Cause
Mechanism
Shift from extracellular to intracellular compartment
Glucose
Transcellular distribution
Insulin
Transcellular distribution
Catecholamines
Transcellular distribution
Hyperalimentation
Glucose-induced cellular uptake
Respiratory alkalosis
Transcellular distribution
Refeeding syndrome
Glucose and insulin-induced transcellular distribution, consumption during glucose metabolism and ATP production
Rapid cellular proliferation
Cellular uptake
Decreased intestinal absorption
Poor dietary intake/starvation
↓ intestinal absorption
Malabsorption
Disorders of duodenum and jejunum (celiac disease, tropical and nontropical sprue, regional enteritis), ↓ intestinal absorption
Phosphate binders
Calcium acetate or bicarbonate, aluminum hydroxide, and magnesium salts bind phosphate in the gut
Vitamin deficiency
↓ intestinal absorption
Vitamin D-dependent (VDD) rickets
Type I VDD rickets
Low or deficiency of 1,25(OH)2D3
Type 2 VDD rickets
Resistance to 1,25(OH)2D3 action
Increased renal loss
Primary and secondary hyperparathyroidism
↓ renal absorption
Increased fibroblast growth factor (FGF)-23 production or activity
Inherited disorders
X-linked hypophosphatemia
Mutations in PHEX gene
Autosomal dominant hypophosphatemia
Mutations in FGF-23 gene
Autosomal recessive hypophosphatemia
Mutations in DMP1 and ENPP1 genes
Acquired disorder
Tumor-induced osteomalacia
Increased FGF-23 secretion and activity
Proximal tubule defect in phosphate reabsorption
Hereditary hypophosphatemic rickets with hypercalciuria
Mutations in the gene encoding Na/Pi-IIc cotransporter
Autosomal recessive renal phosphate wasting
Mutations in the gene encoding Na/Pi-IIa cotransporter
Fanconi syndrome
A disorder causing decreased reabsorption of glucose, phosphate, amino acids, uric acid, bicarbonate, calcium, and potassium. Can be genetic or acquired
Renal transplantation
Tertiary hyperparathyroidism, excess FGF-23, immunosuppressive drugs, low 25(OH)D3 and 1,25(OH)2D3 levels
Volume expansion, postobstructive diuresis, hepatectomy
↓ renal reabsorption and phosphaturia
Drugs
Osmotic diuretics
↓ renal reabsorption and phosphaturia
Carbonic anhydrase inhibitor
↓ renal reabsorption and phosphaturia
Loop diuretics
↓ renal reabsorption and phosphaturia
Metolazone
↓ renal reabsorption and phosphaturia
Acyclovir
Inhibition of Na/Pi-IIa cotransporter
Acetaminophen poisoning
↓ renal reabsorption and phosphaturia
Intravenous iron administration
Increase in FGF-23 secretion and activity by inhibiting 1α-hydroxilase
Tyrosine kinase inhibitors (imatinib, sorafenib)
Ca2 + and phosphate reabsorption and secondary hyperparathyroidism
Corticosteroids
↓ intestinal phosphate absorption and phosphaturia
Bisphosphonates
Inhibit bone resorption
Cyclophosphamide, cisplatin
↑ phosphaturia
Ifosfamide, streptozotocin, suramin
Induction of Fanconi syndrome
Aminoglycosides, tetracyclines
Induction of Fanconi syndrome
Valproic acid
Induction of Fanconi syndrome
Tenofovir, cidofovir, adefovir
Induction of Fanconi syndrome
Miscellaneous causes
Alcoholism
Poor intake, frequent use of phosphate binders, vitamin D deficiency, respiratory alkalosis, proximal tubule defect, ↓ intestinal absorption
Diabetic ketoacidosis
↓ total body phosphate due to osmotic diuresis at onset, and hypophosphatemia after insulin administration
Toxic shock syndrome
Cellular uptake probably due to respiratory alkalosis
Some Specific Causes of Hypophosphatemia
X-Linked Hypophosphatemia
It is the most common disorder inherited as an autosomal dominant disease, caused by inactivating mutations in the PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) gene
Presents within 2 years of life
Characterized by hypophosphatemia, phosphaturia, short stature, rickets and osteomalacia, and dental abscesses. Decreased intestinal Ca2+ and phosphate absorption and decreased renal phosphate absorption have been described
Increased fibroblast growth factor (FGF)-23 levels are characteristic of this disorder. Serum Ca2+ and parathyroid hormone (PTH) levels are normal, but 1,25(OH)2D3 levels are low owing to high FGF-23 activity
Treatment with oral calcitriol and phosphate improves growth retardation
Autosomal Dominant Hypophosphatemic Rickets (ADHR)
ADHR is a rare disorder caused by activating mutations in the FGF-23 gene, and these mutations prevent proteolytic cleavage of FGF-23 with the resultant increase in circulating levels of this hormone
The phenotype is similar to that of X-linked hypophosphatemia
Treatment includes calcitriol and phosphate
Autosomal Recessive Hypophosphatemic Rickets (ARHR)
ARHR is caused by inactivating mutations in the DMP (dentin matrix protein) 1 gene. DMP 1 is derived from osteoblasts and osteocytes, and participates in bone mineralization of extracellular matrix
The deficiency of DMP 1 results in increased FGF-23 expression and levels and clinical manifestation similar to that of ADHR
Another inactivating mutation in the ENPPI (endonucleotide pyrophosphatase/phosphodiesterase I) gene has been shown to cause ARHR
Treatment is calcitriol and phosphate
Tumor-Induced Osteomalacia (TIO)
TIO or oncogenic osteomalacia is an acquired paraneoplastic (usually mesenchymal tumor) syndrome that occurs during the sixth decade of life
In addition to FGF-23, three other phosphaturic factors, namely, sFRP-4 (frizzled-related protein-4), MEPE (matrix extracellular phosphoglycoprotein), and FGF-7 have been identified with the tumor
Biochemical findings are similar to ADHR (phosphaturia, elevated FGF-23, and normal Ca2+, as well as PTH levels)
Treatment includes identification of the tumor followed by resection or chemotherapy, calcitriol, and phosphate
Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) Due to Type IIc Mutation
It is a rare autosomal recessive disorder caused by mutations in the gene that encodes Na/Pi-type IIc cotransporter
It is characterized by growth retardation, rickets, and increased renal phosphate and Ca2+ excretion
Unlike other hypophosphatemic rickets, HHRH is characterized by elevated levels of 1,25(OH)2D3, which cause hypercalciuria and hypercalcemia
Choice of treatment is only phosphate supplementation
Note that calcitriol is not recommended, as it further causes hypercalcemia and renal stone formation
Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) Due to Type IIa Mutation
This is another recessive disorder, similar to the above disease, due to mutations in the gene that encodes Na/Pi-type IIa cotransporter
Unlike type IIc disease, type IIa disease is associated with Fanconi syndrome
Refeeding Syndrome (RFS)
Refeeding syndrome (RFS) occurs in malnourished individuals following administration of oral, enteral, or parenteral nutrition
Commonly seen in hospitalized patients, who are malnourished because of poor oral intake, starvation, anorexia nervosa, or systemic illness such as malignancy
Hypophosphatemia is the most commonly observed electrolyte abnormality induced by RFS
Many mechanisms contribute to hypophosphatemia: (1) a high carbohydrate meal causing intracellular shift of phosphate; (2) increased consumption of phosphate during glycolysis; (3) depleted body stores of phosphate during poor oral intake; and (4) consumption of phosphate for formation of ATP and increased production of products such as creatine kinase and 2,3-diphosphoglycerate
Sudden deaths also have been reported following RFS with high caloric diet owing to hypophosphatemia. Almost all organ systems fail
To prevent hypophosphatemia, the feeding should consist of low calories with gradual increase to maintain the target caloric intake
Along with hypophosphatemia, other electrolyte abnormalities such as hypokalemia and hypomagnesemia also occur due to high glucose
Supplementation of K+, Mg2+, and phosphate along with nutrition will prevent RFS
Hypophosphatemia in Critical Care Units
Electrolyte disorders are common in critically ill patients during their stay in the intensive care unit
Hypophosphatemia is a frequently observed electrolyte disorder
Common causes include glucose-containing solutions, insulin administration, starvation, refeeding, sepsis, shock, trauma, postoperative state, respiratory alkalosis, metabolic acidosis, medications such as catecholamines and diuretics, and renal replacement therapies
Clinical Manifestations
The clinical manifestations of hypophosphatemia depend on its onset and severity. Two biochemical abnormalities underlie the manifestations of phosphate deficiency. One is depletion of ATP and the second is a reduction in erythrocyte 2,3-diphosphoglycerate. Both depletions lead to altered cellular function and hypoxia. Table 21.2 shows clinical and biochemical manifestations of severe hypophosphatemia.
Table 21.2
Clinical and biochemical abnormalities of hypophosphatemia
Neurologic | Confusion |
Iirritability | |
Anorexia | |
Ataxia, dysarthria, paresthesia | |
Seizures, coma | |
Cardiovascular | Cardiomyopathy |
Decreased cardiac output | |
Altered membrane potential | |
Skeletal muscle | Muscle weakness |
Rhabdomyolysis | |
Bone | Bone pain |
Rickets | |
Osteomalacia | |
Pseudofractures | |
Osteopenia | |
Hematologic | Red blood cells |
Decreased 2,3-diphosphoglycerate content | |
Decreased ATP production | |
Increased oxygen affinity | |
Hemolysis | |
Decreased life span | |
Leukocytes | |
Impaired phagocytosis | |
Impaired bactericidal activity | |
Impaired chemotaxis | |
Platelets | |
Thrombocytopenia | |
Decreased life span | |
Megakaryocytosis | |
Carbohydrate metabolism | Decreased glucose metabolism |
Insulin resistance
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