What are the differentials for hypocalcemia?

Differential Diagnosis of Hypocalcemia

Hypocalcemia has two major mechanistic categories: PTH-mediated (hypoparathyroidism) and non-PTH-mediated causes, with the most common etiology being postsurgical hypoparathyroidism, followed by chronic kidney disease, vitamin D deficiency, and hypomagnesemia. 1, 2

PTH-Mediated Causes (Hypoparathyroidism)

Surgical/Iatrogenic

• Postsurgical hypoparathyroidism is the most frequent cause of hypocalcemia overall, occurring after anterior neck surgery (thyroidectomy, parathyroidectomy, radical neck dissection) 2, 3

Genetic/Congenital Disorders

• 22q11.2 deletion syndrome carries an 80% lifetime prevalence of hypocalcemia due to parathyroid dysfunction and can manifest at any age, even without prior neonatal hypocalcemia 1, 4
• Other genetic abnormalities affecting parathyroid development or function 3

Autoimmune

• Autoimmune destruction of parathyroid glands, often part of polyglandular autoimmune syndromes 3

Infiltrative/Destructive

• Infiltration of parathyroid glands by granulomatous disease, malignancy, or hemochromatosis 3
• Radiation damage to parathyroid glands 3

Functional Impairment

• Hypomagnesemia impairs PTH secretion and creates PTH resistance; hypocalcemia will not resolve until magnesium is corrected 5, 4
• Hypermagnesemia can also impair PTH secretion 3

Non-PTH-Mediated Causes

Vitamin D Disorders

• Vitamin D deficiency reduces intestinal calcium absorption 6, 1
• Impaired vitamin D activation in chronic kidney disease 6, 4
• Malabsorption syndromes affecting vitamin D absorption 7
• Vitamin D-dependent rickets (genetic defects in vitamin D metabolism) 7

Chronic Kidney Disease

• Phosphate retention in CKD leads to decreased ionized calcium, which stimulates PTH release and causes secondary hyperparathyroidism 6, 4
• Decreased 1,25-dihydroxyvitamin D production compounds the problem by reducing intestinal calcium absorption 6, 4
• Progressive loss of kidney function decreases vitamin D receptors and calcium-sensing receptors in parathyroid glands 6

Medication-Induced

• Loop diuretics induce hypocalcemia through increased urinary calcium excretion 4
• Bisphosphonates can cause severe hypocalcemia, particularly in patients with multiple myeloma 1
• Calcium channel blockers may reduce calcium levels by affecting calcium homeostasis 4
• Antiepileptic drugs are associated with hypocalcemia 8
• Aminoglycosides can contribute to low calcium levels 8
• Proton pump inhibitors may cause hypocalcemia 8
• Cisplatin chemotherapy is associated with hypocalcemia 8
• Antipsychotic medications can precipitate hypocalcemia in vulnerable patients 4
• Citrate in blood transfusions causes acute hypocalcemia during massive transfusion 1, 4

Acute Critical Illness

• Acute pancreatitis with calcium sequestration 7
• Tumor lysis syndrome with hyperphosphatemia 7
• Rhabdomyolysis with phosphate release and calcium deposition 7
• Hungry bone syndrome after parathyroidectomy for severe hyperparathyroidism 7

Pseudohypoparathyroidism

• PTH resistance at target organs with elevated PTH levels, hypocalcemia, and hyperphosphatemia 3

Diagnostic Approach

Initial Laboratory Evaluation

• Measure pH-corrected ionized calcium (most accurate) rather than total calcium alone 1, 4
• Check PTH levels to distinguish PTH-mediated from non-PTH-mediated causes 1
• Assess magnesium levels in all hypocalcemic patients, as hypomagnesemia must be corrected first before calcium will normalize 5, 4
• Measure 25-hydroxyvitamin D to evaluate vitamin D status 1
• Check serum phosphorus (elevated in hypoparathyroidism and CKD, low in vitamin D deficiency) 1
• Assess renal function (creatinine) to evaluate for CKD 1

Additional Considerations

• Review medication list for drugs that can cause hypocalcemia 8
• Consider genetic testing for 22q11.2 deletion in appropriate clinical contexts 1, 4
• Evaluate for underlying malignancy, autoimmune disorders, or infiltrative diseases 3

Critical Clinical Pitfalls

• Hypomagnesemia must be corrected first—administering calcium without correcting magnesium will be ineffective, and calcium normalization requires approximately 4 days after initiating magnesium therapy 5
• Less than 1% of total body magnesium is extracellular, so patients can have magnesium deficiency despite normal serum concentrations 5
• Hypocalcemia symptoms may be confused with psychiatric conditions such as anxiety or depression 1, 4
• In patients with 22q11.2 deletion syndrome, hyperprolinemia can contribute to seizure risk independent of calcium levels 4
• Drug-induced hypocalcemia is easily missed when multiple factors contribute to low calcium 8