What are the causes of hypocalcaemia?

Causes of Hypocalcemia

Hypocalcemia results from either inadequate parathyroid hormone (PTH) or vitamin D, resistance to these hormones, or conditions that sequester or eliminate calcium from the circulation. 1, 2

PTH-Mediated Causes (Low or Inappropriately Normal PTH)

Hypoparathyroidism

• Postsurgical hypoparathyroidism is the most common cause of chronic hypocalcemia, occurring after anterior neck surgery including thyroidectomy or parathyroidectomy 2, 3
• Genetic disorders, particularly 22q11.2 deletion syndrome, carry an 80% lifetime prevalence of hypocalcemia due to underlying parathyroid dysfunction and can emerge at any age 1, 4
• Autoimmune destruction of the parathyroid glands causes hypoparathyroidism 3
• Infiltrative disorders (hemochromatosis, Wilson's disease, metastatic disease) can destroy parathyroid tissue 3

Impaired PTH Secretion

• Magnesium deficiency impairs PTH secretion and creates PTH resistance—hypocalcemia will not resolve until magnesium levels are corrected 1, 4
• Severe hypermagnesemia can paradoxically suppress PTH secretion 3

PTH Resistance

• Pseudohypoparathyroidism is characterized by elevated PTH levels but end-organ resistance, resulting in hypocalcemia and hyperphosphatemia 3
• Activating mutations of the calcium-sensing receptor cause inappropriate suppression of PTH despite low calcium 3

Non-PTH-Mediated Causes (Normal or Elevated PTH)

Vitamin D Deficiency or Resistance

• Impaired production of 1,25-dihydroxyvitamin D reduces intestinal calcium absorption, which is the primary mechanism for maintaining calcium balance 4, 5
• Decreased vitamin D activation in chronic kidney disease compounds hypocalcemia by reducing intestinal calcium absorption 6, 4
• Vitamin D-dependent rickets (genetic defects in vitamin D metabolism or receptor function) causes hypocalcemia despite adequate vitamin D intake 5

Chronic Kidney Disease

• In CKD, phosphate retention leads to decreased ionized calcium, which stimulates PTH release and causes secondary hyperparathyroidism 6, 1
• Three interrelated mechanisms explain CKD-associated hypocalcemia: phosphate retention, skeletal resistance to the calcemic action of PTH, and altered vitamin D metabolism 6
• Progressive loss of kidney function decreases vitamin D receptors (VDR) and calcium-sensing receptors (CaR) in parathyroid glands, rendering them resistant to vitamin D and calcium 6

Medication-Induced Hypocalcemia

• Loop diuretics induce hypocalcemia through increased urinary calcium excretion 1, 4
• Calcium channel blockers may reduce calcium levels by affecting calcium homeostasis 1, 4
• Denosumab (RANKL inhibitor) directly suppresses bone resorption, increasing hypocalcemia risk, particularly in patients with impaired renal function (creatinine clearance <30 mL/min) 7
• Bisphosphonates can cause hypocalcemia, especially in patients with vitamin D deficiency or renal insufficiency 8
• Antipsychotic medications can precipitate hypocalcemia in vulnerable patients 4
• Citrate in blood transfusions 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

Calcium Sequestration or Loss

• Acute pancreatitis causes calcium deposition in necrotic fat (saponification) 5
• Tumor lysis syndrome releases phosphate, which binds calcium 8
• Osteoblastic metastases (particularly prostate cancer) sequester calcium in bone 8
• Hungry bone syndrome after parathyroidectomy causes rapid calcium uptake into previously suppressed bone 5

Precipitating Factors and High-Risk Situations

Biological Stress

• Surgery, fractures, injuries, childbirth, infection, fever, ischemia, and hypoxia increase hypocalcemia risk in patients with underlying parathyroid dysfunction 1, 4
• Perioperative periods, acute illness, puberty, and pregnancy are particularly vulnerable times for calcium decompensation 1, 4

Dietary and Lifestyle Factors

• Decreased oral calcium intake contributes to hypocalcemia 1, 4
• Alcohol consumption worsens hypocalcemia 1, 4
• Carbonated beverages, especially colas, may exacerbate hypocalcemia 1, 4

Critical Diagnostic Pitfalls

• 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, 4
• Check magnesium levels in all hypocalcemic patients—magnesium deficiency must be corrected first, as calcium supplementation will be ineffective without adequate magnesium 1, 7
• Hypocalcemia symptoms may be confused with psychiatric conditions such as anxiety or depression 1, 4
• Check PTH levels to distinguish between PTH-mediated (low/normal PTH) and non-PTH-mediated (elevated PTH) causes 1
• Assess renal function (creatinine) and phosphorus levels to evaluate for CKD and guide treatment 1
• Evaluate vitamin D status (25-OH vitamin D levels) in all patients with hypocalcemia 1