HypoPhosphatemia Flashcards
Causes of Hypophosphatemia
Reduced intake: alcoholics, eating disorders (anorexia, bulimia), old/debilitated/poor patients with poor access to high-phosphate-containing food
Causes of Hypophosphatemia
Reduced GI absorption:
a. Vitamin D deficiency
b. Vitamin D-dependent rickets:
1. Defect in renal 1α-hydroxylase (vitamin D-dependent rickets type 1)
1a. Laboratory findings: low 1,25 vitamin D, hypocalcemia, secondary hPTH, hypophosphatemia
1b. 50% of patients may have alopecia.
1c. Treatment: low-dose calcitriol
2. VDR deficiency (vitamin D-dependent rickets type 2):
2a. Laboratory findings: high 1,25 vitamin D level
2b. Treatment: high-dose calcitriol
c. Malabsorptive GI disorders, extensive bowel resection
Causes of Hypophosphatemia
Cellular shift:
Acute respiratory alkalosis: acute respiratory alkalosis leads to extracellular CO2 diffusion which in turn leads to a rise in intracellular pH. The increased intracellular pH increases glycolysis, a process where phosphates are needed to produce adenosine triphosphates (ATP). The requirement for cellular phosphate uptake leads to hypophosphatemia. Acute metabolic alkalosis does not cause hypophosphatemia because bicarbonate cannot freely cross cell membranes to cause a rapid rise in intracellular pH.
Causes of Hypophosphatemia
Cellular Shift cont’d:
NOTE: Chronic respiratory alkalosis is associated with HYPERphosphatemia due to renal resistance to PTH +/− reduced PTH secretion.
Refeeding syndrome
Causes of Hypophosphatemia
Cellular Shift cont’d:
Total parenteral nutrition with insulin-mediated intracellular phosphate shift or low phosphate content
Diabetic ketoacidosis following insulin administration
Causes of Hypophosphatemia
Increased renal excretion:
Increased renal excretion:
Volume expansion
Mutations leading to increased levels of FGF-23 and resultant downregulation of Na-Pi 2a expression in the proximal tubules. Affected individuals present with various skeletal deformities.
a. Autosomal-dominant hypophosphatemic rickets:
1. Mutation in FGF-23 that renders FGF-23 resistant to proteolysis
2. Associated skeletal abnormalities: bowing of long bones and widening of costochondral joints
Causes of Hypophosphatemia
Increased renal excretion cont’d:
b. Autosomal-recessive hypophosphatemic rickets: Mutations in DMP1 can lead to increased FGF-23 levels. DMP1 is gene encoding the dentin matrix protein 1, a molecule thought to normally suppress bone secretion of FGF-23.
c. X-linked hypophosphatemic rickets:
1. Mutations of the PHEX gene encoding the phosphate-regulating endopeptidase (on X chromosome). PHEX is thought to play a role in the proteolysis of FGF-23.
2. Associated skeletal deformities: short stature, osteomalacia
Causes of Hypophosphatemia
Increased renal excretion cont’d:
Intrinsic renal defect leading to reduced renal phosphate reabsorption: Fanconi syndrome:
a. Mutation of NPT2a: autosomal-recessive Fanconi syndrome with associated hypophosphatemic rickets and renal failure
b. Mutation of NPT2c: hereditary hypophosphatemia with rickets and hypercalciuri (HHRH)
1. Phenotype: hypophosphatemia, normal SCa, normal PTH, low FGF-23, high 1,25 vitamin D, and hypercalciuria
2. NOTE: Hypophosphatemia is independent of FGF-23 or PTH.
3. Secondary hypercalciuria is due to FGF-23 suppression, followed by 1,25 vitamin D activation, and hypercalciuria.
Causes of Hypophosphatemia
Increased renal excretion cont’d:
Oncogenic hypophosphatemic osteomalacia:
a. Mostly associated with benign mesenchymal tumors (e.g., hemagiopericytoma, fibroma, angiosarcoma, and more recently, metastatic prostate carcinoma)
b. Malignant tissue secretion of phosphatonins (i.e., FGF-23 and other phosphaturic factors)
Causes of Hypophosphatemia
Increased renal excretion cont’d:
c. Laboratory findings:
1. Affected individuals present with impaired bone mineralization and hypophosphatemia caused by reduced renal phosphate reabsorption, paradoxically low levels of calcitriol, the production of which is typically enhanced by hypophosphatemia. Calcitriol is inappropriately low to normal in this condition due to reduced 1α-hydroxylase activity with increased FGF-23 levels.
2. Intact PTH may be elevated due to low 1,25-vitamin D levels or excessive phosphate replacement.
3. Alkaline phosphatase levels are often elevated.
4. SCa levels are normal to low.
5. Diagnosis: clinical presentation above, elevated FGF-23 (commercially available)
Causes of Hypophosphatemia
Increased renal excretion cont’d:
Post-renal transplant hypophosphatemia:
a. Persistent secondary hPTH in new functioning allograft
b. Persistently high circulating levels of FGF-23—although this is more commonly seen in patients with markedly elevated pretransplant FGF-23 levels
c. Note, however, that persistent hypophosphatemia beyond 1 year post-transplant has been attributed to persistent hPTH rather than increased FGF-23 levels.
Causes of Hypophosphatemia
Others:
a. Drugs: corticosteroids, diuretics, bicarbonate, sunitinib/imatinib (tyrosine kinase inhibitors associated with hPTH, normal to high SCa levels, hypophosphatemia)
b. Ferric carboxymaltose injection: It is thought that carboxymaltose can inhibit the cleavage and inactivation of FGF-23 within osteocytes, resulting in increased levels of active FGF-23, phosphaturia, hypophosphatemia, and decreased 1,25-vitamin D.
Causes of Hypophosphatemia
Others cont’d:
c. Alcoholism: malnutrition, hypomagnesemia-associated renal phosphate wasting, intracellular shift due to hyperventilation or glucose infusion
d. Hungry bone syndrome
e. Hypophosphatemia following hepatectomy: This is thought to be due to increased proximal tubular expression of nicotinamide phosphoribosyl-transferase (Nampt), a protein associated with reduced renal expression of the sodium phosphate transporter.
Clinical Manifestations of Hypophosphatemia
Symptoms typically not evident unless serum phosphate level is <2.0 mg/dL.
Respiratory distress/arrest due to poor-functioning/weak diaphragm presumably because of inability to produce adequate ATPs, rhabdomyolysis (alcoholics with underlying alcoholic myopathy are particularly at risk), cardiomyopathy, metabolic encephalopathy, hemolysis, red and white blood cell dysfunction.
Management of Hypophosphatemia
Phosphate supplementation: Estimating phosphate deficit (i.e., repletion dose):
Phosphate dose (mmol) = 0.5 body weight (kg) × (1.25 − [serum phosphate mmol/L]). The factor 0.5 indicates that the volume of distribution of phosphate is approximately 50% of total body weight.
Treatment of underlying etiology whenever possible
