Hypocalcemia

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) ^[1]
• 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) ^[2]
• Factitious hypocalcemia: an asymptomatic decrease in total calcium 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 ionized calcium
  • Approx. 40% of the total serum calcium is bound to proteins (mostly albumin) and is physiologically inactive. ^[3]
  • Hypoproteinemia (due to, e.g., nephrotic syndrome, liver cirrhosis, severe malnutrition, malabsorption) → ↓ total Ca²⁺ level but ionized Ca²⁺ level is unaffected; → factitious hypocalcemia
  • pH influences the binding of calcium to serum proteins.
    • ↑ pH → ↓ H⁺ in serum binding to proteins → ↑ Ca²⁺ binding to proteins → ↓ ionized Ca²⁺ concentration compensatory ↑ PTH
    • ↓ pH → ↑ H⁺ in serum binding to proteins → ↓ Ca²⁺ binding to proteins → ↑ ionized Ca²⁺ concentration compensatory ↓ PTH
• Ionized calcium: the calcium fraction that is not bound to any proteins but is physiologically active
  • ∼ 45% of the total serum calcium ^[3]
  • Functions as the main regulator of PTH secretion
  • PTH secretion is influenced by pH variations but not by changes in albumin levels.
  • An excess causes true hypercalcemia whereas a deficiency causes true hypocalcemia.

To remember the effect pH has on PTH, think: ↑ pH = ↑ PTH and ↓ pH = ↓ PTH.

The physiological role of calcium ^[4]

• Ionized Ca²⁺ is responsible for stabilizing the resting membrane potential of cells.
  • ↓ Serum Ca²⁺ → ↑ membrane excitability
  • ↑ Serum Ca²⁺ → ↓ membrane excitability
• 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

Calcium homeostasis

Calcium homeostasis is a complex process, involving many organs (kidneys, gastrointestinal tract, bones, liver, and skin) and hormones (PTH, calcitonin, vitamin D).

The acronym “PTH” describes the action of parathyroid hormone: P = Phosphate T = Trashing H = Hormone.

To remember that calcitonin keeps the calcium in the bones, think: Calci-bone-in!

References:^{[5][6][7][8][9][10]}

Hypocalcemia is most often due to hypoparathyroidism or vitamin D deficiency (e.g., malabsorption, chronic kidney disease).

Suspect hypocalcemia in the postoperative thyroidectomy patient with new-onset paresthesias and muscle spasms or cramping.

References:^{[6][8][11][12]}

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 ^{[1][13][14][15]}

• 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) ^[1]
    • Trousseau sign: ipsilateral carpopedal spasm occurring several minutes after inflation of a blood pressure cuff to pressures above the systolic blood pressure ^[1]
• Seizure: may be the initial or only symptom ^[14]

Signs of neuromuscular irritability (e.g., paresthesias, spasms and cramps) are the most characteristic features of hypocalcemia.

Cardiovascular manifestations ^{[1][13][14][15]}

• Congestive heart failure
• Hypotension
• Cardiac arrhythmias (symptoms may include palpitations, irregular pulse, syncope)

Manifestations of chronic hypocalcemia ^{[1][13][14][15]}

• 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

Approach

• Confirm hypocalcemia: Order total and ionized calcium or correct serum calcium for albumin level
• Determine etiology: Obtain serum intact PTH level.
  • Elevated PTH levels: Consider and investigate other causes (e.g., renal failure, vitamin D deficiency, medication side effects, familial or genetic disorders).
  • Normal or low PTH levels: hypoparathyroidism is the likely cause.

Acute symptomatic hypocalcemia is a medical emergency that is potentially fatal, diagnostics should not delay treatment.

Laboratory studies ^[2][13]

Routine studies

• Confirm true hypocalcemia
  • Measure total and ionized calcium
  • AND/OR check serum albumin and calculate corrected calcium
• Evaluate for other electrolyte abnormalities
  • BMP
  • Serum phosphate and magnesium
• ABG/VBG

Additional studies

• Serum intact PTH:
  • Indication: best initial study for confirmed hypocalcemia with no clear etiology
  • Interpretation
    • Low (or normal) PTH suggests hypoparathyroidism
    • High PTH suggests parathyroid gland function is preserved
• Further serum studies: conducted based on clinical suspicion
  • Alkaline phosphatase
  • Amylase
  • 25-hydroxyvitamin D (calcidiol)
• Urine studies: 24-hour urinary excretion of calcium and magnesium

The typical laboratory findings of vitamin D deficiency are ↓ calcium, ↓ (or normal) phosphate, and ↑ PTH.

ECG

• Indication: acute, severe, and/or symptomatic hypocalcemia
• ECG findings of hypocalcemia include: ^[14]
  • Prolonged QT interval
  • Ventricular arrhythmias: torsades de pointes, ventricular tachycardia, ventricular fibrillation
  • QRS complex and ST-segment changes (may mimic myocardial infarction)
  • AV block

Fundoscopy

• Recommended in severe/symptomatic cases
• Possible findings: papilledema ^[15]

The mainstay of therapy of hypocalcemia consists of calcium supplementation and the treatment of the underlying cause.

Calcium supplementation ^[2]

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)
  • IV calcium supplementation: calcium gluconate or calcium chloride
  • Continuous telemetry ^[2]
  • Consider transfer to critical care unit
• 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)
  • Oral calcium supplementation: calcium citrate, calcium carbonate

IV calcium can trigger life threatening arrhythmias in patients simultaneously receiving cardiac glycosides (digoxin or digitoxin). ^[1]

Treatment of the underlying condition

• Hypoparathyroidism
  • Calcium supplementation (See “Repletion regimens for hypocalcemia” and “Treatment” in “Hypoparathyroidism”)
  • PLUS vitamin D supplementation
• 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.

Neonatal hypocalcemia