Parathyroid Adenoma

Parathyroid adenoma is a benign tumour of one parathyroid gland, and the commonest cause of primary hyperparathyroidism (80 to 85% of cases). Double adenomas account for 2 to 5%. Hyperplasia of all glands accounts for about 10 to 15%.

Primary hyperparathyroidism affects about 1 in 500 women and 1 in 2,000 men, with peak onset after age 50. Radiation to the neck, lithium therapy and family history are risk factors.

Most patients are now diagnosed with mild hypercalcaemia on routine tests, without symptoms. Tumours may be ectopic (mediastinum, thymus, thyroid), in about 10 to 15% of cases.

Pathophysiology.

A single clone of parathyroid cells overproduces parathyroid hormone because of cyclin D1 (PRAD1) overexpression or MEN1 inactivation. The calcium set point rises, so hormone secretion is not suppressed by calcium.

High hormone levels increase bone resorption, renal calcium reabsorption and calcitriol production, leading to hypercalcaemia, hypercalciuria and hypophosphataemia.

• Often asymptomatic. Fatigue, low mood, poor concentration, constipation, thirst and polyuria.
• Kidney stones, osteoporosis and fractures, hypertension, peptic ulcer, pancreatitis and short QT interval.
• Rare severe disease: bone pain, brown tumours, muscle weakness and calcium over 3.5 mmol/L.

Red flags.

• Calcium over 3.5 mmol/L, confusion, or kidney injury.
• Young age, family history or a very high calcium suggesting a syndrome or carcinoma.

• Albumin adjusted calcium raised on 2 occasions with parathyroid hormone high or inappropriately normal, phosphate low or low normal, 25-hydroxyvitamin D measured (correct to at least 50 nmol/L before concluding).
• 24-hour urinary calcium (and calcium to creatinine clearance ratio over 0.02 favours primary hyperparathyroidism over familial hypocalciuric hypercalcaemia) and eGFR.
• DXA of lumbar spine, hip and distal radius. Spine imaging for vertebral fractures and abdominal imaging for kidney stones.
• Localisation only after surgery is decided: neck ultrasound, technetium sestamibi with SPECT, or four dimensional CT.
• Genetic testing in patients under 40 years, with multiglandular disease or a family history (MEN1, CDC73, CASR, CDKN1B).

Differential diagnosis.

• Familial hypocalciuric hypercalcaemia, parathyroid hyperplasia and parathyroid carcinoma.
• Malignancy associated hypercalcaemia (low parathyroid hormone), thiazide and lithium effects, and vitamin D excess.
• Sarcoidosis and other granulomatous disease.

• Parathyroidectomy is the only cure. Offer surgery to symptomatic patients and to those with: calcium over 0.25 mmol/L higher than the upper limit, age under 50 years, T-score of -2.5 or lower or a vertebral fracture, eGFR under 60 mL/min, kidney stones or hypercalciuria over 10 mmol in 24 hours.
• Focused (minimally invasive) parathyroidectomy when imaging agrees, with intraoperative parathyroid hormone fall of over 50% at 10 minutes. Bilateral exploration when imaging is negative or discordant.
• Hungry bone syndrome: calcium carbonate 1 to 2 g elemental calcium daily in divided doses with calcitriol 0.5 to 1 microgram daily, and intravenous calcium gluconate (10 mL of 10%, 2.25 mmol, over 10 minutes with monitoring) for tetany.
• Non-surgical patients: hydration, vitamin D replacement (to at least 50 nmol/L), alendronate 70 mg weekly for bone loss, and cinacalcet 30 mg twice daily increased as needed up to 90 mg four times daily for calcium control.
• Hypercalcaemic crisis: intravenous 0.9% sodium chloride 1000 mL over the first hour, zoledronic acid 4 mg intravenously over 15 minutes, calcitonin 4 units/kg every 12 hours, and urgent surgery.
• Avoid thiazides, lithium and excess calcium or vitamin D supplements.

Special groups. Pregnancy: surgery in the second trimester for symptomatic or severe disease. Older adults: observation with yearly review is reasonable if asymptomatic.

Monitoring. After surgery: calcium and parathyroid hormone at 24 hours, 6 weeks and 6 months, then yearly. Untreated: calcium and creatinine yearly, and DXA every 1 to 2 years.

Referral and escalation. Endocrine surgery for all patients meeting criteria; endocrinology for genetic or complex disease; urgent admission for calcium over 3.5 mmol/L.