Tertiary hyperparathyroidism characterized by excessive secretion of parathyroid hormone (PTH) after long-standing secondary (renal) hyperparathyroidism in which hypercalcemia has ensued. Although both secondary and tertiary hyperparathyroidism result from a chronic stimulus to PTH secretion, the serum calcium is always normal in the former, whereas it is always elevated in the latter. Tertiary hyperparathyroidism can be the end result of long-standing secondary hyperparathyroidism in which the stimulated parathyroid glands are no longer in a reactive mode but have assumed a quasi-autonomous function, not too dissimilar from PHPT. The distinction between PHPT and tertiary hyperparathyroidism is usually self-evident in that a clearly definable disorder is present, such as long-standing malabsorption or renal failure. Tertiary hyperparathyroidism is most commonly observed in patients with long-standing chronic kidney disease (CKD) and often after renal transplantation. Long-standing CKD is associated with several metabolic disturbances that lead to increased secretion of PTH, including hyperphosphatemia, calcitriol deficiency, and hypocalcemia. Hyperphosphatemia has a direct stimulatory effect on the parathyroid gland cell resulting in nodular hyperplasia and increased PTH secretion. The size of the parathyroid glands progressively increases as CKD worsens, and gland size is positively correlated with serum PTH levels. Because the parathyroid glands are autonomously functioning, in some patients, PTH levels remain persistently high despite serum calcium levels that are within the reference range or even above normal after a renal transplant and so called tertiary hyperparathyroidism.
Most commonly, these patients are identified by the presence of persistent hyperparathyroidism and hypercalcemia after renal transplantation. Although tertiary hyperparathyroidism characterized by the combination of simultaneous hypercalcemia with elevated PTH levels is most often seen in severe CKD patients after renal transplantation, it is important to exclude other either pre- or coexisting conditions that might have this same biochemical combination. These include a preexisting and uncorrected PHPT, continual prescribing of drugs designed to suppress PTH during severe CKD that might also cause hypercalcemia (eg, calcitriol), or continual use of drugs indicated for psychiatric disorders (eg, lithium).
Symptoms and signs of tertiary hyperparathyroidism may be similar to PHPT attributed to the level of PTH or level of hypercalcemia, and can include bone pain, decreased bone mineral density (BMD), fractures, pruritus, nephrolithiasis, peptic ulcer disease, pancreatitis, soft tissue or vascular calcifications, muscle weakness, mental status changes, and impaired graft function
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. Although there are no universally accepted clinical guidelines as to when to intervene, the most obvious indication is long-term sustained hypercalcemia (>11.0 mg/dL), similar to 1 of the indications established by the National Institutes of Health for intervention in asymptomatic PHPT. Although there is no specific cutoff level of serum PTH that dictates intervention, sustained PTH levels (a trend rather than a single measurement), 2 - 9 times above the upper limit of normal, even with normocalcemia, should lead to consideration of parathyroidectomy. It is important to stress that mild hypercalcemia and/or hyperparathyroidism are common during the first 12 months after renal transplantation, and decisions regarding management should be delayed for 12 months fallowing the return of phosphorus, calcium, and vitamin D homeostasis to normal unless a more severe ‘‘hypercalcemic crisis’’ dictates earlier intervention. In addition, because severe hypophosphatemia can be observed early after renal transplantation, careful replacement and monitoring of the serum phosphorus may be indicated in early hypercalcemia after transplantation.
Surgical strategies can be broadly divided into subtotal or total parathyroidectomy with or without autotransplantation. It is important to remove superior parts of thymus as well.
Another potential treatment option is calcimimetics, such as cinacalcet. Calcimimetics inhibit PTH secretion by modulating the CASR in the parathyroid gland. Although calcimimetics are not approved for treating tertiary hyperparathyroidism, there have been a few small, open-label trials of short duration.
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