Table 1.

Causes of Hypophosphatemia

Decreased Intestinal Absorption	Examples	Pathogenesis	Targeted Interventions
Genetic
1–25(OH)2 Vit D deficiency	CYP27B1 and CYP2R1 mutations in infantile forms of vitamin D-dependent rickets	Deficiency of 1-α hydroxylase or 25-α hydroxylase causing lower 1–25(OH)2 resulting in less Pi absorption	Active vitamin D supplementation
Acquired
Low phosphate intake	Chronic low intake (<100 mg/day)	Rarely, chronic low Pi intake may exceed renal capacity for reabsorption
Medication use	Magnesium- and aluminum-based antiacids, niacin	Binding phosphorus by antiacids or inhibition of Npt2b by niacin
Chronic diarrhea	Inflammatory bowel disease, pancreatic insufficiency	Concomitant impairment of vitamin D and Pi intestinal absorption
Increased urinary excretion
Genetic Npt2c mutations	HHRH	Pi wasting in the proximal tubule, low levels of FGF-23, high vitamin D with increase in calcium-phosphate in renal tubule	Pi supplementation. Avoid vitamin D
Elevated iFGF-23	XLH, ADHR, ARHR	Missense mutations involving the cleavage site at RXXR leading to high levels of intact FGF-23 (ADHR), involving PHEX (XLH) or DMP1, ENPP1, FAM20 C (ARHR).	Vitamin D supplementation. Monoclonal antibody anti-FGF-23 in XLH
Acquired
Elevated iFGF-23	Tumor-induced osteomalacia, iron infusions	Mesenchymal tumors with unregulated secretion of FGF-23 or certain IV iron preparations	Tumor removal in tumor-induced osteomalacia
Proximal tubule dysfunction	Multiple myeloma, tenofovir, severe hypokalemia	Pi wasting in the proximal tubule by direct toxicity with or without Fanconi syndrome	Pi supplementation
Extracellular clearance
Acquired Intracellular redistribution	Refeeding syndrome, respiratory alkalosis	Insulin mediated intracellular redistribution (refeeding). Increased cellular pH and glycolysis (respiratory alkalosis)
Increased skeletal uptake	Hungry bone syndrome	Postparathyroidectomy in patients with tertiary hyperparathyroidism	Control of PTH during CKD
Dialysis	Hemodialysis, CRRT (both diffusion and convective clearance modalities)	Nonselective clearance delivered with low Pi dialysate/replacement solution lowers serum Pi	Use of Pi containing replacement fluids, adjusting dialysis clearance, pre-emptive Pi replacement protocols
Critical illness	Hospitalized patients, especially in the ICU	Redistribution by glycolysis activation, hormonal triggers. Decreased intestinal absorption of Pi and use of CRRT without pre-emptive Pi replacement	Dynamic monitoring and pre-emptive Pi replacement

Abbreviations: ADHR, autosomal dominant hypophosphatemic rickets; ARHR, autosomal recessive hypophosphatemic rickets; CRRT, continuous renal replacement therapy, DMP1, dentin matrix acidic phosphoprotein 1; ENPP1, ectonucleotide pyrophosphatase/phosphodiesterase 1; FAM20C, family with sequence similarity 20 member C; FGF-23, fibroblast growth factor 23; Gsa, alpha subunit of stimulatory G protein; HHRH, hereditary hypophosphatemia rickets with hypercalciuria; Npt-2a, type II sodium phosphate cotransporter a; Npt-2b, type II sodium phosphate cotransporter b; Npt-2c, type II sodium phosphate cotransporter c; PHEX, phosphate regulating endopeptidase homolog X-linked; PTH, parathyroid hormone; TIO, tumor-induced osteomalacia; XLH, X-linked hypophosphatemia.