Hypocalcemia is a state of low serum calcium levels (total Ca2+ < 8.5 mg/dL or ionized Ca2+ < 4.65 mg/dL). Total calcium comprises physiologically-active ionized calcium as well as anion-bound and protein-bound, physiologically-inactive calcium. Calcium plays an important role in various cellular processes in the body, such as stabilizing the resting membrane potential of cells, cell signaling, coagulation, and hormone release. In addition to hormonal control by parathyroid hormone (PTH) and calcitriol, calcium homeostasis is also influenced by serum protein levels and acid-base status, both of which impact the ratio of protein-bound Ca2+ to ionized Ca2+ in the serum. Severity and chronicity of calcium deficiency in addition to the patient's age and comorbidities contribute to the overall clinical presentation of hypocalcemia. Symptoms are variable; the most characteristic features include prolongation of the QT interval and signs of neuromuscular excitation (e.g., tetany, carpopedal spasm, paresthesias). Management consists of calcium supplementation and identifying and treating the underlying cause.
- Hypocalcemia: total serum calcium concentration < 8.5 mg/dL (< 2.12 mmol/L), or ionized (free) calcium concentration < 4.65 mg/dL (< 1.16 mmol/L) 
- Severe hypocalcemia: total serum calcium concentration ≤ 7.5 mg/dL (< 1.9 mmol/L), or ionized (free) calcium concentration < 3.6 mg/dL (< 0.9 mmol/L) 
- Factitious hypocalcemia: an asymptomatic decrease in with a normal ionized Ca2+ level (typically occurs due to low serum protein levels)
Total and ionized calcium concentrations
Total calcium: the total amount of calcium circulating in the serum, comprising protein-bound, anion-bound, and
- Approx. 40% of the total serum calcium is bound to proteins (mostly albumin) and is physiologically inactive. 
- (due to, e.g., nephrotic syndrome, liver cirrhosis, severe malnutrition, malabsorption) → ↓ total Ca2+ level but ionized Ca2+ level is unaffected; →
- pH influences the binding of calcium to serum proteins.
- Ionized calcium: the calcium fraction that is not bound to any proteins but is physiologically active
The physiological role of calcium 
- Ionized Ca2+ is responsible for stabilizing the resting membrane potential of cells.
- Acts as a second messenger in signaling pathways
- Cofactor for several enzymes (e.g., phospholipase A, gamma-glutamyltransferase)
- Required for the promotion of coagulation pathways
|Effect on serum [calcium]||Effect on serum [phosphate]||Mechanism of action||Regulation|
|Parathyroid hormone||↑|| |
|Calcitriol (vitamin D3)||↑||↑|
To remember that calcitonin keeps the calcium in the bones, think: Calci-bone-in!
|Types of hypocalcemia||Etiology||Pathophysiology|
|High PTH ()||Vitamin D deficiency|
|Chronic kidney disease|
|Acute necrotizing pancreatitis (see )|| |
|Multiple blood transfusions and hemolysis|
|Hypomagnesemia (see )|
|Renal tubular disorders|| |
|Hungry bone syndrome|
Manifestations of hypocalcemia are influenced by the severity and chronicity of the hypocalcemia as well as by the patient's age and comorbidities.
Neurological manifestations 
Tetany: increased neuromuscular excitability (when caused by respiratory alkalosis = hyperventilation-induced tetany)
- Paresthesias: typically tingling or pins-and-needles sensation in extremities and/or in the perioral area
- Spasms (e.g., carpopedal spasm , bronchospasm or laryngospasm ), and cramps (possible in any muscle)
- Stiffness, myalgia
- Maneuvers to elicit latent tetany on physical exam
- Chvostek sign: short contractions (twitching) of the facial muscles elicited by tapping the facial nerve below and in front of the ear (∼ 2 cm ventral to the ear lobe) 
- Trousseau sign: ipsilateral carpopedal spasm occurring several minutes after inflation of a blood pressure cuff to pressures above the systolic blood pressure 
- Seizure: may be the initial or only symptom 
Signs of neuromuscular irritability (e.g., paresthesias, spasms and cramps) are the most characteristic features of hypocalcemia.
Cardiovascular manifestations 
- Congestive heart failure
- Cardiac arrhythmias (symptoms may include palpitations, irregular pulse, syncope)
Manifestations of chronic hypocalcemia 
- Psychiatric manifestations (variable and usually mild; may be reversible), such as emotional instability, anxiety, depression, confusion/delirium, hallucinosis, or psychosis
- Ophthalmologic manifestations: papilledema (in severe cases), cataracts, calcifications of the cornea
- Neurological manifestations: pseudotumor cerebri, paradoxical CNS calcifications
- Dental changes: altered morphology, dental enamel hypoplasia
- Growth plate abnormalities and osteomalacia
- Confirm hypocalcemia: Order total and ionized calcium or correct serum calcium for albumin level
- Determine etiology
- In cases of evident etiology (e.g., postsurgical hypocalcemia after thyroidectomy, hypomagnesemia, critically ill patients), no further diagnostic workup is needed 
- Non-evident cause: Obtain serum intact PTH level.
Acute symptomatic hypocalcemia is a medical emergency that is potentially fatal, diagnostics should not delay treatment.
Laboratory studies 
- Confirm true hypocalcemia
- Evaluate for other electrolyte abnormalities
- Serum intact PTH:
- Further serum studies: conducted based on clinical suspicion
- Urine studies: 24-hour urinary excretion of calcium and magnesium
|Interpretation of laboratory findings in hypocalcemia |
|PTH level||Additional findings||Conditions|
|Low PTH|| |
- Recommended in severe/symptomatic cases
- Possible findings: papilledema 
The mainstay of therapy of hypocalcemia consists of calcium supplementation and the treatment of the underlying cause.
Calcium supplementation 
Calcium supplementation should be provided based on severity. See “Repletion regimens for hypocalcemia” for more details on calcium supplementation with specific dosages.
- Severe and/or symptomatic hypocalcemia: e.g., tetany, seizures, prolonged QT interval, serum calcium ≤ 7.5 mg/dL (< 1.9 mmol/L)
- Mild and/or chronic hypocalcemia: no symptoms or only mild neuromuscular irritability (e.g., paresthesias), serum calcium 7.6–8.4 mg/dL (1.9–2.12 mmol/L)
Treatment of the underlying condition
- Secondary to loop diuretics: consider discontinue loop diuretic and change medication to thiazides
- Vitamin D deficiency: vitamin D supplementation
- Hypomagnesemia-induced hypocalcemia: magnesium supplementation (See “Repletion regimens for hypomagnesemia”)
- Hyperphosphatemia in chronic kidney disease: calcium supplementation
Loop diuretics Lose calcium. Discontinue them in hypocalcemia.
|Overview of neonatal hypocalcemia |
|Early hypocalcemia||Late hypocalcemia|
|Onset|| || |
|Clinical features|| || |
|Diagnosis || |
Preterm infants < 1500 g