Causes

Calcium homeostasis is maintained by vitamin D and parathyroid hormone (PTH), and the major causes of hypocalcemia are vitamin D deficiency and hypoparathyroidism.

The main dietary sources of vitamin D are fatty fish and fortified foods, such as milk. Vitamin D is also synthesized from 7-dehydrocholesterol in skin, when exposed to ultraviolet light. The liver metabolizes vitamin D to calcidiol (25-hydroxyvitamin D), which is then converted to calcitriol (1,25-dihydroxyvitamin D) in the kidney by a process stimulated by PTH and hypophosphatemia and inhibited by calcium and phosphate. Vitamin D deficiency can result from:

  • poor dietary intake
  • intestinal malabsorption
  • decreased hepatic production of calcidiol
  • increased hepatic metabolism of calcidiol to inactive metabolites (a process stimulated by enzyme-inducing antiepileptic drugs)
  • decreased renal production of calcitriol in patients with kidney failure

As plasma calcium concentration falls, PTH secretion increases, resulting in increased calcium release from bone (a process dependent on calcitriol) and enhanced renal production of calcitriol, which in turn increases calcium absorption in the gut and feeds back and inhibits further PTH secretion.

The ionized (free) calcium fraction, not protein-bound calcium, affects the excitability of muscle cells and neurons. The normal serum concentration of ionized calcium is 4.0-5.2 mg/dL, which represents slightly less than half of total serum calcium concentration. Symptomatic hypocalcemia is usually defined as an abnormal reduction in the serum ionized calcium concentration, or as a serum calcium level less than 7.5 mg/dL in the presence of normal levels of serum proteins. (The total serum calcium concentration is reduced approximately 0.8 mg/dL for every 1 g/dL reduction in serum albumin concentration.) Occasionally, symptomatic hypocalcemia can occur with normal total serum calcium concentration. For example, acute respiratory alkalosis causes increased protein binding of ionized calcium.

Hypocalcemia is a common finding in intensive care units, particularly among patients with pancreatitis, hypomagnesemia, and septic shock.38,39 It is also a frequent finding in the intensive care nursery, because neonatal hypocalcemia is usually associated with premature or difficult birth or perinatal asphyxia. It may also occur in newborns of mothers with diabetes or hyperparathyroidism or in small-for-gestational-age newborns.

Clinical presentation

The symptoms of hypocalcemia generally reflect the degree of hypocalcemia and the acuteness of the fall in serum ionized calcium concentration. Even slowly developing hypocalcemia may produce an encephalopathy, dementia, depression, or psychosis, however.

Acute hypocalcemia primarily causes neurologic symptoms because of increased neuromuscular excitability. Symptoms include:

  • numbness and tingling of the fingers, toes, and circumoral region
  • muscle cramping, stiffness
  • carpopedal spasm, tetany (flexor spasms in the arms and extensor spasms in the legs)
  • laryngeal stridor
  • tremor and chorea (may be misdiagnosed as seizures)
  • seizures

Hypocalcemic newborns may present with hypotonia, apnea, poor feeding, jitteriness, or seizures.

Seizures may or may not occur in conjunction with tetany. Types are generalized tonic-clonic, focal motor, and less frequently, atypical absence and akinetic seizures.3,40,41 They occur in 20-25% of patients presenting with hypocalcemia as a medical emergency42 and in 30-70% of patients with symptomatic hypoparathyroidism, usually in conjunction with tetany, altered mental status, and hypocalcemia.3

Tetany, which may be mistaken for motor seizures, results from spontaneous action potentials originating in peripheral nerves when the serum ionized calcium concentration falls below 4.3 mg/dL (usually corresponding to a total serum calcium concentration of 7.0-7.5 mg/dL). Tetany can also be induced by respiratory alkalosis, hypomagnesemia, and hypokalemia.43

Evaluation

The examination shows mental status changes, including irritability, depression, and psychosis. Papilledema may be present, as may Trousseau's and Chvostek's signs.

Trousseau's sign — carpal spasm due to regional ischemia to the hand — may be observed by inflating a blood pressure cuff on the upper arm above systolic pressure for 2 to 3 minutes. This sign is present in 6% of healthy persons and is also associated with alkalotic states, hypomagnesemia, hypokalemia, and hyperkalemia.

Chvostek's sign — contraction of the facial muscles, especially the upper lip or nasal alae, elicited by lightly tapping the facial nerve below the zygomatic arch — may also be present in healthy patients and absent in patients with chronic hypocalcemia.

The diagnosis of hypocalcemia should be confirmed by repeated measurement of serum calcium. If the diagnosis of hypocalcemia is uncertain (e.g., if the patient has hypoalbuminemia), serum ionized calcium should be measured for verification.

Other laboratory tests that may establish the underlying cause in selected patients are:

  • creatinine
  • amylase
  • magnesium
  • phosphate
  • PTH
  • calcidiol
  • calcitriol

Hyperphosphatemia with normal alkaline phosphatase and renal function are indicative of hypoparathyroidism, which may be confirmed by a low or undetectable PTH concentration. Hyperphosphatemia with elevated creatinine suggests renal failure. Normal or low serum phosphorus should prompt measurement of vitamin D metabolites and assessment of gastrointestinal function to check for vitamin D deficiency and malabsorption. In these situations, PTH levels are elevated because normal parathyroid glands attempt to compensate for hypocalcemia.

The electrocardiogram (ECG) may show prolongation of the Q-T interval, and the EEG may demonstrate slowing and generalized bursts of spikes.44

Treatment

Patients with symptomatic hypocalcemia should be treated immediately because of the high associated morbidity and mortality.39 Intravenous calcium is the most appropriate treatment, unless severe hypomagnesemia is present. Ten to 20 mL of 10% calcium gluconate (containing 10 mg of elemental calcium per mL) should be administered over 10 to 20 minutes. Calcium should not be given more rapidly because of the risk of serious cardiac dysfunction, including systolic arrest. (Patients taking cardiac glycosides are at particularly high risk.)

In less urgent settings, slow IV infusion (over 4-8 hours) of 20 mg/kg of elemental calcium may be given.

Hypomagnesemia is a common cause of hypocalcemia, because it can both induce resistance to PTH and diminish its secretion.39,45-47 Thus, if seizures continue despite adequate therapy with calcium replacement, hypomagnesemia should be investigated as the possible cause of the hypocalcemia and should be treated appropriately.

An infusion raises the serum calcium concentration for up to 3 hours, so additional slow infusions of calcium are usually necessary. The dose should be 0.5-1.5 mg/kg per hour. Either 10% calcium gluconate (90 mg of elemental calcium per 10-mL ampule) or 10% calcium chloride (360 mg per 10-mL ampule) can be used. The calcium should be diluted in dextrose and water or saline, because concentrated calcium solutions are irritating to veins. Calcium gluconate is less likely to cause tissue necrosis, if extravasated, than calcium chloride. Intramuscular injection of calcium gluconate is contraindicated because it can cause local necrosis.

Intravenous calcium should be continued until the patient is able to take an effective regimen of oral calcium and vitamin D. Calcitriol, in a dose of 0.25-0.50 mg per day, is the preferred preparation of vitamin D for patients with severe acute hypocalcemia, because of its rapid onset of action. Patients with hypoparathyroidism require chronic vitamin D and calcium therapy.40

Adapted from: Schachter SC and Lopez MR. Metabolic disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;195?208. With permission from Elsevier (www.elsevier.com).

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Reviewed By: 
Steven C. Schachter, MD
on: 
Wednesday, March 31, 2004