Lymphoma, Hypercalcemia, and the Sunshine Vitamin

Under normal circumstances, parathyroid hormone and 1 α,25-dihydroxycholecalciferol (calcitriol) jointly defend the plasma calcium concentration. Parathyroid hormone increases renal distal tubular calcium reabsorption and mobilizes calcium from bone. Calcitriol, the active product of vitamin D metabolism, enhances gastrointestinal calcium absorption and also mobilizes calcium from bone. The roles of parathyroid hormone and calcitriol in calcium homeostasis are intimately interrelated. Parathyroid hormone is the primary trophic stimulator of renal 1 α-hydroxylase, the enzyme that converts 25-hydroxycholecalciferol into calcitriol. Calcitriol, in turn, inhibits parathyroid hormone secretion by at least two different mechanisms: direct repression of the preproparathyroid hormone gene and inhibition of the synthesis and release of the hormone as an indirect consequence of the increase in the plasma calcium concentration. Thus, parathyroid hormone is a primary regulator of vitamin D metabolism, and calcitriol is a primary feedback inhibitor of parathyroid hormone secretion.

Abnormalities in this elaborate control system underlie most cases of hypercalcemia. The many clinical and laboratory similarities between primary hyperparathyroidism and the hypercalcemia associated with various nonhematologic tumors led to the suspicion that parathyroid hormone was also responsible for so-called “malignancy-associated” hypercalcemia. With the identification, isolation, and cloning of parathyroid hormone-related protein [1-4], this theory has been disproved—at least its classic formulation as an “ectopic parathyroid hormone” syndrome. Nonetheless, it is ironic that parathyroid hormone-related protein, a protein quite distinct in structure from parathyroid hormone (save for partial homology in the 13 amino acid N-terminal region), produces hypercalcemia by masquerading as parathyroid hormone [5].

Little doubt now exists that parathyroid hormone-related protein is an important cause of malignancy-associated hypercalcemia [6-9]. What is less clear is whether other humoral factors act permissively or synergistically with parathyroid hormone-related protein in the genesis of the hypercalcemia. For example, although high circulating levels of this protein have been documented in …