Introduction

• Definition: serum inorganic phosphate >2.00 mmol/l.
• Phosphate is the major intracellular anion. Has structural role in cell membranes, hydroxyapatite of bone, nucleic acids and phosphoproteins including adenosine triphosphate (ATP). Important in oxygen transports (2,3-diphosphoglycerate), second messenger systems (cyclic adenosine monophosphate), coenzyme systems (nicotinamide adenine dinucleotide phosphate). Important in the regulation of protein, fat and carbohydrate metabolism. Involved in the activation of vitamin D and calcium homeostasis.
• Phosphorus exists as organic (phospholipids, phosphate esters) and inorganic (orthophosphoric acid, pyrophosphoric acid) forms. 80-90% of total body phosphate is inorganic in bone as hydroxyapatite. 15% is organic and in soft tissues. Most serum phosphorus is inorganic orthophosphoric acid. 10-20% of inorganic is protein bound. 80-90% is free or bound to magnesium, sodium and calcium.
• <1% of total body phosphate found as extracellular active forms with only 33% of this being ionized.
• Total body phosphate levels closely regulated in conjunction with calcium.

Pathogenesis

Etiology

• Decreased excretion: post-renal failure (urinary tract obstruction or rupture), renal failure (acute or chronic).
• Although the mechanisms are unclear, early chronic renal failure Kidney: chronic kidney disease (CKD) leads to increased levels of parathyroid hormone (PTH). This causes enhanced excretion of phosphate by the kidneys. However, by late chronic renal failure this mechanism is inadequate leading to hyperphosphatemia. The increased level of PTH PTH assay continues to stimulate calcium and phosphate release from the bone. Hyperphosphatemia also inhibits production of calcitriol and therefore reduces intestinal calcium absorption.
• Decreased glomerular filtration rate in acute renal failure Kidney: acute kidney injury (AKI) may lead to reduced phosphate excretion.
• Increased intake:
  • Phosphate enemas (small dogs and cats).
  • Vitamin D toxicosis Vitamin D poisoning (cholecalciferol) calcipotriol/calcipotriene-containing skin preparations, cholecalciferol-containing rodenticides, day-flowering jasmines.
  • Iatrogenic due to over-administration of phosphate supplements (enemas).
• Acute tumor-lysis syndrome/reperfusion injury:
  • Rapid cell destruction releases large amounts of phosphate (and potassium) into circulation. Seen most commonly with high stage lymphomas Lymphoma.
  • Similar release can be seen with any condition causing lysis of large numbers of cells (rhabdomyolysis, soft tissue trauma, hemolysis).
• Hypoparathyroidism Primary hypoparathyroidism associated with hypocalcemia.
• Hyperthyroidism due to increased bone metabolism and enhanced renal reabsorption.
• Osteolysis.
• Acromegaly Acromegaly.
• Spurious - hyperlipidemia, hyperproteinemia, thrombocytosis, monoclonal gammopathy.

Predisposing factors

• Factors causing hypocalcemia generally lead to secondary hyperparathyroidism. PTH and Vitamin D (and analogues) both act to increase plasma calcium and phosphate levels.

Pathophysiology

• 60-70% of ingested phosphate is hydrolyzed to an inorganic form that is absorbed actively and passively. Active transport is increased by the presence of calcitriol primarily in the presence of hypophosphatemia.
• Passive absorption is largely dependent on the phosphorus content of the diet as well as the type of protein. Phosphorus is excreted in the urine and primarily reabsorbed in the proximal tubules as a result of the effects of PTH. Increases in PTH decreases reabsorption in the proximal tubules.
• Other hormones that can increase reabsorption of phosphorus in the proximal tubules include growth hormone, insulin and thyroxine. ACTH, glucocorticoids and calcitonin decrease proximal tubular reabsorption of phosphorus.

Diagnosis

Treatment