Hypophosphatemia

Chronic phosphorus deficiency is commonly caused by inadequate feed intake or inadequate phosphorus content in the ration over an extended time. This can be seen in grazing animals in arid regions with low phosphorus content in soil. Phosphorus depletion can also result from chronic renal tubular disease due to impaired renal reabsorption of phosphorus (eg, Fanconi syndrome) or primary hyperparathyroidism causing increased renal phosphorus excretion. Hypophosphatemia is a common finding in horses with chronic renal failure.

Acute phosphorus losses associated with hypophosphatemia are a well-recognized problem in high-yielding dairy cows at the onset of lactation. The sudden onset of phosphorus losses through the mammary gland at the onset of lactation and the decreased feed intake around parturition are believed to be the major contributors to periparturient hypophosphatemia of dairy cows. Nonetheless, periparturient hypophosphatemia has also been documented in mastectomized cows, indicating that other mechanisms, such as compartmental shifts, impaired intestinal absorption, or increased losses through the digestive or urinary tracts, must contribute to this phenomenon.

Hypophosphatemia without phosphorus depletion may occur after oral or parenteral carbohydrate administration and after parenteral insulin administration as a result of increased cellular phosphorus uptake in combination with glucose. Alkalemia and respiratory alkalosis enhance cellular phosphorus uptake and therefore also have a hypophosphatemic effect.

Signs of chronic phosphorus depletion are most commonly seen in cattle fed a phosphorus-deficient diet over several months. Young animals grow slowly, develop rickets, and tend to have a rough hair coat, whereas adult animals in early stages may become lethargic, anorectic, and lose weight. Decreased milk production and fertility have erroneously been attributed to phosphorus depletion. These signs appear to be the result of decreased energy and protein intake in animals that are anorectic due to phosphorus depletion. In later stages, animals may develop pica, osteomalacia, abnormal gait, and lameness, and eventually become recumbent.

Acute hypophosphatemia has been associated with anorexia, muscle weakness, muscle and bone pain, rhabdomyolysis, increased fragility of RBCs, and ensuing intravascular hemolysis. Other potential effects of hypophoshatemia are neurologic signs presumably related to the altered energy metabolism, impaired cardiac and respiratory function (decreased contractility of striated and heart muscle), and dysfunction of WBCs and platelets that are believed to be caused by ATP depletion.

In cattle, hypophosphatemia occurring at the onset of lactation is widely believed to be associated with periparturient recumbency and the downer cow syndrome (see Bovine Secondary Recumbency). However, this association is based on empirical observation and is not supported by unequivocal evidence. Postparturient hemoglobinuria is another but rare condition seen in high-yielding dairy cows in the first days of lactation. It is characterized by acute intravascular hemolysis and hemoglobinuria, frequently with fatal outcome.

It is currently not well understood whether the above-mentioned clinical signs and conditions are caused by low levels of phosphorus in the blood or by overall depletion of phosphorus in the body.

Necropsy findings in cases of chronic phosphorus depletion are those specific to rickets or osteomalacia. Carcasses appear emaciated with a dull hair coat. Fractures of ribs, vertebrae, or the pelvis, as well as widened growth plates and costochondral junctions, angular deformities, and shortened long bones are common.

Phosphorus depletion is not readily diagnosed in living animals. Because chronically phosphorus-depleted animals can maintain the serum Pi concentration within normal limits by mobilizing Pi from bone, and because the serum Pi concentration can be decreased even in the absence of phosphorus depletion, the Pi concentration in serum is an unreliable proxy to diagnose chronic phosphorus depletion. Although acute phosphorus depletion can reflect accurately in the serum Pi concentration, the considerable diurnal variation, effects of physical activity, and feed intake complicate the interpretation of results from a single blood sample. Dextrose administered parenterally shortly before blood sampling can decrease the serum Pi concentration by >30%; 4–6 hr should elapse between the end of dextrose infusion and blood sampling to allow the serum Pi concentration to return to baseline. Other factors that can affect the serum Pi concentration include physical exercise shortly before blood sampling or the site of blood collection. Vigorous physical activity can result in markedly decreased serum or plasma Pi concentrations for >1 hr.

Determination of the bone density or bone phosphorus content in a rib biopsy has been proposed as a reliable parameter to diagnose chronic phosphorus depletion in cattle. Nonetheless, the bone phosphorus content is slow to respond to changes in dietary phosphorus supply, which means the nutritional history has a strong impact on the mineral content of fresh bone. The phosphorus content in fresh bone is therefore a good indicator of body phosphorus reserves but not of current dietary phosphorus supply. Furthermore, obtaining bone biopsies is impractical under field conditions, and determination of bone phosphorus content is generally restricted to postmortem examination or research activities. Alternatively, the extent of bone resorption activity can be determined by measuring the urinary hydroxyproline concentration, an amino acid liberated from collagen as bone is demineralized. Radiographic examination of bone will reveal reduced radiopacity of the bones in chronically phosphorus-depleted animals.

Feed samples can be submitted to determine the phosphorus content in the ration, allowing an estimate of phosphorus intake if the daily feed intake is known. In grazing animals, the phosphorus concentration in either soil or in a fecal sample can be determined and used as an indirect and crude parameter to assess adequacy of the dietary phosphorus content.

Chronic phosphorus depletion and hypophosphatemia is most effectively treated by providing sufficient amounts of feed with adequate phosphorus content; however, the most appropriate treatment approach for acute phosphorus depletion and hypophosphatemia is controversial. IV administration of phosphorus-containing solutions is often recommended as the most appropriate approach. In small animals, this is achieved by slow IV infusion of sodium phosphate salt solutions, or in case of concomitant hypokalemia of potassium phosphate solutions. In cattle, rapid administration of sodium phosphate salt solutions is commonly practiced. Mono- or dibasic phosphate salts (either Na₂HPO₄ or NaH₂PO₄) infused IV rapidly increase the serum Pi concentration. Tribasic phosphate (Na₃PO₄) is a caustic detergent that cannot be used under any circumstances for PO or IV phosphorus supplementation. An issue with the IV infusion of phosphorus salt solutions is that unbound Pi in plasma reaching the kidney is filtered by the renal glomeruli and must then be reabsorbed in the renal tubules. Because tubular reabsorption is a saturable process, infusing Pi at a rate that increases plasma Pi concentration above the renal threshold disproportionally increases renal Pi excretion and therefore only transiently increases the plasma Pi concentration. This explains the short-lived effect (<2 hr) of sodium phosphate solutions when administered as an IV bolus as recommended for cattle. Rapid administration of sodium phosphate salts causes transient but severe hyperphosphatemia and therefore bears the risk of causing hypocalcemia due to precipitation of calcium phosphate salts. This risk of calcium phosphate precipitation also precludes the parenteral administration of phosphate salts in combination with parenteral calcium or magnesium infusions. Infusing phosphorus salts slowly over several hours results in a more sustained effect and reduces the risk of hypocalcemia. Currently, no sodium phosphate salt–containing solutions are approved by the FDA for IV administration in cattle; therefore, any effective IV phosphate administration is off-label.

In cattle, solutions containing not phosphate but phosphite (PO₃), hypophosphite, or organic phosphorus compounds such as butaphosphan or toldimphos are often used to supplement phosphorus IV, frequently in combination with calcium, magnesium, and other minerals. However, these phosphorus compounds are not suitable to correct hypophosphatemia, because mammals are unable to convert phosphite or the above-mentioned organic compounds into phosphate (PO₄) and so do not contribute to the biologically active plasma Pi pool. Even when organic phosphorus compounds are usable metabolically, pharmaceutical products containing organic phosphorus compounds administered at label dose do not provide nearly enough phosphorus to correct severe phosphorus depletion, which would be the primary indication for IV treatment.

Mild to moderate phosphorus depletion can be treated effectively by oral Pi supplementation either by adding dairy products to the diet (monogastric species) or by providing solutions of sodium phosphate salts for oral consumption. Oral Pi administration rapidly increases plasma Pi concentration and is safe and effective, but it may not be appropriate in vomiting and possibly in diarrheic animals. In cattle, oral sodium phosphate salts increase the plasma Pi concentration within 3–4 hr and exert a sustained effect lasting >12 hr. Other phosphate salts that have been proposed for rapid correction of hypophosphatemia in cattle include monopotassium phosphate and monocalcium phosphate. Dicalcium phosphate is commonly used for longterm supplementation of phosphorus-deficient diets but because of its poor solubility characteristics is unsuitable for rapid correction of hypophosphatemia.

Phosphorus depletion in healthy grazing animals is prevented by assuring sufficient feed intake with adequate phosphorus content. In animals grazing on phosphorus-deficient soils, depletion may be prevented by fertilizing the soils with phosphorus or by supplementing feeds or the water supply with phosphate salts. In the dairy industry, overfeeding phosphorus is more common because of the widely held but incorrect assumption that feeding phosphorus in excess of the daily requirements improves fertility and milk production. Research consistently confirms that phosphorus concentration of 0.42% in dry matter is adequate for high-yielding dairy cows.

Currently, no effective approach to prevent hypophosphatemia and phosphorus depletion at the onset of lactation is known. Feeding higher amounts of dietary phosphorus during the last weeks of gestation is contraindicated, because it decreases the intestinal absorption rate of phosphorus and increases the risk of periparturient hypocalcemia. The dietary Ca:P ratio that appears to be essential in horses and other species to prevent secondary hypo- or hyperparathyroidism is not important in ruminants. Cattle tolerate Ca:P ratios between 1:1 and 8:1, provided the ration meets minimal requirements for both minerals. This peculiarity in ruminants can be explained by the high salivary phosphorus concentration (5- to 10-fold the concentration in serum) and the large amounts of saliva produced that alter the Ca:P ratio of the rumen content considerably.