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By James L. Lewis, III, MD

(Hypocalcemia in neonates is discussed on see page Neonatal Hypocalcemia.)

Hypocalcemia is total serum Ca concentration < 8.8 mg/dL (< 2.20 mmol/L) in the presence of normal plasma protein concentrations or a serum ionized Ca concentration < 4.7 mg/dL (< 1.17 mmol/L). Causes include hypoparathyroidism, vitamin D deficiency, and renal disease. Manifestations include paresthesias, tetany, and, when severe, seizures, encephalopathy, and heart failure. Diagnosis involves measurement of serum Ca with adjustment for serum albumin concentration. Treatment is administration of Ca, sometimes with vitamin D.


Hypocalcemia has a number of causes, including

  • Hypoparathyroidism

  • Pseudohypoparathyroidism

  • Vitamin D deficiency and dependency

  • Renal disease


Hypoparathyroidism is characterized by hypocalcemia and hyperphosphatemia 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 h 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

  • 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) are present. Other inherited forms include polyglandular autoimmune failure syndrome, autoimmune hypoparathyroidism associated with mucocutaneous candidiasis, 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.

Patients with type Ia pseudohypoparathyroidism (Albright hereditary osteodystrophy) have a mutation in the stimulatory Gs-α1 protein of the adenylyl cyclase complex ( GNAS1 ). The result is failure of normal renal phosphaturic response or increase in urinary cAMP to PTH. Patients are usually hypocalcemic as a result of hyperphosphatemia. 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.

Less is known about type Ib pseudohypoparathyroidism. Affected patients have hypocalcemia, hyperphosphatemia, 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 Ca or urinary phosphate (PO4). An intracellular resistance to cAMP has been proposed.

Vitamin D deficiency and dependency

Vitamin D deficiency and dependency are discussed in full elsewhere (see page Vitamin D Deficiency and Dependency). 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. 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 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. 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 (see also Vitamin D Deficiency and Dependency).

Type I vitamin D–dependent rickets (pseudovitamin D–deficiency rickets) is an autosomal recessive disorder involving a mutation in the gene encoding the 1-α-hydroxylase enzyme. Normally expressed in the kidney, 1-α-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 disease

Renal tubular disease, including acquired proximal renal tubular acidosis due to nephrotoxins (eg, heavy metals) and distal renal tubular acidosis, can cause severe hypocalcemia due to abnormal renal loss of Ca and decreased renal conversion to 1,25(OH)2D. Cadmium, in particular, causes hypocalcemia by injuring proximal tubular cells and interfering with vitamin D conversion.

Renal failure can result in hypocalcemia due to diminished formation of 1,25(OH)2D from direct renal cell damage as well as suppression of 1-α-hydroxylase by hyperphosphatemia.

Other causes

Other causes of hypocalcemia include

  • Mg depletion (can cause relative PTH deficiency and end-organ resistance to PTH action, usually when serum Mg concentrations are < 1.0 mg/dL [< 0.5 mmol/L]; Mg repletion increases PTH concentrations and improves renal Ca conservation)

  • Acute pancreatitis (when lipolytic products released from the inflamed pancreas chelate Ca)

  • Hypoproteinemia (reduces the protein-bound fraction of serum Ca; hypocalcemia due to diminished protein binding is asymptomatic—because ionized Ca is unchanged, this entity has been termed factitious hypocalcemia)

  • Hungry bone syndrome (persistent hypocalcemia and hypophosphatemia occurring after surgical or medical correction of moderate to severe hyperparathyroidism in patients in whom serum Ca 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)

  • Septic shock (due to suppression of PTH release and decreased conversion of 25(OH)D to 1,25(OH)2D)

  • Hyperphosphatemia (causes hypocalcemia by poorly understood mechanisms; patients with renal failure and subsequent PO4 retention are particularly prone)

  • Drugs including anticonvulsants (eg, phenytoin, phenobarbital) and rifampin, which alter vitamin D metabolism, and drugs generally used to treat hypercalcemia (see page Hypercalcemia : Treatment)

  • Transfusion of > 10 units of citrate-anticoagulated blood and use of radiocontrast agents containing the divalent ion-chelating agent ethylenediaminetetraacetate (EDTA—can decrease the concentration of bioavailable ionized Ca while total serum Ca concentrations remain unchanged)

  • Infusion of gadolinium (may spuriously lower Ca concentration)

Although excessive secretion of calcitonin might be expected to cause hypocalcemia, low serum Ca concentrations rarely occur in patients with large amounts of circulating calcitonin due to medullary carcinoma of the thyroid.

Symptoms and Signs

Hypocalcemia is frequently asymptomatic. The presence of hypoparathyroidism is often suggested by the clinical manifestations of the underlying disorder (eg, short stature, round facies, intellectual disability, basal ganglia calcification in type Ia pseudohypoparathyroidism).

Major clinical manifestations of hypocalcemia are due to disturbances in cellular membrane potential, resulting in neuromuscular irritability.

Neurologic manifestations

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 Ca < 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 Ca 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 Ca 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 carpopedal spasm by reduction of the blood supply to the hand with a tourniquet or BP cuff inflated to 20 mm Hg above systolic BP applied to the forearm for 3 min. Trousseau sign also occurs in alkalosis, hypomagnesemia, hypokalemia, and hyperkalemia and in about 6% of people with no identifiable electrolyte disturbance.

Other manifestations

Many other abnormalities may occur 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 Ca.


  • Estimation or measurement of ionized Ca

  • Sometimes further testing with Mg, PTH, PO4, alkaline phosphatase, and vitamin D concentrations in blood and cAMP and PO4 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 Ca concentration < 8.8 mg/dL (< 2.20 mmol/L). However, because low plasma protein can lower total, but not ionized, serum Ca, ionized Ca should be estimated based on albumin concentration (see Estimation of Ionized Calcium Concentration). Suspicion of low ionized Ca mandates its direct measurement, despite normal total serum Ca. Hypocalcemic patients should undergo measurement of renal function (eg, BUN, creatinine), serum PO4, Mg, and alkaline phosphatase.

When no etiology (eg, alkalosis, renal failure, drugs, or massive blood transfusion) is obvious, further testing is needed (see Typical Laboratory Test Results in Some Disorders Causing Hypocalcemia). Additional testing begins with serum concentrations of Mg, PO4, PTH, alkaline phosphatase, and occasionally vitamin D levels (25(OH)D, and 1,25(OH)2D). Urinary PO4 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 should be elevated in 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 PO4 and normal alkaline phosphatase.

In type I pseudohypoparathyroidism, despite the presence of a high concentration of circulating PTH, urinary cAMP and urinary PO4 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 and measurement of vitamin D concentrations are discussed in Vitamin D Deficiency and Dependency.

Typical Laboratory Test Results in Some Disorders Causing Hypocalcemia



Surgical hypoparathyroidism

Low or low-normal PTH

Normal or high serum PO4

Low urinary PO4

Normal serum alkaline phosphatase

Idiopathic hypoparathyroidism

Undetectable PTH

High serum PO4

Low urinary PO4

Normal serum alkaline phosphatase

Type Ia pseudohypoparathyroidism (Albright hereditary osteodystrophy)

High PTH

High serum PO4

No urinary cAMP or increase in PO4 excretion even after injection of parathyroid extract or PTH

Skeletal and other abnormalities

Type Ib pseudohypoparathyroidism

High PTH

High serum PO4

No urinary cAMP or increase in PO4 excretion even after injection of parathyroid extract or PTH

No skeletal abnormalities

Type II pseudohypoparathyroidism

High PTH

High serum PO4

No urinary cAMP or PO4

Injection of PTH increases urinary cAMP but not urinary PO4

Normal or high vitamin D concentrations

Vitamin D deficiency

High PTH

Low serum PO4

High alkaline phosphatase

Low 25(OH)D*

Type I hereditary vitamin D–dependent rickets

High PTH

Low serum PO4

High alkaline phosphatase

X-ray evidence of rickets

Normal serum 25(OH)D

Low serum 1,25(OH)2D

Type II hereditary vitamin D–dependent rickets

High PTH

Low serum PO4

High alkaline phosphatase

X-ray evidence of rickets

Normal or high serum 25(OH)D

Normal or high 1,25(OH)2D

*Measurement of serum 25(OH)D and 1,25(OH)2D may help distinguish vitamin D deficiency from vitamin D–dependent states.

1,25(OH)2D = 1,25-dihydroxychoecalciferol or calcitriol ; 25(OH)D = inactive vitamin D; PO4= phosphate; PTH = parathyroid hormone.

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 hypocalcemia does not mandate ECG testing.


  • IV Ca gluconate for tetany

  • Oral Ca for postoperative hypoparathyroidism

  • Oral Ca and vitamin D for chronic hypocalcemia

For tetany, Ca gluconate 10 mL of 10% solution IV over 10 min 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% Ca gluconate in 1 L of 5% D/W over the next 12 to 24 h may be needed. Infusions of Ca are hazardous in patients receiving digoxin and should be given slowly and with continuous ECG monitoring. When tetany is associated with hypomagnesemia, it may respond transiently to Ca or K administration but is permanently relieved only by repletion of Mg, typically given as a 10% Mg sulfate (MgSO4) solution (1 g/10 mL) IV, followed by oral Mg salts (eg, Mg gluconate 500 to 1000 mg po tid).

In transient hypoparathyroidism after thyroidectomy or partial parathyroidectomy, supplemental oral Ca may be sufficient: 1 to 2 g of elemental Ca/day may be given as Ca gluconate (90 mg elemental Ca/1 g) or Ca carbonate (400 mg elemental Ca/1 g). However, hypocalcemia may be particularly severe and prolonged after subtotal parathyroidectomy, particularly in patients with chronic kidney disease or in patients from whom a large tumor was removed. Prolonged parenteral administration of Ca may be necessary postoperatively; supplementation with as much as 1 g/day of elemental Ca (eg, 111 mL of Ca gluconate, which contains 90 mg elemental Ca/10 mL) may be required for 5 to 10 days before oral Ca and vitamin D are sufficient. Elevated serum alkaline phosphatase in such patients may be a sign of rapid uptake of Ca into bone. The need for large amounts of parenteral Ca usually does not fall until the alkaline phosphatase concentration begins to decrease.

In chronic hypocalcemia, oral Ca and occasionally vitamin D supplements are usually sufficient: 1 to 2 g of elemental Ca/day may be given as Ca gluconate or Ca carbonate. In patients without renal failure, vitamin D is given as a standard oral supplement (eg, cholecalciferol 800 IU once/day). Vitamin D therapy is not effective unless adequate dietary or supplemental Ca and PO4 (see page Hypophosphatemia : Treatment) are supplied.

For patients with renal failure, calcitriol or another 1,25(OH)2D analog is used because these drugs require no renal metabolic alteration. Patients with hypoparathyroidism have difficulty converting cholecalciferol to its active form and also usually require calcitriol, usually 0.5 to 2 μg po once/day. Pseudohypoparathyroidism can occasionally be managed with oral Ca supplementation alone. When used, calcitriol requires 1 to 3 μg/day.

Vitamin D analogs include dihydrotachysterol (usually given orally at 0.8 to 2.4 once/day for a few days, followed by 0.2 to 1.0 mg once/day) and calcidiol (eg, 4000 to 6000 IU po once/wk). Use of vitamin D analogs, particularly the longer-acting calcidiol, can be complicated by vitamin D toxicity, with severe symptomatic hypercalcemia. Serum Ca concentration should be monitored weekly at first and then at 1- to 3-mo intervals after Ca concentrations have stabilized. The maintenance dose of calcitriol or its analog, dihydrotachysterol, usually decreases with time.

Key Points

  • Causes of hypocalcemia include hypoparathyroidism, pseudohypoparathyroidism, vitamin D deficiency, and renal failure.

  • Mild hypocalcemia may be asymptomatic or cause muscle cramps.

  • Severe hypocalcemia (serum Ca < 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 Ca.

  • Typically, measure serum concentrations of Mg, PO4, PTH, alkaline phosphatase, and occasionally vitamin D levels.

  • Give IV Ca gluconate to patients with tetany; treat others with oral Ca supplements.

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