What is the appropriate workup for hypocalcemia?

Hypocalcemia Workup

Initial Laboratory Assessment

Measure ionized calcium immediately, as it is the most accurate indicator of physiologically active calcium and should guide all treatment decisions, especially when symptoms are present despite "normal" corrected calcium levels. 1, 2

Essential First-Line Tests

• Ionized calcium (reference range 1.15–1.36 mmol/L or 1.1–1.3 mmol/L): This is the gold standard and must be obtained in all patients with suspected hypocalcemia, as total calcium adjusted for albumin or protein has poor sensitivity (only 50%) for detecting true hypocalcemia. 1, 3

• Corrected total calcium using the formula: Corrected Ca (mg/dL) = Total Ca (mg/dL) + 0.8 × [4 – Serum albumin (g/dL)]. 1 However, recognize that this calculation performs poorly in hospitalized patients and should never replace ionized calcium measurement when clinical suspicion exists. 3

• Serum phosphate: This single test divides hypocalcemia into two major categories and immediately narrows your differential diagnosis. 4

  • Low to low-normal phosphate suggests vitamin D deficiency, malabsorption, renal losses, or hungry bone syndrome. 4
  • High-normal to elevated phosphate indicates hypoparathyroidism, pseudohypoparathyroidism, or chronic kidney disease. 4

• Intact parathyroid hormone (PTH): Obtain this simultaneously with calcium to distinguish PTH-deficient hypoparathyroidism (low or inappropriately normal PTH) from secondary hyperparathyroidism (elevated PTH in response to hypocalcemia). 1, 4

• Serum magnesium: Measure this immediately in every hypocalcemic patient, as hypomagnesemia is present in 28% of cases and prevents calcium correction by impairing PTH secretion and causing end-organ PTH resistance. 1, 2 Calcium supplementation will fail without magnesium repletion. 2

• Serum creatinine and estimated GFR: Essential to identify chronic kidney disease as the underlying cause and to guide calcium replacement strategies. 1

• 25-hydroxyvitamin D: Measure this in all patients with elevated PTH to identify vitamin D deficiency (defined as <30 ng/mL), which is a common and easily correctable cause of hypocalcemia. 1

Critical Severity Assessment

• 12-lead ECG: Obtain immediately to assess for QT prolongation (QTc >500 ms or >60 ms above baseline), which indicates severe hypocalcemia and risk of torsades de pointes. 2, 5 Continuous cardiac monitoring is mandatory during acute treatment. 2

• Physical examination for acute symptoms: Check specifically for Chvostek's sign (facial twitching with tapping over facial nerve), Trousseau's sign (carpopedal spasm with blood pressure cuff inflation), paresthesias (perioral or distal extremities), tetany, laryngospasm, bronchospasm, or seizures. 1, 2 These findings mandate immediate intravenous calcium replacement. 2

Diagnostic Algorithm Based on Phosphate and PTH

Hypocalcemia with Low Phosphate

• Vitamin D deficiency: 25-hydroxyvitamin D <30 ng/mL with elevated PTH. 1
• Malabsorption syndromes: Consider celiac disease, inflammatory bowel disease, or short bowel syndrome. 1
• Renal tubular losses: Fanconi syndrome or other tubulopathies. 4
• Hungry bone syndrome: Occurs after parathyroidectomy when bone rapidly takes up calcium; look for recent neck surgery and elevated alkaline phosphatase. 1, 4

Hypocalcemia with High-Normal to High Phosphate

• Hypoparathyroidism: Low or inappropriately normal PTH in the setting of hypocalcemia. 4

  • Surgical (75% of cases): History of thyroid or parathyroid surgery, even decades prior. 1, 6
  • Autoimmune (25% of cases): Check for parathyroid autoantibodies and associated autoimmune conditions. 1, 4
  • Genetic causes: Consider 22q11.2 deletion syndrome (DiGeorge), which causes hypocalcemia in 80% of patients at some point in life, often precipitated by stress, surgery, or infection. 1, 2

• Pseudohypoparathyroidism: Elevated PTH with end-organ resistance; look for characteristic physical features (short stature, brachydactyly, subcutaneous ossifications). 4

• Chronic kidney disease: Elevated creatinine with secondary hyperparathyroidism; measure calcium-phosphorus product (must be <55 mg²/dL²). 1, 5

• Acute hyperphosphatemia: Tumor lysis syndrome, rhabdomyolysis, or acute phosphate load causing calcium-phosphate precipitation. 1

Additional Workup for Specific Clinical Contexts

Post-Surgical Patients

• Measure ionized calcium every 4–6 hours for the first 48–72 hours after thyroid or parathyroid surgery, then twice daily until stable. 1 Post-parathyroidectomy hypocalcemia is the most common cause of severe acute hypocalcemia. 1, 7

Massive Transfusion or Trauma

• Monitor ionized calcium continuously, as each unit of blood products contains approximately 3 g of citrate that chelates calcium. 1, 5 Citrate metabolism is impaired by hypoperfusion, hypothermia, and hepatic insufficiency. 1, 5 Hypocalcemia within 24 hours of critical bleeding predicts mortality better than fibrinogen, acidosis, or platelet count. 1

Chronic Kidney Disease Patients

• Measure corrected total calcium, phosphorus, calcium-phosphorus product, intact PTH, and magnesium at least every 3 months. 1 Target corrected calcium in the low-normal range (8.4–9.5 mg/dL) to reduce vascular calcification risk. 1, 5

Patients with 22q11.2 Deletion Syndrome

• Obtain baseline calcium, PTH, magnesium, and thyroid-stimulating hormone (TSH), as hypothyroidism occurs in 25% and compounds symptoms. 1, 2 Targeted calcium monitoring is critical during stress periods (surgery, childbirth, infection, pregnancy). 1, 2

Drug-Induced Hypocalcemia

• Review medication list for bisphosphonates, denosumab, cisplatin, cetuximab, calcimimetics (which cause severe hypocalcemia in 7–9% of patients), loop diuretics, or proton pump inhibitors. 1, 2, 5 The 2025 KDIGO Controversies Conference shifted away from permissive hypocalcemia in patients on calcimimetics due to underreported severe complications. 1, 5

Common Pitfalls to Avoid

• Never rely on albumin-corrected calcium alone: It has only 50% sensitivity for hypocalcemia in hospitalized patients; always confirm with ionized calcium when clinical suspicion exists or when total calcium is in the lower normal range. 3

• Never attempt calcium correction without checking magnesium first: Hypomagnesemia prevents calcium normalization and is present in 28% of hypocalcemic patients. 1, 2 Administer magnesium sulfate 1–2 g IV before repeating calcium if magnesium is <1.0 mg/dL. 2

• Never give calcium when phosphate is markedly elevated (>5.5 mg/dL or calcium-phosphorus product >55 mg²/dL²): This dramatically increases the risk of calcium-phosphate precipitation in tissues and kidneys. 1 Lower phosphate first with non-calcium-containing binders. 1

• Never assume childhood-resolved hypocalcemia is permanent: In 22q11.2 deletion syndrome, hypocalcemia may recur at any age despite apparent resolution, especially during biological stress. 1, 2

• Never overlook cardiac monitoring: Obtain ECG in all patients with confirmed hypocalcemia to assess QT interval, as severe hypocalcemia (ionized calcium <0.9 mmol/L) causes life-threatening arrhythmias. 2, 5