Tertiary Hyperparathyroidism

Tertiary hyperparathyroidism is autonomous parathyroid hormone secretion with hypercalcaemia that persists, or appears, after long standing secondary hyperparathyroidism has been removed from the stimulus, typically after successful kidney transplantation (or after correction of hypocalcaemia and hyperphosphataemia).

Hyperplastic parathyroid glands, with monoclonal nodules that lose calcium sensing receptor and vitamin D receptor expression, no longer respond to normalised mineral balance. Persistent hyperparathyroidism is found in 30 to 50% of kidney transplant recipients at 1 year, and hypercalcaemia in about 10 to 20%.

Consequences: hypercalcaemia (with raised graft calcium load, nephrocalcinosis and impaired graft function), bone loss and fractures, post-transplant hypophosphataemia, kidney stones, pancreatitis, peptic ulcer, vascular calcification, and cardiovascular events.

• Frequently asymptomatic; hypercalcaemia noted on routine tests within the first 3 to 12 months after transplantation.
• Symptoms of hypercalcaemia: polyuria, polydipsia, constipation, nausea, abdominal pain, fatigue, depression, confusion; bone pain and fractures; renal colic; pancreatitis; short QT.
• Bone loss at the hip and distal radius; muscle weakness; low phosphate with osteomalacic pain.

Red flags

• Corrected calcium above 3.0 mmol/L, or any hypercalcaemia with confusion, vomiting or acute kidney injury: hypercalcaemic crisis.
• Persistent hypercalcaemia above 2.85 mmol/L beyond 12 months after transplant.
• Falling graft function with hypercalcaemia (nephrocalcinosis, dehydration).
• Pancreatitis, fractures or recurrent stones.

• Corrected calcium (and ionised calcium), intact parathyroid hormone, phosphate, magnesium, alkaline phosphatase, 25-hydroxyvitamin D, creatinine and bicarbonate, repeated 3 to 4 times in the first year. Typical pattern: high calcium, high or inappropriately normal parathyroid hormone, low phosphate.
• 24-hour urine calcium or calcium:creatinine ratio to exclude familial hypocalciuric hypercalcaemia.
• Review drugs: calcium and vitamin D supplements, thiazides, lithium.
• Imaging: neck ultrasound and sestamibi scan with SPECT-CT or four dimensional CT to locate adenomatous or ectopic glands before surgery. Graft ultrasound for nephrocalcinosis. DXA of hip, spine and distal radius.
• Exclude malignancy related hypercalcaemia (parathyroid hormone related peptide, suppressed parathyroid hormone), sarcoidosis (ACE, 1,25-dihydroxyvitamin D), myeloma, thyrotoxicosis, immobilisation, milk alkali syndrome, and granulomatous disease.

Differential diagnosis

• Persistent secondary hyperparathyroidism with normal calcium; primary hyperparathyroidism arising by coincidence; vitamin D toxicity; post-transplant immobilisation; adynamic bone disease (low parathyroid hormone with high calcium).

Mild disease (calcium below 2.85 mmol/L, asymptomatic, within 12 months of transplant)

• Observe: spontaneous improvement occurs in many cases as glands involute. Check calcium and parathyroid hormone monthly for 3 months, then every 3 months.
• Stop calcium supplements, active vitamin D (alfacalcidol, calcitriol), calcium based binders and thiazides. Maintain oral hydration at 2 to 3 litres daily. Give cholecalciferol 800 to 2000 units daily if 25-hydroxyvitamin D is below 50 nmol/L.

Medical therapy

• Cinacalcet 30 mg orally daily with food, titrated every 2 to 4 weeks (60, 90, 120, 180 mg) to a maximum of 180 mg daily. Check calcium weekly for the first month; stop if calcium is below 2.2 mmol/L. Reduces calcium and parathyroid hormone but does not correct bone loss or hypophosphataemia, and may raise urinary calcium. Not licensed for transplant recipients; weigh benefits where surgery is not possible.
• Phosphate replacement only if symptomatic or phosphate is below 0.5 mmol/L (phosphate replacement can worsen hyperparathyroidism and nephrocalcinosis).

Acute severe hypercalcaemia (corrected calcium 3.5 mmol/L or more, or symptomatic)

• 0.9% sodium chloride 1 litre intravenously over 4 to 6 hours, then 100 to 150 mL/hour while the patient is non-oliguric and not fluid overloaded (caution with cardiac disease or graft dysfunction); add furosemide 20 to 40 mg intravenously only after rehydration and only for overload.
• Zoledronic acid 4 mg intravenously over at least 15 minutes if eGFR is at least 60 mL/min; dose reduce when eGFR is 30 to 60 (3.5 mg at 50 to 60, 3.3 mg at 40 to 49, 3.0 mg at 30 to 39) and avoid below 30; check calcium at 48 hours. Because bisphosphonates risk adynamic bone, use only once in the acute setting unless a bone biopsy shows otherwise.
• Calcitonin 4 units/kg subcutaneously or intramuscularly every 12 hours for 48 hours as a bridge. Denosumab 60 to 120 mg subcutaneously may be used where bisphosphonates are contraindicated, with close calcium monitoring.
• For dialysis patients, reduce dialysate calcium to 1.0 mmol/L.

Parathyroidectomy

• Indications: persistent hypercalcaemia above 2.85 mmol/L beyond 12 months after transplant, or symptomatic hypercalcaemia at any time, nephrolithiasis or nephrocalcinosis, fractures or osteoporosis, progressive graft dysfunction with hypercalcaemia, calciphylaxis, or severe refractory symptoms.
• Subtotal or total parathyroidectomy with autotransplantation. Warn that transient fall in eGFR of 10 to 20% is common after surgery, and that hungry bone syndrome occurs in 10 to 25%. Manage postoperative hypocalcaemia with calcium gluconate 10% 10 to 20 mL intravenously over 10 minutes, infusion 100 mL of 10% in 1 litre of 5% glucose at 50 mL/hour, oral calcium and alfacalcidol 1 to 3 microg daily.

Bone protection. DXA before and after transplant; for osteoporosis in the transplant setting, alendronate 70 mg weekly when eGFR is at least 35, or denosumab 60 mg subcutaneously every 6 months with calcium and vitamin D.

Referral and escalation. Refer to the transplant team and endocrine surgery for hypercalcaemia persisting beyond 6 months or for any symptomatic hypercalcaemia. Urgent admission for calcium above 3.0 mmol/L with symptoms.

Special groups

• Pregnancy: hypercalcaemia raises risk of neonatal tetany; parathyroidectomy in the second trimester if severe.
• Dialysis patients not transplanted: use the medical measures for secondary hyperparathyroidism (phosphate control, vitamin D, calcimimetics) and refer early for parathyroidectomy when the disease is autonomous.