Hypophosphatemia

Essentials of Diagnosis

• Severe hypophosphatemia may cause tissue hypoxia and rhabdomyolysis

• Renal loss of phosphate can be diagnosed by calculating the fractional excretion of phosphate (F_EPO₄)

• Parathyroid hormone (PTH) and fibroblast growth factor (FGF23) are the major factors that increase urine phosphate

General Considerations

• Leading causes of hypophosphatemia are listed in Table 21–8

• May occur in the presence of normal phosphate stores

• Serious depletion of body phosphate stores may exist with low, normal, or high serum phosphate concentrations

• Moderate hypophosphatemia (1.0–2.4 mg/dL [or 0.32–0.79 mmol/L])

  • Occurs commonly in hospitalized patients

  • May not reflect decreased phosphate stores

• Severe hypophosphatemia (< 1 mg/dL [or 0.32 mmol/L])

  • The affinity of hemoglobin for oxygen increases, impairing tissue oxygenation and cell metabolism, resulting in muscle weakness or even rhabdomyolysis

  • Common and multifactorial in alcoholic patients

• In chronic obstructive pulmonary disease and asthma, hypophosphatemia can occur from

  • Xanthine derivatives causing shifts of phosphate intracellularly

  • Phosphaturic effects of beta-adrenergic agonists, loop diuretics, xanthine derivatives, and corticosteroids

Symptoms and Signs

• Acute, severe hypophosphatemia (< 1.0 mg/dL [or < 0.32 mmol/L])

  • Can lead to rhabdomyolysis, paresthesias, and encephalopathy (irritability, confusion, dysarthria, seizures, and coma)

  • Respiratory failure or failure to wean from mechanical ventilation may occur as a result of diaphragmatic weakness

  • Arrhythmias and heart failure are uncommon but serious manifestations

  • Hematologic manifestations include acute hemolytic anemia from erythrocyte fragility, platelet dysfunction with petechial hemorrhages, and impaired chemotaxis of leukocytes (leading to increased susceptibility to gram-negative sepsis)

• Chronic severe depletion may cause

  • Anorexia

  • Pain in muscles and bones

  • Fractures

• In patients with alcoholism

  • Vomiting, diarrhea, and poor dietary intake contribute to hypophosphatemia

  • Long-term use results in a decrease in the renal threshold of phosphate excretion

Laboratory Tests

• Serum phosphate levels decrease transiently after food intake, thus fasting samples are recommended for accuracy

• Urine phosphate excretion

  • The normal renal response to hypophosphatemia is to decrease urinary phosphate excretion to < 100 mg/day

  • F_EPO₄ should be < 5%

  • Fractional excretion (FE) of an electrolyte X (FE_x) can be calculated from a spot urine sample and serum sample, using creatinine (Cr):

  • 

• The main factors regulating F_EPO₄ are PTH and phosphate intake

• Increased PTH or phosphate intake decreases F_EPO₄ (ie, more phosphate is excreted into the urine)

• Measurement of plasma PTH or PTHrP levels may be helpful

• The clinical utility of serum FGF levels is undetermined except in uncommon diseases

• Other clinical features may be suggestive of hypophosphatemia, such as hemolytic anemia and rhabdomyolysis

• Fanconi syndrome may present with any combination of uricosuria, aminoaciduria, normoglycemic glucosuria, normal anion gap metabolic acidosis, and phosphaturia

Imaging Studies

• In chronic hypophosphatemia, radiographs and bone biopsies show changes resembling osteomalacia

Medications

• Hypophosphatemia can be prevented by including phosphate in repletion and maintenance fluids

• A rapid decline in calcium levels can occur with parenteral administration of phosphate; oral replacement of phosphate is preferable

• Moderate hypophosphatemia (1.0–2.5 mg/dL [or 0.32–0.79 mmol/L]) is usually asymptomatic and does not require treatment

• Chronic hypophosphatemia

  • Can be treated with oral phosphate repletion

  • Mixtures of sodium and potassium phosphate salts may be given to provide 0.5–1 g (16–32 mmol) of phosphate per day

• For severe, symptomatic hypophosphatemia (< 1 mg/dL [or < 0.32 mmol/L])

  • An infusion should provide 279–310 mg/12 h (or 9–10 mmol/12 h) until the serum phosphorus exceeds 1 mg/dL

  • Then, the patient can be switched to oral therapy

  • Infusion rate should be decreased if hypotension occurs

  • Magnesium deficiency often coexists and should be treated simultaneously

• Contraindications to phosphate replacement

  • Hypoparathyroidism

  • Advanced chronic kidney disease

  • Tissue damage and necrosis

  • Hypercalcemia

Therapeutic Procedures

• Hypophosphatemia in patients with diabetic ketoacidosis will usually correct with normal dietary intake

Follow-Up

• Monitoring of plasma phosphate, calcium, and potassium every 6 hours is necessary because the response to phosphate supplementation is not predictable

Complications

• Refeeding or glucose administration to phosphate-depleted patients may cause fatal hypophosphatemia

Prevention

• Include phosphate in repletion and maintenance fluids

When to Refer

• Patients with refractory hypophosphatemia with increased urinary phosphate excretion may require evaluation by an endocrinologist (eg, for hyperparathyroidism and vitamin D disorders) or by a nephrologist (eg, for renal tubular defects)

• Patients with decreased gastrointestinal absorption may require referral to a gastroenterologist

When to Admit

• Patients with severe or refractory hypophosphatemia will require intravenous phosphate