum calcium levels.