What are the causes of hypocalcemia?

Causes of Hypocalcemia

Hypocalcemia results from either PTH-mediated or non-PTH-mediated mechanisms, with post-surgical hypoparathyroidism being the single most frequent cause (75% of all hypoparathyroidism cases), followed by vitamin D deficiency and disorders of vitamin D metabolism. 1

PTH-Mediated Causes (Low or Inappropriately Normal PTH)

Post-Surgical Hypoparathyroidism

• Accounts for 75% of all hypoparathyroidism cases, occurring after anterior neck surgery including thyroidectomy or parathyroidectomy 1
• Represents the most common overall cause of chronic hypocalcemia 1

Primary Hypoparathyroidism (25% of cases)

• Autoimmune destruction of parathyroid glands 1
• Genetic abnormalities affecting parathyroid development or function 1
• 22q11.2 deletion syndrome carries an 80% lifetime prevalence of hypocalcemia due to underlying parathyroid dysfunction and can emerge at any age 2, 3
• Infiltrative disorders of the parathyroids 1

Magnesium Deficiency

• Impairs PTH secretion and creates PTH resistance—hypocalcemia will not resolve until magnesium levels are corrected 2, 3
• This is a critical pitfall: calcium supplementation will be ineffective without adequate magnesium 3

Non-PTH-Mediated Causes (Elevated PTH)

Vitamin D Deficiency and Metabolism Disorders

• Impaired production of 1,25-dihydroxyvitamin D reduces intestinal calcium absorption, which is the primary mechanism for maintaining calcium balance 3
• Decreased vitamin D activation compounds hypocalcemia by reducing duodenal and jejunal calcium absorption 1

Chronic Kidney Disease

• Phosphate retention leads to decreased ionized calcium, which stimulates compensatory PTH release and causes secondary hyperparathyroidism 4, 1, 3
• Reduced vitamin D activation in diseased kidneys decreases intestinal calcium absorption 4, 1
• Impaired passive intestinal calcium absorption can be partially compensated by increasing calcium intake 1

Post-Parathyroidectomy Hungry Bone Syndrome

• Rapid bone remineralization after correction of hyperparathyroid bone disease 1
• Bones avidly take up calcium after prolonged hyperparathyroid state is corrected 1

Medication-Induced Hypocalcemia

Bisphosphonates and Denosumab

• Can cause severe hypocalcemia, particularly in patients with vitamin D deficiency or renal impairment 1, 5
• Denosumab (RANKL inhibitor) directly suppresses bone resorption, increasing hypocalcemia risk especially in patients with creatinine clearance <30 mL/min 3
• Risk is related to the potency of the bisphosphonate administered 5

Diuretics and Other Medications

• Loop diuretics induce hypocalcemia through increased urinary calcium excretion 2, 3
• Calcium channel blockers may reduce calcium levels by affecting calcium homeostasis 2
• Antipsychotic medications can precipitate hypocalcemia, particularly in vulnerable patients 2
• Antiepileptics (particularly phenytoin) can impair vitamin D metabolism 5
• Aminoglycosides and proton pump inhibitors may contribute to hypocalcemia 6

Citrate in Blood Transfusions

• Citrate in blood products chelates calcium and causes acute hypocalcemia during massive transfusion—ionized calcium below 0.9 mmol/L predicts mortality better than fibrinogen, acidosis, or platelet count 1, 3

Precipitating Factors and High-Risk Situations

Biological Stressors

• Surgery, fractures, injuries, childbirth, and infection increase hypocalcemia risk in patients with underlying parathyroid dysfunction 1, 2, 3
• Perioperative periods represent particularly vulnerable times for calcium decompensation 1, 2
• Fever, ischemia, and hypoxia can trigger hypocalcemic episodes 2
• Acute illness of any type increases vulnerability 2
• Puberty and pregnancy are high-risk periods for hypocalcemia manifestation 1, 2

Dietary and Lifestyle Factors

• Decreased oral calcium intake contributes to hypocalcemia 1, 2
• Alcohol consumption worsens hypocalcemia 1, 2, 3
• Carbonated beverages, especially colas, may exacerbate hypocalcemia 1, 2, 3

Critical Diagnostic Pitfalls to Avoid

Measurement Considerations

• Always measure pH-corrected ionized calcium (most accurate) rather than total calcium alone, as a 0.1 unit increase in pH decreases ionized calcium by approximately 0.05 mmol/L 1, 2, 3
• Acid-base status significantly affects ionized calcium measurements 1

Essential Laboratory Workup

• Check magnesium levels in all hypocalcemic patients—magnesium deficiency must be corrected first 2, 3
• Check PTH levels to distinguish between PTH-mediated (low/normal PTH) and non-PTH-mediated (elevated PTH) causes 1, 3
• Evaluate vitamin D status (25-OH vitamin D levels) in all patients with hypocalcemia 1, 3
• Assess renal function (creatinine) to evaluate for potential kidney damage 1

Clinical Recognition Challenges

• Hypocalcemia can occur at any age in patients with underlying parathyroid dysfunction, even without prior history of hypocalcemia or seizures 1, 2
• Symptoms may be subtle and confused with psychiatric conditions such as anxiety or depression 1, 2
• Hyperprolinemia, seen in some genetic syndromes, can contribute to seizure risk independent of calcium levels 2