Etiology of hypercalcemia
- Elizabeth Shane, MD
Elizabeth Shane, MD
- Professor of Medicine
- Columbia University 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. As examples, hypervitaminosis D increases both intestinal calcium absorption and bone resorption, and primary hyperparathyroidism increases bone resorption, tubular calcium reabsorption, and renal synthesis of calcitriol (1,25-dihydroxyvitamin D, the most active metabolite of vitamin D), and intestinal calcium absorption.
Among all causes of hypercalcemia, primary hyperparathyroidism and malignancy are the most common, accounting for greater than 90 percent of cases (table 1).
This topic will review the etiology of hypercalcemia. The clinical manifestations, diagnostic approach, and treatment are reviewed separately. (See "Clinical manifestations of hypercalcemia" and "Diagnostic approach to hypercalcemia" and "Treatment of hypercalcemia".)
Primary hyperparathyroidism — Hypercalcemia in primary hyperparathyroidism is due to parathyroid hormone (PTH)-mediated activation of osteoclasts, leading to increased bone resorption. In addition, intestinal calcium absorption is elevated. Primary hyperparathyroidism is most often due to a parathyroid adenoma. Patients typically have only small elevations in serum calcium concentrations (less than 11 mg/dL or 2.75 mmol/L), and many have mostly high-normal values with intermittent hypercalcemia. Thus, when one suspects primary hyperparathyroidism, as with high-normal serum calcium values in a patient with calcium nephrolithiasis, it may be necessary to obtain a series of serum calcium measurements to detect hypercalcemia. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)
Secondary and tertiary hyperparathyroidism — Patients with severe chronic kidney disease and secondary hyperparathyroidism usually have low or normal serum calcium concentrations but, with prolonged disease, may develop hypercalcemia. The rise in plasma calcium most often occurs in patients with adynamic bone disease and markedly reduced bone turnover. In such patients, hypercalcemia is due to a marked reduction in the bone uptake of calcium after a calcium load, as with calcium carbonate to treat hyperphosphatemia . (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Abnormalities in bone turnover, mineralization, volume linear growth, or strength'.)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:
- Meric F, Yap P, Bia MJ. Etiology of hypercalcemia in hemodialysis patients on calcium carbonate therapy. Am J Kidney Dis 1990; 16:459.
- Burman KD, Monchik JM, Earll JM, Wartofsky L. Ionized and total serum calcium and parathyroid hormone in hyperthyroidism. Ann Intern Med 1976; 84:668.
- Iqbal AA, Burgess EH, Gallina DL, et al. Hypercalcemia in hyperthyroidism: patterns of serum calcium, parathyroid hormone, and 1,25-dihydroxyvitamin D3 levels during management of thyrotoxicosis. Endocr Pract 2003; 9:517.
- Alikhan Z, Singh A. Hyperthyroidism manifested as hypercalcemia. South Med J 1996; 89:997.
- Stewart AF, Adler M, Byers CM, et al. Calcium homeostasis in immobilization: an example of resorptive hypercalciuria. N Engl J Med 1982; 306:1136.
- Alborzi F, Leibowitz AB. Immobilization hypercalcemia in critical illness following bariatric surgery. Obes Surg 2002; 12:871.
- Massagli TL, Cardenas DD. Immobilization hypercalcemia treatment with pamidronate disodium after spinal cord injury. Arch Phys Med Rehabil 1999; 80:998.
- Cano-Torres EA, González-Cantú A, Hinojosa-Garza G, Castilleja-Leal F. Immobilization induced hypercalcemia. Clin Cases Miner Bone Metab 2016; 13:46.
- Legha SS, Powell K, Buzdar AU, Blumenschein GR. Tamoxifen-induced hypercalcemia in breast cancer. Cancer 1981; 47:2803.
- Valentin-Opran A, Eilon G, Saez S, Mundy GR. Estrogens and antiestrogens stimulate release of bone resorbing activity by cultured human breast cancer cells. J Clin Invest 1985; 75:726.
- Bhalla K, Ennis DM, Ennis ED. Hypercalcemia caused by iatrogenic hypervitaminosis A. J Am Diet Assoc 2005; 105:119.
- Hammoud D, El Haddad B, Abdallah J. Hypercalcaemia secondary to hypervitaminosis a in a patient with chronic renal failure. West Indian Med J 2014; 63:105.
- Villablanca JG, Khan AA, Avramis VI, Reynolds CP. Hypercalcemia: a dose-limiting toxicity associated with 13-cis-retinoic acid. Am J Pediatr Hematol Oncol 1993; 15:410.
- Niesvizky R, Siegel DS, Busquets X, et al. Hypercalcaemia and increased serum interleukin-6 levels induced by all-trans retinoic acid in patients with multiple myeloma. Br J Haematol 1995; 89:217.
- Akiyama H, Nakamura N, Nagasaka S, et al. Hypercalcaemia due to all-trans retinoic acid. Lancet 1992; 339:308.
- Jacobus CH, Holick MF, Shao Q, et al. Hypervitaminosis D associated with drinking milk. N Engl J Med 1992; 326:1173.
- Scanlon KS, Blank S, Sinks T, et al. Subclinical health effects in a population exposed to excess vitamin D in milk. Am J Public Health 1995; 85:1418.
- Hoeck HC, Laurberg G, Laurberg P. Hypercalcaemic crisis after excessive topical use of a vitamin D derivative. J Intern Med 1994; 235:281.
- Selby PL, Davies M, Marks JS, Mawer EB. Vitamin D intoxication causes hypercalcaemia by increased bone resorption which responds to pamidronate. Clin Endocrinol (Oxf) 1995; 43:531.
- Jacobs TP, Bilezikian JP. Clinical review: Rare causes of hypercalcemia. J Clin Endocrinol Metab 2005; 90:6316.
- Evron E, Goland S, von der Walde J, et al. Idiopathic calcitriol-induced hypercalcemia. A new disease entity? Arch Intern Med 1997; 157:2142.
- Heath DA. Primary hyperparathyroidism. Clinical presentation and factors influencing clinical management. Endocrinol Metab Clin North Am 1989; 18:631.
- Stewart AF, Hoecker JL, Mallette LE, et al. Hypercalcemia in pheochromocytoma. Evidence for a novel mechanism. Ann Intern Med 1985; 102:776.
- Bridgewater JA, Ratcliffe WA, Bundred NJ, Owens CW. Malignant phaeochromocytoma and hypercalcaemia. Postgrad Med J 1993; 69:77.
- Mune T, Katakami H, Kato Y, et al. Production and secretion of parathyroid hormone-related protein in pheochromocytoma: participation of an alpha-adrenergic mechanism. J Clin Endocrinol Metab 1993; 76:757.
- Muls E, Bouillon R, Boelaert J, et al. Etiology of hypercalcemia in a patient with Addison's disease. Calcif Tissue Int 1982; 34:523.
- Montoli A, Colussi G, Minetti L. Hypercalcaemia in Addison's disease: calciotropic hormone profile and bone histology. J Intern Med 1992; 232:535.
- Vasikaran SD, Tallis GA, Braund WJ. Secondary hypoadrenalism presenting with hypercalcaemia. Clin Endocrinol (Oxf) 1994; 41:261.
- Fujikawa M, Kamihira K, Sato K, et al. Elevated bone resorption markers in a patient with hypercalcemia associated with post-partum thyrotoxicosis and hypoadrenocorticism due to pituitary failure. J Endocrinol Invest 2004; 27:782.
- Ahn SW, Kim TY, Lee S, et al. Adrenal insufficiency presenting as hypercalcemia and acute kidney injury. Int Med Case Rep J 2016; 9:223.
- Schipani E, Langman CB, Parfitt AM, et al. Constitutively activated receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansen's metaphyseal chondrodysplasia. N Engl J Med 1996; 335:708.
- Saarela T, Similä S, Koivisto M. Hypercalcemia and nephrocalcinosis in patients with congenital lactase deficiency. J Pediatr 1995; 127:920.
- BONE RESORPTION
- Primary hyperparathyroidism
- Secondary and tertiary hyperparathyroidism
- CALCIUM ABSORPTION
- Increased calcium intake
- - Chronic kidney disease
- - Milk-alkali syndrome
- Hypervitaminosis D
- MISCELLANEOUS CAUSES
- Thiazide diuretics
- Adrenal insufficiency
- Rhabdomyolysis and acute renal failure
- Theophylline toxicity
- Familial hypocalciuric hypercalcemia
- Metaphyseal chondrodysplasia
- Congenital lactase deficiency
- SUMMARY AND RECOMMENDATIONS