Recognizing and treating disorders of calcium metabolism in horses (Proceedings)

Calcium is a macronutrient that is essential for many cellular processes. The majority of body calcium is found in the skeleton, where it provides mechanical support and also serves as a large reserve of calcium and as a source of positive ion to the body.  Non-skeletal calcium is found in several forms. It is primarily an extracellular element, although trace amounts of intracellular calcium are crucial for cellular function.

Extracellular calcium is either protein bound (40%), complexed (5%), or in the free or ionized state (55%). It is the ionized calcium that is biologically active, and the form that is closely regulated via the PTH-calcitonin-Vitamin D system.  Low ionized calcium concentrations lead to the clinical signs of hypocalcemia. Horses with hypercalcemia have few characteristic clinical signs, but often exhibit signs associated with the primary disease that caused the metabolic derangement.

Overview of Calcium metabolism

Extracellular ionized calcium concentrations are closely monitored by cells in the parathyroid glands. A decrease in ionized calcium (iCa++) results in immediate secretion of parathyroid hormone (PTH). PTH has 3 distinct actions: it stimulates resorption of calcium from the skeleton, it increases renal retention of calcium and secretion of phosphorus. Finally, it also stimulates the conversion of vitamin D from inactive to active forms. Vitamin D subsequently acts on GI receptors to increase dietary absorption of calcium as well as further stimulates renal calcium retention and phosphorus excretion.

When blood ionized calcium concentrations are too high, calciton is secreted from the C-cells in the thyroid gland. Calciton acts to decrease bone resorption of calcium. Horses are unique among domestic animal species in that they absorb a large percent of dietary calcium, even when metabolic demand is low. The kidney is the primary regulatory organ for calcium metabolism. Healthy horses on a high calcium diet will routinely excrete urine that is supersaturated for calcium, containing calcium carbonate crystals.

The relationship between blood magnesium and calcium concentrations is complex and extremely species-specific.  Magnesium plays a permissive role in calcium metabolism, and animals regulate calcium levels more poorly in the face of hypomagnesemia. This is due to decreased secretion of PTH and target organ resistance to the actions of Vit D. Horses do not appear to develop hypocalcemia when they are primarily hypomagnesemic. In this regard they resemble rats more than they do humans or cattle.

Equine dietary requirements are for calcium to comprise between 0.15-1.5% of the daily ration on a dry matter basis with a Ca:P ratio of 1:1 or greater. Requirements are higher on a per pound basis for animals with actively growing bones and mare in late pregnancy or during lactation.

Hypocalcemia

Clinical signs of hypocalcemia are related to decreased ionized calcium concentrations.  The more rapid the decrease, the more pronounced the clinical signs. Acid/base disturbances can shift the percentage of calcium that is ionized so that rapid shifts in blood pH will result in rapid changes in iCa++   as well. Animals that are acidemic are relatively protected from developing clinical hypocalcemia while alkalemic horses will be more prone to developing hypocalcemia.

The clinical signs of hypocalcemia are related to the element's importance in maintaining resting membrane potentials in nerve and muscle cells. Low extracellular calcium levels result in hyper-excitability.  Thus, clinical signs of hypocalcemia include muscle fasciculations, tetany, and tremors. The gait is often stilted and hypermetric.  GI stasis occurs, and gastric reflux may be found on nasogastric intubation. Increased sweating and colic may also occur. In later stages, lateral recumbency, seizures, and then death ensue. Tachycardia may be present initially, possibly due to the horse's anxiety caused by lack of normal motor movements.  Cardiac arrhythmias or bradycardia may also be present. 

The combination of sweating, ileus, anxiety or depression, and abnormal gait makes it easy to mistake a horse with hypocalcemia for one with colic. As with other infrequent diseases of the horse, the most important factor in making the distinction between hypocalcemia and severe GI disease such as a strangulation/obstruction is an index of suspicion by the attending veterinarian. Close examination can often reveal a “lights are on but nobody's home” aspect to the sensorium of a horse with hypocalcemia where the animal reacts strongly to stimuli while simultaneously appearing unaware of its outside surroundings.

Synchronous diaphragmatic flutter is a less severe manifestation of hypocalcemia. It is caused by depolarization of the  phrenic nerve as it is stimulated by cardiac contractions. The result is a spasm of the diaphragm that occurs with the heart beat. Clinically, it appears as if the flank area of the horse is twitching. Auscultation of the heart will confirm that the spasm occurs at the same rate as the heart rate.

Specific syndromes of hypocalcemia

Tetany in lactating mares

Hypocalcemic tetany can occur at any stage of a mare's lactation. Unlike cattle, mares rarely experience problems in the periparturient period. Onset of clinical signs is often related to a stressful event, which may explain why many cases occur at the time of weaning. Clinical cases are associated with mares that are high producers, on a poor, low calcium diet, or have recently been transported or undergone strenuous exercise.

Idiopathic hypocalcemia associated with sepsis

Seizures associated with hypocalcemia and sepsis have been reported in foals. Some cases are refractory to repeated treatments with calcium and magnesium. Decreased serum calcium is a relatively common finding in horses with severe septic conditions associated with endotoxemia such as enterocolitis and strangulating obstruction.  Although classic signs of hypocalcemia are rarely observed, decreased GI motility and prolonged morbidity are associated with low blood calcium concentration. The cause of sepsis-associated hypocalcemia is multifactorial and includes anorexia, depressed PTH secretion, and sequestration of calcium in intracellular spaces.

Blister Beetle toxicosis

Blister beetles ( Epicauta spp. )prey on grasshoppers, and swarms of the beetles can follow grasshopper populations that feed in hay fields. This is a particular problem in hay from the southwestern United States. The beetles produce cantharidin, a toxic mucosal irritant that causes necrosis in the GI and urinary tract. The end result is acute renal failure, colic, and diarrhea. Profound hypocalcemia and hypomagnesemia are consistent clinical findings. This hypocalcemia persists until it is specifically treated, and does not resolve with rehydrating the horse and correcting acid base imbalances.

Endurance trail horse alkalosis

Synchronous diaphragmatic flutter (“thumps”) can occur in any animal with hypocalcemia, but is most classically associated with the gradual hypocalcemia and alkalosis that are associated with endurance trail riding. Depolarization of the right atrium during the cardiac cycle causes the irritated phrenic nerve to depolarize as well.

Horse sweat is hypertonic, and contains calcium, chloride, and sodium. Horses that exercise for prolonged periods of time can develop a hypochloremic metabolic alkalosis due to the loss of chloride in the sweat. The increased blood pH tends to favor the non-ionized form of calcium over the ionized leading to a decrease in the metabolically active form of the element.  Equine sweat also contains calcium, leading to a loss of the element from the extracellular space and further increasing the chances of synchronous diaphragmatic flutter developing.

Primary hypoparathyroidism

If the parathyroid gland does not secrete PTH in response to decreased ionized calcium concentrations, a profound hypocalcemia will result.  Diagnosis is made by the finding of low or normal PTH concentrations in the face of decreased ionized calcium levels. Hyperphosphatemia is a consistent feature.  Although a triggering factor such as general anesthesia or concomitant disease may be present in the history may be present in the history, the hypocalcemia persists after the inciting cause has resolved.

Treatment consists of calcium supplementation. As long as the animal's calcium needs are met orally it may be asymptomatic for prolonged periods of time.  Affected horses may require very large volumes of calcium supplement; up to 300 grams of calcium per day in the form of calcium diphosphate may be needed. In at least one instance at Purdue University, the horse gradually regained PTH function after several months and no longer required supplementation.

Treatment

Hypocalcemia can be a gratifying condition to treat as even a horse with extreme signs,  such as comatose condition and lateral recumbency will respond rapidly to calcium replacement therapy. Even if no overt clinical signs are noted, an ionized calcium concentration less than 1.0 mM warrants therapy to prevent ileus or cardiac side effects. Calcium gluconate 23% solution is the standard intravenous therapy. Initial doses of 50-100 ml in 1-2 liters of a balanced polyionic electrolyte solution administered over 30 minutes or longer should be given. If there is not improvement in clinical signs, a second course of therapy can be attempted. 

If calcium gluconate is not available, calcium chloride at a dose of .5 mg/kg as a 10% solution can be used. The heart should be ausculted periodically while the calcium is being administered, and infusion should be stopped if any sudden change in heart rate or rhythms is heard.  Calcium administration can be resumed at a slower rate once the heart has stabilized. Oral calcium supplement can be given as either calcium carbonate or dicalcium phosphate.  The amount given should be to effect until an amount that maintains normocalcemia is found. This can be up to 300 grams per day.

Hypercalcemia

Unlike hypocalcemia, there are no distinctive clinical signs associated with hypercalcemia. Often the only signs are referable to the primary disease process in the case of neoplasia or renal disease. Shifting leg lameness and stiffness have been reported with Ca/P imbalance as is seen with nutritional hyperparathyroidism.

Vitamin D toxicosis.

There are several plants that contain Vit. D analog compounds, but the majority of horses that receive toxic levels of Vit. D do so through mixing or formulation errors of enriched feeds.  Ingesting too much Vit. D3 (cholecalciferol) or Vit. D2 (ergocalciferol) will cause clinical signs. Metastatic mineralization of the soft tissues is the most severe manifestation of the problem, and  intoxicated horses can be found dead due to rupture of the aorta after it has mineralized.

Also reported are lameness, a stiff gait, and weight loss. Vit. D toxicosis is noteworthy in that it is the only condition that causes elevation in both Ca and P concentrations in the blood.  Once a horse has profound clinical signs the prognosis is quite poor. Treatment consists of immediately removing the Vit. D source as well as administration  of dexamethasone. Glucocorticoids increase urinary Ca loss while decreasing intestinal absorption. 

Primary, secondary, and nutritional hyperparathyroidism

If a horse presents with an elevated total calcium in the face of normal albumin or high serum ionized calcium concentrations, the next order of business is to attempt to determine the reason for the excess. Submitting a PTH panel, which compares whole molecule PTH to ionized calcium can help determine whether a horse is suffering from primary hyperparathyroidism (normal or high PTH in the face of high ionized calcium), secondary hyperparathyroidism, or pseudohyperparathyroidism (high calcium of malignancy).

High blood calcium concentrations caused by inappropriate increase in PTH secretion from the parathyroid gland is termed primary hyperparathyroidism. Because parathyroid tissue is found up and down a horse's neck from the thoracic inlet to the thyroid gland, identifying the causative tissue and removing it is often extremely difficult. Imaging techniques using scintigraphy to locate the area have been attempted, but are of low yield.

Secondary hyperparathyroidism occurs when calcium is wasted and phosphorus is in excess. If this occurs via dietary imbalance, it is termed nutritional hyperparathyroidism. In instances of renal failure, the increased blood P due to decreased renal clearance results in increased PTH secretion. In extreme cases “big head”, or fibrous osteodystrophy can develop. In less severe cases, horses may present with indeterminate lameness and stiffness.

n most instances, a careful dietary history and clinical chemistry will help make the diagnosis. If not, normal or low serum calcium in the face of increased PTH are both very suggestive of the condition. Urinary fractional excretions can be used to document decreased Ca excretion. The hypercalcemia observed in horses on high calcium diets with renal failure also falls into the category of secondary hyperparathyroidism as the body responds to chronically elevated P with PTH secretion.

The hypercalcemia of malignancy is a paraneoplastic syndrome where a parathyroid-like substance is secreted by a tumor and exerts hormonal effects similar to PTH. Several types of tumors have been reported to cause the problem, although in horses the tumors most often responsible are either gastric squamous cell carcinoma or intestinal lymphoma.

Correction of dietary calcium:phosophorus ratio can be easily accomplished if nutritional hyperparathyroidism is suspected. In all other cases, specific treatment of hypercalcemia is often difficult.  Treatment with diuretics such as furosemide will result in renal wasting and may improve blood calcium values.  Generally, however, the underlying disease is not treatable and the long-term prognosis is poor.