Causes of Hypocalcemia
Primary Etiologic Categories
Hypocalcemia results from either PTH-mediated or non-PTH-mediated mechanisms, with hypoparathyroidism being the single most frequent cause, followed by vitamin D deficiency and disorders of vitamin D metabolism 1.
PTH-Mediated Causes (Low or Inappropriately Normal PTH)
Post-Surgical Hypoparathyroidism
- Represents 75% of all hypoparathyroidism cases, occurring after anterior neck surgery including thyroidectomy or parathyroidectomy 1.
- This is the most common cause of chronic hypocalcemia overall 1.
Primary Hypoparathyroidism
- Accounts for 25% of hypoparathyroidism cases and includes autoimmune destruction, genetic abnormalities, and infiltrative disorders of the parathyroids 1.
Genetic Disorders
- 22q11.2 deletion syndrome carries an 80% lifetime prevalence of hypocalcemia due to underlying parathyroid dysfunction and can emerge at any age, even after apparent childhood resolution 1, 2.
- This genetic syndrome requires heightened surveillance during biological stress periods throughout life 1.
Magnesium Deficiency
- Hypomagnesemia impairs PTH secretion and creates PTH resistance—hypocalcemia will not resolve until magnesium levels are corrected 2.
- Magnesium deficiency is present in 28% of hypocalcemic patients 3.
- Alcohol consumption is a common precipitant of hypomagnesemia, which subsequently leads to hypocalcemia 1.
Non-PTH-Mediated Causes (Elevated PTH)
Vitamin D Deficiency and Disorders of Vitamin D Metabolism
- Impaired production of 1,25-dihydroxyvitamin D reduces intestinal calcium absorption, which is the primary mechanism for maintaining calcium balance 2.
- Vitamin D deficiency should be corrected with native vitamin D (cholecalciferol or ergocalciferol) supplementation 1.
Chronic Kidney Disease
- In CKD, phosphate retention leads to decreased ionized calcium, which stimulates PTH release and causes secondary hyperparathyroidism 1, 2.
- Reduced vitamin D activation in diseased kidneys decreases duodenal and jejunal calcium absorption 1.
- Impaired passive intestinal calcium absorption can be partially compensated by increasing calcium intake 1.
Medication-Induced Hypocalcemia
Diuretics
Bone-Targeted Therapies
- Bisphosphonates and denosumab can cause severe hypocalcemia, particularly in patients with vitamin D deficiency or renal impairment 1.
- Denosumab (RANKL inhibitor) directly suppresses bone resorption, increasing hypocalcemia risk especially in patients with impaired renal function (creatinine clearance <30 mL/min) 2.
- Patients on bisphosphonate therapy should receive oral calcium and vitamin D3 supplementation to prevent severe hypocalcemia 1.
Calcium Channel Blockers
- Calcium channel blockers may potentially reduce calcium levels by affecting calcium homeostasis 1.
Iatrogenic and Acute Causes
Post-Parathyroidectomy Hungry Bone Syndrome
- Rapid bone remineralization after correction of hyperparathyroid bone disease causes acute hypocalcemia 1.
Massive Transfusion
- Citrate in blood transfusions chelates calcium and causes acute hypocalcemia—ionized calcium below 0.9 mmol/L predicts mortality better than fibrinogen, acidosis, or platelet count 2.
- Citrate metabolism may be impaired by hypoperfusion, hypothermia, and hepatic insufficiency 1.
- Early hypocalcemia following traumatic injury correlates with the amount of colloids and blood products infused 3.
Precipitating Factors and High-Risk Situations
Biological Stressors
- Surgery, fractures, injuries, childbirth, infection, fever, ischemia, and hypoxia increase hypocalcemia risk in patients with underlying parathyroid dysfunction 1, 2.
- Perioperative periods, acute illness, puberty, and pregnancy are also risk factors for hypocalcemia 1.
Dietary and Lifestyle Factors
- Alcohol consumption worsens hypocalcemia 1, 2.
- Carbonated beverages, especially colas, may exacerbate hypocalcemia 1, 2.
- Decreased oral calcium intake can contribute to hypocalcemia 1.
Critical Diagnostic Pitfalls
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.
Essential Concurrent Testing
- Check magnesium levels in all hypocalcemic patients—magnesium deficiency must be corrected first, as calcium supplementation will be ineffective without adequate magnesium 1, 2.
- Check PTH levels to distinguish between PTH-mediated (low/normal PTH) and non-PTH-mediated (elevated PTH) causes 1, 2.
- Evaluate vitamin D status (25-OH vitamin D levels) in all patients with hypocalcemia 1, 2.
- Assess renal function (creatinine) to evaluate for potential kidney damage 1.
- Monitor thyroid function, as hypothyroidism may be associated with hypocalcemia 1.