Vitamin D, parathyroid hormone, and calcium: a complex regulatory network

In this issue of the Journal, Silverberg et al (1) show that many patients with mild primary hyperparathyroidism also have diminished circulating 25-hydroxyvitamin D levels. The authors believe that the concurrence of vitamin D insufficiency and primary hyperparathyroidism causes a more severe pattern of primary hyperparathyroidism than the mild form of this disease that is usually found in the United States. The study raises many interesting questions about the complex interactions among parathyroid hormone, vitamin D, and calcium. The regulation of serum calcium by the vitamin D–parathyroid hormone axis is now fairly well understood on the cellular and molecular level (2). Vitamin D can be of dietary origin or it can be synthesized in the skin using the energy of sunlight. Dietary vitamin D derived from plant sources is ergosterol (vitamin D2), whereas vitamin D from animal sources is cholecalciferol (vitamin D3). Vitamin D requires two hydroxylations to be converted into its active hormonal form, 1,25-dihydroxyvitamin D3 or calcitriol. The liver is the usual source of 25-hydroxylation, whereas the kidney is the major source of 1-hydroxylation, the final step in the synthesis of the active hormone. Calcitriol then acts as a steroid hormone by activating the nuclear vitamin D receptor to regulate target genes. Among the many genes regulated are those that determine calcium absorption and homeostasis. Therefore vitamin D is essential for normal bone mineralization. Inadequate mineralization leads to rickets in children and osteomalacia in adults. The gene encoding the 1-hydroxylase enzyme has recently been cloned (3,4). Deficiency of this enzyme activity, due to mutations in the gene, results in the disease known as vitamin D dependent rickets-type I, or pseudovitamin D deficiency rickets (4,5). On the other hand, mutations in the vitamin D receptor cause resistance to the action of calcitriol, thus leading to vitamin D dependent rickets-type II, or hereditary vitamin D-resistant rickets (6). Besides the kidney, the 1-hydroxylase enzyme is also present in several vitamin D target cells including monocytes, keratinocytes, osteoblasts, prostate epithelial cells, and other tissues in which the production and action of calcitriol is most likely autocrine or paracrine in nature (7). However, when there are increased numbers of cells containing the 1-hydroxylase enzyme, as in granulomatous diseases, sarcoid, Hodgkin’s disease, or lymphocytic leukemia, there may be increased conversion of 25-hydroxyvitamin D to calcitriol, resulting in the development of hypercalcemia (8). More commonly, patients with renal failure have decreased 1-hydroxylase activity and require supplementation with calcitriol (9). The loss of renal 1-hydroxylase cannot be compensated for by normal local production of calcitriol. The interactions of parathyroid hormone and vitamin D are shown in the accompanying Figure. Parathyroid hormone is the major regulator of renal 1-hydroxylase. In the presence of hypocalcemia, the decreased calcium is sensed in the parathyroid glands by the calcium-sensing receptor (10). Parathyroid hormone secretion is increased and acts to restore calcium to normal by its effects on bone and kidney. It also stimulates renal 1-hydroxylase, thereby accelerating the conversion of 25-hydroxyvitamin D to calcitriol; the latter acts on intestinal calcium absorption as well as in conjunction with parathyroid hormone on bone and kidney to restore calcium levels to normal. Parathyroid hormone secretion is returned to normal by the restoration of normocalcemia and also by the direct suppressive and antiproliferative effects of calcitriol on the parathyroid glands. Vitamin D receptors are present in the parathyroid glands and act as sensors for the detection of adequate levels of calcitriol, thus regulating parathyroid hormone synthesis and release (11). The study by Silverberg et al (1) demonstrates the coexistence of vitamin D insufficiency in many patients with primary hyperparathyroidism and brings up a number of interesting questions regarding the concurrence of these two diseases. The first question is whether primary hyperparathyroidism causes the 25-hydroxyvitamin D insufficiency by consumption of 25-hydroxyvitamin D and increased production of calcitriol. Silverberg et al argue that is not the case. Although it is true that elevated parathyroid hormone levels cause increased 1-hydroxylase activity and augmented conversion of 25-hydroxyvitamin D to calcitriol, there was no association between low 25-hydroxyvitamin D levels and high calcitriol levels, as would be expected if consumption of 25-hydroxyvitamin D were the cause of vitamin D insufficiency. A second question is whether the insufficient 25-hydroxyvitamin D causes secondary hyperparathyroidism and whether such patients do not actually have primary hyperparathyroidism. It is clear that 25-hydroxyvitamin Am J. Med. 1999;107:637– 639. From the Endocrinology Division, Stanford University School of Medicine, Stanford, California. Correspondence should be addressed to David Feldman, MD, Endocrinology Division, Stanford University School of Medicine, Room S-005, Medical Center, Stanford, California 9435-5103.