Hypophosphatemia

Introduction

• Phosphate is an essential electrolyte in the body, important for structural and metabolic function.5 Most body phosphate (85%) is found in the skeleton.¹
• Physiological serum levels in adults range from 2.5 to 4.5 mg/dL.⁵
• Serum levels are maintained by a balance between intestinal absorption and renal reabsorption.¹
• Fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D (the activated form of vitamin D) are the main hormones involved in phosphate absorption and excretion, with opposing mechanisms.¹
• Vitamin D has a net positive effect on phosphate levels. It can increase phosphate absorption in the gut. It also increases renal reabsorption via sodium-dependent phosphate cotransporters (NPT2a and NPT2c) in the proximal convoluted tubule of the kidney.¹
• PTH and FGF-23 have a net negative effect on serum levels, primarily by decreasing renal absorption. FGF-23 also inhibits the conversion of 25-hydroxyvitamin D to its active form of vitamin D.¹

Physiologic Roles of Phosphate and Pathologic Correlates with Depletion

Musculoskeletal

• Phosphate is essential in bone mineralization; it combines with calcium to form hydroxyapatite, the major structural component of bone.⁵
  • Deficits can cause decreased bone density, leading to rickets (children) or osteomalacia (adults).^2,6
• Phosphate is required for adenosine triphosphate (ATP) synthesis and, consequently, muscle contraction.³
  • Hypophosphatemia can cause profound muscle weakness and rhabdomyolysis.²

Acid/Base Balance

• Phosphate is necessary for titratable acid secretion in renal tubules and proper bicarbonate reabsorption.⁷
  • Low phosphate levels can cause a hyperchloremic metabolic acidosis.⁷

Hematologic

• Phosphate is involved in the metabolism of erythrocytes and leukocytes, as well as maintaining membrane integrity.⁶
  • Deficiency can result in hemolytic anemia due to erythrocyte fragility and decreased immune response.^4,6
• Additionally, phosphate is necessary for 2,3-DPG synthesis, which affects the affinity of erythrocytes for oxygen. Hypophosphatemia decreases the available levels of 2,3-DPG, thereby increasing its affinity.⁷
  • This can present with neurologic complications of hypoxia, including fatigue, paresthesias, confusion, seizures, and encephalopathy.^5,6

Cardiopulmonary

• ATP (and, therefore, phosphate) is essential for cardiac contractility and proper electrical conduction.^3,6
  • Depletion can present with reversible cardiomyopathy, arrhythmias, and acute heart failure.⁶
• ATP is also essential for diaphragm strength and skeletal muscle contractility.
• Hypophosphatemia can impair both, leading to difficulty ventilating and, in extreme cases, may require intubation. Patients with severe depletion may have more difficulty weaning from mechanical ventilation.^3,5,6
• Most patients with hypophosphatemia are asymptomatic; symptoms usually occur with extreme depletion, with levels less than 1 mg/dL.⁶

Etiologies of Hypophosphatemia

• Hypophosphatemia can occur due to an intracellular shift of body potassium or decreased total-body stores, whether through impaired absorption or increased losses.^2,6

Intracellular Shift

• This is most commonly seen with refeeding syndrome, diabetic ketoacidosis, respiratory alkalosis, sepsis, and insulin administration.^2,6
• These states increase ATP production, thereby promoting cellular uptake of phosphorus.⁶

Decreased Absorption

• Absorptive pathologies include vitamin D deficiency, malnutrition, chronic alcoholism, malabsorption syndromes (e.g., celiac disease), and phosphate-binding antacids.⁶
• Whether by decreased levels of phosphate in the gut or by impaired absorption of sufficient levels, these mechanisms contribute to hypophosphatemia.⁶

Increased Renal Losses

• This occurs with hyperparathyroidism (primary and secondary), excess FGF23 (e.g., X-linked hypophosphatemia), proximal tubular dysfunction (e.g., Fanconi syndrome), and drug-induced tubular dysfunction.^2,6
• These pathologies affect the sodium-potassium cotransporter (NPT2) in the proximal convoluted tubule, or affect the proximal tubule itself, both of which result in renal phosphate wasting.⁶

Pseudohypophosphatemia

• Falsely low serum phosphate lab values can occur due to interference of certain proteins with the laboratory analysis. This is an error and does not reflect true depletion.⁸
• Pseudohypophosphatemia can be seen in various situations, including lymphoproliferative disorders (multiple myeloma, Waldenstrom macroglobulinemia).⁸

Typical Situations and Management

• Hypophosphatemia is one of the diagnostic criteria of refeeding syndrome.²
• Disorders requiring insulin administration (diabetic ketoacidosis, hyperglycemic hyperosmolar syndrome) decrease serum concentrations of several electrolytes, including phosphate.²
• Hungry bone syndrome occurs after correction of hyperparathyroidism and presents with hypophosphatemia due to increased phosphate uptake from increased bone turnover.⁵
• Critically ill patients can have multifactorial hypophosphatemia, including metabolic alkalosis, malnutrition, and sepsis.⁵
• Drug-associated hypophosphatemia is seen with diuretics, glucocorticoids, aminoglycosides, antiretrovirals, and anticancer agents.⁵
• Importantly, serum phosphate levels do not always reflect total body stores; thus, the degree of hypophosphatemia may not correlate to the symptoms present.⁵

Management and Adverse Effects of Repletion

• For severe (less than 1 mg/dL) or symptomatic hypophosphatemia, initiate intravenous (IV) phosphate repletion and postpone elective surgeries.⁵
• IV sodium or potassium phosphate formulations can be selected based on concurrent electrolyte abnormalities and the patient’s volume status.^2,5
• Mild (2-2.5 mg/dL) or moderate (1-1.9 mg/dL) hypophosphatemia can be managed with increased dietary phosphate or with oral supplementation and active vitamin D.^2,5
• Recognize and correct the underlying etiology of the deficiency.²
• In patients with chronic kidney disease, decrease the repletion dose by 50%, as this population is more susceptible to adverse effects associated with supplementation.⁶
• Pseudohypophosphatemia does not require repletion.⁸
• Adverse effects of repletion can include arrhythmias, acute kidney injury, hypocalcemia, and ectopic calcification in hypercalcemic patients.⁵

Anesthetic Considerations

• Diaphragmatic and skeletal muscle weakness may result in respiratory insufficiency and require ventilation; additionally, weaning from ventilation may be more challenging.^3,5
• Hypophosphatemia can decrease cardiac contractility and predispose to arrhythmias, though without highly specific electrocardiographic changes.⁵
• Respiratory alkalosis can precipitate hypophosphatemia.³
• Some operations, specifically partial hepatectomies, increase the risk of postoperative hypophosphatemia.^4,5