Chapter 22-8: Secondary & Tertiary Hyperparathyroidism

DISEASE HIGHLIGHTS

1. Secondary and tertiary hyperparathyroidism occur in patients with CKD.

2. Secondary hyperparathyroidism is usually associated with hypocalcemia. It is most commonly caused by kidney disease, which causes an underproduction of 1,25,dihydroxy vitamin D which, in turn, causes hypocalcemia and a compensatory increase in PTH. Therapy for the hyperphosphatemia associated with secondary hyperparathyroidism, however, can lead to hypercalcemia.

   1. Hyperphosphatemia develops in patients with CKD as the renal clearance of phosphate falls.

   2. Early in the course of CKD, hypocalcemia, hypovitaminosis D, and hyperphosphatemia lead to (secondary) hyperparathyroidism. The elevated PTH is adaptive, increasing calcium release from bones and enhancing renal phosphate excretion.

   3. As CKD worsens, hyperparathyroidism becomes counterproductive as the kidneys no longer respond to PTH by excreting phosphate while phosphate continues to be released, with calcium, from the bones.

   4. Treatment of hyperphosphatemia in CKD

      1. Calcium carbonate and calcium acetate have been the traditional first-line therapy for hyperphosphatemia in CKD.

         1. Calcium carbonate and calcium acetate are effective phosphate binders, decreasing the gastrointestinal absorption of phosphate.

         2. Calcium-based phosphate binders rarely bring phosphate into the normal range and may cause hypercalcemia.

         3. This hypercalcemia (and hyperphosphatemia) may be exacerbated by exogenous calcitriol, also used to treat secondary hyperparathyroidism.

         4. The combination of high levels of calcium and phosphate have deleterious cardiovascular effects.

      2. Newer therapies offer alternatives for lowering phosphate without leading to hypercalcemia.

         1. Sevelamer is a synthetic phosphate-binding polymer.

         2. The calcium mimetics cinacalcet and etelcalcetide target the calcium-sensing receptor in the parathyroid glands, lowering PTH levels.

         3. Newer vitamin D analogs may be able to lower PTH levels with less of a tendency to cause hypercalcemia and hyperphosphatemia.

3. Tertiary hyperparathyroidism occurs when the parathyroid hyperplasia of secondary hyperparathyroidism becomes so severe that PTH production becomes autonomous, causing hypercalcemia beyond that expected by calcium and calcitriol therapy.

EVIDENCE-BASED DIAGNOSIS

1. In patients with CKD, an elevated calcium level, usually in the setting of calcium-based phosphate binders, and an elevated PTH, is diagnostic of secondary hyperparathyroidism.

2. Tertiary hyperparathyroidism is diagnosed when PTH reaches higher levels and does not respond to calcium supplementation and vitamin D.

TREATMENT

1. The treatment of secondary hyperparathyroidism is very complicated and is predicated on treating the factors that stimulate PTH secretion in CKD: hypocalcemia, hypovitaminosis D, and hyperphosphatemia.

2. Treatment involves phosphate binders, calcium and/or calcimimetics, and vitamin D analogs in an effort to control the levels of PTH, calcium, and phosphate.

3. If tertiary hyperparathyroidism occurs and is symptomatic (based on hypercalcemia, bone disease, metastatic calcifications) parathyroidectomy is often required.