Phosphate Disorders

Chapter 58 Phosphate Disorders



Janet Aldrich, DVM, DACVECC



KEY POINTS



• Energy-rich phosphates provide power for cell membrane pumps and ion channels to maintain electrochemical gradients and electrical currents that operate most biologic systems.

• Severe hypophosphatemia can cause hemolysis, rhabdomyolysis, impaired renal function and acid-base regulation, and impaired glucose metabolism.

• Hyperphosphatemia can cause hypocalcemia, renal secondary hyperparathyroidism, and metastatic calcification.


INTRODUCTION


Phosphorus is essential for many important biologic processes including those requiring energy from adenosine triphosphate (ATP), one of the most important substances in nature. Hyperphosphatemia and hypophosphatemia are diagnostically important as indicators of underlying disease and therapeutically important because phosphorus-directed therapy may improve patient care and outcome.



CHEMISTRY


Plasma phosphorus consists of organic (phospholipids, phosphate esters) and inorganic forms (orthophosphate, pyrophosphate). Clinical laboratories report inorganic phosphorus levels, which may be taken to be the orthophosphate fractions because the pyrophosphate amount is small. The orthophosphates are in three forms: free (55%), protein bound (10%), and complexed to magnesium or calcium (35%). The free fractions are mainly present as divalent HPO42− or monovalent H2PO4− species; these ionic species are the active forms and their levels are regulated. At a pH of 7.4 they exist in a 4:1 divalent-to-monovalent ratio (i.e., 4 mmol HPO42− to 1 mmol H2PO4−).


Clinical laboratories report the elemental phosphorus bound in phosphate molecules in the sample as phosphorus (inorganic) in mg/dl. But it is the phosphate molecule that participates in biologic processes, usually expressed in mEq/L or mmol/L. Unit conversion reveals that 3.1 mg/dl of phosphorus = 1 mmol/L phosphate = 1.8 mEq/L phosphate.1



TERMS


Confusion can arise because the terms phosphorus (the element) and phosphate (the molecule) are often used interchangeably. For simplicity in this chapter, the term phosphate is used to mean either phosphorus or phosphate.



DISTRIBUTION AND FUNCTION


Total body phosphate is distributed as follows: 85% hydroxyapatite in bone (a complex of calcium, phosphate, and hydroxyl ions), 15% in soft tissue, and less than 1% in the extracellular compartment. Phosphate has an important structural and functional role, essential to many biologic processes. For example, phosphate-dependent energy systems are responsible for the maintenance of electrochemical gradients across cell membranes, for the generation of electrical currents, and for driving muscle contractions. Phosphate is also involved in protein function regulation; it is a component of deoxyribonucleic acid and ribonucleic acid, and it is essential to the structure of bone and teeth in addition to having acid-base effects.



HOMEOSTASIS


Phosphate homeostasis is maintained by intestinal absorption of phosphate balanced by renal regulation of serum phosphate concentration, [P]. Phosphate is conserved by renal reabsorption, decreases in fecal excretion, and growth cessation. Phosphate exchange between extracellular and soft tissue or bone compartments plays a role in metabolism but is not primarily involved in homeostasis. Phosphate homeostasis is affected by parathyroid hormone (PTH), vitamin D, and calcitonin, but can occur without hormonal influence.1



Intestinal


Dietary phosphate is absorbed in the small intestine passively and by vitamin D–dependent transport. Passive transport is by diffusional flux through the paracellular pathway and is the most important means of absorption. Factors promoting intestinal absorption are sodium stimulation of a 1,25-(OH)2vitD (calcitriol)–sensitive apical sodium-phosphate cotransporter, decreasing pH, and growth hormone. If luminal phosphate is in short supply, because of either low dietary phosphate or the presence of phosphate-binding drugs, vitamin D–dependent active transport becomes important. Hyperphosphatemia regulates vitamin D metabolism by stimulating production of an inactive form of vitamin D, thus decreasing active vitamin D and therefore decreasing intestinal phosphate absorption.



Renal


Phosphate is reabsorbed in the proximal tubule by a transcellular sodium-phosphate symporter on the apical side and a phosphate anion antiporter on the basolateral side ofthe renal epithelial cells. When maximal tubular reabsorption of phosphate (TmP) is reached, the rest is excreted in the urine. This is the set point for serum [P]. The normal filtered load of phosphate is just a little higher than the TmP so that a small amount spills in to the urine. Tubular reabsorption is decreased by diuresis. Growth hormone increases TmP so that reabsorption is increased. This is the likely mechanism of increased serum [P] in young animals.


The three most important hormones affecting renal handling of phosphate are PTH, calcitriol, and calcitonin, although regulation of phosphate can be maintained without them. The effect of PTH is to decrease renal reabsorption of phosphate by inhibiting the sodium-phosphate symporter while increasing reabsorption of calcium. Calcitriol plays a small role in phospate reabsorption, mostly by its primary effect of decreasing PTH. Calcitonin has a hypophosphatemic effect (see Bone, next).



Bone


Acutely, PTH promotes transfer of calcium, but not phosphate, from the soluble part of bone where ions cross the membrane barrier created by osteoblasts and osteocytes. In stable bone, PTH stimulates increased osteoclastic and decreased osteoblastic activity, resulting in release of calcium and phosphate. In spite of the increased release of phosphate from bone to the extracellular fluid, the phosphaturic effect of PTH prevents hyperphosphatemia if renal function is normal.


Calcitonin’s hypophosphatemic effect is attributable to inhibition of bone resorption (by inhibiting osteoclasts) and promoting movement of phosphate from extracellular fluid into bone.



SERUM PHOSPHATE CONCENTRATION


Normal values for [P] are approximately 3 to 6 mg/dl in adult dogs and cats.2 In young dogs and cats [P] is significantly higher than in adults. Values for [P] as high as 11 mg/dl are normal in growing puppies.3 In kittens from birth to 8 weeks, a reference interval of 7 to 11 mg/dl was determined.4 Values decrease to adult levels by 12 months of age. Interpretation of [P] should be made with awareness that serum levels may not parallel intracellular stores, because phosphate is mostly intracellular. Diurnal variation in [P] has been observed in dogs with concentrations lowest in morning, highest at midnight.1


Autoanalyzers dependent on a color reaction for phosphate analysis may produce falsely increased values because of the turbidity caused by proteins in hyperglobulinemic patients.5 Hyperlipidemia may cause a false increase, and in vitro hemolysis may cause release of intracellular phosphate. A falsely low value may be found in samples containing mannitol, because it binds the molybdate used in the colorimetric assay in some analyzers. Conjugated bilirubin may increase or decrease the [P] value depending on the assay used.



HYPOPHOSPHATEMIA



Definition


Hypophosphatemia refers to a decrease in [P] below the normal range. Values of concern are those less than 2 mg/dl. Phosphate-deficient diets or depletion of phosphate body stores are not always reflected in decreases in [P]. In phosphate deprivation there is no net loss from the body. In starvation, which is caloric deprivation, phosphate is lost proportionately to other cellular elements so that the phosphate content of the remaining cells is normal.



Causes


Three mechanisms of hypophosphatemia or phosphate depletion are decreased intestinal absorption, redistribution of phosphate from extracellular to intracellular sites, and renal (or dialysis-associated) loss (Box 58-1).



Box 58-1 Causes of Hypophosphatemia or Phosphate Depletion



Decreased Intestinal Absorption or Increased Loss



Phosphate-binding drugs

Omission of phosphate from diet

Vomiting, diarrhea

Malabsorption

Vitamin D deficiency


Redistribution From Extracellular Fluid to Cells and Bone



Intravenous glucose, high insulin levels (exogenous, endogenous)

Diabetes mellitus, diabetic ketoacidosis

Hyperalimentation (refeeding syndrome)

Hepatic lipidosis

Respiratory alkalosis

Metabolic acidosis

Epinephrine

Salicylate poisoning

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Sep 10, 2016 | Posted by in SMALL ANIMAL | Comments Off on Phosphate Disorders

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