What are the causes of hypophosphatemia?

Causes of Hypophosphatemia

Hypophosphatemia results from three primary mechanisms: inadequate phosphate intake or absorption, excessive renal or gastrointestinal losses, or transcellular shifts from extracellular to intracellular compartments. 1, 2

Mechanism-Based Classification

Renal Phosphate Wasting

The most critical distinction is whether hypophosphatemia is due to renal phosphate wasting, which can be determined by calculating fractional excretion of phosphate or TmP/GFR—if elevated (>15%), this confirms renal losses. 3, 2

FGF23-Mediated Disorders (Non-Suppressed FGF23)

• X-linked hypophosphatemia (XLH) accounts for approximately 80% of hereditary hypophosphatemic rickets, caused by PHEX gene mutations leading to elevated FGF23 4
• Autosomal dominant hypophosphatemic rickets due to FGF23 gene mutations 4
• Autosomal recessive hypophosphatemic rickets (types 1 and 2) caused by DMP1 or ENPP1 mutations 4
• Tumor-induced osteomalacia from FGF23-secreting tumors 4
• Intravenous iron therapy (ferric carboxymaltose or iron isomaltoside) causing "6H-syndrome" (high FGF23, hyperphosphaturia, hypophosphatemia, hypovitaminosis D, hypocalcaemia, secondary hyperparathyroidism) 4
• Alcohol-induced FGF23 syndrome 4
• Ectopic FGF23 syndrome in advanced malignancies (prostate, lung cancer) 4
• Other rare conditions: fibrous dysplasia, Raine syndrome, cutaneous skeletal hypophosphataemia syndrome, epidermal nevus syndrome, osteoglophonic dysplasia, neurofibromatosis 1 4

Primary Renal Tubular Defects (Suppressed FGF23)

• Fanconi syndrome variants including cystinosis, Dent disease, hypophosphataemia with nephrocalcinosis, reno-tubular syndrome 2 4
• Hereditary hypophosphataemic rickets with hypercalciuria (HHRH) 4
• These disorders show metabolic acidosis, glucosuria, aminoaciduria, and low molecular weight proteinuria 4, 3

Hyperparathyroidism-Related

• Primary hyperparathyroidism (elevated serum calcium) 2
• Secondary hyperparathyroidism from vitamin D deficiency (low serum calcium) 4, 2

Transcellular Shifts (Redistribution)

• Refeeding syndrome is a critical cause where phosphate shifts from extracellular to intracellular compartments during nutritional repletion 1, 5, 6
• Diabetic ketoacidosis recovery as insulin drives phosphate intracellularly 6, 7, 8
• Respiratory alkalosis causing intracellular phosphate shift 6

Gastrointestinal Losses or Malabsorption

• Chronic diarrhea causing intestinal phosphate losses 1
• Phosphate-binding antacids preventing absorption 9
• Malnutrition/starvation with inadequate dietary intake 6, 9
• Vitamin D deficiency impairing intestinal phosphate absorption 4, 2

Hospital and ICU-Related Causes

• Kidney replacement therapy (KRT) with prevalence rising to 80% during prolonged modalities 1, 5
• Diuretic use precipitating phosphate losses 1
• Post-surgical states, particularly after partial hepatectomy 6
• Critical illness with 60-80% prevalence among ICU patients 1, 5

Chronic Alcoholism

• Severe chronic alcoholism represents one of the most severe forms of phosphate deficiency, combining poor intake, increased losses, and transcellular shifts 6, 9, 7, 8

Critical Diagnostic Approach

When evaluating hypophosphatemia, first calculate TmP/GFR or fractional excretion of phosphate from spot urine; if >15%, proceed to measure FGF23 levels to distinguish FGF23-mediated disorders (non-suppressed FGF23) from primary tubular defects (suppressed FGF23). 4, 3

Always exclude generalized Fanconi syndrome by checking for metabolic acidosis, glucosuria, aminoaciduria, and low molecular weight proteinuria, as this indicates a more complex tubular disorder rather than isolated phosphate wasting. 4, 3

Measure urinary calcium excretion to distinguish HHRH (hypercalciuria) from other causes of renal phosphate wasting. 4, 3