Etiology and Pathogenesis of Hypophosphatemia in Animals
The most common cause of chronic phosphorus deficiency is inadequate feed intake or inadequate phosphorus content in the diet over an extended time. This can be seen in sick animals that are anorectic for prolonged periods but also 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 Renal Tubular Defects in Small Animals The form of metabolic acidosis that occurs in acute kidney injury and Stages 2–4 of chronic kidney disease, referred to as uremic acidosis, is due to reduced urine-acidifying ability of diseased... read more ) or primary or secondary hyperparathyroidism Hypercalcemia in Dogs and Cats Hypercalcemia is diagnosed when calcium is elevated outside of normal reference ranges. This usually indicates an underlying disease process causing the dysregulation of calcium homeostasis... read more causing increased renal phosphorus excretion. Hypophosphatemia is a common finding in horses with chronic renal failure.
In cattle, transient hypophosphatemia is commonly seen during the periparturient period, particularly in high-yielding dairy cows. The primary cause of this hypophosphatemia at the onset of lactation is often attributed to disturbance of the phosphorus balance, because large amounts of phosphorus are suddenly lost through the mammary gland. Transient but pronounced hypophosphatemia, however, was also shown to occur in previously mastectomized periparturient cows, indicating that other mechanisms, such as depressed feed intake around calving, decreased GI motility related to the concomitantly occurring hypocalcemia, or hormonally driven shifts of inorganic phosphorus toward the intracellular space are likely to be at least equally important causal factors.
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.
Clinical Findings and Lesions of Hypophosphatemia in Animals
Signs of chronic phosphorus deficiency are most commonly seen in animals fed a phosphorus-deficient diet over several months. Phosphorus-deprived young animals grow slowly, develop rickets Rickets in Animals Rickets is a disorder affecting the skeleton of growing animals. Primary causes are insufficient dietary phosphorus or calcium, an inappropriate ratio between these minerals in the diet, or... read more , and tend to have a rough hair coat, whereas adult animals in early stages may become lethargic, anorectic, and lose weight. Indeed, anorexia is the one sign of chronic phosphorus deprivation most consistently reported across species. In later stages, animals may develop pica, osteomalacia Osteomalacia in Animals Osteomalacia is a disturbance of the bone metabolism of adult animals. The primary cause is an inadequate mineral supply over prolonged periods of time. Diagnosis is based on clinical presentation... read more , abnormal gait, and lameness, and eventually become recumbent.
In cattle, decreased milk production and fertility were found to be associated with dietary phosphorus depletion but are thought to be the result of the chronically reduced energy intake in anorectic animals rather than a direct effect of phosphorus deprivation.
Periparturient hypophosphatemia of dairy cattle has been associated empirically with:
muscle and bone pain
Other potential effects of hypophosphatemia include 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 all believed to be caused by reduced availability of ATP in states of phosphorus deficiency in the cells of the various affected tissues.
Periparturient hypophosphatemia in cattle is widely believed to be associated with periparturient recumbency and downer cow syndrome Bovine Secondary Recumbency . Thus far, however, it has not been possible to experimentally induce hypophosphatemic recumbency nor has a physiologically plausible mechanism been identified through which hypophosphatemia may cause recumbency.
Postparturient hemoglobinuria Postparturient Hemoglobinuria in Dairy Cows Postparturient hemoglobinuria most often affects high-yielding dairy cows at the onset of lactation. Clinical signs can include a drop in milk production, anorexia, lethargy, and pale, icteric... read more is another condition seen in high-yielding dairy cows that has been empirically associated with hypophosphatemia during early lactation. The disease that is observed only incidentally is characterized by pronounced intravascular hemolysis associated with hemoglobinuria and predominantly occurs in the first weeks of lactation. It is frequently fatal.
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.
Diagnosis of Hypophosphatemia in Animals
Blood phosphorus measurement
Hypophosphatemia is easily diagnosed through blood biochemical analysis; the blood phosphorus concentration, however, is a poor surrogate parameter to diagnose phosphorus deficiency. Due to the lack of a reliable parameter to assess the phosphorus status of an individual animal, indirect approaches, such as estimating daily phosphorus intake while taking into account phosphorus losses through the kidney, gut, and mammary gland, should be considered.
Phosphorus depletion is not readily diagnosed in living animals. Sustained phosphorus deprivation induces pronounced osteoclastic activity, releasing phosphorus together with calcium from bone. At the same time, phosphorus deprivation stimulates the activation of vitamin D3, presumably through a downregulation of production of fibroblast growth factor 23 in bone. Chronically phosphorus-depleted animals can maintain the serum inorganic phosphorus concentration within or at least near the normal limits through the mechanisms mentioned above. On the other hand, the serum phosphorus concentration can be decreased even in the absence of phosphorus depletion due to compartmental shifts between the intra- and extracellular space.
Other factors that affect serum phosphorus concentration include diurnal variation, the effect of physical activity, the site of blood sample collection, or administered treatments such as IV dextrose or parenteral administration of insulin. It follows that the phosphorus concentration in serum or plasma will not reliably reflect the phosphorus homeostasis of the organism.
Determination of the bone density or bone phosphorus content in a biopsy of a rib or the pelvic bone has been proposed as a tool to diagnose chronic phosphorus depletion in cattle. The bone phosphorus content, however, is slow to respond to phosphorus deprivation and also to return to normal values after initiation of phosphorus supplementation. 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, making the determination of the bone phosphorus content a method restricted to postmortem examination or research activities. Radiographic examination of bone will reveal reduced radiopacity of the bones in chronically phosphorus-depleted animals.
Alternatively, bone resorption can be assessed by measuring the concentration of collagen breakdown products in serum or urine, such as hydroxyproline. Enhanced bone resorption, however, is not pathognomonic for phosphorus deficiency but also occurs with deficient dietary calcium supply or with chronic metabolic acidosis.
Feed samples can be submitted to determine the phosphorus content in the diet, 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.
Treatment and Prevention of Hypophosphatemia in Animals
Oral administration of phosphate salts
Providing feed with adequate phosphorus
Chronic phosphorus depletion and hypophosphatemia is most effectively treated by providing sufficient amounts of feed with adequate phosphorus content. This is typically achieved by switching to feed ingredients with higher phosphorus content or by using mineral supplements enriched with phosphorus.
The need for therapeutic intervention with acute hypophosphatemia, because it commonly occurs in animals that are anorectic for a few days or in fresh dairy cows, is controversial. Although there do not appear to be clinical signs that can be unequivocally attributed to acute hypophosphatemia, the condition is often treated in practice.
Orally administered phosphate salts are effective, safe, and cost-efficient and have a rapid and sustained effect even with pronounced hypophosphatemia. Oral treatment, however, requires adequate GI motility and may not be suitable for patients with diarrhea or persistent vomiting. Phosphate salts used for this purpose are mono- or disodium phosphate. Monopotassium phosphate can be used in cases with concomitant hypokalemia. In cattle, other salts, such as dicalcium phosphate or magnesium phosphate, are used in drench ingredients. These compounds, however, are unsuitable for the rapid correction of hypophosphatemia due to their poor solubility.
IV treatment of hypophosphatemia may be indicated in patients with chronic vomiting. persistent diarrhea, or other major impairment of normal GI function. IV treatment consists of administration of phosphate salt solutions that currently, however, are not available for veterinary use in most countries. Phosphorus-containing products labeled for the parenteral use in animals in general contain organic phosphorus such as toldimphos, butaphsphan, phosphite, or hypophosphite. These compounds do not appear to provide any phosphate (PO4), the biologically active form of phosphorus the organism depends on.
In companion animals, treatment includes IV drip infusion of sodium phosphate salt solutions, or monopotassium phosphate solutions in patients with concomitant hypokalemia. In cattle, rapid administration of sodium phosphate salt solutions has been recommended in the older literature. Mono- or dibasic phosphate salts (either Na2HPO4 or NaH2PO4) infused IV rapidly increase the serum inorganic phosphorus 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 phosphorus at a rate that increases the plasma concentration above the renal threshold disproportionally increases renal phosphorus excretion and therefore only transiently increases the plasma concentration. This explains the short-lived effect (< 2 hours) of sodium phosphate solutions when administered as an IV bolus, as is sometimes used in cattle practice.
Rapid administration of sodium phosphate salts causes transient but severe hyperphosphatemia and therefore creates a risk of suddenly dropping the blood calcium and magnesium concentration due to precipitation of calcium and magnesium phosphate salts. This is also the reason that the simultaneous parenteral administration of phosphate with calcium- or magnesium-containing solutions should be avoided. Infusing phosphorus salts slowly over several hours, as is done in human or companion animal practice, results in a more sustained effect and reduces risk of hypocalcemia. Currently, no sodium phosphate salt-containing solutions are approved by the FDA for IV administration in animals; therefore, any effective IV phosphate administration is off-label.
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 with phosphate salts. In the dairy industry, overfeeding phosphorus is more common because of concerns with current recommendations for dietary phosphorus content for cattle that are sometimes thought not to be adequate for high-yielding dairy cows, particularly in early lactation. Research consistently confirms that a 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.
Low blood phosphorus concentrations are often considered to indicate phosphorus deficiency in the body. This concept, however, is misleading because there is no fixed association between the phosphorus concentration in blood and the phosphorus content of various tissues.
Although clinical signs associated with chronic phosphorus deficiency are well defined (ie, anorexia, ill thrift, and hampered productivity), the clinical relevance of transient hypophosphatemia is controversial.
In patients with adequate GI function, oral administration of phosphate salts is an effective, cost-efficient, and safe treatment with rapid and sustained effect. Parenteral administration of organic phosphorus compounds such as phosphite or hypophosphite are unsuitable for increasing plasma phosphorus because they do not provide the form (ie, phosphate, PO4) needed by the organism.