Summary
Overproduction of the active metabolite of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D) has been described in sarcoidosis and other granulomatous diseases. High circulating concentrations of 1,25(OH)2D lead to increased intestinal absorption of calcium, possibly to enhanced bone resorption, and may result in hypercalcaemia and/or hypercalciuria. Data obtained in vivo and in vitro demonstrated that the unregulated production of 1,25(OH)2D lies within the granulomatous tissue and is controlled by glucocorticoids. This abnormal production of 1,25(OH)2D seems to be a general phenomenon of granulomatous processes, which is not exceptional in sarcoidosis, but appears seldom in tuberculosis. These abnormalities, however, are not pathognomonic of granulomatous processes, since they have been described in other diseases such as lymphomas.
Similar content being viewed by others
References
Harrel, G.T., Fisher, S. Blood chemical changes in Boeck's sarcoid with particular reference to protein, calcium and phosphatase values. J Clin Invest, 1939, 18, 687–693.
Anderson, J., Harper, C., Dent, C.E., Philpot, G.R. Effect of cortisone on calcium metabolism in sarcoidosis with hypercalcaemia. Possibly antagonistic actions of cortisone and vitamin D. Lancet, 1954, ii: 720–724.
Winnacker, J.L., Becker, K.L., Katz, S. Endocrine aspects of sarcoidosis. N Engl J Med, 1968, 278, 427–434.
Shai, F., Baker, R.K., Addrizzo, J.R., Wallach, S. Hypercalcemia in mycobacterial infection. J Clin Endocrinol Metab, 1972, 34, 251–256.
Braman, S.S., Goldman, A.L., Schwartz, M.I. Steroid responsive hypercalcemia in disseminated bone tuberculosis. Arch Intern Med, 1973, 132, 269–271.
Bradley, G.W., Sterling, G.M. Hypercalcemia and hypokalemia in tuberculosis. Thorax, 1978, 33, 64–467.
Ryzen, E., Singer, F.R. Hypercalcemia in leprosy. Arch Intern Med, 1985, 145, 1305–1306.
Hoffman, V.N., Korzeniowski, O.M. Leprosy, hypercalcaemia, and elevated serum calcitriol levels. Ann Intern Med, 1986, 105, 890–891.
Lee, J.C., Catanzaro, A., Parthemore, J.G., Roach, B., Deftos, L.J. Hypercalcaemia in disseminated coccidioidomycosis. N Engl J Med, 1977, 297, 431–433.
Walter, R.M., Lawrence, R.M. Total ionized serum calcium and parathyroid hormone levels in patients with disseminated coccidioidomycosis. Am J Med Sci, 1981, 281, 97–99.
Walker, J.V., Baran, D., Yakub, Y.N., Freeman, R.B., Histoplasmosis with hypercalcaemic renal failure, and papillary necrosis. Confusion with sarcoidosis. JAMA, 1977, 237, 1350–1352.
Murray, J.J., Heim, C.R. Hypercalcemia in disseminated histoplasmosis. Aggravation by vitamin D. Am J Med, 1985, 78, 881–884.
Kantarjian, H.M., Saad, M.F., Estey, E.M., Sellin, R.V., Samaan, N.A. Hypercalcemia and disseminated candidiasis. Am J Med, 1982, 74, 721–724.
Jurney, T.H. Hypercalcaemia in a patient with eosinophilic granuloma. Am J Med, 1984, 76, 527–528.
Hellikson, M.A., Havey, A.D., Zerwekh, J.E., Breslau, N.A., Gardner, D.W. Plasma-cell granuloma producing calcitriol and hypercalcaemia. Ann Intern Med, 1986, 105, 379–381.
Stoeckle, J.D., Hardy, H.L., Weber, A.L. Chronic beryllium disease. Am J Med, 1969, 46, 545–561.
Kozeny, G.A., Barbato, A.L., Bansal, V.K., Vertuno, L.L., Hano J.E. Hypercalcemia associated with silicone-induced granulomas. N Engl J Med, 1984, 311, 1103–1105.
Henneman, P.H., Dempsey, E.F., Carroll, E.L., Albright, F. The cause of hypercalciuria in sarcoid and its treatment with cortisone and sodium phytate. J Clin Invest, 1956, 35, 1229–1242.
Bell, N.H., Gill, J.R., Bartter, F.C. On the abnormal calcium absorption in sarcoidosis. Am J Med, 1964, 36, 500–513.
Papapoulos, S.E., Fraher, L.J., Sandler, L.M., Clemens, T.L., Lewin, I.G., O'Riordan, J.L.H. 1,25-dihydroxycholecalciferol in the pathogenesis of the hypercalcaemia of sarcoidosis. Lancet, 1979, ii, 627–630.
Bell, N.H., Stern, P.H., Pantzer, E., Sinha, T.K., De Luca, H.F. Evidence that increased circulating 1 alpha, 25-dihydroxyvitamin D is the probable cause for abnormal calcium metabolism in sarcoidosis. J Clin Invest, 1979, 64, 218–225.
Fraser, D.R., Kodicek, E. Unique biosynthesis by kidney of a biologically active vitamin D metabolite. Nature, 1979, 228, 764–766.
Fuss, M., Bergans, A., Gillet, C., Karmali, R., Pepersack, T., Bagon, J., Mandart, G., Corvilain J, Calcium metabolism disturbances in sarcoidosis. Acta Clin Belg, 1987, 42, 421–430.
Nosal, A., Schleissner, L.A., Mishkin, F.S., Lieberman, J. Angiotensin-I-converting enzyme and gallium scan in non-invasive evaluation of sarcoidosis. Ann Intern Med, 1979, 90, 328–331.
Katz, P., Fauci, A.S., Yeager, H. Jr., Reen, B.M. Serum angiotensin-converting enzyme and lysosyme in granulomatous diseases of unknown cause. Ann Intern Med, 1981, 94, 359–361.
Fuss, M., Bergans, A., Steppe, C., Dupont, E., Brauman, H., Corvilain, J. Effect of renal transplantation on serum 1,25 dihydroxyvitamine D3. In: Vitamin D, Chemical, Biochemical and Clinical Endorinology of Calcium Metabolism. Eds.: Norman A.W., Schaefer, K., von Herrath, D., Grigoleit, H.G., Berlin, New York, Walter de Gruyter & Co, 1982, 561–563.
Dent, C.E. Cortisone test for hyperparathyroidism. Br Med J, 1956, 1, 230–234.
Taylor, R.L., Lynch, H.J. Seasonal influence of sunlight on the hypercalcemia of sarcoidosis. Am J Med, 1963, 34, 221–227.
Phillips, R.W., Kirkpatrick, D.P. Steroid therapy of hypercalcaemia and renal insufficiency in sarcoidosis. N Engl J Med, 1956, 254, 1216–1222.
Scholz, D.A. Effect of steroid therapy on hypercalcaemia and renal insufficiency in sarcoidosis. JAMA, 1964, 169, 682–687.
Romer, F.K. Renal manifestations and abnormal calcium metabolism in sarcoidosis. Q J Med, 1980, 195, 233–247.
Zerwekh, J.E., Pak, C.Y.C., Kaplan, R.A., MacGuire, J.L., Upchurch, K., Breslau, N., Johnson, R. jr. Pathogenetic role of 1 alpha, 25-dihydroxyvitamin D in sarcoidosis and absorptive hypercalciuria: different response to prednisolone therapy. J Clin Endocrinol Metab, 1980, 51, 381–386.
Sandler, L.M., Winearls, C.G., Fraher, L.J., Clemens, T.L., Smith, R., O'Riordan, J.L.H. Studies of the hypercalcaemia of sarcoidosis: effect of steroids and exogenous vitamin D3 on the circulating concentrations of 1,25-dihydroxyvitamin D3. Q J Med, 1984, 210, 165–180.
Insogna, K.L., Dreyer, B.E., Mitnick, M., Ellison, A.F., Broadus, A.E. Enhanced production rate of 1,25-dihydroxyvitamin D in sarcoidosis. J Clin Endocrinol Metab, 1988, 66, 72–75.
Zimmerman, J., Holick, M.F., Silver, J. Normocalcaemia in a hypoparathyroid patient with sarcoidosis: evidence for parathyroid hormone-independent synthesis of 1,25 dihydroxyvitamin D. Ann Intern Med, 1983, 98, 338.
Mitchell, Th., Stamp, T.C.B., Jenkins, M.V., Mawer, E.B., Berry, J.L. Hypercalcaemic sarcoidosis in hypoparathyroidism. Br Med J, 1983, 286, 764–765.
Maesaka, J.K., Batuman, V., Pablo, M.C., Shakamuri, S. Elevated 1,25-dihydroxyvitamin D levels. Occurrence with sarcoidosis with end-stage renal disease. Arch Intern Med, 1982, 142, 1206–1207.
Koide, Y., Kugal, N., Kimura, S., Fujita, T., Yamashita, N., Hiramoto, T., Sukegawa, J., Ogata, E., Yamashita, K. Increased 1,25-dihydroxycholecalciferol as a cause of abnormal calcium metabolism in sarcoidosis. J Clin Endocrinol Metab, 1981, 52, 494–498.
Barbour, G.L., Coburn, J.W., Slatopolsky, E., Norman, A.W., Horst, R.L. Hypercalcaemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D: N Engl J Med, 1981, 305, 440–443.
Korkor, A., Gray, R., Lemann, J. Jr. Further evidence for extrarenal synthesis of 1,25(OH)2 vitamin D in sarcoidosis. Kidney Int, 1985, 27, 119.
Mason, R.S., Frankel, T., Chan, Y-L., Lissner, D., Posen, S. Vitamin D conversion by sarcoid lymph node homogenate. Ann Intern Med, 1984, 100, 59–61.
Adams, J.S., Sharma, O.P., Gacad, M.A., Singer, F.R. Metabolism of 25-hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis. J Clin Invest, 1983, 72, 1856–1860.
Fraher, L.J., Sandler, L.M., Karmali, R., Barker, S., Flint, K.C., Hudspith, B.N., Johnson, N.M., O'Riordan, J.L.H. The control of production of 1,25-dihydroxyvitamine D3 in men: studies of vitamin D deficiency and sarcoidosis. In: Vitamin D. A Chemical, Biochemical and Clinical Update. Eds: Norman A.W., Schaefer, K., Grigoleit H.G., von Herrath D. Berlin, New York, Walter de Gruyter & Co, 1985, 1064–1073.
Adams, J.S., Singer, F.R., Gacad, M.A., Sharma, O.P., Hayes, M.J., Vouros, P., Holick, M.F. Isolation and structural identification of 1,25-dihydroxyvitamin D3 produced by cultured alveolar macrophages in sarcoidosis. J Clin endocrinol Metab, 1985, 60, 960–966.
Adams, J.S., Gacad, M.A. Characterization of 1, alpha-hydroxylation of vitamin D3 sterols by cultured alveolar macrophages on patients with sarcoidosis. J Exp Med, 1985, 161, 755–765.
Reichel, H., Koeffler, H.P., Norman, A.W. Synthesis in vitro of 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 by interferon-gamma-stimulated normal human bone marrow and alveolar macrophages. J Biol Chem, 1987, 262, 10931–10935.
Rigby, W.F.C., Denome, S., Fanger, M.W. Regulation of lymphokine production and human T lymphocyte activation by 1,25-dihydroxyvitamin D3. J Clin Invest, 1987, 1659–1664.
Reiner, M., Sigurdsson, G., Nunziata, V., Malik, M.A., Poole, G.W., Joplin, G.F. Abnormal calcium metabolism in normocalcemic sarcoidosis. Br Med J, 1976, 2, 1473–1476.
Breslau, N.A., Zerwekh, J.E., Nicar, M.J., Pak, C.Y.C. Effects of short term glucocorticoid administration in primary hyperparathyroidism: comparison to sarcoidosis. J Clin Endocrinol Metab, 1982, 54, 824–830.
Jackson, W.P.V., Doncaster, C.D. A consideration of the hypercalcaemia in sarcoidosis, idiopathic hypercalciuria, and that produced by vitamin D. J Clin Endocrinol Metab, 1959, 19, 658–680.
Bell, N.H., Bartter, F.C. Studies of47Ca metabolism in sarcoidosis: evidence for increased sensitivity of bone to vitamin D. Acta Endocrinol, 1967, 54, 173–180.
Dwarakanathan, A., Ryan, W.G. Hypercalcaemia of sarcoidosis treated with cellulose sodium phosphate. Bone Mineral, 1987, 2, 333–336.
Fallon, M.D., Perry, H.M., Teitelbaum, S.L. Skeletal sarcoidosis with osteopenia. Metab Bone Dis Relat Res, 1981, 3, 171–174.
Alexandre, C., Chappard, D., Vergnon, J.M., Emonot, A., Riffat, J. L'os dans la sarcoidose. Rev Rhum Mal Osteoartic, 1987, 54, 159–162.
Dent, C.E., Flynn, F.V., Nabarro, J.D.N. Hypercalcaemia and impairement of renal function in generalized sarcoidosis. Br Med J, 1953, ii, 808–810.
Scholz, D.A., Keating, R.F. Renal insufficiency, renal calculi and nephrocalcinosis in sarcoidosis. Am J Med, 1956, 21, 75–84.
Goldstein, R.A., Israel, H.L., Becker, K.L., More, C.F. The infrequency of hypercalcalcaemia in sarcoidosis. Am J Med, 1971, 51, 21–30.
Adams, J.S., Gacad, M.A., Singer, F.R., Sharma, O.P. Production of 1,25-dihydroxyvitamin D3 by pulmonary alveolar macrophages from patients with sarcoidosis. Ann N Y Acad Sci, 1986, 465, 585–594.
Sharma, O.P., Lamon, J., Winsor, D. Hypercalcaemia and tuberculosis. JAMA, 1972, 222, 582.
Abbasi, A.A., Chemplavil, J.K., Farah, S., Muller, B.F., Arnstein, R. Hypercalcaemia in active pulmonary tuberculosis. Ann Intern Med, 1979, 90, 324–328.
Need, A.G., Philips, P.J., Chiu, F.T.S., Prisk, H.M. Hypercalcaemia associated with tuberculosis. Br Med J, 1980, 280, 831.
Kitrou, M.P., Phytou-Pallikari, A., Tzannes, S.E., Virvidakis, K., Mountokalakis, T.D., Serum calcium during chemotherapy for active pulmonary tuberculosis. Eur J Respir Dis, 1983, 64, 347–354.
Gnokos, P.J., London, R., Hendler, E.D. Hypercalcaemia and elevated 1,25-dihydroxyvitamin D levels in a patient with end-stage renal disease in active tuberculosis. N Engl J Med, 1984, 311, 1683–1685.
Bell, N.H., Shary, J., Shaw, S., Turnere, R.T. Hypercalcaemia associated with increased circulating 1,25 dihydroxyvitamin D in a patient with pulmonary tuberculosis. Calcif Tissue Int 1985, 37, 588–591.
Isaacs, R.D., Nicholson, G.I., Holdaway, I.M. Miliary tuberculosis with hypercalcaemia and raised vitamin D concentrations. Thorax, 1987, 42, 555–556.
Peces, R., Alvarez, J. Hypercalcaemia and elevated 1,25(OH)2D3 levels in a dialysis patient with disseminated tuberculosis. Nephron, 1987, 46, 377–379.
Felsenfeld, A.J., Drezner, M.K., Llach, F. Hypercalcaemia and elevated calcitriol in a maintenance dialysis patient with tuberculosis. Arch Intern Med, 1986, 146, 1941–1945.
Cadranel, J., Hance, A.J., Minneron, B., Paillard, F., Akoun, J.M., Garabedian, M. Vitamin D metabolism in tuberculosis. Production of 1,25(OH)2D3 by cells recovered by bronchoalveolar lavage and the role of this metabolite in calcium homeostasis. Am Rev Respir Dis, 1988, 138, 984–989.
Adams, J.S., Modlin, R.L., Diz, M.M., Barnes, P.F. Potentiation of the macrophage 25-hydroxyvitamin D-1-hydroxylation reaction by human tuberculous pleural effusion fluid. J Clin Endocrinol Metab, 1989, 69, 457–460.
Fuss, M., Karmali, R., Pepersack, T., Bergans, A., Dierckx, P., Prigogine, T., Bergmann, P., Corvilain, J. Are tuberculous patients at risk from hypercalcaemia. Q J Med, 1988, 259, 869–878.
Fuss, M., Verbeelen, D., Geurts, J., Simon, J., Bergans, A., De Backer, M., Six, R., Corvilain, J. The use of a test for the differential diagnosis of hypercalciuria. Eur Urol, 1978, 4, 324–329.
Davies, P.D.O., Brown, R.C., Woodhead, J.S. Serum concentrations of vitamin D metabolism. Clin Parmacol Ther, 1982, 32, 525–530.
Brodie, M.J., Boobis, A.R., Hillyard, C.J., Abeyasekera, G., Stevenson, J.C., MacIntyre, I., Park, B.K. Effect of rifampicin and isoniazid on vitamin D metabolism. Clin Parmacol Ther, 1982, 32, 525–530.
Brodie, M.J., Boobis, A.R., Hillyard, C.J., Abeyasekera, G., MacIntyre, I., Park, B.K. Effect of isoniazid on vitamin D metabolism and hepatic monooxygenase activity. Clin Pharmacol Ther, 1981, 30, 363–367.
Singhellakis, P.N., Kitrou, M.P., Alevizaki, C.C., Gonis, A.L., Tzannes, S.E., Virvidakis, C.E., Mountokalakis, T.D., Ikkos, D.G. Intestinal calcium absorption in patients with active pulmonary tuberculosis. Acta Endocrinol, 1983, 261, 36–37.
Kaminsky, J., Davidson, D.L. Serum calcium in pulmonary tuberculosis. Am Rev Tubercul, 1931, 23, 422–428.
Sharma, S.C. Serum calcium in pulmonary tuberculosis. Postgrad Med J, 1981, 57, 694–696.
Epstein, S., Stern, P.H., Bell, N.H., Dowdeswell, I., Turner, R.T. Evidence for abnormal regulation of circulating 1 alpha, 25-dihydoxyvitamin D in patients with pulmonary tuberculosis and normal cal calcium metabolism. Calcif Tissue Int, 1984, 36, 541–544.
Gwinup, G., Randazzo, G., Elias, A. The influence of vitamin D intake on serum calcium in tuberculosis. Acta Endocrinol, 1981, 97, 114–117.
Ralston, S.H., Cowan, R.A., Robertson, A.G., Gardner, M.D., Boyle, I.A. Circulating vitamin D metabolites and hypercalcaemia of malignancy. Acta Endocrinol, 1984, 106, 556–563.
Breslau, N.A., McGuire, J.L., Zerwekh, J.E., Frenkel, E.P., Pak, C.Y.C. Hypercalcemia associated with increased serum 1,25 dihydroxyvitamin D in 3 patients with lymphoma. Ann Intern Med, 1984, 100, 1–4.
Rosenthal, N., Insonga, K.L., Godsall, J.W., Smaldone, L., Waldron, J.A., Stewart, A.F. Elevations in circulating 1,25-dihydroxyvitamin D in 3 patients with lymphoma-associated hypercalcaemia. J Clin Endocrinol Metab, 1985, 60, 29–33.
Zaloga, J.P., Eil, C., Medbery, C.A. Humoral hypercalcaemia in Hodgkin's disease: association with elevated 1,25 dihydroxycholecalciferol levels and subperiosteal bone resorption. Arch Intern Med, 1985, 145, 155–157.
Davies, M., Hayes, M.E., Mawer, E.B., Lumb, J.A. Abnormal vitamin D3 metabolism in Hodgkin's lymphoma. Lancet, 1985b, i, 1186–1188.
Lambrecht, L., Boelaert, J., Louwagie, A., Criel, A., Daneels, R., Bouillon, R. Hypercalcaemia in Hodgkin's disease. Acta Clin Belg, 1986, 41, 37–42.
Mercier, R.J., Thompson, J.M., Harman, J.S., Messerschmidt, J.L. Recurrent hypercalcaemia and elevated 1,25 dihydroxyvitamin D levels in Hodgkin's disease. Am J Med, 1988, 84, 165–168.
Mude, A.H., Van Den Bergh, H., Boshuys, P.G., Breetveld, F.C., Marcus, H.M., Pluym, P.M., Bijvoet, O.L.M., Papapoulos, S.E. Ectopic production of 1,25-dihydroxyvitamin D by B-cell lymphoma as a cause of hypercalcaemia. Cancer, 1987, 59, 1543–1546.
Fetchick, D., Bertolini, D., Sarin, P., Weintraub, S., Mundy, G., Dunn, J. Production of 1,25-dihydroxyvitamin D3 by human T-cells lymphotropic virus-I-transformed lymphocytes. J Clin Invest, 1986, 78, 592–596.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Fuss, M., Pepersack, T., Gillet, C. et al. Calcium and vitamin D metabolism in granulomatous diseases. Clin Rheumatol 11, 28–36 (1992). https://doi.org/10.1007/BF02207080
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02207080