What are the causes of low ionized calcium?

Causes of Low Ionized Calcium

Low ionized calcium results from disorders affecting parathyroid hormone secretion, vitamin D metabolism, magnesium homeostasis, or from acute clinical situations including massive transfusion, critical illness, and certain medications.

Primary Pathophysiological Mechanisms

Parathyroid Hormone Deficiency or Resistance

• Hypoparathyroidism is a classic cause of chronic hypocalcemia, characterized by impaired secretion of PTH, which is essential for maintaining calcium homeostasis. 1
• Patients with 22q11.2 deletion syndrome have an 80% lifetime risk of hypocalcemia due to relative or absolute hypoparathyroidism, which may arise or recur at any age despite apparent childhood resolution. 2
• Post-surgical hypoparathyroidism following thyroid or parathyroid surgery is a common precipitating factor for acute hypocalcemia. 3

Vitamin D Disorders

• Vitamin D deficiency (25-hydroxyvitamin D <30 ng/mL) leads to chronic hypocalcemia because vitamin D is responsible for increasing gut absorption of dietary calcium. 2, 1
• Disorders that disrupt vitamin D metabolism can cause chronic hypocalcemia through impaired intestinal calcium absorption. 1

Magnesium Abnormalities

• Hypomagnesemia is present in 28% of hypocalcemic ICU patients and prevents calcium correction through two mechanisms: impaired PTH secretion and end-organ resistance to PTH. 2, 3
• Hypocalcemia cannot be fully corrected without adequate magnesium levels, making magnesium deficiency a critical underlying cause. 2

Acute Clinical Situations

Massive Transfusion and Citrate Toxicity

• Citrate in blood products binds ionized calcium, causing hypocalcemia during massive transfusion, particularly with FFP and platelet transfusion which contain high citrate concentrations. 4
• Each unit of blood products contains approximately 3 grams of citrate that chelates calcium. 2
• Citrate metabolism is dramatically impaired by hypoperfusion, hypothermia, and hepatic insufficiency, worsening hypocalcemia in critically ill patients. 4, 2

Critical Illness and Sepsis

• Low ionized calcium at admission is associated with increased mortality and need for massive transfusion in trauma patients. 4
• Hypocalcemia during the first 24 hours predicts mortality better than fibrinogen levels, acidosis, or platelet counts. 4, 2
• Critical surgical illness with shock and sepsis is commonly associated with low ionized calcium. 5

Fluid Resuscitation

• Colloid infusions (but not crystalloids) independently contribute to hypocalcemia beyond citrate toxicity. 4, 2
• Early hypocalcemia following traumatic injury shows significant correlation with the amount of colloids infused. 4

Medication-Induced Hypocalcemia

Common Culprits

• Bisphosphonates and denosumab are well-recognized causes of drug-induced hypocalcemia. 3, 6
• Cisplatin and cetuximab can precipitate acute hypocalcemia in cancer patients. 2, 3
• Antiepileptics, aminoglycosides, and proton pump inhibitors may cause hypocalcemia in everyday clinical practice, though this is often missed due to multiple contributing factors. 6

Calcimimetics

• Severe hypocalcemia occurs in 7-9% of patients on calcimimetics and is likely underreported, associated with muscle spasms, paresthesia, and myalgia. 3

Renal Disease

• Chronic kidney disease is a common cause of chronic hypocalcemia through multiple mechanisms including impaired vitamin D activation and secondary hyperparathyroidism. 2, 3
• Acute kidney disease can precipitate hypocalcemia in critically ill patients. 7

Other Important Causes

Acid-Base Disturbances

• pH influences ionized calcium levels: a 0.1 unit increase in pH decreases ionized calcium concentration by approximately 0.05 mmol/L. 4
• Correction of acidosis may paradoxically worsen hypocalcemia as pH rises. 2

Pancreatitis and Tumor Lysis Syndrome

• Acute pancreatitis is associated with hypocalcemia in critically ill patients. 7
• Tumor lysis syndrome causes hypocalcemia through hyperphosphatemia and calcium-phosphate precipitation. 2

Critical Pitfalls to Avoid

• Standard coagulation tests may appear normal despite significant hypocalcemia-induced coagulopathy because laboratory samples are citrated then recalcified before analysis, masking the true impact. 2
• Even mild hypocalcemia impairs the coagulation cascade (factors II, VII, IX, X activation) and platelet adhesion, so seemingly minor reductions should not be ignored in critically ill patients. 2
• Always check magnesium first when evaluating hypocalcemia, as calcium supplementation alone will fail without magnesium correction. 2, 3