Calcium is a critical cation involved in cellular transport, membrane function, and bone metabolism. Hypercalcemia, or calcium in systemic excess, is deleterious to the function of excitable membranes leading to skeletal muscle and GI 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. High calcium may lead to precipitation in soft tissues such as the kidney where renal function may be severely damaged.  Hypercalcemia also causes dehydration by inducing renal resistance to vasopression, leading to nephrogenic diabetes insipidus. Dehydration, in turn, leads to a corresponding further increase in serum calcium concentration.
Phosphate solubility is closely related with calcium. Any factor causing a rise in phosphate, such as renal failure, will lead to a fall in ionized calcium. Also, calcium is absorbed at about 10% efficiency and the absorption relies upon vitamin D. Vitamin D3 is either dietary or synthesized in the sun-exposed skin from cholesterol antecedents. Vitamin D3 is synthesized in the skin by the reaction of its cholesterol antecedents with ultraviolet light in B wavelength; 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. Only about 1% of the total body calcium is in the extracellular fluid, the rest being in bone and intracellular compartments.  About half the circulating calcium is bound to protein while the remainder is ionized and constitutes the physiologically pertinent fraction. Calcium levels are strictly controlled by PTH, released from the parathyroid glands when the ionized calcium is perceived as low. When calcium is perceived as high, the parathyroids stop release of PTH. Thyrocalcitonin from the "c" cells of the thyroid can drive calcium down, but is not the critical control for calcium. PTH raises calcium by enhancement of vitamin metabolism in the kidney, stimulating bone resorption, and increasing phosphate excretion in the kidney.
Hypercalcemia may be mild and occur without symptoms. History may also identify symptoms of high calcium such as renal stones typical of hyperparathyroidism, or lethargy, easy fatigue, confusion, depression, irritability, constipation, and polyuria and polydipsia. Chronic symptoms are more consistent with hyperparathyroidism, whereas more recent onset of symptoms suggests malignancy.
There may be no need for intervention in mild hypercalcemia other than monitoring for complications.   Elevated calcium may require an intervention to prevent complications such as osteoporosis. The symptoms or consequences of severe hypercalcemia may constitute a catastrophic electrolyte emergency requiring prompt recognition and urgent response to prevent death.
Consultant Endocrine and General Surgeon
National University Cancer Institute, Singapore
RP declares that he has no competing interests.
Endocrine and Minimally invasive Surgery
National University Hospital
HS declares that he has no competing interests.
Dr Rajeev Parameswaran and Dr Hirshikesh Salgaonkar would like to gratefully acknowledge Dr Ronald Merrell, the previous contributor to this monograph. RM declares that he has no competing interests.
Department of Internal Medicine
VA Medical Center
University of Iowa
UK declares that he has no competing interests.
Department of Family Medicine
University of North Carolina
Assistant Program Director
MAHEC Rural Family Medicine Residency
WM declares that he has no competing interests.
Consultant and Senior Lecturer
Newcastle University and Royal Victoria Infirmary
RQ has been reimbursed by Amgen, the manufacturer of Cinacalcet, for attending a conference and for giving an educational seminar (total under £1,200 over past 3 years).
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