Calcium is a critical cation involved in cellular transport, membrane function, and bone metabolism. Hypercalcemia, or calcium in systemic excess, is harmful to the function of excitable membranes leading to skeletal muscle and gastrointestinal smooth muscle fatigue. Effects on cardiac muscle include a shortened QT interval and increased risk of cardiac arrest at very high calcium levels. Neurologic sequelae include depression, irritability, and, with high enough levels, coma. Hypercalcemia quickly exceeds renal capacity for calcium reabsorption, and calcium spills into urine, complexing with phosphate, leading to nephrolithiasis. Precipitation of calcium salts within the kidney can lead to severe renal damage.[1]Sayer JA, Carr G, Simmons NL. Nephrocalcinosis: molecular insights into calcium precipitation within the kidney. Clin Sci (Lond). 2004 Jun;106(6):549-61.
https://www.doi.org/10.1042/CS20040048
http://www.ncbi.nlm.nih.gov/pubmed/15027893?tool=bestpractice.com
Hypercalcemia also causes dehydration by inducing renal resistance to vasopressin, leading to nephrogenic diabetes insipidus. Dehydration, in turn, leads to further increase in serum calcium concentration.
Hypercalcemia is diagnosed when the concentration of serum calcium is two standard deviations above the mean value found in people with normal calcium levels, in at least two samples taken at least 1 week apart.[2]Minisola S, Pepe J, Piemonte S, et al. The diagnosis and management of hypercalcaemia. BMJ. 2015 Jun 2;350:h2723.
https://www.doi.org/10.1136/bmj.h2723
http://www.ncbi.nlm.nih.gov/pubmed/26037642?tool=bestpractice.com
Normal serum or plasma total calcium should be 8.5 to 10.5 mg/dL and ionized calcium should be 4.6 to 5.1 mg/dL.[3]Sinton TJ, Cowley DM, Bryant SJ. Reference intervals for calcium, phosphate, and alkaline phosphatase as derived on the basis of multichannel-analyzer profiles. Clin Chem. 1986 Jan;32(1 pt 1):76-9.
http://www.ncbi.nlm.nih.gov/pubmed/3940739?tool=bestpractice.com
Pathophysiology
Only about 1% of the total body calcium is in the extracellular fluid, the rest being in bone and intracellular compartments.[4]Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999;69:842-56.
http://www.ncbi.nlm.nih.gov/pubmed/10232622?tool=bestpractice.com
About half the circulating calcium is bound to proteins, primarily albumin, while the remainder is ionized and constitutes the physiologically pertinent fraction.
Calcium levels are strictly controlled by parathyroid hormone (PTH), released from the parathyroid glands when the ionized calcium is perceived as low. PTH raises calcium by enhancement of vitamin D metabolism in the kidney, stimulating bone resorption, and increasing phosphate excretion in the kidney.[5]Moe SM. Calcium homeostasis in health and in kidney disease. Compr Physiol. 2016 Sep 15;6(4):1781-800.
https://www.doi.org/10.1002/cphy.c150052
http://www.ncbi.nlm.nih.gov/pubmed/27783859?tool=bestpractice.com
When calcium is perceived as high, the parathyroid glands stop releasing PTH. Thyrocalcitonin from the "c" cells of the thyroid can lower calcium levels, but its role in calcium balance is minor.
Calcium is absorbed at about 25% to 35% efficiency in adults, but is higher in infancy and decreases with age.[6]Ross AC, Taylor CL, Yaktine AL, et al, eds. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium: Dietary reference intakes for calcium and vitamin D. Washington (DC): National Academies Press (US); 2011.
https://nap.nationalacademies.org/catalog/13050/dietary-reference-intakes-for-calcium-and-vitamin-d
http://www.ncbi.nlm.nih.gov/pubmed/21796828?tool=bestpractice.com
[7]Wolf RL, Cauley JA, Baker CE, et al. Factors associated with calcium absorption efficiency in pre- and perimenopausal women. Am J Clin Nutr. 2000 Aug;72(2):466-71.
https://www.doi.org/10.1093/ajcn/72.2.466
http://www.ncbi.nlm.nih.gov/pubmed/10919942?tool=bestpractice.com
The absorption of calcium relies upon vitamin D. Vitamin D₃ is synthesized in the skin by the reaction of its cholesterol antecedents with ultraviolet B light (290-320 nm); the reaction is triggered when sunlight strikes exposed skin. Dietary sources are usually negligible, except among Arctic peoples who consume a large amount of vitamin D₃ from oily fish and mammals. Vitamin D₃ is converted to the 25-hydroxy metabolite by hepatic pathways and a second hydroxylation to calcitriol or 1,25-dihydroxy vitamin D₃ occurs in renal parenchyma. 1,25-dihydroxy vitamin D₃ increases intestinal calcium absorption.[5]Moe SM. Calcium homeostasis in health and in kidney disease. Compr Physiol. 2016 Sep 15;6(4):1781-800.
https://www.doi.org/10.1002/cphy.c150052
http://www.ncbi.nlm.nih.gov/pubmed/27783859?tool=bestpractice.com
Phosphate solubility is closely related to calcium balance. Any factor causing a rise in phosphate, such as renal failure, will lead to a fall in ionized calcium.
Symptoms and signs
Hypercalcemia may be mild and occur without symptoms. History may also identify symptoms of high calcium such as renal stones (typical of hyperparathyroidism), lethargy, easy fatigue, confusion, depression, irritability, constipation, and polyuria and polydipsia.[2]Minisola S, Pepe J, Piemonte S, et al. The diagnosis and management of hypercalcaemia. BMJ. 2015 Jun 2;350:h2723.
https://www.doi.org/10.1136/bmj.h2723
http://www.ncbi.nlm.nih.gov/pubmed/26037642?tool=bestpractice.com
Chronic symptoms are more consistent with hyperparathyroidism, whereas more recent onset of symptoms suggests malignancy.
Elevated calcium may require an intervention to prevent complications such as osteoporosis. Severe hypercalcemia is a life-threatening electrolyte emergency requiring prompt recognition and urgent response.
Patients with asymptomatic primary hyperparathyroidism (mild hypercalcemia, generally within 1 mg/dL of the upper limit of the normal range), may undergo parathyroid surgery in the absence of medical contraindications.[8]Bilezikian JP, Brandi ML, Eastell R, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab. 2014 Oct;99(10):3561-9.
https://www.doi.org/10.1210/jc.2014-1413
http://www.ncbi.nlm.nih.gov/pubmed/25162665?tool=bestpractice.com
Surgery is not, however, mandatory in all patients with asymptomatic disease; recommendations for monitoring those who do not undergo parathyroid surgery should be followed.[8]Bilezikian JP, Brandi ML, Eastell R, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab. 2014 Oct;99(10):3561-9.
https://www.doi.org/10.1210/jc.2014-1413
http://www.ncbi.nlm.nih.gov/pubmed/25162665?tool=bestpractice.com
[9]National Institute for Health and Care Excellence. Hyperparathyroidism (primary): diagnosis, assessment and initial management. May 2019 [internet publication].
https://www.nice.org.uk/guidance/ng132
