Tertiary hyperparathyroidism is state of hyperparathyroidism characterized by excessive secretion of parathyroid hormone after long-standing secondary hyperparathyroidism, even after the correction of the cause of hyperparathyroidism.
The term is also used in patients who have undergone kidney transplants but their parathyroid function does not return to normal. The cause is the same. The parathyroid glands have functioned abnormally for so long while patients had kidney failure and were on dialysis that they never return to normal.
Causes of Tertiary Hyperparathyroidism
Tertiary hyperparathyroidism is most commonly observed in patients with long-standing chronic kidney disease and often after renal transplantation.
The stimulatory effect of hyperphosphatemia [increased phosphate levels have a direct stimulatory effect on the parathyroid gland cells] results in nodular hyperplasia and increased parathyroid hormone secretion.
With worsening of chronic kidney disease, the size of the parathyroid glands progressively increases leading to high parathyroid levels.
After a renal transplant, these levels remain high in spite of calcium being normal.
Tertiary hyperparathyroidism occurs most commonly in cases where patients with secondary hyperparathyroidism continue to have elevated parathyroid levels after receiving a renal transplant.
This disease is observed in up to 30% of kidney transplant recipients.
Tertiary hyperparathyroidism can also develop after any long-standing gastrointestinal malabsorption causing prolonged hypocalcemia which leads to parathyroid hyperplasia.
After correction of the primary disorder, the hypertrophied parathyroid tissue fails to resolve and secretion of parathyroid hormone is continued.
Consequently, serum calcium levels are normal or even elevated in these patients because the hyperplastic glands function autonomously despite the withdrawal of calcium and calcitriol therapy. Tertiary hyperparathyroidism is classically caused by hyperplasia of all four glands, though some reports indicate that over 20% of patients may have single or double adenomas as the underlying pathology.
Tertiary hyperparathyroidism is differentiated from primary by the presence of long-standing condition such as malabsorption or renal failure.
Prolonged hyperphosphatemia, calcitriol deficiency, and hypocalcemia are often the causes of persistent stimulation in kidney disease.
Presentation
The patient would have a history of secondary hyperparathyroidism and long-standing kidney disease requiring dialysis or some kind of malabsorption syndrome.
It is important to exclude uncorrected primary hyperparathyroidism , drug intake that cause hypercalcemia like calcitriol [commonly prescribed in renal diseases] and lithium.
Symptoms and signs of tertiary hyperparathyroidism are due to high levels of parathyroid or hypercalcemia and are similar to primary and secondary hyperparathyroidism. These include bone pain, decreased bone mineral density, fractures, pruritus, renal stones, peptic ulcer disease, pancreatitis, soft tissue or vascular calcifications and muscle weakness. Psychiatric disorders can be present.
For details on the spectrum of symptoms due to hyperparathyroidism read Primary Hyperparathyroidism and Secondary Hyperparathyroidism.
Diagnosis
The diagnosis of tertiary hyperparathyroidism combines both clinical and laboratory investigation. These patients would have normal or elevated serum calcium concentrations and moderately elevated intact parathyroid levels.
Lab Studies
- Parathyroid hormone levels – raised
- Vitamin D (1,25-dihydroxycholecalciferol) levels – decreased or normal
- Calcium levels – Raised
- Phosphate levels – raised
Xrays
Not required for diagnosis but to note skeletal changes of hyperparathyroidism.
For details on skeletal changes in hyperparathyroidism, read primary hyperparathyroidism.
Other Studies
In patients with primary hyperparathyroidism and single adenomas, localizing studies like Tc-sestimibi scintigraphy, ultrasound, or MRI are advantageous but these studies do not carry any benefit in tertiary hyperparathyroidism [secondary too] because the standard treatment is bilateral neck exploration is for all patients with tertiary hyperparathyroidism.
Treatment of tertiary Hyperparathyroidism
The main indication for treatment is persistent hypercalcemia and/or an increased PTH, and the primary treatment is surgery. The purpose of surgical treatment is to reduce the parathyroid mass and cell number and, thus, normalize the serum calcium concentration.
Surgical options are subtotal or total parathyroidectomy with or without autotransplantation.
Surgical management is safe and effective at correcting bone mineralization and metabolic disturbances. It results in improved neuropsychiatric symptoms, survival, and quality of life.
Indications for Parathyroidectomy in Patients with Tertiary hyperparathyroidism are
- Severe hypercalcemia (serum calcium > 11.5 or 12 mg/dL)
- Persistent hypercalcemia (serum calcium > 10.2 mg/dL
- more than three months to one year after surgery)
- Severe Osteopenia (low bone mineral density)
- Symptomatic hyperparathyroidism
- Fatigue
- Pruritis
- Bone pain or pathologic bone fracture
- Peptic ulcer disease
- Mental status changes
- History of renal calculi
Drug Therapy
In patients with tertiary hyperparathyroidism, medical treatment does not help and is not indicated.
In patients where surgery cannot be done, another potential treatment option is calcimimetics, such as cinacalcet which inhibit parathyroid secretion.
Calcimimetics are still in trial phase.
References
- Yang RL, Kelz RR, Doyle A. Tertiary hyperparathyroidism: choosing an appropriate treatment-an enigma. Transplantation. 2012 Dec 15;94(11):e64-5.
- Gioviale MC, Bellavia M, Damiano G, Lo Monte AI. Post-transplantation tertiary hyperparathyroidism . Ann Transplant. 2012 Jul-Sep;17(3):111-9.
- Ramakant P, Agarwal G. Surgical treatment of tertiary hyperparathyroidism: the choice of procedure matters: surgical management of tertiary hyperparathyroidism: an enigma. World J Surg. 2008 Aug;32(8):1894; author reply 1895-6.
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