Primary Hyperparathyroidism

Primary hyperparathyroidism is autonomous parathyroid hormone secretion causing hypercalcaemia with raised or inappropriately normal parathyroid hormone.

It affects roughly 1 in 500 women and 1 in 2000 men, with a peak at 50 to 60 years and a female to male ratio of about 3 to 1. Most patients are now found by routine calcium testing.

Causes are a single adenoma (80 to 85%), multigland hyperplasia (10 to 15%), double adenoma and carcinoma (under 1%). Familial forms include MEN1, MEN2A, CDC73 and CASR variants.

Pathophysiology.

Raised parathyroid hormone increases bone resorption, renal calcium reabsorption and calcitriol synthesis, which raises intestinal calcium absorption. Loss of cortical bone and hypercalciuria cause fractures and kidney stones.

Radiation to the neck and lithium are associated.

• Most are asymptomatic. Symptoms: polyuria, thirst, constipation, nausea, fatigue, low mood, cognitive slowing, bone pain, kidney stones.
• Complications: osteoporosis, fragility fracture, nephrocalcinosis, hypertension, peptic ulcer and pancreatitis. Severe disease causes bone cysts (osteitis fibrosa cystica).

Red flags.

• Adjusted calcium over 3.5 mmol/L (14 mg/dL), vomiting, dehydration or confusion (hypercalcaemic crisis).
• Palpable neck mass with very high parathyroid hormone (carcinoma).

• Albumin adjusted calcium (or ionised calcium) raised on two occasions with parathyroid hormone raised or in the upper half of normal.
• Phosphate, eGFR, 25-hydroxyvitamin D (correct deficiency to at least 50 nmol/L, 20 ng/mL), magnesium and alkaline phosphatase.
• 24-hour urinary calcium and creatinine to exclude familial hypocalciuric hypercalcaemia (calcium to creatinine clearance ratio under 0.01 suggests it). Hypercalciuria over 10 mmol (400 mg) daily supports surgery.
• DXA of lumbar spine, hip and distal one third of the radius. Vertebral imaging and renal ultrasound or CT for stones.
• Imaging localises the gland only after biochemical diagnosis: ultrasound, technetium sestamibi, four dimensional CT or choline PET-CT.
• Genetic testing if under 40 years, multigland disease or a family history.

Differential diagnosis.

• Familial hypocalciuric hypercalcaemia and normocalcaemic variants.
• Malignancy (parathyroid hormone suppressed), lithium or thiazide effect, sarcoidosis and vitamin D excess.
• Tertiary hyperparathyroidism and hyperthyroidism.

• Parathyroidectomy is the only cure. Offer it to all symptomatic patients and to asymptomatic patients with any of: adjusted calcium 0.25 mmol/L (1 mg/dL) or more over the upper reference limit, age under 50 years, T-score of -2.5 or lower or a fragility fracture, eGFR under 60 mL/min, a kidney stone or nephrocalcinosis, or hypercalciuria.
• After surgery check calcium and parathyroid hormone within 24 hours and at 6 months. Hungry bone syndrome (severe prolonged hypocalcaemia): calcium carbonate 1 to 2 g elemental calcium daily in divided doses with calcitriol 0.5 to 1 microgram daily.
• Medical therapy for patients who cannot have surgery: cinacalcet starting 30 mg twice daily, titrated every 2 to 4 weeks through 60 and 90 mg twice daily to a maximum of 90 mg four times daily; check calcium within 1 week of each change. Alendronate 70 mg weekly for osteoporosis.
• Avoid thiazides, lithium and dehydration. Keep dietary calcium 1000 mg daily and correct vitamin D deficiency.
• Hypercalcaemic crisis: intravenous 0.9% sodium chloride 1 to 2 L over the first 4 to 6 hours if not in heart or kidney failure, zoledronic acid 4 mg intravenously over 15 minutes, and calcitonin 4 units/kg subcutaneously every 12 hours for up to 48 hours. Urgent surgery once stable.

Special groups. Pregnancy: surgery in the second trimester for symptomatic or severe disease; foetal hypocalcaemia can follow. MEN1 and MEN2A need subtotal or total parathyroidectomy.

Monitoring. Observed patients: calcium and creatinine yearly, DXA every 1 to 2 years, and renal imaging if symptoms develop.

Referral and escalation. Endocrine surgeon for any surgical indication, and urgent admission for hypercalcaemic crisis.