(See also Overview of Disorders of Calcium Concentration Overview of Disorders of Calcium Concentration Calcium is required for the proper functioning of muscle contraction, nerve conduction, hormone release, and blood coagulation. In addition, proper calcium concentration is required for various... read more and Hypocalcemia in neonates Neonatal Hypocalcemia Hypocalcemia is a total serum calcium concentration 8 mg/dL ( 2 mmol/L) in term infants or 7 mg/dL ( 1.75 mmol/L) in preterm infants. It is also defined as an ionized calcium level 3.0 to 4... read more .)
Etiology of Hypocalcemia
Hypocalcemia has a number of causes, including
Vitamin D deficiency and dependency
Hypoparathyroidism Hypoparathyroidism Hypoparathyroidism is a deficiency of parathyroid hormone often caused by an autoimmune disorder or by iatrogenic damage or removal of the glands during thyroidectomy or parathyroidectomy. Symptoms... read more is characterized by hypocalcemia and hyperphosphatemia Hyperphosphatemia Hyperphosphatemia is a serum phosphate concentration > 4.5 mg/dL (> 1.46 mmol/L). Causes include chronic kidney disease, hypoparathyroidism, and metabolic or respiratory acidosis. Clinical features... read more and often causes chronic tetany. Hypoparathyroidism results from deficient parathyroid hormone (PTH), which can occur in autoimmune disorders or after the accidental removal of or damage to several parathyroid glands during thyroidectomy. Transient hypoparathyroidism is common after subtotal thyroidectomy, but permanent hypoparathyroidism occurs after < 3% of such thyroidectomies done by experienced surgeons. Manifestations of hypocalcemia usually begin about 24 to 48 hours postoperatively but may occur after months or years. PTH deficiency is more common after radical thyroidectomy for cancer or as the result of surgery on the parathyroid glands (subtotal or total parathyroidectomy). Risk factors for severe hypocalcemia after subtotal parathyroidectomy include
Severe preoperative hypercalcemia
Removal of a large adenoma
Elevated alkaline phosphatase
Evidence of osteitis fibrosa cystica on bone x-rays
Chronic kidney disease
Idiopathic hypoparathyroidism is an uncommon sporadic or inherited condition in which the parathyroid glands are absent or atrophied. It manifests in childhood. The parathyroid glands are occasionally absent and thymic aplasia and abnormalities of the arteries arising from the brachial arches ( DiGeorge syndrome DiGeorge Syndrome DiGeorge syndrome is thymic and parathyroid hypoplasia or aplasia leading to T-cell immunodeficiency and hypoparathyroidism. Infants with DiGeorge syndrome have low-set ears, midline facial... read more ) are present. Other inherited forms include polyglandular autoimmune failure syndrome Polyglandular Deficiency Syndromes Polyglandular deficiency syndromes (PDS) are characterized by sequential or simultaneous deficiencies in the function of several endocrine glands that have a common cause. Etiology is most often... read more , autoimmune hypoparathyroidism associated with mucocutaneous candidiasis Candidiasis (Mucocutaneous) Candidiasis is skin and mucous membrane infection with Candida species, most commonly Candida albicans. Infections can occur anywhere and are most common in skinfolds, digital... read more , and X-linked recessive idiopathic hypoparathyroidism.
Pseudohypoparathyroidism is an uncommon group of disorders characterized not by hormone deficiency but by target organ resistance to PTH. Complex genetic transmission of these disorders occurs.
Type Ia pseudohypoparathyroidism (Albright hereditary osteodystrophy) is caused by a mutation in the stimulatory Gs-alpha1 protein of the adenylyl cyclase complex (GNAS1). The result is failure of normal renal phosphaturic response or increase in urinary cAMP (cyclic adenosine monophosphate) to PTH. Patients are usually hypocalcemic and hyperphosphatemic. Secondary hyperparathyroidism and hyperparathyroid bone disease can occur. Associated abnormalities include short stature, round facies, intellectual disability with calcification of the basal ganglia, shortened metacarpal and metatarsal bones, mild hypothyroidism, and other subtle endocrine abnormalities. Because only the maternal allele for GNAS1 is expressed in the kidneys, patients whose abnormal gene is paternal, although they have many of the somatic features of the disease, do not have hypocalcemia, hyperphosphatemia, or secondary hyperparathyroidism; this condition is sometimes described as pseudopseudohypoparathyroidism.
Type Ib pseudohypoparathyroidism is less well known. Affected patients have hypocalcemia, hyperphosphatemia Hyperphosphatemia Hyperphosphatemia is a serum phosphate concentration > 4.5 mg/dL (> 1.46 mmol/L). Causes include chronic kidney disease, hypoparathyroidism, and metabolic or respiratory acidosis. Clinical features... read more , and secondary hyperparathyroidism but do not have the other associated abnormalities.
Type II pseudohypoparathyroidism is even less common than type I. In affected patients, exogenous PTH raises the urinary cAMP normally but does not raise serum calcium or urinary phosphate. An intracellular resistance to cAMP has been proposed.
Vitamin D deficiency and dependency
Vitamin D deficiency and dependency Vitamin D Deficiency and Dependency Inadequate exposure to sunlight predisposes to vitamin D deficiency. Deficiency impairs bone mineralization, causing rickets in children and osteomalacia in adults and possibly contributing... read more are discussed in full elsewhere.
Vitamin D is ingested in foods naturally high in vitamin D or fortified with it. It is also formed in the skin in response to sunlight (ultraviolet light). Vitamin D deficiency may result from inadequate dietary intake or decreased absorption due to hepatobiliary disease or intestinal malabsorption. It can also result from alterations in vitamin D metabolism as occur with certain drugs (eg, phenytoin, phenobarbital, rifampin) or from decreased formation in the skin due to lack of exposure to sunlight. Aging also decreases skin synthetic capacity.
Decreased skin synthesis is an important cause of acquired vitamin D deficiency among people who spend a great deal of time indoors, who live in high northern or southern latitudes, and who wear clothing that covers them completely or frequently use sunblocking agents. Accordingly, subclinical vitamin D deficiency is fairly common, especially during winter months in temperate climates among the elderly. The institutionalized elderly are at particular risk because of decreased skin synthetic capacity, undernutrition, and lack of sun exposure. In fact, most people with deficiency have both decreased skin synthesis and dietary deficiency. However, most clinicians feel that the significant dangers of skin cancer outweigh the as yet unproven risk of moderately low vitamin D levels so increasing sun exposure or doing without sunblocks is not recommended; vitamin D supplements are readily available for patients with concerns.
Vitamin D–dependency results from the inability to convert vitamin D to its active form or decreased responsiveness of end-organs to adequate levels of active vitamin.
Type I vitamin D–dependent rickets (pseudovitamin D–deficiency rickets) is an autosomal recessive disorder involving a mutation in the gene encoding the 1-alpha-hydroxylase enzyme. Normally expressed in the kidney, 1-alpha-hydroxylase is needed to convert inactive vitamin D to the active form calcitriol.
In type II vitamin D–dependent rickets, target organs cannot respond to calcitriol. Vitamin D deficiency, hypocalcemia, and severe hypophosphatemia occur. Muscle weakness, pain, and typical bone deformities can occur.
Renal tubular disease, including proximal and distal renal tubular acidosis, can cause severe hypocalcemia due to abnormal renal loss of calcium and decreased renal conversion of vitamin D to active 1,25(OH)2D.
Renal failure can result in diminished formation of 1,25(OH)2D due to
Direct renal cell damage
Suppression of 1-alpha-hydroxylase (needed for the vitamin D conversion) by hyperphosphatemia
Other causes of hypocalcemia include
Acute pancreatitis Acute Pancreatitis Acute pancreatitis is acute inflammation of the pancreas (and, sometimes, adjacent tissues). The most common triggers are gallstones and alcohol intake. The severity of acute pancreatitis is... read more (when lipolytic products released from the inflamed pancreas chelate calcium)
Drugs, including antiseizure drugs (eg, phenytoin, phenobarbital) and rifampin, which alter vitamin D metabolism, and drugs generally used to treat hypercalcemia Treatment Hypercalcemia is a total serum calcium concentration > 10.4 mg/dL (> 2.60 mmol/L) or ionized serum calcium > 5.2 mg/dL (> 1.30 mmol/L). Principal causes include hyperparathyroidism, vitamin... read more
Hungry bone syndrome (persistent hypocalcemia and hypophosphatemia occurring after surgical or medical correction of moderate to severe hyperparathyroidism in patients in whom serum calcium concentrations had been supported by high bone turnover induced by greatly elevated PTH—hungry bone syndrome has been described after parathyroidectomy, after renal transplantation, and rarely in patients with end-stage renal disease treated with calcimimetics)
Hyperphosphatemia Hyperphosphatemia Hyperphosphatemia is a serum phosphate concentration > 4.5 mg/dL (> 1.46 mmol/L). Causes include chronic kidney disease, hypoparathyroidism, and metabolic or respiratory acidosis. Clinical features... read more (causes hypocalcemia by poorly understood mechanisms; patients with renal failure and subsequent phosphate retention are particularly prone)
Hypoproteinemia (reduces the protein-bound fraction of serum calcium; hypocalcemia due to diminished protein binding is asymptomatic—because ionized calcium is unchanged, this entity has been termed factitious hypocalcemia)
Infusion of gadolinium (may spuriously lower calcium concentration)
Magnesium depletion Etiology Hypomagnesemia is serum magnesium concentration 1.8 mg/dL ( 0.70 mmol/L). Causes include inadequate magnesium intake and absorption or increased excretion due to hypercalcemia or drugs such... read more (can cause relative parathyroid hormone deficiency and end-organ resistance to PTH action, usually when serum magnesium concentrations are < 1.0 mg/dL [< 0.5 mmol/L]; magnesium repletion increases PTH concentrations and improves renal calcium conservation)
Septic shock Sepsis and Septic Shock Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection. In septic shock, there is critical reduction in tissue perfusion; acute failure... read more due to suppression of PTH release and decreased conversion of 25(OH)D to 1,25(OH)2D
Transfusion of > 10 units of citrate-anticoagulated blood
Use of radiocontrast agents containing the divalent ion-chelating agent ethylenediaminetetraacetate (EDTA—can decrease the concentration of bioavailable ionized calcium while total serum calcium concentrations remain unchanged)
Although excessive secretion of calcitonin might be expected to cause hypocalcemia, calcitonin actually has only a minor effect on serum calcium. For example, low serum calcium concentrations rarely occur in patients with large amounts of circulating calcitonin due to medullary carcinoma of the thyroid Medullary Thyroid Carcinoma There are 4 general types of thyroid cancer. Most thyroid cancers manifest as asymptomatic nodules. Rarely, lymph node, lung, or bone metastases cause the presenting symptoms of small thyroid... read more .
Symptoms and Signs of Hypocalcemia
Hypocalcemia is frequently asymptomatic.
The presence of hypoparathyroidism may be suggested by the clinical manifestations of the underlying disorder (eg, short stature, round facies, intellectual disability, basal ganglia calcification in type Ia pseudohypoparathyroidism; vitiligo with autoimmune hypoparathyroidism).
Major clinical manifestations of hypocalcemia are due to disturbances in cellular membrane potential, resulting in neuromuscular irritability.
Muscle cramps involving the back and legs are common.
Insidious hypocalcemia may cause mild, diffuse encephalopathy and should be suspected in patients with unexplained dementia, depression, or psychosis.
Papilledema occasionally occurs.
Severe hypocalcemia with serum calcium < 7 mg/dL (< 1.75 mmol/L) may cause hyperreflexia, tetany, laryngospasm, or generalized seizures.
Tetany characteristically results from severe hypocalcemia but can result from reduction in the ionized fraction of serum calcium without marked hypocalcemia, as occurs in severe alkalosis. Tetany is characterized by the following:
Sensory symptoms consisting of paresthesias of the lips, tongue, fingers, and feet
Carpopedal spasm, which may be prolonged and painful
Generalized muscle aching
Spasm of facial musculature
Tetany may be overt with spontaneous symptoms or latent and requiring provocative tests to elicit. Latent tetany generally occurs at less severely decreased serum calcium concentrations: 7 to 8 mg/dL (1.75 to 2.20 mmol/L).
Chvostek and Trousseau signs are easily elicited at the bedside to identify latent tetany.
Chvostek sign is an involuntary twitching of the facial muscles elicited by a light tapping of the facial nerve just anterior to the exterior auditory meatus. It is present in ≤ 10% of healthy people and in most people with acute hypocalcemia but is often absent in chronic hypocalcemia.
Trousseau sign is the precipitation of carpal spasm by reduction of the blood supply to the hand with a tourniquet or blood pressure cuff inflated to 20 mm Hg above systolic blood pressure applied to the forearm for 3 minutes. Trousseau sign also occurs in alkalosis, hypomagnesemia, hypokalemia, and hyperkalemia and in about 6% of people with no identifiable electrolyte disturbance.
Many other abnormalities may occur in patients with chronic hypocalcemia, such as dry and scaly skin, brittle nails, and coarse hair. Candida infections occasionally occur in hypocalcemia but most commonly occur in patients with idiopathic hypoparathyroidism. Cataracts occasionally occur with long-standing hypocalcemia and are not reversible by correction of serum calcium.
Diagnosis of Hypocalcemia
Estimation or measurement of ionized calcium (the physiologically active form of calcium)
Sometimes further testing, including measurement of magnesium, PTH, phosphate, alkaline phosphatase, and vitamin D concentrations in blood and cAMP and phosphate concentrations in urine
Hypocalcemia may be suspected in patients with characteristic neurologic manifestations or cardiac arrhythmias but is often found incidentally. Hypocalcemia is diagnosed by a total serum calcium concentration < 8.8 mg/dL (< 2.2 mmol/L). However, because low plasma protein can lower total, but not ionized, serum calcium, ionized calcium should be estimated based on albumin concentration.
Suspicion of low ionized calcium mandates its direct measurement, despite normal total serum calcium. A serum ionized calcium concentration < 4.7 mg/dL (< 1.17 mmol/L) is low.
Hypocalcemic patients should undergo measurement of renal function (eg, BUN [blood urea nitrogen], creatinine), serum phosphate, magnesium, and alkaline phosphatase.
When no etiology (eg, alkalosis, renal failure, drugs, or massive blood transfusion) is obvious, further testing is needed (see table Typical Laboratory Test Results in Some Disorders Causing Hypocalcemia Typical Laboratory Test Results in Some Disorders Causing Hypocalcemia ).
Additional testing begins with serum concentrations of magnesium, phosphate, parathyroid hormone, alkaline phosphatase, and occasionally vitamin D levels, both 25(OH)D and 1,25(OH)2D. Urinary phosphate and cAMP concentrations are measured when pseudohypoparathyroidism is suspected.
PTH concentration should be measured as an assay of the intact molecule. Because hypocalcemia is the major stimulus for PTH secretion, PTH normally should be elevated in response to hypocalcemia. Thus,
Low or even low-normal PTH concentrations are inappropriate and suggest hypoparathyroidism.
An undetectable PTH concentration suggests idiopathic hypoparathyroidism.
A high PTH concentration suggests pseudohypoparathyroidism or an abnormality of vitamin D metabolism.
Hypoparathyroidism is further characterized by high serum phosphate and normal alkaline phosphatase.
In type I pseudohypoparathyroidism, despite the presence of a high concentration of circulating PTH, urinary cAMP and urinary phosphate are absent. Provocative testing by injection of parathyroid extract or recombinant human PTH fails to raise serum or urinary cAMP. Patients with type Ia pseudohypoparathyroidism frequently also have skeletal abnormalities, including short stature and shortened 1st, 4th, and 5th metacarpals. Patients with type Ib disease have renal manifestations without skeletal abnormalities.
In vitamin D deficiency, osteomalacia or rickets may be present, usually with typical skeletal abnormalities on x-ray. Diagnosis of vitamin D deficiency and dependency Diagnosis Inadequate exposure to sunlight predisposes to vitamin D deficiency. Deficiency impairs bone mineralization, causing rickets in children and osteomalacia in adults and possibly contributing... read more and measurement of vitamin D concentrations are discussed elsewhere.
Severe hypocalcemia can affect the ECG. It typically shows prolongation of the QTc and ST intervals. Changes in repolarization, such as T-wave peaking or inversion, also occur. ECG may show arrhythmia or heart block occasionally in patients with severe hypocalcemia. However, evaluation of isolated hypocalcemia does not mandate ECG testing.
Estimation of ionized calcium concentration
Ionized calcium concentration can be estimated from routine laboratory tests, usually with reasonable accuracy.
In hypoalbuminemia, measured serum calcium is often low, mainly reflecting a low concentration of protein-bound calcium, while ionized calcium can be normal. Measured total serum calcium decreases or increases by about 0.8 mg/dL (0.2 mmol/L) for every 1 g/dL decrease or increase in albumin. Thus, an albumin concentration of 2.0 g/dL (20 g/L) (normal, 4.0 g/dL [40 g/L]) should itself reduce measured serum calcium by 1.6 mg/dL (0.4 mmol/L).
Similarly, increases in serum proteins, as occur in multiple myeloma Multiple Myeloma Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations include lytic lesions in bones causing... read more , can raise total serum calcium. Acidosis increases ionized calcium by decreasing protein binding, whereas alkalosis decreases ionized calcium.
Treatment of Hypocalcemia
IV calcium gluconate for tetany
Oral calcium for postoperative hypoparathyroidism
Oral calcium and vitamin D for chronic hypocalcemia
For tetany, calcium gluconate 10 mL of 10% solution IV over 10 minutes is given. Response can be dramatic but may last for only a few hours. Repeated boluses or a continuous infusion with 20 to 30 mL of 10% calcium gluconate in 1 L of 5% dextrose in water (D/W) over the next 12 to 24 hours may be needed. Infusions of calcium are hazardous in patients receiving digoxin and should be given slowly and with continuous ECG monitoring after checking for (and correcting) hypokalemia Hypokalemia Hypokalemia is serum potassium concentration 3.5 mEq/L ( 3.5 mmol/L) caused by a deficit in total body potassium stores or abnormal movement of potassium into cells. The most common cause is... read more .
When tetany is associated with hypomagnesemia Hypomagnesemia Hypomagnesemia is serum magnesium concentration 1.8 mg/dL ( 0.70 mmol/L). Causes include inadequate magnesium intake and absorption or increased excretion due to hypercalcemia or drugs such... read more , it may respond transiently to calcium or potassium administration but is permanently relieved only by repletion of magnesium, typically given as a 10% magnesium sulfate solution (1 g/10 mL) IV, followed by oral magnesium salts (eg, magnesium gluconate 500 to 1000 mg orally 3 times a day).
Pearls & Pitfalls
In transient hypoparathyroidism after thyroidectomy or partial parathyroidectomy, supplemental oral calcium may be sufficient: 1 to 2 g of elemental calcium/day may be given as calcium gluconate (90 mg elemental calcium/1 g) or calcium carbonate (400 mg elemental calcium/1 g).
Subtotal parathyroidectomy may cause hypocalcemia that is particularly severe and prolonged, particularly in patients with chronic kidney disease or in patients from whom a large tumor was removed. Prolonged parenteral administration of calcium may be necessary postoperatively; supplementation with as much as 1 g/day of elemental calcium (eg, 111 mL/day of calcium gluconate, which contains 90 mg elemental calcium/10 mL) may be required for 5 to 10 days before oral calcium and vitamin D are sufficient. Elevated serum alkaline phosphatase in such patients may be a sign of rapid uptake of calcium into bone. The need for large amounts of parenteral calcium usually does not fall until the alkaline phosphatase concentration begins to decrease.
In chronic hypocalcemia, oral calcium and occasionally vitamin D supplements are usually sufficient: 1 to 2 g of elemental calcium/day may be given as calcium gluconate or calcium carbonate. In patients without renal failure or hypoparathyroidism, vitamin D is given as a standard oral supplement (eg, vitamin D3, cholecalciferol 20 mcg [800 IU] once/day). Vitamin D therapy is not effective unless adequate dietary or supplemental calcium and phosphate are also supplied.
For patients with renal failure, calcitriol or another vitamin D analog that does not require renal metabolic alteration (eg, alfacalcidiol, dihydrotachysterol) should be used. Patients with hypoparathyroidism also have difficulty converting cholecalciferol to its active form and also usually require calcitriol, usually 0.5 to 2 mcg orally once a day. Pseudohypoparathyroidism can occasionally be managed with oral calcium supplementation alone, but calcitriol at the above dose may be needed. Dihydrotachysterol is usually given orally at 0.8 to 2.4 mg once a day for a few days, followed by 0.2 to 1.0 mg once a day. Alfacalcidiol is not available in the US.
Use of vitamin D analogs can be complicated by vitamin D toxicity, with severe symptomatic hypercalcemia. Serum calcium concentration should be monitored weekly at first and then at 1- to 3-month intervals after calcium concentrations have stabilized. The maintenance dose of calcitriol or its analog, dihydrotachysterol, usually decreases with time.
Hypoparathyroidism that does not respond adequately to calcium and vitamin D supplementation may require treatment with recombinant parathyroid hormone (rhPTH 1-84), which also may decrease the risk of long-term hypoparathyroidism complications (eg, hypercalciuria, decreased bone strength), and lower the doses of calcium and vitamin D needed. Dosing of rhPTH 1-84 begins with 50 mcg subcutaneously once a day along with a decrease in vitamin D dosing by 50%. Serum calcium and phosphate are monitored closely, and the dose of rhPTH 1-84 is increased or decreased at intervals of several weeks as needed up to a maximum of 100 mcg once a day or down to 25 mcg once a day. Although rhPTH 1-34 also has been shown to be effective in treating chronic hypoparathyroidism, it is not approved for this use in the US.
Causes of hypocalcemia include hypoparathyroidism, pseudohypoparathyroidism, vitamin D deficiency, and renal failure.
Mild hypocalcemia may be asymptomatic or cause muscle cramps.
Severe hypocalcemia (serum calcium < 7 mg/dL [< 1.75 mmol/L]) may cause hyperreflexia, tetany (paresthesias of the lips, tongue, fingers, and feet, carpopedal and/or facial spasms, muscle aches), or generalized seizures.
Diagnose by estimation or measurement of ionized (not total) serum calcium.
Typically, measure serum concentrations of magnesium, phosphate, parathyroid hormone, alkaline phosphatase, and occasionally vitamin D levels.
Give IV calcium gluconate to patients with tetany; treat others with oral calcium supplements.
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