Hypophosphatemia is defined as an abnormally low concentration of phosphorus in the blood. In practice, hypophosphatemia is often equated with phosphorus deficiency; this, however, is incorrect and potentially misleading, because blood phosphorus concentration is a poor surrogate marker for phosphorus content throughout the body. The clinical relevance of hypophosphatemia is poorly understood, because the clinical signs are not well defined. Hypophosphatemia is diagnosed through blood biochemical analysis. Treatment includes administration of phosphate salts orally or parenterally.
Hypophosphatemia is defined as a concentration of inorganic phosphorus in blood that is below the physiological reference range. This blood biochemical abnormality is regularly diagnosed in sick animals and is often interpreted as phosphorus deficiency. Although hypophosphatemia has been associated with a variety of diseases on the basis of empirical observation, the clinical and diagnostic relevance of this laboratory result remains uncertain.
The concentration of inorganic phosphate in the extracellular space and thus in serum is dictated by the equilibrium between the uptake of phosphorus from the digestive tract; the excretion of phosphorus in urine (monogastric species), saliva (ruminants), and milk; the movement of phosphorus between ECS and the skeleton; as well as compartmental phosphorus shifts between the ECS and intracellular space. Accordingly, hypophosphatemia can be caused by decreased oral uptake, increased loss, a shift into the ICS, or a combination of these factors.
Only the loss of phosphorus from the body and a decrease in phosphorus uptake in the diet will result in a depletion of the amount of phosphorus in the body. Compartmental shifts between the ICS and ECS, in contrast, can strongly alter the Pi concentration in the ECS and thus in blood. However, they are not associated with a loss of phosphorus from the body. It follows that the Pi concentration in serum or plasma is an unreliable parameter to assess the phosphorus status of an animal. Despite the difficult interpretation of serum Pi concentration, it is still the most commonly used measurement of phosphorus status in veterinary medicine.
Prolonged phosphorus deprivation stimulates activation of osteoclasts to release phosphorus and calcium from the skeleton. The concentration of phosphorus in serum or plasma will therefore increase in response to phosphorus entering the extracellular pool from bone, and the blood phosphorus concentration will not reflect the true level of phosphorus deficiency.
Etiology and Pathogenesis of Hypophosphatemia in Animals
The most common cause of chronic phosphorus deficiency is inadequate feed intake, sometimes over an extended period of time. This can be observed in sick animals that are anorectic for prolonged periods and also in herbivores kept in regions with low phosphorus content in soil.
Phosphorus depletion can also result from chronic renal tubular disease because of impaired renal reabsorption of phosphorus (eg, Fanconi syndrome) or primary or secondary hyperparathyroidism causing increased renal phosphorus excretion. Hypophosphatemia is a common finding in horses with chronic renal failure.
In cattle, transient hypophosphatemia is commonly present in early lactation, particularly in high-yielding dairy cows. The primary cause of this postparturient hypophosphatemia is often attributed to the sudden onset of milk production leading to excretion of large amounts of phosphorus through the mammary gland. Transient but pronounced hypophosphatemia after calving, however, also occurs in previously mastectomized cows, indicating that other mechanisms, such as depressed feed intake around calving, decreased GI motility in subclinically hypocalcemic cows, or hormonally driven shifts of phosphorus toward the intracellular space, might be equally important causative factors.
Hypophosphatemia without actual loss of phosphorus from the body can occur after carbohydrate or insulin administration, as a result of increased cellular phosphorus uptake together 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
Clinical signs of chronic phosphorus deficiency are most commonly observed in animals fed a phosphorus-deficient diet over several months. Phosphorus-deprived young animals grow slowly, develop rickets, and tend to have a rough coat, whereas adult animals in early stages can become lethargic, anorectic, and lose weight. Indeed, anorexia is the one clinical sign of chronic phosphorus deprivation most consistently reported across species. In later stages, animals can develop pica, osteomalacia, abnormal gait, and lameness, and eventually become recumbent.
In cattle, decreased milk production and decreased fertility were found to be associated with dietary phosphorus depletion (1). However, these are thought to be the result of the chronically decreased dietary intake in anorectic animals rather than a direct effect of phosphorus deprivation.
Postparturient hypophosphatemia of dairy cattle has been associated empirically with:
anorexia
impaired milk production
muscle weakness and recumbency
muscle and bone pain
rhabdomyolysis
intravascular hemolysis and hemoglobinuria
Other potential effects of hypophosphatemia include neurological signs presumably related to altered energy metabolism, impaired cardiac and respiratory function (decreased contractility of striated and heart muscle), and dysfunction of WBCs and platelets, all of which are believed to be caused by decreased availability of ATP in states of phosphorus deficiency in the cells of the various affected tissues.
Postparturient hypophosphatemia in cattle is widely believed to be associated with postparturient recumbency and downer cow syndrome (2). Thus far, however, it has not been possible to experimentally induce hypophosphatemic recumbency, nor has a physiologically plausible mechanism been identified through which hypophosphatemia can cause recumbency.
Postparturient hemoglobinuria is another condition observed in high-yielding dairy cows that has been empirically associated with hypophosphatemia during early lactation. This disease is observed only incidentally and is characterized by pronounced intravascular hemolysis associated with hemoglobinuria. It predominantly occurs in the first weeks of lactation and is frequently fatal (3).
Necropsy findings in cases of chronic phosphorus depletion are those specific to rickets or osteomalacia. Carcasses appear emaciated, with a dull 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. Because of 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 and 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 a serum phosphorus concentration within or at least near the normal limits through the mechanisms mentioned above. On the other hand, serum phosphorus concentration can be decreased even in the absence of phosphorus depletion because of 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, and 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.
Bone density or bone phosphorus content in a biopsy of a rib or the pelvic bone is used in research to diagnose chronic phosphorus depletion in cattle. The bone phosphorus content, however, is slow to respond to phosphorus deprivation and also slow 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 determination of the bone phosphorus content a method restricted to postmortem examination or research activities. Radiographic examination of bone will reveal decreased 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. It also occurs with deficient dietary calcium supply, with chronic metabolic acidosis, and with other ailments associated with osteodystrophy.
Feed samples can be submitted to determine 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 soil or 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 are 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 is controversial, because it commonly occurs in animals that are anorectic for a few days or in fresh dairy cows and should resolve once the animal resumes eating. 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 might not be suitable for patients with diarrhea or persistent vomiting. Phosphate salts used for this purpose are monosodium 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 because of their poor solubility.
Dosage recommendations for treatment of hypophosphatemia found in the veterinary literature are empirical and are mostly derived from recommendations for humans. Appropriate dosages for oral treatment are particularly difficult to determine for patients suffering from anorexia, diarrhea, or vomiting, in which cases IV drip infusion is preferred over oral therapy.
In hypophosphatemic cattle, phosphorus is administered either as an oral bolus or as salts dissolved in several liters of water and administered via orogastric tube. A wide range of commercial products are available for this purpose. Single doses of phosphate salts providing 40–60 g of phosphorus that can be repeated 12–24 hours apart, as needed, have been recommended. This corresponds to a single dose of approximately 200 g of anhydrous monosodium or disodium phosphate for an adult cow (1).
IV treatment of hypophosphatemia might 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. However, these are not available for veterinary use in most countries. Notably, many phosphorus-containing products that are labeled for parenteral use in animals, such as toldimphos, butaphosphan, phosphite, or hypophosphite, contain organic phosphorus, which does not provide metabolically utilizable phosphorus to the organism.
In companion animals, hypophosphatemia 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 (4). Monobasic or dibasic phosphate salts (either Na2HPO4 or NaH2PO4) infused rapidly IV increase the serum phosphorus concentration. An issue with the IV infusion of phosphate salt solutions is that unbound phosphorus in plasma reaching the kidney is filtered by the renal glomeruli and must then be reabsorbed in the renal tubules.
Tribasic phosphate (Na3PO4) is a caustic detergent that cannot be used under any circumstances for oral or IV phosphorus supplementation.
Pearls & Pitfalls
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Because tubular phosphorus 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 as an IV bolus infusion has been recommended for the treatment of hypophosphatemia in cattle (5). This, however, causes transient but severe hyperphosphatemia and therefore creates a risk of suddenly dropping the blood calcium and magnesium concentrations because of precipitation of calcium and magnesium phosphate salts. This is also the reason simultaneous parenteral administration of phosphate with calcium- or magnesium-containing solutions must be avoided. Infusing phosphate salts slowly over several hours, as is done in human or companion animal practice, results in a more sustained effect and decreases the 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 extralabel. In companion animals, the extralabel use of parenteral phosphate solutions containing 3 mmol/L (93 mg/mL) of phosphorus at IV infusion rates of between 0.01 and 0.2 mmol/L/kg/h to rapidly reverse hypophosphatemia has been successful (6).
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 can be prevented by fertilizing the soils with phosphorus or by supplementing feeds with phosphate salts.
In the dairy industry, overfeeding phosphorus is more common than hypophosphatemia because of 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 (7).
Currently, no effective approach for prevention of 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 calcium to phosphorus (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.
Key Points
Low blood phosphorus concentrations do not indicate phosphorus deficiency in the body.
Chronic phosphorus deficiency is associated with anorexia, ill thrift, and decreased productivity, but transient hypophosphatemia might not be clinically relevant to the animal.
In patients with adequate GI function, oral administration of phosphate salts is an effective, cost-efficient, and safe treatment with rapid and sustained effect.
For More Information
Schropp DM, Kovacic J. Phosphorus and phosphate metabolism in veterinary patients. J Vet Emerg Crit Care (San Antonio). 2007;17(2):127-134.
Grünberg W. Treatment of phosphorus balance disorders. Vet Clin North Am Food Anim Pract. 2014;30(2):383-408, vi.
Forrester SD, Moreland KJ. Hypophosphatemia: causes and clinical consequences. J Vet Intern Med. 1989;3(3):149-159.
References
Grünberg W. Treatment of phosphorus balance disorders. Vet Clin North Am Food Anim Pract. 2014;30(2):383-408, vi. doi:10.1016/j.cvfa.2014.03.002
Grünberg W. Phosphorus Metabolism During Transition. Vet Clin North Am Food Anim Pract. 2023;39(2):261-274. doi:10.1016/j.cvfa.2023.02.002
Van den Brink LM, Cohrs I, Golbeck L, et al. Effect of dietary phosphate deprivation on red blood cell parameters of periparturient dairy cows. Animals. 2023;13(3):404. doi:10.3390/ani13030404
Goff JP. Treatment of calcium, phosphorus, and magnesium balance disorders. Vet Clin North Am Food Anim Pract. 1999;15(3):619-639, viii. doi:10.1016/s0749-0720(15)30167-5
Cheng YH, Goff JP. Horst RL. Restoring normal blood phosphorus concentrations in hypophosphatemic cattle with sodium phosphate. Vet Med. 1998;93:383-388.
Forrester SD, Moreland KJ. Hypophosphatemia: causes and clinical consequences. J Vet Intern Med. 1989;3(3):149-159. doi:10.1111/j.1939-1676.1989.tb03091.x
National Academies of Sciences, Engineering, and Medicine. Nutrient Requirements of Dairy Cattle. 8th rev ed. National Academies Press; 2021:502
