Severe hypercalcemia (>11.5 mg/dL)
Calciphylaxis
Persistent hypercalcemia more than 3–12 months post transplant
Persistent hypercalciuria or phosphate wasting
Fractures, bone pain, or rapid bone loss
Nephrocalcinosis
Pruritis
PTH gland size > 500 mg (by ultrasound)
Severe fatigue
Peptic ulcer disease
Mental status changes
Nephrolithiasis
Severe myopathy
The timing of the treatment of posttransplant tertiary hyperparathyroidism is controversial. PTH levels fall most acutely during the 3 months following transplant, and may continue to fall more slowly for up to a year [33]. However, there is some evidence that prolonged hyperparathyroidism and hypercalcemia may have an adverse effect on allograft function [32, 34]. Therefore, in the setting of mild to moderate posttransplant elevations in serum calcium, most authors recommend waiting 6–12 months before making the diagnosis of tertiary hyperparathyroidism and proceeding with parathyroidectomy [31].
Just as there is no widespread agreement on patient selection or the timing of parathyroidectomy, consensus on the specific type of operation is also lacking. Total parathyroidectomy with autotransplantation of a small amount of parathyroid tissue into the forearm was the operation of choice for decades. The advantages of this approach include a high degree of success in resolving hyperparathyroidism and an easily accessible parathyroid remnant should hyperparathyroidism recur. However, this operation can be complicated by the development of hypoparathyroidism and hypocalcemia [35], along with variations in the viability of the transplanted tissue. At the other end of this surgical spectrum is a subtotal or limited parathyroidectomy. This approach is successful in the primary goal of treating hypercalcemia, but in one report was associated with a fivefold increase in persistent or recurrent hyperparathyroidism [36]. More recently, near-total (3½ gland) parathyroidectomy has been gaining acceptance as the procedure of choice in patients who require surgery for tertiary hyperparathyroidism [7, 31, 37, 38]. Although evidence remains limited, this “middle ground” attempts to balance the need for a major reduction in parathyroid tissue mass with the goal of avoiding postoperative complications including permanent hypoparathyroidism [30].
Medical Treatment
The approval of the calcium-sensitizing agent cinacalcet in the United States in 2004 provided a medical option for the treatment of patients with hyperparathyroidism as a result of end-stage renal disease . Cinacalcet acts as calcium receptor agonist, resulting in decreased PTH secretion. The most common use of cinacalcet in end-stage renal disease is in the treatment of secondary hyperparathyroidism, with the goal of reducing elevated PTH levels and preventing the development of tertiary hyperparathyroidism. However, cinacalcet has also been used in the treatment of patients with tertiary disease. Two studies published in 2005 [39, 40] reported the effects of cinacalcet on patients with tertiary hyperparathyroidism. In both studies, calcium levels fell into the normal range. In Serra’s trial of 11 patients studied for 10 weeks, PTH levels decreased by 21 %, phosphate levels rose but stayed in the normal range, and renal function remained stable. In Kruse’s study of 14 patients treated for 3 months, calcium levels normalized in 12, but changes in PTH and phosphate levels were not statistically significant. Renal function slightly declined from 1.58 mg/dL at baseline to 1.67 mg/dL after 3 months.
Yang retrospectively compared patients with tertiary hyperparathyroidism who were either observed, treated with cinacalcet , or who underwent parathyroidectomy [32]. Not surprisingly, the patients treated with parathyroidectomy had higher calcium levels and a shorter time before surgery than the patients who were started on cinacalcet . Parathyroidectomy reduced calcium levels compared to observed patients, but the differences were smaller when parathyroidectomy and cinacalcet treatment were compared. Renal function remained stable in all three groups. Somnay retrospectively examined the effects of parathyroidectomy on patients who were receiving cinacalcet at the time of their surgeries [41]. Patients who were treated with cinacalcet had a higher incidence of hungry bone syndrome compared to untreated patients undergoing parathyroidectomy, but cure rates were equivalent and no other cinacalcet-related complications were reported. The authors note that the increased incidence of hungry bone syndrome in the cinacalcet-treated patients may have been a consequence of prolonged duration of their tertiary hyperparathyroidism prior to surgery. Overall, cinacalcet treatment appears to be a reasonable choice in patients with mild tertiary hyperparathyroidism who do not wish to proceed with parathyroidectomy or who are not good operative candidates.
Summary
Tertiary hyperparathyroidism occurs in the setting of longstanding secondary hyperparathyroidism and represents the development of autonomous PTH secretion after prolonged parathyroid gland stimulation. While any cause of secondary hyperparathyroidism may progress to tertiary disease, it is most commonly seen in patients who have had renal transplants. Calcium levels in this group of patients typically fall over the first year following transplantation. However, persistent hypercalcemia and the development of related symptoms and signs (Table 8.1) are indications for parathyroidectomy. Near-total parathyroidectomy appears to be the procedure of choice, balancing the risks of postoperative hypoparathyroidism and disease recurrence. Cinacalcet therapy is another treatment option for patients who may not be candidates for parathyroidectomy.
Society Guidelines
Lorenz K, Bartsch DK, Sancho JJ, Guigard S, Triponez F. Surgical management of secondary hyperparathyroidism in chronic kidney disease—a consensus report of the European Society of Endocrine Surgeons. Langenbecks Arch Surg. 2015.
Best Practices
Pitt SC, Sippel RS, Chen H. Secondary and tertiary hyperparathyroidism, state of the art surgical management. Surg Clin North Am. 2009;89(5):1227–39.
Expert Opinion
The diagnosis and treatment of tertiary hyperparathyroidism remain areas of active research. However, emphasis on the management of secondary hyperparathyroidism in the setting of end-stage renal disease is critically important in preventing the development of tertiary disease. Advances in both medical and surgical therapy have the potential to reduce the incidence and sequela of this disorder.
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