INTRODUCTIONThe major factors that influence the serum calcium concentration are parathyroid hormone (PTH), vitamin D, fibroblast growth factor 23 (FGF23), the calcium ion itself [1,2], and phosphate. Low serum calcium concentrations are most often caused by disorders of PTH or vitamin D. Other causes of hypocalcemia include disorders that result in a decrease in serum ionized calcium concentration by binding of calcium within the vascular space or by its deposition in tissues, as can occur with hyperphosphatemia.
The causes of hypocalcemia in adults will be reviewed here. The etiology of hypocalcemia in neonates and children and the clinical manifestations, evaluation, and treatment of hypocalcemia in adults are discussed elsewhere. (See "Etiology of hypocalcemia in infants and children" and "Clinical manifestations of hypocalcemia" and "Diagnostic approach to hypocalcemia" and "Treatment of hypocalcemia".)
CALCIUM HOMEOSTASISSerum calcium concentrations are normally maintained within the very narrow range that is required for the optimal activity of the many extra- and intracellular processes calcium regulates. Calcium in the blood is transported partly bound to plasma proteins (approximately 45 percent), notably albumin; partly bound to small anions such as phosphate and citrate (approximately 15 percent); and partly in the free or ionized state (approximately 40 percent). (See "Relation between total and ionized serum calcium concentrations".)
Although only the ionized calcium is metabolically active (ie, subject to transport into cells), most laboratories report total serum calcium concentrations. Concentrations of total calcium in normal serum generally range between 8.5 and 10.5 mg/dL (2.12 to 2.62 mmol/L), and levels below this are considered to be consistent with hypocalcemia. The normal range of ionized calcium is 4.65 to 5.25 mg/dL (1.16 to 1.31 mmol/L).
Hypoalbuminemia — When protein concentrations (particularly albumin) fluctuate substantially, total calcium levels may vary, whereas the ionized calcium (whose level is hormonally regulated) remains relatively stable. Thus, total serum calcium concentrations may not accurately reflect the physiologically important ionized (or free) calcium concentration. As an example, in volume overload, chronic illness, and malnutrition or nephrotic syndrome (where serum protein can be reduced), total plasma calcium is low but the ionized calcium is normal. This phenomenon is called pseudohypocalcemia.
- Riccardi D, Brown EM. Physiology and pathophysiology of the calcium-sensing receptor in the kidney. Am J Physiol Renal Physiol 2010; 298:F485.
- Vantour L, Goltzman D. Regulation of calcium homeostasis. In: rimer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 9th ed, Bilezikian JP (Ed), Wiley-Blackwell, Hoboken, NJ 2018. p.163.
- Dickerson RN, Alexander KH, Minard G, et al. Accuracy of methods to estimate ionized and "corrected" serum calcium concentrations in critically ill multiple trauma patients receiving specialized nutrition support. JPEN J Parenter Enteral Nutr 2004; 28:133.
- Goltzman D, Cole DEC. Hypoparathyroidism. In: Primer on the Metabolic Bone Diseases and Disorders of Bone Metabolism, 6th ed, Favus MJ (Ed), American Society of Bone and Mineral Research, Washington DC 2006. p.216.
- Fitzpatrick LA, Arnold A. Hypoparathyroidism. In: Endocrinology, 3rd ed, DeGroot LJ (Ed), Saunders, Philadelphia 1995. p.1123.
- Blizzard RM, Chee D, Davis W. The incidence of parathyroid and other antibodies in the sera of patients with idiopathic hypoparathyroidism. Clin Exp Immunol 1966; 1:119.
- Neufeld M, Maclaren NK, Blizzard RM. Two types of autoimmune Addison's disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore) 1981; 60:355.
- Angelopoulos NG, Goula A, Rombopoulos G, et al. Hypoparathyroidism in transfusion-dependent patients with beta-thalassemia. J Bone Miner Metab 2006; 24:138.
- Toumba M, Sergis A, Kanaris C, Skordis N. Endocrine complications in patients with Thalassaemia Major. Pediatr Endocrinol Rev 2007; 5:642.
- Carpenter TO, Carnes DL Jr, Anast CS. Hypoparathyroidism in Wilson's disease. N Engl J Med 1983; 309:873.
- Goddard CJ, Mbewu A, Evanson JM. Symptomatic hypocalcaemia associated with metastatic invasion of the parathyroid glands. Br J Hosp Med 1990; 43:72.
- Hannan FM, Thakker RV. Investigating hypocalcaemia. BMJ 2013; 346:f2213.
- Lee S, Mannstadt M, Guo J, et al. A Homozygous [Cys25]PTH(1-84) Mutation That Impairs PTH/PTHrP Receptor Activation Defines a Novel Form of Hypoparathyroidism. J Bone Miner Res 2015; 30:1803.
- Smallridge RC, Wray HL, Schaaf M. Hypocalcemia with osteoblastic metastases in patient with prostate carcinoma. A cause of secondary hyperparathyroidism. Am J Med 1981; 71:184.
- Murray RM, Grill V, Crinis N, et al. Hypocalcemic and normocalcemic hyperparathyroidism in patients with advanced prostatic cancer. J Clin Endocrinol Metab 2001; 86:4133.
- Dettelbach MA, Deftos LJ, Stewart AF. Intraperitoneal free fatty acids induce severe hypocalcemia in rats: a model for the hypocalcemia of pancreatitis. J Bone Miner Res 1990; 5:1249.
- McKay C, Beastall GH, Imrie CW, Baxter JN. Circulating intact parathyroid hormone levels in acute pancreatitis. Br J Surg 1994; 81:357.
- Zivin JR, Gooley T, Zager RA, Ryan MJ. Hypocalcemia: a pervasive metabolic abnormality in the critically ill. Am J Kidney Dis 2001; 37:689.
- Desai TK, Carlson RW, Geheb MA. Prevalence and clinical implications of hypocalcemia in acutely ill patients in a medical intensive care setting. Am J Med 1988; 84:209.
- Zaloga GP, Chernow B. The multifactorial basis for hypocalcemia during sepsis. Studies of the parathyroid hormone-vitamin D axis. Ann Intern Med 1987; 107:36.
- Sperber SJ, Blevins DD, Francis JB. Hypercalcitoninemia, hypocalcemia, and toxic shock syndrome. Rev Infect Dis 1990; 12:736.
- Lepage R, Légaré G, Racicot C, et al. Hypocalcemia induced during major and minor abdominal surgery in humans. J Clin Endocrinol Metab 1999; 84:2654.
- Cholst IN, Steinberg SF, Tropper PJ, et al. The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects. N Engl J Med 1984; 310:1221.
- van den Bergh WM, van de Water JM, Hoff RG, et al. Calcium homeostasis during magnesium treatment in aneurysmal subarachnoid hemorrhage. Neurocrit Care 2008; 8:413.
- Rutledge R, Sheldon GF, Collins ML. Massive transfusion. Crit Care Clin 1986; 2:791.
- Bolan CD, Cecco SA, Wesley RA, et al. Controlled study of citrate effects and response to i.v. calcium administration during allogeneic peripheral blood progenitor cell donation. Transfusion 2002; 42:935.
- Cairns CB, Niemann JT, Pelikan PC, Sharma J. Ionized hypocalcemia during prolonged cardiac arrest and closed-chest CPR in a canine model. Ann Emerg Med 1991; 20:1178.
- Kido Y, Okamura T, Tomikawa M, et al. Hypocalcemia associated with 5-fluorouracil and low dose leucovorin in patients with advanced colorectal or gastric carcinomas. Cancer 1996; 78:1794.
- Jacobson MA, Gambertoglio JG, Aweeka FT, et al. Foscarnet-induced hypocalcemia and effects of foscarnet on calcium metabolism. J Clin Endocrinol Metab 1991; 72:1130.
- Gessner BD, Beller M, Middaugh JP, Whitford GM. Acute fluoride poisoning from a public water system. N Engl J Med 1994; 330:95.
- Harinarayan CV, Kochupillai N, Madhu SV, et al. Fluorotoxic metabolic bone disease: an osteo-renal syndrome caused by excess fluoride ingestion in the tropics. Bone 2006; 39:907.
- Boink AB, Wemer J, Meulenbelt J, et al. The mechanism of fluoride-induced hypocalcaemia. Hum Exp Toxicol 1994; 13:149.
- Mark PB, Mazonakis E, Shapiro D, et al. Pseudohypocalcaemia in an elderly patient with advanced renal failure and renovascular disease. Nephrol Dial Transplant 2005; 20:1499.
- Gandhi MJ, Narra VR, Brown JJ, et al. Clinical and economic impact of falsely decreased calcium values caused by gadoversetamide interference. AJR Am J Roentgenol 2008; 190:W213.
- Prince MR, Choyke PL, Knopp MV. More on pseudohypocalcemia and gadolinium-enhanced MRI. N Engl J Med 2004; 350:87.
- Doorenbos CJ, Ozyilmaz A, van Wijnen M. Severe pseudohypocalcemia after gadolinium-enhanced magnetic resonance angiography. N Engl J Med 2003; 349:817.
- Prince MR, Erel HE, Lent RW, et al. Gadodiamide administration causes spurious hypocalcemia. Radiology 2003; 227:639.