16. Kashket S, Zhang J, Van Houte J.

Accumulation of fermentable sugars and metabolic acids in food particles that become entrapped on the dentition. J Dent Res. Nov 1996;75(11):1885-91. [Medline]. 17. Nguyen LT, Mohr WJ, Ahrenholz DH. Treatment of hydrofluoric acid burn to the face by carotid artery infusion of calcium gluconate. J Burn Care Rehabil. SepOct 2004;25(5):421-4. [Medline]. 18. NIH Consensus Development Conference. Optimal calcium intake. NIH Consensus Development Program and Abstracts. 1994. [Medline]. 19. Reber PM, Heath H. Hypocalcemic emergencies. Med Clin North Am. Jan 1995;79(1):93-106. [Medline]. 20. Rickels MR, Mandel SJ. Celiac disease manifesting as isolated hypocalcemia. Endocr Pract. May-Jun 2004;10(3):203-7. [Medline]. 21. Sorva A. 'Correction' of serum calcium values for albumin biased in geriatric patients. Arch Gerontol Geriatr. Jul-Aug 1992;15(1):59-69. [Medline]. 22. Tohme JF, Bilezikian JP. Hypocalcemic emergencies. Endocrinol Metab Clin North Am. Jun 1993;22(2):363-75. [Medline]. 23. Ungvari Z, Pacher P, Koller A. Serotonin reuptake inhibitor fluoxetine decreases arteriolar myogenic tone by reducing smooth muscle [Ca2+]i. J Cardiovasc Pharmacol. Jun 2000;35(6):849-54. [Medline]. 24. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. Dec 27 2006;296(24):2947-53. [Medline]. 25. Zaloga GP. Hypocalcemia in critically ill patients. Crit Care Med. Feb 1992;20(2):25162. [Medline]. [ CLOSE WINDOW ]

Further Reading
[ CLOSE WINDOW ]

Keywords
hypocalcemia, calcium, calcium regulation, smooth muscle contraction, hypoalbuminemia, calcitonin, calcium homeostasis, spurious hypocalcemia, hyperparathyroidism, celiac sprue, low calcium, low blood calcium, calcium deficiency, ionized hypocalcemia, cardiovascular collapse, hypotension, dysrhythmias, tetany, seizures, muscle cramping, congestive heart failure, CHF, angina, laryngeal stridor, dysphagia, biliary colic, intestinal colic, gluten intolerance, preterm labor, detrusor dysfunction, focal numbness, muscle spasms, Chvostek sign, Trousseau sign, carpal spasm, irritability, confusion, hallucinations, dementia, extrapyramidal manifestations hypomagnesemia, hyperphosphatemia, PTH deficiency, PTH resistance, vitamin D deficiency, vitamin D resistance, cirrhosis, nephrosis, malnutrition, burns, sepsis, acute pancreatitis, alcoholism, rhabdomyolysis, toxic shock syndrome, high calcitonin levels, osteoblastic

metastases, breast cancer, prostate cancer, tumor lysis syndrome, hepatic insufficiency, renal insufficiency, sarcoidosis, tuberculosis, hemochromatosis, hydrofluoric acid burn, hydrofluoric acid ingestion, renal failure, mesenteric ischemia, massive blood transfusion, pancreatectomy, small bowel syndrome, DiGeorge syndrome, idiopathic hypoparathyroidism, Wilson disease, metastatic cancer, pseudohypoparathyroidism, Albright disease, rickets, hepatorenal disease [ CLOSE WINDOW ]

Contributor Information and Disclosures

Author Christopher B Beach, MD, FACEP, FAAEM, Associate Professor and Vice Chair of Emergency Medicine, Department of Emergency Medicine, Associate Professor of Institute for Healthcare Studies, Institute for Patient Safety, Feinberg School of Medicine, Northwestern University Christopher B Beach, MD, FACEP, FAAEM is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine Disclosure: Nothing to disclose. Medical Editor Robin R Hemphill, MD, MPH, Associate Professor, Director, Quality and Safety, Department of Emergency Medicine, Emory University Robin R Hemphill, MD, MPH is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine Disclosure: Nothing to disclose. Pharmacy Editor Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine Disclosure: eMedicine Salary Employment Managing Editor Jeffrey L Arnold, MD, FACEP, Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center Jeffrey L Arnold, MD, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physicians Disclosure: Nothing to disclose. CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine Disclosure: Nothing to disclose. Chief Editor Erik D Schraga, MD, Staff Physician, Department of Emergency Medicine, Mills-Peninsula Emergency Medical Associates Disclosure: Nothing to disclose.

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2. Sumber: http://emedicine.medscape.com/article/241893-overview Hypocalcemia

Author: Manish Suneja, MD, Assistant Professor, Department of Internal Medicine, Division of Nephrology, University of Iowa Hospitals and Clinics Coauthor(s): Heather A Muster, MD, MS, Assistant Professor, Division of Nephrology, University of Iowa Contributor Information and Disclosures Updated: Sep 3, 2010

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Introduction
Background

Hypocalcemia is frequently encountered in patients who are hospitalized. Presentations vary widely, from asymptomatic to life-threatening situations. A 70 kg person has approximately 1.2 kg of calcium in the body, most of which is stored as hydroxyapatite in bones (>99%). Less than 1% (5-6 g) of this calcium is located in the intracellular and extracellular compartments, with only 1.3 g located extracellularly. The total calcium concentration in the plasma is 4.5-5.1 mEq/L (9-10.2 mg/dL). Fifty percent of plasma calcium is ionized, 40% is bound to proteins (90% of which binds to albumin), and 10% circulates bound to anions (eg, phosphate, carbonate, citrate, lactate, sulfate). At a plasma pH of 7.4, each gram of albumin binds 0.8 mg/dL of calcium. This bond is dependent on the carboxyl groups of albumin and is highly dependent on pH. Acute acidemia decreases calcium binding to albumin, whereas alkalemia increases binding, which decreases ionized calcium. Clinical signs and symptoms are observed only with decreases in ionized calcium concentration (normally 4.5-5.5 mg/dL).1,2
Pathophysiology

Ionized calcium is the necessary plasma fraction for normal physiologic processes. In the neuromuscular system, ionized calcium levels facilitate nerve conduction, muscle contraction, and muscle relaxation. Calcium is necessary for bone mineralization and is an important cofactor for hormonal secretion in endocrine organs. At the cellular level, calcium is an important regulator of ion transport and membrane integrity. The calcium turnover is estimated at 10-20 mEq/d. Approximately 500 mg of calcium are removed from the bones daily and replaced by an equal amount. Normally, the amount of calcium absorbed by the intestines is matched by urinary calcium excretion. Despite these enormous fluxes of calcium, the levels of ionized calcium remain stable because of the rigid control of parathyroid hormone (PTH) and vitamin D levels. Normocalcemia requires PTH and normal target-organ response to PTH. The parathyroid gland has a remarkable sensitivity to ionized serum calcium changes. These changes are recognized by the calcium-sensing receptor (CaSR), a 7-transmembrane receptor linked to G-protein with a large extracellular amino-terminal region. Binding of calcium to the CaSR induces activation of phospholipase C and inhibition of PTH secretion. On the other hand, a slight decrease in calcium stimulates the chief cells of the parathyroid gland to secrete PTH. CaSR is crucial in PTH secretion. A loss of CaSR function leads to pathological states, such as familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. In renal failure, CaSR agonists suppress the progression of hyperparathyroidism and parathyroid gland

growth. PTH stimulates osteoclastic bone reabsorption and distal tubular calcium reabsorption and mediates 1,25-dihydroxyvitamin D (1,25[OH]2 D) intestinal calcium absorption.3 Vitamin D stimulates intestinal absorption of calcium, regulates PTH release by the chief cells, and mediates PTH-stimulated bone reabsorption. Patients with a decrease in total serum calcium may not have "true" hypocalcemia, which is defined as a decrease in ionized calcium. A reduction in total serum calcium can result from a decrease in albumin secondary to liver disease, nephrotic syndrome, or malnutrition. Hypocalcemia causes neuromuscular irritability and tetany. Alkalemia induces tetany due to a decrease in ionized calcium, whereas acidemia is protective. This pathophysiology is important in patients with renal failure who have hypocalcemia because rapid correction of acidemia or development of alkalemia may trigger tetany.4,5,6
Frequency

United States Hypocalcemia is less frequent than hypercalcemia. In order of frequency, hypocalcemia occurs in patients with chronic and acute renal failure; vitamin D deficiency; magnesium (Mg) deficiency; acute pancreatitis; hypoparathyroidism and pseudohypoparathyroidism; and infusion of phosphate, citrate, or calcium-free albumin.
Mortality/Morbidity

Hypocalcemia can present with subtle findings, but it also can be associated with significant clinical manifestations.

Cardiovascular complications: In severe cases, hypocalcemia may lead to arrhythmias, hypotension, and heart failure. Some patients may manifest digitalis insensitivity. Neurologic complications: In addition to acute seizures or tetany, hypocalcemia may lead to basal ganglia calcification, parkinsonism, hemiballismus, and choreoathetosis. Although some patients with hypocalcemia may improve with treatment, the calcification typically is not reversible.

Sex

Hypocalcemia occurs with similar frequency in men and women.

Age

The age distribution is contingent on the disorder that led to hypocalcemia. In children, nutritional deficiencies are more frequent; in adults, renal failure predominates. However, the recognition of the high prevalence of vitamin D deficiency, particularly in elderly patients, may change our understanding of hypocalcemia in the general population.

Clinical

History

Once laboratory results demonstrate hypocalcemia, the first question is whether the hypocalcemia is true, that is, representative of a decrease in ionized calcium.

Patient history o The presence of chronic diarrhea or intestinal disease, such as is observed with Crohn disease, sprue, or chronic pancreatitis, suggests the possibility of hypocalcemia due to malabsorption of calcium and/or vitamin D. o Previous neck surgery suggests hypoparathyroidism; a history of seizures suggests hypocalcemia secondary to anticonvulsants. o The length of time that a disorder is present is an important clue. Hypoparathyroidism and pseudohypoparathyroidism are lifelong disorders. Instead, acute transient hypocalcemia may be associated with acute gastrointestinal illness, nutritional deficiency, or acute or chronic renal failure. o In an elderly patient, a nutritional deficiency may be associated with a low intake of vitamin D. o A history of alcoholism can help diagnose hypocalcemia due to magnesium deficiency, malabsorption, or chronic pancreatitis. o Family history of hypocalcemia o Low-calcium diet o Lack of sun exposure o Use of certain medications, such as the calcimimetic agent, cinacalcet, and anticonvulsants Clinical symptoms7 8 o Neuromuscular Numbness and tingling sensations in the perioral area or in the fingers and toes Muscle cramps, particularly in the back and lower extremities; may progress to carpopedal spasm (ie, tetany) Wheezing; may develop from bronchospasm Dysphagia Voice changes (due to laryngospasm) 9 o Neurologic Irritability, impaired intellectual capacity, depression, and personality changes Fatigue Seizures (eg, grand mal, petit mal, focal) Other uncontrolled movements o Cardiac Shortness of breath Symptoms of congestive heart failure (possible) o Skin Coarse hair Brittle nails Psoriasis Dry skin

Physical

Physical examination findings may include the following:

General: Patients may appear confused or disoriented. They may exhibit signs of dementia or overt psychosis. Head: Hair may appear coarse. Alopecia may be present. Eyes: Subcapsular cataracts or papilledema can be seen. Oral: If chronic (since childhood), patients may be at an increased risk of dental caries and enamel hypoplasia. Respiratory: Inspiratory or expiratory wheezes may be present. Cardiac: Signs of heart failure may be present (see Other Tests). Skin: Dry skin or patches of psoriasis and eczema may be present, particularly in patients with chronic hypocalcemia. Neurologic o Chvostek sign: Tapping the skin over the facial nerve immediately in front of the external auditory meatus will cause an ipsilateral contraction of the facial muscles. Up to 10% of the population will have a positive Chvostek sign. This test, while suggestive, is not diagnostic of hypocalcemia. o Trousseau sign: Place a blood pressure cuff on the patients arm and inflate to 20 mm Hg above systolic blood pressure for 3-5 minutes. This increases the irritability of the nerves, and a flexion of the wrist and metacarpal phalangeal joints can be observed with extension of the interphalangeal joints and adduction of the thumb (carpal spasm). Trousseau sign is more specific than Chvostek sign, but the test result can be negative. Movement abnormalities include the following: 10 o Choreoathetosis o Dystonic spasm o Parkinsonism o Hemiballism

Causes

Hypocalcemia has a variety of causes.

Hypoalbuminemia

The first step in evaluation of hypocalcemia it to measure the serum albumin levels, as low serum albumin levels can cause a reduction in total, but not the ionized, fraction of serum calcium. Patients do not have any signs or symptoms of hypocalcemia. Each 1 g/dL reduction in the serum albumin concentration will lower the total calcium concentration by approximately 0.8 mg/dL without affecting the ionized calcium concentration. This is not a completely precise method, and ionized calcium measurements in the serum can confirm whether true hypocalcemia is present.

Pseudohypocalcemia

Gadolinium-based contrast agents (used in magnetic resonance imaging and angiography), gadodiamide and gadoversetamide, may interfere with the colorimetric assays for calcium that are frequently used in hospital laboratories. This effect is not observed with other gadoliniumbased agents: dimeglumine gadopentetate, gadoteridol, or gadoterate meglumine. The interaction can result in a marked reduction in the measured calcium concentration of as much as 6 mg/dL if a blood sample is obtained soon after the test. This effect is rapidly reversible as the gadolinium is excreted in the urine, and the patient has no symptoms or signs of hypocalcemia. Awareness of this phenomenon is particularly important in patients with renal insufficiency who may retain the contrast agent for prolonged periods. There is no reason to treat this type of hypocalcemia.11,12,13
Parathyroid hormone related

Hypoparathyroidism This condition can be hereditary or acquired. Both varieties share the same symptoms, although hereditary hypoparathyroidism tends to have a gradual onset.14 Acquired hypoparathyroidism may result from the following:

Neck irradiation/radioiodine therapy15 Postparathyroidectomy in dialysis patients16 Inadvertent surgical removal (can be transient or permanent) Infiltrative disease is similar to hemachromatosis, granulomatous disease (sarcoidosis), thalassemia, amyloidosis, or metastatic malignant infiltration of the glands. Late-onset hypoparathyroidism can be seen as a part of a complex autoimmune disorder involving ovarian failure and adrenal failure. Mucocutaneous candidiasis, alopecia, vitiligo, and pernicious anemia are associated with this disorder, which is referred to as polyglandular autoimmune disease (PGA I).

Hereditary hypoparathyroidism may be familial or sporadic, and it can occur as an isolated entity or can be associated with other endocrine manifestations.

The familial forms include autosomal dominant and autosomal recessive, as well as a sex-linked form of early onset, for which the gene has been located on the long arm of the X chromosome. Sporadic, late-onset hypoparathyroidism is associated with DiGeorge syndrome, which is also associated with congenital heart disease, cleft palate/lip, and abnormal facies. Some cases are associated with Kearns-Sayre syndrome, which presents with heart block, retinitis pigmentosa, and ophthalmoplegia. Kenny-Caffey syndrome is associated with hypoparathyroidism and includes medullary stenosis of the long bones and growth retardation.

Pseudohypoparathyroidism This condition is characterized by end-organ resistance to the effects of PTH. PTH binds to the

PTH receptor, which, in turn, activates cyclic adenosine monophosphate (cAMP) through guanine nucleotide regulatory proteins (Gs). These proteins consist of alpha, beta, and gamma subunits. Pseudohypoparathyroidism is classified into types I and II. Type I is further subdivided into Ia, Ib, and Ic.14

Type Ia Pseudohypoparathyroidism type Ia results from a decrease in the Gs-alpha protein. In 1942, Albright et al described a disorder, known as Albright hereditary osteodystrophy (AHO), comprised of short stature, mental retardation, obesity, round-shaped face, brachymetacarpia, brachymetatarsia, and subcutaneous bone formation. These somatic features of Albright hereditary osteodystrophy and the presence of the biochemical features of pseudohypoparathyroidism constitute type Ia. o Laboratory findings include hypocalcemia, hyperphosphatemia (with normal or high PTH levels), and low calcitriol. Vitamin D may be decreased because of inhibition by elevated levels of phosphorus and by decreased PTH stimulation of the 25-hydroxyvitamin D 1alpha-hydroxylase. The low calcitriol levels, in turn, may cause the resistance to the hypercalcemic effects of PTH in the bone. o The defect of the Gs-alpha protein is not confined to the effects of PTH but also affects other hormonal systems (eg, resistance to glucagon, thyroid-stimulating hormone, gonadotropins). The gene for the Gs-alpha protein is located on chromosome 20. Some family members carry the mutation and display the AHO phenotype but do not have pseudohypoparathyroidism. This is termed pseudo-pseudohypoparathyroidism. Type Ib: These patients do not present with the somatic features of Albright hereditary osteodystrophy. These patients have normal Gs-alpha protein, with hormonal resistance to PTHan impaired cAMP response to PTH, suggesting that the defect lies on the receptor. At what level the receptor is affected is not yet clear. Type Ic: Patients with this type present with resistance to multiple hormonal receptors but have normal Gs-alpha protein expression. Type II: In patients with this type of pseudohypoparathyroidism, PTH raises cAMP normally but fails to increase levels of serum calcium or urinary phosphate excretion, suggesting that the defect is located downstream of the generation of cAMP. If the patient presents with hypocalcemia, hypophosphaturia, and elevated immunoreactive parathyroid hormone (iPTH) levels, first rule out vitamin D deficiency, which has a similar presentation. In patients with a vitamin D deficiency, all parameters return to normal after vitamin D administration.
o

Hypomagnesemia Severe hypomagnesemia can lead to hypocalcemia, which is resistant to the administration of calcium and vitamin D. The usual cause of hypomagnesemia is due to loss through the kidney (eg, osmotic diuresis, drugs) or the gastrointestinal tract (eg, chronic diarrhea, severe pancreatitis, bypass or resection of small bowel). These patients present with low or inappropriately normal PTH levels in the presence of hypocalcemia. The mechanism of hypocalcemia includes resistance to PTH in the bone and kidneys, as well as a decrease in PTH secretion. Acute magnesium restoration rapidly corrects the PTH level, suggesting the hypomagnesemia affects the release of PTH, rather than its synthesis.

Ineffective PTH

Vitamin D is a necessary cofactor for the normal response to PTH, and deficiency renders PTH ineffective. Poor nutritional intake, chronic renal insufficiency, or reduced exposure to sunlight may cause vitamin D deficiency.
Vitamin D related

Nutritional deficiency Current federal guidelines recommend 200-600 IU of vitamin D per day for adults, depending upon age. Studies have recognized that vitamin D insufficiency can still occur and lead to an increased PTH and subsequent bone turnover. Studies have also shown that dietary intake of vitamin D varies greatly by race and age. In one review of National Health and Nutrition Examination Survey (NHANES) III data, 42% of African American women had low blood levels of vitamin D compared to 4% in Caucasian women.17 Another observational study in elderly adults found that 74% of those studied were deficient in vitamin D, despite adequate intake.18 The authors of this study suggested that the current guidelines for the elderly be increased to 800-1000 IU per day. The recognition of mild hypovitaminosis D may not be trivial. In an elderly population with an increased PTH and osteoporosis, response to alendronate was attenuated. This attenuation was improved when vitamin D was administered.19,20 Impaired absorption Numerous conditions can impair the absorption of vitamin D. Small bowel diseases, such as celiac disease, gastric bypass (particularly long limb Roux-en-Y gastric bypass), steatorrhea, and pancreatic diseases can all lead to low vitamin D levels.21 Inheritable conditions

Pseudovitamin D deficiency rickets (type I) or 1-alpha-hydroxylase deficiency: This condition is secondary to an autosomal mutation of the 1-hydroxylase gene. Ultimately, calcidiol is not hydroxylated to calcitriol and calcium is not absorbed appropriately. This condition is considered pseudovitamin D deficiency because high doses of vitamin D can overcome the clinical and biochemical findings of this disease. Hereditary vitamin D resistance rickets: This condition is extremely rare and is caused by a mutation in the vitamin D receptor. Typically, this condition presents within the first 2 years of life.

Hepatic disease Liver disease with decreased synthetic function can cause vitamin D deficiency from several

sources, as follows: impaired 25-hydroxylation of vitamin D, decreased bile salts with malabsorption of vitamin D, decreased synthesis of vitamin Dbinding protein, or other factors. Patients with cirrhosis and osteomalacia have low or normal levels of calcitriol, suggesting that other factors may interfere with vitamin D function or are synergistic with malabsorption or decreased sun exposure. These patients require administration of calcidiol or calcitriol for the treatment of hypocalcemia. Renal failure Chronic kidney disease leads to a decrease in the conversion of 25-hydroxyvitamin D to its active form 1,25-dihydroxyvitamin D, particularly when the glomerular filtration rate (GFR) falls below 30 mL/min. This results in an increase in PTH. Ultimately, the increased absorption of phosphorus and calcium can lead to calcium-phosphorus mineral deposition in the soft tissues. In the early stages of renal failure, hypocalcemia can be seen due to the decrease in calcitriol production and a subsequent decrease in the intestinal absorption of calcium.
Critical illness and severe sepsis

A patient with acute illness may experience hypocalcemia for multiple reasons. In one study, the 3 most common factors identified in patients with hypocalcemia associated with acute illness were hypomagnesemia, acute renal failure, and transfusions. In gram-negative sepsis, there is a reduction in total and ionized serum calcium. The mechanism for this remains unknown, but it appears to be associated with multiple factors, including elevated levels of cytokines (eg, interleukin-6, interleukin-1, TNF-alpha), hypoparathyroidism, and vitamin D deficiency or resistance. Mortality rates increase among patients with sepsis and hypocalcemia, compared with patients who are normocalcemic.22,23 However, there is no clear evidence that treating critically ill patients with supplemental calcium alters outcomes.24
Hungry bone syndrome

Surgical correction of primary or secondary hyperparathyroidism may be associated with severe hypocalcemia due to a rapid increase in bone remodeling. Hypocalcemia results if the rate of skeletal mineralization exceeds the rate of osteoclast-mediated bone resorption. A less severe picture is also observed after correction of thyrotoxicosis, after institution of vitamin D therapy for osteomalacia, and with tumors associated with bone formation (eg, prostate, breast, leukemia). All of these disease states result in hypocalcemia due to mineralization of large amounts of unmineralized osteoid.25
Acute pancreatitis

Pancreatitis can be associated with tetany and hypocalcemia. It is caused primarily by precipitation of calcium soaps in the abdominal cavity, but glucagon-stimulated calcitonin release and decreased PTH secretion may play a role. When the pancreas is damaged, free fatty acids are generated by the action of pancreatic lipase. Insoluble calcium salts are present in the pancreas, and the free fatty acids avidly chelate the salts, resulting in calcium deposition in the retroperitoneum. In addition, hypoalbuminemia may be a part of the clinical picture, resulting in

a reduction in total serum calcium. In patients with concomitant alcohol abuse, a poor nutritional intake of calcium and vitamin D, as well as accompanying hypomagnesemia, may predispose these patients to hypocalcemia.26
Hyperphosphatemia

Hyperphosphatemia (due to renal failure, phosphate administration, or excess tissue breakdown because of rhabdomyolysis or tumor lysis) causes acute hypocalcemia. In acute hyperphosphatemia, calcium is deposited mostly in the bone but also in the extraskeletal tissue. In contrast, in chronic hyperphosphatemia, which is nearly always due to chronic renal failure, calcium efflux from the bone is inhibited and the calcium absorption is low, due to reduced renal synthesis of 1,25-dihydroxyvitamin D. However, other consequences of renal failure, including a primary impairment in calcitriol synthesis, also contribute to hypocalcemia.
Medications and other causes

Cinacalcet (calcimimetic agent) Patients receiving the calcimimetic agent to help control secondary hyperparathyroidism in renal failure may experience hypocalcemia as a result of acute inhibition of PTH release. Clinically significant hypocalcemia occurs in approximately 5% of patients treated with cinacalcet.27 Chemotherapy Hypocalcemia can occur in patients treated with some chemotherapeutic drugs. Cisplatin can induce hypocalcemia by causing hypomagnesemia. Combination therapy with 5-fluorouracil and leucovorin can also cause mild hypocalcemia (65% of patients in one series), possibly by decreasing calcitriol production.28 Bisphosphonates Hypocalcemia may result from the treatment of hypercalcemia with bisphosphonates, particularly zoledronic acid, which is significantly more potent than other bisphosphates in suppressing the formation and function of osteoclasts. Patients who are affected appear to lack an adequate PTH response to decreasing serum calcium levels.29 Anticonvulsant therapy Hypocalcemia and osteomalacia have been described with prolonged therapy with anticonvulsants, such as phenytoin or phenobarbital.30 Foscarnet Foscarnet is a drug used to treat refractory cytomegalovirus and herpes infections in patients who are immunocompromised. It complexes ionized calcium and, therefore, lowers ionized calcium concentrations, potentially causing symptomatic hypocalcemia. Therefore, the ionized calcium

concentration should be measured at the end of an infusion of foscarnet. Citrated blood Symptomatic hypocalcemia during transfusion of citrated blood or plasma is rare, because healthy patients rapidly metabolize citrate in the liver and kidney. However, a clinically important fall in serum ionized calcium concentration can occur if citrate metabolism is impaired due to hepatic or renal failure or if large quantities of citrate are given rapidly, for example, during plasma exchange or massive blood transfusion. Sodium phosphate preparations These agents, which come in aqueous and tablet forms of preparation, are used to cleanse the bowel prior to GI procedures, such as colonoscopy. In certain populations (those consisting of persons with renal failure, advanced age, congestive heart failure, hepatic insufficiency, or volume depletion, or of individuals who use of other drugs, such as angiotensin-converting enzyme [ACE] inhibitors and nonsteroidal anti-inflammatory drugs [NSAIDS]), these agents can lead to acute hyperphosphatemia and subsequent hypocalcemia.31,32 Ethylenediaminetetraacetic acid (EDTA) Some radiographic contrast dyes may contain EDTA, which chelates calcium in serum, thereby reducing serum ionized calcium concentration, resulting in hypocalcemia. Fluoride poisoning Rarely, an excess intake of fluoride can cause hypocalcemia; this effect is presumably mediated by inhibition of bone resorption. Overfluorinated public water supplies and ingestion of fluoridecontaining cleaning agents have been associated with low serum calcium levels. In this case, hypocalcemia is thought to be due to excessive rates of skeletal mineralization secondary to formation of calcium difluoride complex.