The first documented association of hypercalcemia with sarcoidosis was reported by Harrel and Fisher (
1
) in 1939. Subsequent studies have confirmed this association; recent estimates are that about 10% of patients with sarcoidosis have hypercalcemia. Hypercalciuria is much more common, with an estimated frequency of 30% to 40% (2
).The development of hypercalcemia is frequently associated with progression of renal insufficiency, which can be a consequence of stone disease related to hypercalciuria. With a reduction in glomerular filtration rate, the ability to excrete the increased calcium load imposed by excessive calcium absorption from the gut and calcium mobilization from bone is compromised, leading to elevations of serum calcium levels that may extend into the frankly hypercalcemic range.
Hypercalcemia in sarcoidosis can also be provoked by increased endogenous or dietary vitamin D, and is seen more frequently during the summer months, when sunlight exposure and vitamin D generation in the skin are increased (
2
). Vitamin D is derived either from endogenous production through the interaction of ultraviolet light with vitamin D precursors in the deeper layers of the skin or from consumption of dietary vitamin D. Vitamin D, in the first of two processing events, is metabolized to 25-hydroxyvitamin D in the liver. The latter is subsequently converted to the more polar metabolite, 1,25-dihydroxyvitamin D, in the proximal tubule cells of the kidney. The 1,25-dihydroxyvitamin D binds with high affinity to the intranuclear vitamin D receptor and is the most active vitamin D metabolite. Conversion of 25-hydroxyvitamin D to 1,25-D is controlled by a P450 enzyme called 1α-hydroxylase. This enzyme is tightly regulated in the proximal tubule cell. Parathyroid hormone, calcitonin, and hypophosphatemia increase its activity, while 1,25-dihydroxyvitamin D and hyperphosphatemia suppress its activity.The work of Papapoulos et al (
3
) and Bell et al (4
) were the first to suggest that levels of 1,25-dihydroxyvitamin D are elevated in patients with sarcoidosis. Soon thereafter, Barbour et al (5
) described a sarcoid patient who was hypercalcemic but anephric, implying that the 1,25-dihydroxyvitamin D is derived from an extrarenal source. Subsequent studies localized the source to the granulomatous process itself. Both sarcoid lymph node homogenates (6
) and alveolar macrophages (7
) from sarcoid patients proved capable of generating 1,25-dihydroxyvitamin D from the 25-hydroxyvitamin D precursor. In the case of the macrophage, production was increased markedly after treatment with γ-interferon (7
).Demonstration of the enzymatic activity, however, did not prove that the gene product responsible for generating the 1α-hydroxylase activity in the kidney was responsible for that detected in alveolar macrophages in sarcoidosis. At least initially, there were reasons to think otherwise. Despite similar substrate specificities and kinetic characteristics, renal and macrophage enzyme activity are regulated quite differently: the renal enzyme is activated by parathyroid hormone and calcitonin and suppressed by 1,25-dihydroxyvitamin D. The macrophage enzyme is unaffected by any of these factors. Instead, one of its major trophic activators is the cytokine γ-interferon.
Resolution of this paradox had to await the molecular cloning of the human 1α-hydroxylase gene, which was accomplished in 1997 by Monkawa et al (
8
). The same group identified 1α-hydroxylase gene expression in a human monocytic cell line, THP-1 (9
). Interestingly, although neither parathyroid hormone nor calcitonin proved capable of stimulating 1α-hydroxylase gene expression in these cells, mimicry of their activated effector mechanism with 8-bromo-cAMP resulted in stimulation, as did treatment with γ-interferon. 1,25-dihydroxyvitamin D failed to suppress 1α-hydroxylase gene expression, although it stimulated expression of a second gene product (the 24-hydroxyvitamin D 25-hydroxylase). This study eliminated at least some of the confusion surrounding the differential regulation of 1α-hydroxylase activity in the macrophage and renal tubule. By showing that the gene products were identical, it became apparent that differential regulation would have to be explained by differences in the ligand receptors in the two target cells. That the surrogate second messenger 8-bromo-cAMP proved capable of doing what parathyroid hormone and calcitonin could not supports this hypothesis.The study from Inui et al (
10
) in this issue of The Green Journal extends this paradigm one step further. They demonstrated 1α-hydroxylase gene expression in alveolar macrophages of patients with sarcoidosis and established a correlation between levels of expression and disease activity. This finding forges a critical link between the disease process and activation of the 1α-hydroxylase gene, but a number of important issues remain unresolved. First, the absence of feedback inhibition of 1,25-dihydroxyvitamin D on macrophage 1α-hydroxylase remains paradoxic, particularly in view of the demonstrated presence of functional vitamin D receptors in these cells (9
). This is an important issue to resolve from a clinical standpoint, as failure in this feedback control mechanism is likely to be a major contributor to the development of hypercalcemia in sarcoid patients. Second, it remains to be proved that vitamin D toxicity is the sole cause of hypercalcemia in sarcoid or other granulomatous diseases. Levels of 1,25-dihydroxyvitamin D are not uniformly elevated in sarcoid patients with hypercalcemia. The recent demonstration of parathyroid hormone-related protein in lymph node homogenates from patients with sarcoidosis offers a potential alternative explanation for the abnormalities in calcium metabolism (11
). Finally, while support for the link between vitamin D and hypercalcemia is compelling, it has also been largely indirect, such as correlations among disease activity, 1,25-dihydroxyvitamin D levels, 1α-hydroxylase activity, and hypercalcemia. Although ketoconazole and chloroquine effectively control hypercalcemia in some patients with sarcoidosis, putatively through 1α-hydroxylase inhibition, correcting hypercalcemia with more selective vitamin D antagonists has yet to be demonstrated.The results of Invi et al (
10
) also raise important questions regarding the physiologic role of 1,25-dihydroxyvitamin D production in the activated macrophage. This metabolite suppresses proliferation of T lymphocytes and reduces γ-interferon production and interleukin-2 activity (2
). That the alveolar enzyme is activated by γ-interferon suggests that vitamin D may function in an autocrine-paracrine feedback loop to control activation of the local inflammatory process—and raises the possibility that this agent, or perhaps more appropriately one of the newer nonhypercalcemic analogues of 1,25-dihydroxyvitamin D (12
), might prove useful in managing sarcoidosis as well as other granulomatous disease.References
- Blood chemical changes in Boeck’s sarcoid with particular reference to protein, calcium and phosphatase values.J Clin Invest. 1939; 18: 687-693
- Clinical impact of bone and calcium metabolism changes in sarcoidosis.Thorax. 1998; 53: 425-429
- 1,25-Dihydroxycholecalciferol in the pathogenesis of the hypercalcemia of sarcoidosis.Lancet. 1979; 1: 627-630
- Evidence that increased circulating 1,25-dihydroxyvitamin D is the probable cause for abnormal calcium metabolism in sarcoidosis.J Clin Invest. 1979; 64: 218-225
- Hypercalcemia in an anephric patient with sarcoidosis.N Engl J Med. 1981; 305: 440-443
- Vitamin D conversion by sarcoid lymph node homogenata.Ann Intern Med. 1984; 100: 59-61
- Metabolism of 25-hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis.J Clin Invest. 1983; 72: 1856-1860
- Molecular cloning of cDNA and genomic DNA for human 25-hydroxyvitamin D 1α-hydroxylase.Biochem Biophys Res Commun. 1997; 239: 527-533
- Identification of 25-hydroxyvitamin D3 1α-hydroxylase gene expression in macrophages.Kidney Int. 2000; 58: 559-568
Inui N, Murayama A, Sasaki S, et al. Correlation between 25-hydroxyvitamin D3 1α-hydroxylase gene expression in alveolar macrophages and activity of sarcoidosis. Am J Med. 2001;110:687–693.
- Parathyroid-hormone-related protein in sarcoidosis.Am J Pathol. 1998; 152: 17-21
- Growth inhibition of HT-29 human colon cancer cells by analogues of 1,25-dihydroxyvitamin D3.Cancer Res. 1994; 54: 4057-4064
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© 2001 Excerpta Medica Inc. Published by Elsevier Inc. All rights reserved.
