Hypercalcemia in granulomatous diseases
- Naim Maalouf, MD
Naim Maalouf, MD
- Associate Professor of Medicine
- University of Texas Southwestern Medical Center
Hypercalcemia is a relatively common clinical problem. It results when the entry of calcium into the circulation exceeds the excretion of calcium into the urine or deposition in bone. This occurs when there is accelerated bone resorption, excessive gastrointestinal absorption, or decreased renal excretion of calcium. In some disorders, however, more than one mechanism may be involved.
Hypercalcemia has been described in patients with most granulomatous disorders. This topic card will review hypercalcemia associated with granulomatous diseases. Other disorders that lead to hypercalcemia are reviewed separately. (See "Etiology of hypercalcemia" and "Diagnostic approach to hypercalcemia".)
The signs and symptoms of hypercalcemia are similar regardless of the etiology (see "Clinical manifestations of hypercalcemia"). Symptoms and signs of chronic hypercalcemia (nephrolithiasis, nephrocalcinosis, renal insufficiency, and polyuria due to reduced responsiveness to antidiuretic hormone) can occur (see "Renal disease in sarcoidosis"). However, many patients with hypercalcemia and granulomatous disease are asymptomatic.
GRANULOMATOUS DISORDERS ASSOCIATED WITH HYPERCALCEMIA
Hypercalcemia has been described in patients with most granulomatous disorders [1-3]. Among them, sarcoidosis [4-10] and tuberculosis [11-15] are probably most common. Other causes include berylliosis , coccidioidomycosis , paracoccidioidomycosis , histoplasmosis [19,20], candidiasis , Crohn's disease [22,23], Langerhans-cell histiocytosis (also called histiocytosis X, and including eosinophilic granuloma) , leprosy [25,26], silicone-induced granulomas [27,28], methacrylate injection , talc granuloma , cat-scratch disease , Wegener's granulomatosis , and Pneumocystis carinii pneumonia .
Sarcoidosis — The mechanism responsible for the abnormal calcium metabolism in granulomatous disease has been most completely evaluated in sarcoidosis. Approximately 30 to 50 percent of patients with this disorder have hypercalciuria, and 10 to 20 percent have hypercalcemia, which is aggravated by exposure to sunlight [1,4,5]. Increased intestinal calcium absorption induced by high serum calcitriol concentrations (1,25-dihydroxyvitamin D, the most active metabolite of vitamin D) is the primary abnormality, although a calcitriol-induced increase in bone resorption may also contribute [6-9].To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Adams JS. Vitamin D metabolite-mediated hypercalcemia. Endocrinol Metab Clin North Am 1989; 18:765.
- Jacobs TP, Bilezikian JP. Clinical review: Rare causes of hypercalcemia. J Clin Endocrinol Metab 2005; 90:6316.
- Tebben PJ, Singh RJ, Kumar R. Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment. Endocr Rev 2016; 37:521.
- Winnacker JL, Becker KL, Katz S. Endocrine aspects of sarcoidosis. N Engl J Med 1968; 278:427.
- Sharma OP. Vitamin D, calcium, and sarcoidosis. Chest 1996; 109:535.
- Adams JS, Sharma OP, Gacad MA, Singer FR. Metabolism of 25-hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis. J Clin Invest 1983; 72:1856.
- Adams JS, Singer FR, Gacad MA, et al. Isolation and structural identification of 1,25-dihydroxyvitamin D3 produced by cultured alveolar macrophages in sarcoidosis. J Clin Endocrinol Metab 1985; 60:960.
- Mason RS, Frankel T, Chan YL, et al. Vitamin D conversion by sarcoid lymph node homogenate. Ann Intern Med 1984; 100:59.
- Insogna KL, Dreyer BE, Mitnick M, et al. Enhanced production rate of 1,25-dihydroxyvitamin D in sarcoidosis. J Clin Endocrinol Metab 1988; 66:72.
- Adams JS, Diz MM, Sharma OP. Effective reduction in the serum 1,25-dihydroxyvitamin D and calcium concentration in sarcoidosis-associated hypercalcemia with short-course chloroquine therapy. Ann Intern Med 1989; 111:437.
- Abbasi AA, Chemplavil JK, Farah S, et al. Hypercalcemia in active pulmonary tuberculosis. Ann Intern Med 1979; 90:324.
- Shai F, Baker RK, Addrizzo JR, Wallach S. Hypercalcemia in mycobacterial infection. J Clin Endocrinol Metab 1972; 34:251.
- Gkonos PJ, London R, Hendler ED. Hypercalcemia and elevated 1,25-dihydroxyvitamin D levels in a patient with end-stage renal disease and active tuberculosis. N Engl J Med 1984; 311:1683.
- Cadranel J, Garabedian M, Milleron B, et al. 1,25(OH)2D2 production by T lymphocytes and alveolar macrophages recovered by lavage from normocalcemic patients with tuberculosis. J Clin Invest 1990; 85:1588.
- Shek CC, Natkunam A, Tsang V, et al. Incidence, causes and mechanism of hypercalcaemia in a hospital population in Hong Kong. Q J Med 1990; 77:1277.
- Stoeckle JD, Hardy HL, Weber AL. Chronic beryllium disease. Long-term follow-up of sixty cases and selective review of the literature. Am J Med 1969; 46:545.
- Lee JC, Catanzaro A, Parthemore JG, et al. Hypercalcemia in disseminated coccidioidomycosis. N Engl J Med 1977; 297:431.
- Silva LC, Ferrari TC. Hypercalcaemia and paracoccidioidomycosis. Trans R Soc Trop Med Hyg 1998; 92:187.
- Murray JJ, Heim CR. Hypercalcemia in disseminated histoplasmosis. Aggravation by vitamin D. Am J Med 1985; 78:881.
- Kamili Qu, Menter A. Atypical presentation of histoplasmosis in a patient with psoriasis and psoriatic arthritis on infliximab therapy. J Drugs Dermatol 2010; 9:57.
- Kantarjian HM, Saad MF, Estey EH, et al. Hypercalcemia in disseminated candidiasis. Am J Med 1983; 74:721.
- Bosch X. Hypercalcemia due to endogenous overproduction of 1,25-dihydroxyvitamin D in Crohn's disease. Gastroenterology 1998; 114:1061.
- Tuohy KA, Steinman TI. Hypercalcemia due to excess 1,25-dihydroxyvitamin D in Crohn's disease. Am J Kidney Dis 2005; 45:e3.
- Jurney TH. Hypercalcemia in a patient with eosinophilic granuloma. Am J Med 1984; 76:527.
- Ryzen E, Singer FR. Hypercalcemia in leprosy. Arch Intern Med 1985; 145:1305.
- Hoffman VN, Korzeniowski OM. Leprosy, hypercalcemia, and elevated serum calcitriol levels. Ann Intern Med 1986; 105:890.
- Kozeny GA, Barbato AL, Bansal VK, et al. Hypercalcemia associated with silicone-induced granulomas. N Engl J Med 1984; 311:1103.
- Schanz J, Flux K, Kircher C, et al. Mirror, mirror on the wall: hypercalcemia as a consequence of modern cosmetic treatment with liquid silicone. Med Sci Monit 2012; 18:CS5.
- Negri AL, Rosa Diez G, Del Valle E, et al. Hypercalcemia secondary to granulomatous disease caused by the injection of methacrylate: a case series. Clin Cases Miner Bone Metab 2014; 11:44.
- Woywodt A, Schneider W, Goebel U, Luft FC. Hypercalcemia due to talc granulomatosis. Chest 2000; 117:1195.
- Bosch X. Hypercalcemia due to endogenous overproduction of active vitamin D in identical twins with cat-scratch disease. JAMA 1998; 279:532.
- Edelson GW, Talpos GB, Bone HG 3rd. Hypercalcemia associated with Wegener's granulomatosis and hyperparathyroidism: etiology and management. Am J Nephrol 1993; 13:275.
- Ahmed B, Jaspan JB. Case report: hypercalcemia in a patient with AIDS and Pneumocystis carinii pneumonia. Am J Med Sci 1993; 306:313.
- Inui N, Murayama A, Sasaki S, et al. Correlation between 25-hydroxyvitamin D3 1 alpha-hydroxylase gene expression in alveolar macrophages and the activity of sarcoidosis. Am J Med 2001; 110:687.
- Dusso AS, Kamimura S, Gallieni M, et al. gamma-Interferon-induced resistance to 1,25-(OH)2 D3 in human monocytes and macrophages: a mechanism for the hypercalcemia of various granulomatoses. J Clin Endocrinol Metab 1997; 82:2222.
- Basile JN, Liel Y, Shary J, Bell NH. Increased calcium intake does not suppress circulating 1,25-dihydroxyvitamin D in normocalcemic patients with sarcoidosis. J Clin Invest 1993; 91:1396.
- Zeimer HJ, Greenaway TM, Slavin J, et al. Parathyroid-hormone-related protein in sarcoidosis. Am J Pathol 1998; 152:17.
- Kuno Y, Iyoda M, Aoshima Y, et al. A case of tuberculous peritonitis in a hemodialysis patient with high serum soluble interleukin-2 receptor and CA-125 levels. Intern Med 2010; 49:1783.
- Martinez ME, Gonzalez J, Sanchez-Cabezudo MJ, et al. Evidence of absorptive hypercalciuria in tuberculosis patients. Calcif Tissue Int 1993; 53:384.
- Tan TT, Lee BC, Khalid BA. Low incidence of hypercalcaemia in tuberculosis in Malaysia. J Trop Med Hyg 1993; 96:349.
- Keleştimur F, Güven M, Ozesmi M, Paşaoğlu H. Does tuberculosis really cause hypercalcemia? J Endocrinol Invest 1996; 19:678.
- Chan TY. Differences in vitamin D status and calcium intake: possible explanations for the regional variations in the prevalence of hypercalcemia in tuberculosis. Calcif Tissue Int 1997; 60:91.
- Caldwell JW, Arsura EL, Kilgore WB, et al. Hypercalcemia in patients with disseminated coccidioidomycosis. Am J Med Sci 2004; 327:15.
- Kogan BA, Konnak JW, Lau K. Marked hyperoxaluria in sarcoidosis during orthophosphate therapy. J Urol 1982; 127:339.
- Seymour JF, Gagel RF. Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin's disease and non-Hodgkin's lymphomas. Blood 1993; 82:1383.
- Sandler LM, Winearls CG, Fraher LJ, et al. Studies of the hypercalcaemia of sarcoidosis: effect of steroids and exogenous vitamin D3 on the circulating concentrations of 1,25-dihydroxy vitamin D3. Q J Med 1984; 53:165.
- Conron M, Beynon HL. Ketoconazole for the treatment of refractory hypercalcemic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2000; 17:277.
- Adams JS, Sharma OP, Diz MM, Endres DB. Ketoconazole decreases the serum 1,25-dihydroxyvitamin D and calcium concentration in sarcoidosis-associated hypercalcemia. J Clin Endocrinol Metab 1990; 70:1090.
- Tercelj M, Rott T, Rylander R. Antifungal treatment in sarcoidosis--a pilot intervention trial. Respir Med 2007; 101:774.
- Doty JD, Mazur JE, Judson MA. Treatment of sarcoidosis with infliximab. Chest 2005; 127:1064.
- Huffstutter JG, Huffstutter JE. Hypercalcemia from sarcoidosis successfully treated with infliximab. Sarcoidosis Vasc Diffuse Lung Dis 2012; 29:51.
- O'Leary TJ, Jones G, Yip A, et al. The effects of chloroquine on serum 1,25-dihydroxyvitamin D and calcium metabolism in sarcoidosis. N Engl J Med 1986; 315:727.
- Barré PE, Gascon-Barré M, Meakins JL, Goltzman D. Hydroxychloroquine treatment of hypercalcemia in a patient with sarcoidosis undergoing hemodialysis. Am J Med 1987; 82:1259.
- Gibbs CJ, Peacock M. Hypercalcaemia due to sarcoidosis corrects with bisphosphonate treatment. Postgrad Med J 1986; 62:937.
- Westphal SA. Disseminated coccidioidomycosis associated with hypercalcemia. Mayo Clin Proc 1998; 73:893.
- Rizwan A, Islam N. Middle aged male with pulmonary tuberculosis and refractory hypercalcemia at a tertiary care centre in South East Asia: a case report. Cases J 2009; 2:6316.