eMedicine Specialties > Emergency Medicine > Endocrine & Metabolic

Hypocalcemia

Author: Christopher B Beach, MD, FACEP, FAAEM, Assistant Professor and Vice Chair, Department of Emergency Medicine, Assistant Professor of Institute for Healthcare Studies, Institute for Patient Safety, Feinberg School of Medicine, Northwestern University
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Updated: Mar 9, 2009

Introduction

Background

Calcium regulation is critical for normal cell function, neural transmission, membrane stability, bone structure, blood coagulation, and intracellular signaling. The essential functions of this divalent cation continue to be elucidated, particularly in head injury/stroke and cardiopulmonary effects. Depending on the cause, unrecognized or poorly treated hypocalcemic emergencies can lead to significant morbidity or death.

Pathophysiology

Metabolic and endocrine emergencies require an understanding of normal physiology.

Calcium regulation is maintained by parathyroid hormone (PTH), vitamin D, and calcitonin through complex feedback loops. These compounds act primarily at bone, renal, and GI sites. Calcium also is affected by magnesium and phosphorus.

Distribution

Approximately 99% of calcium is found in bone, and 1% is found in extracellular fluid. Of this 1%, 50% is in the free (active) ionized form (1-1.15 mmol/L), 40% is bound to protein (predominantly albumin), and 10% is complexed with anions (eg, citrate).

Homeostasis is maintained by an extracellular to intracellular gradient, which is largely due to abundant high-energy phosphates intracellularly.

Intracellular calcium regulates cAMP-mediated messenger systems and most cell organelle functions. Ion pumps control levels.

Extracellular calcium levels are maintained at 8.7-10.4 mg/dL. Variations depend upon serum pH, protein and anion levels, and calcium-regulating hormone function.

Total body levels of calcium are controlled by a complex feedback system. PTH directly targets the bone and the kidneys to increase serum calcium levels. Indirectly, through vitamin D, it causes intestinal calcium absorption. Vitamin D directly targets GI absorption of calcium to increase calcium levels. Calcitonin lowers calcium by targeting bone, renal, and GI losses.

Frequency

United States

Epidemiology of hypocalcemia versus other electrolyte abnormalities has not been performed. During the last 20 years, laboratory tests have quantified serum and ionized calcium and PTH levels, enabling easier diagnosis. The incidence of ionized hypocalcemia is difficult to quantify, but it has been reported to be 15-50% for ICU patients. In a series of 500 postsurgical patients operated on for hyperparathyroidism, 2% had permanent hypocalcemia.¹

Mortality/Morbidity

Severe, symptomatic hypocalcemia may result in cardiovascular collapse, hypotension unresponsive to fluids and vasopressors, and dysrhythmias. Clinically evident hypocalcemia generally presents in milder forms and is usually the result of a chronic disease state. Chronic or subacute complaints secondary to mild or moderate hypocalcemia are more likely to be a chief complaint in the ED than severe symptomatic hypocalcemia.

• Neurologic sequelae (eg, tetany, seizures) may occur.
• Death is rare but has been reported.
• The disease causing hypocalcemia may have greater impact on morbidity than hypocalcemia itself.

Sex

The incidence in males and females is equal.

Age

Hypocalcemia spans all ages. The differential diagnosis varies depending on the age of the patient and the coexistent medical illnesses.

Clinical

History

• The patient may complain of muscle cramping, shortness of breath secondary to bronchospasm, tetanic contractions, distal extremity numbness, and tingling sensations.
• Chronic manifestations include cataracts, dry skin, coarse hair, brittle nails, psoriasis, chronic pruritus, and poor dentition.
• Acute hypocalcemia may lead to syncope, congestive heart failure (CHF), and angina due to the multiple cardiovascular effects.
• The patient's past medical history should be explored for pancreatitis, anxiety disorders, renal or liver failure, gastrointestinal disorders, and hyperthyroidism or hyperparathyroidism.
• The patient may have a recent history of thyroid, parathyroid, or bowel surgeries or recent neck trauma.
• Inquire about recent radiocontrast, estrogen, loop diuretics, bisphosphonates, calcium supplements, antibiotics, and antiepileptics.
• Evaluate for appropriate dietary intake.

Physical

Neuromuscular and cardiovascular findings predominate. Neural hyperexcitability due to acute hypocalcemia causes smooth and skeletal muscle contractions. The patient should be examined for the following:

• Dry skin and psoriasis (if long-term hypocalcemia)
• Perioral anesthesia, cataracts, papilledema, and laryngeal stridor
• Scars over thyroid region
• Recent trauma or surgery to the neck
• Cardiopulmonary effects
  • Wheezing, dysphagia, stridor, bradycardia, rales, and S₃ may be noted.
  • Acute hypocalcemia causes prolongation of the QT interval, which may lead to ventricular dysrhythmias. It also causes decreased myocardial contractility, leading to CHF, hypotension, and angina. Cardiomyopathy and ventricular tachycardia may be reversible with treatment.
  • Smooth muscle contraction may lead to laryngeal stridor, dysphagia, and bronchospasm.
• Smooth muscle contraction causes biliary colic, intestinal colic, and dysphagia.
• Diarrhea and/or gluten intolerance (celiac sprue) may result in significant malabsorption and electrolyte abnormalities.
• Preterm labor or detrusor dysfunction may result from smooth muscle contraction.
• Peripheral nervous system findings include tetany, focal numbness, and muscle spasms.
• Classic peripheral neurologic findings include the Chvostek sign and Trousseau sign.
  • Chvostek sign: Tap over the facial nerve about 2 cm anterior to the tragus of the ear. Depending on the calcium level, a graded response will occur: twitching first at the angle of the mouth, then by the nose, the eye, and the facial muscles.
  • Trousseau sign: Inflation of a blood pressure cuff above the systolic pressure causes local ulnar and median nerve ischemia, resulting in carpal spasm.
• Irritability, confusion, hallucinations, dementia, extrapyramidal manifestations, and seizures may occur.
  • Calcification of basal ganglia, cerebellum, and cerebrum may occur.
  • Seizures often occur in individuals with preexistent epileptic foci when the excitation threshold is lowered.

Causes

The causes of hypocalcemia include hypoalbuminemia, hypomagnesemia, hyperphosphatemia, multifactorial enhanced protein binding and anion chelation, medication effects, surgical effects, PTH deficiency or resistance, and vitamin D deficiency or resistance.

• Hypoalbuminemia is the most common cause of hypocalcemia and is due to cirrhosis, nephrosis, malnutrition, burns, chronic illness, and sepsis.
  • Calcium level should be corrected in hypoalbuminemic states and often is found to be normal.
  • Calcium level is corrected as follows: Corrected calcium (mg/dL) = measured total Ca (mg/dL) + 0.8 (4.4 - serum albumin [g/dL]), where 4.4 represents the average albumin level.

Note: For unknown reasons, calcium correction based on the above calculation may be inaccurate in geriatric patients. Ionized calcium levels should be obtained if hypocalcemia is considered to be clinically significant in a geriatric patient.

• Hypomagnesemia causes end-organ resistance to PTH and inhibits the hypocalcemic feedback loop through uncertain mechanisms. Causes of hypomagnesemia include pancreatitis, aminoglycoside treatment, amphotericin B, loop diuretics, alcoholism, and malnutrition.
• Hyperphosphatemia may be seen in critical illness and in patients who have ingested phosphate-containing enemas. Phosphate binds calcium avidly, causing acute hypocalcemia.
• Multifactorial causes are probably the most clinically relevant hypocalcemic emergencies in the ED and include the following:
  • Acute pancreatitis: Free fatty acids chelate calcium, causing saponification in the retroperitoneum.
  • Rhabdomyolysis: Increased phosphates from creatine phosphokinase (CPK) and other anions (ie, lactate, bicarbonate) chelate calcium.
  • Sepsis can cause hypocalcemia through many mechanisms.
  • Toxic shock syndrome can cause hypocalcemia.
  • High calcitonin levels cause low calcium.
  • Malignancy: Osteoblastic metastases (eg, breast cancer, prostate cancer) and tumor lysis syndrome may cause hypocalcemia (by differing mechanisms).
  • Hepatic or renal insufficiency: Calciuresis, hypomagnesemia, hypoalbuminemia, and low active vitamin D levels may contribute to poor calcium homeostasis.
  • Infiltrative disease: Sarcoidosis, tuberculosis, and hemochromatosis may infiltrate the parathyroids, causing dysfunction.
  • Toxicologic causes include hydrofluoric acid burn or ingestion.
• Enhanced protein binding and anion chelation
  • Protein binding is enhanced by elevated pH and free fatty acid release in high catecholamine states.
  • Anion chelation is seen in high phosphate states (eg, renal failure, rhabdomyolysis, mesenteric ischemia, oral administration of phosphate-containing enemas); high citrate states (eg, massive blood transfusion, radiocontrast dyes); and high bicarbonate, lactate, and oxalate levels.
• Medication effects
  • Proton pump inhibitors (PPIs) reduce gastric acid production resulting in reduced calcium absorption. An association with these medicines and an increased risk for hip fractures in elderly patients has been made due to decreased calcium absorption.
  • Selective serotonin inhibitors can have a calcium antagonistic effect on smooth muscle, particularly vascular endothelium.
  • Calcitonin and bisphosphonates cause chelation and end-organ inhibition.
  • Phenobarbital and phenytoin enhance vitamin D catabolism and decrease calcium resorption in the gut.
  • Foscarnet complexes with calcium.
  • Fluoride, particularly hydrofluoric acid, chelates calcium avidly and causes profound hypocalcemia.
  • Ethylene glycol complexes with calcium.
  • Estrogen inhibits bone resorption.
  • Cimetidine decreases gastric pH, slowing fat breakdown, which is necessary to complex calcium for gut absorption.
  • Aluminum and alcohol suppress PTH.
  • Gadolinium-based contrast material can falsely lower serum calcium levels and should be considered if levels are drawn shortly after magnetic resonance imaging.
• Postsurgical effects
  • Parathyroid adenoma resection causes a transient hypocalcemia due to end-organ PTH resistance in the first postoperative day.
  • Vascular/parathyroid injury may occur during trauma or as an operative mishap.
  • Pancreatectomy prevents calcium absorption in the duodenum and the jejunum by eliminating necessary enzymes.
  • Small bowel syndrome causes hypocalcemia by reducing the surface available to absorb fatty acids and calcium.
• PTH deficiency/resistance
  • Childhood/congenital causes are rare but include DiGeorge syndrome.
  • Idiopathic hypoparathyroidism interferes with calcium regulation.
  • Infiltrative diseases include Wilson disease and metastatic cancer.
  • Pseudohypoparathyroidism is due to PTH resistance and has many forms, most notably Albright disease.
  • Renal failure can result in a variety of endocrine disorders, occasionally including hypocalcemia.
• Vitamin D deficiency/resistance
  • Rickets may be due to lack of vitamin D or end-organ receptor resistance.
  • Hepatorenal disease: The liver and the kidney provide intermediary enzymes to form active 1,25(OH)₂ D.

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