What are the causes of hypophosphatemia, particularly in critically ill patients?

Causes of Hypophosphatemia

Hypophosphatemia results from three primary mechanisms: excessive renal phosphate loss, decreased intestinal absorption, or intracellular phosphate shifts—with renal phosphate wasting being the most common cause in hospitalized patients, particularly those in intensive care settings where prevalence reaches 60-80%. 1

Primary Mechanisms

Excessive Renal Phosphate Loss

• Renal phosphate wasting is the predominant mechanism in hospitalized patients and can be confirmed when fractional phosphate excretion exceeds 15% despite hypophosphatemia 2
• Hyperparathyroidism (both primary and secondary) causes ongoing phosphaturia through PTH-mediated renal phosphate loss 3, 2
• FGF23-mediated disorders including X-linked hypophosphatemia (XLH), which accounts for approximately 80% of hereditary hypophosphatemic rickets cases 4
• Tumor-induced osteomalacia from phosphaturic substances (particularly FGF23) secreted by often small, difficult-to-detect tumors 5
• Fanconi syndrome and other primary renal tubular defects cause phosphate wasting with normal calcium levels 2
• Vitamin D deficiency leads to secondary hyperparathyroidism and subsequent renal phosphate loss 4, 2

Decreased Intestinal Absorption

• Malabsorptive disorders including inflammatory bowel disease, celiac disease, and post-bariatric surgery states 3
• Phosphate-binding antacids consumed in large amounts, particularly when combined with phosphate-deficient diets 6
• Reduced intestinal phosphorus absorption occurs commonly post-kidney transplant 3

Intracellular Phosphate Shifts

• Refeeding syndrome is the most critical cause of acute severe hypophosphatemia, occurring when nutrition is reintroduced after caloric deprivation, with hypophosphatemia developing in 60-80% of ICU patients 4, 1, 7
• Diabetic ketoacidosis treatment with insulin drives phosphate intracellularly 8
• Respiratory alkalosis causes transcellular phosphate shifts 7

High-Risk Clinical Settings

Critical Care and Hospital Settings

• Kidney replacement therapy (KRT) causes hypophosphatemia in up to 80% of patients during prolonged modalities when standard phosphate-free dialysis solutions are used 1, 3
• Sepsis is frequently associated with hypophosphatemia and may cause leukocyte dysfunction that worsens infection 7
• Post-surgical states, particularly after partial hepatectomy 8
• Severe trauma patients have 30-50% prevalence of hypophosphatemia 5

Chronic Alcohol Overconsumption

• Alcoholism represents one of the most severe phosphate deficiency states, with prevalence reaching 30-50% in this population 6, 5
• Multiple mechanisms contribute: poor dietary intake, increased renal losses, and intracellular shifts 8

Medication-Induced Causes

• Intravenous iron formulations, particularly ferric carboxymaltose (FCM), cause hypophosphatemia in 47-75% of patients through FGF23 elevation, with severe cases lasting up to 6 months 3
• Immunosuppressive drugs, especially post-transplant medications 3
• Diuretics precipitate hypophosphatemia through increased renal losses 1

Diagnostic Approach Algorithm

Step 1: Confirm hypophosphatemia (serum phosphate <0.81 mmol/L or <2.5 mg/dL) and assess severity: mild (2-2.5 mg/dL), moderate (1-1.9 mg/dL), or severe (<1 mg/dL) 2, 8

Step 2: Calculate fractional phosphate excretion—if >15% with hypophosphatemia present, renal phosphate wasting is confirmed 2

Step 3: Measure serum calcium to categorize renal phosphate wasting:

• High calcium = primary hyperparathyroidism 2
• Low calcium = secondary hyperparathyroidism (vitamin D deficiency, malabsorption) 2
• Normal calcium = primary renal phosphate wasting (FGF23-mediated disorders, Fanconi syndrome) 2

Step 4: Measure intact FGF23 levels if renal phosphate wasting with normal calcium is present—elevated or inappropriately normal FGF23 suggests XLH or tumor-induced osteomalacia 4

Step 5: Assess for intracellular shift causes:

• Recent refeeding or nutritional support initiation 4
• Insulin therapy for diabetic ketoacidosis 8
• Respiratory alkalosis 7

Critical Pitfalls to Avoid

• Never ignore persistent hypophosphatemia unresponsive to supplements—this should raise suspicion for tumor-induced osteomalacia, which requires complete tumor resection for symptom reversal 5
• Do not overlook refeeding syndrome risk in patients with BMI <16 kg/m², unintentional weight loss >15% in 3-6 months, little or no intake for >10 days, or pre-existing low potassium, phosphate, and magnesium 4
• Avoid FCM in patients requiring recurrent infusions for blood loss or malabsorption—switch to alternative IV iron formulations to prevent prolonged severe hypophosphatemia 3
• Monitor phosphate closely during continuous renal replacement therapy—proactive supplementation with phosphate-containing dialysis solutions prevents the 60-80% incidence of hypophosphatemia 3
• Recognize that persistent hypophosphatemia causes serious complications including osteomalacia, fractures, rhabdomyolysis, cardiac arrhythmias, respiratory failure requiring prolonged mechanical ventilation, and neurological dysfunction 1, 3, 7