Hypocalcemia in Dogs and Cats: A Case Study and Overview

Kristen R. McFarland, DVM, MEd; Bruce E. LeRoy, DVM, PhD

Class of 2006 (McFarland) and Department of Pathology (LeRoy) College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388

Signalment - 10-year-old M(C) mixed-breed dog

History - Possible seizure, muscle tremors, stiffness

Physical Exam - Dog had a seizure during examination. The remainder of the physical examination was normal.

Diagnostics - Complete blood count, biochemical profile, urinalysis.

Laboratory Data:

Urinalysis

Other tests

Problem list:

• Mature neutrophilia with monocytosis and lymphopenia: These findings are most likely due to a stress (glucocorticoid) leukogram.

• Mild hyperglycemia: likely due to the effects of endogenous glucocorticoids.

• Mildly decreased creatinine: may suggest a loss of muscle mass and is likely not to be of clinical significance.

• Mild hypochloremia: not considered to be of clinical significance.

• Concurrent hypocalcemia and hyperphosphatemia: diagnostic considerations include renal failure, pancreatitis with pre-renal azotemia, excessive intake of a high phosphorus diet, and primary hypoparathyroidism. Renal failure may be eliminated as the dog is not azotemic and the results of the urinalysis are within normal limits. Pancreatitis is unlikely, as there is no history of dietary indiscretion, vomiting, or abdominal pain. This patient is fed a well-balanced commercial diet so a high level of ingested phosphorus is unlikely. In light of these findings, primary hypoparathyroidism was considered the most appropriate provisional diagnosis, and was confirmed by measuring the serum intact parathormone concentration (iPTH). The presence of an iPTH falling within the reference range of a hypocalcemic animal is indicative of hypoparathryoidism. Animals with normally-functioning parathyroid glands respond to hypocalcemia by increasing production of parathyroid hormone above reference concentrations.

Diagnosis

• Primary hypoparathyroidism

Introduction

Calcium is an important divalent cation that is essential for a variety of intracellular and extracellular metabolic processes. Calcium is required for muscle contraction, and ionized calcium mediates acetylcholine release during neuromuscular transmission (2). Calcium also stabilizes nerve cell membranes by decreasing membrane permeability to sodium and in a hypocalcemic state, the nervous system becomes progressively more excitable as a result of increased neuronal membrane permeability. This hyperexcitability causes spontaneous central nervous system stimulation and leads to tetany (random stiffening or tightening of various muscle groups), which is the most commonly reported clinical sign of hypocalcemia (3). Clinical signs associated with hypocalcemia are listed in Table 1 below.

Extracellularly, calcium is involved in cardiac function and blood coagulation. Calcium may serve as both a positive cardiac ionotroph and chronotroph and therefore hypocalcemia may result in a decreased strength of myocardial contractions and, in severe cases, bradycardia and/or heart blocks (3). Consequently, severely hypocalcemic patients should be monitored with an ECG before, during, and after treatment to detect cardiac abnormalities. Calcium is also an important cofactor for many of the proteases involved in both the intrinsic and extrinsic coagulation cascades. However, coagulopathies resulting from low circulating calcium levels have not been reported (3).

Calcium homeostasis and hormonal control

Most calcium is obtained from external (dietary) sources, however the skeletal system also represents an important internal reservoir of calcium. Systemic calcium levels are closely controlled by a tightly regulated system involving parathyroid hormone (PTH), vitamin D, and calcitonin. PTH is responsible for minute-to-minute regulation of serum ionized calcium. In the event of hypocalcemia, the chief cells in the parathyroid glands release PTH which increases osteoclasts-mediated calcium release from bone. Additionally, PTH increases calcium absorption from the gut and kidney, and increases renal phosphorus excretion and activation of vitamin D (1). The role of Vitamin D is chiefly long-term regulation of body calcium and phosphorus stores. The metabolically active form of Vitamin D is 1,25- dihydroxycholecalciferol, which is produced by the kidney and promotes absorption of calcium and phosphorus from the gastrointestinal tract and the kidneys. Finally, calcitonin is produced by thyroid parafollicular C-cells cells in response to hypercalcemia and functions to decrease calcium and phosphorus levels.

Laboratory analysis

Total serum calcium has 3 components: ionized calcium, protein-bound calcium, and calcium complexes. The ionized calcium is approximately 50% of the total serum calcium and is the biologically active form which participates in bone formation, neuromuscular activity, cell signaling processes, and blood coagulation. The clinical signs associated with hypocalcemia are due to decreased serum ionized calcium concentration. 40% of serum calcium is protein-bound to albumin, and therefore animals that are hypoalbuminemic also often have a decreased total calcium concentration. However, these patients do not demonstrate clinical symptoms of hypocalcemia since their ionized calcium concentrations are unaffected by hypoalbuminemia. To obtain a rough estimation of the corrected total calcium concentration in a hypoalbuminemic dog, one can perform the following correction equation:

Corrected calcium (mg/dl) = 3.5- patient's albumin (g/dl) + patient's measured calcium (mg/dl)

It should be noted that this equation was developed in dogs and should not be applied to other species (4). Also, this calculation is at best an approximation, and if possible, ionized calcium measurements should be performed. Recent research has demonstrated that this corrected calcium equation tends to underestimate hypocalcemia and overestimate normocalcemia (5, 6). Protein-bound calcium is thought to function as a readily available plasma reservoir of calcium. The remaining 10% of serum calcium is in the form of c alcium complexes , which are formed mostly with citrate and phosphate anions (1). These complexes are, unlike albumin-bound calcium, able to diffuse through membranes, yet are unavailable for use by cells (4).

While hypocalcemia is a relatively common laboratory abnormality, it is uncommon for serum ionized calcium concentrations to be low enough to cause clinical signs. Serum chemistry analyzers measure total serum calcium levels. Most laboratory reference ranges indicate that total serum calcium levels < 9.5mg/dl in dogs and < 9mg/dl in cats are considered hypocalcemic (3). If a patient is simultaneously hypoalbuminemic, ionized calcium levels should be determined. Ionized calcium levels are most commonly measured using ion-selective electrodes (2). Serum ionized calcium concentrations < 1.3 mmol/L or < 6.5 mg/dL in dogs (1) and < 1.0 mmol/L in cats are usually considered clinically significant hypocalcemic. Tetany can be expected with when serum total calcium concentration reaches 6 mg/dl or lower, and/or serum ionized concentrations are below 0.7 mmol/L (3).

Table 1. Common clinical signs of hypocalcemia

Important Causes of Hypocalcemia

Artifactual

• Hypoalbuminemia

Decreased intake

• Inadequate dietary intake (rare)

Decreased absorption/resorption

• Hypoparathyroidism: Hypoparathyroidism can occur spontaneously by immune-mediated destruction of the parathyroid gland or secondarily due to inadvertent iatrogenic damage during thyroidectomy. Since the parathyroid gland is responsible for ensuring ionized calcium concentrations remain within the physiologic range, a malfunctioning parathyroid gland can cause life-threatening hypocalcemia (2).

• Acute renal failure: Decreased glomerular filtration rate in acute renal failure may result in severe hyperphosphatemia. The increased serum phosphorus concentration may lead to hypocalcemia with clinical signs (2), but many animals with acute renal failure are normocalcemic.

• Chronic renal failure: Dogs or cats with chronic renal failure may be hyperphosphatemic but are most commonly normocalcemic. As mentioned earlier, if the patient has a protein-losing nephropathy it may have a decreased serum total calcium concentration due to the loss of albumin-bound calcium, but have normal ionized calcium concentrations (2). However, since vitamin D is converted to the active form (1,25-dicholecalciferol) in the kidney, chronic renal failure may render the kidney unable to produce activated vitamin D and lead to hypocalcemia. Concurrent hyperphosphatemia may be present due to decreased glomerular filtration rate associated with renal failure.

Increased loss

• Puerperal tetany (eclampsia): This life-threatening condition occurs in lactating bitches and queens due to the sudden increased systemic calcium demand. Affected bitches typically are small breeds within 21 days of the onset of lactation and are severely hypocalcemic (< 6.5 mg/dL) upon presentation. These patients often present as an acute emergency due to severe muscle fasiculations, behavior changes, and/or grand mal seizures, however with treatment, these patients usually recover without residual signs (2).

Sequestration

• Acute pancreatitis: 50% of dogs presenting for acute pancreatitis simultaneously are hypocalcemic, yet do not demonstrate clinical signs of hypocalcemia. While the exact pathogenesis has not been determined, theories include soap formation in the pancreas, hypomagnesemia, decreased parathyroid hormone secretion, and hypoproteinemia (1).

Toxicity

• Phosphate containing enemas: These types of enemas are hypertonic thus causing a hypernatremia, in addition to hyperphosphatemia due to the phosphate. Affected patients present with clinical signs of hypocalcemia and hypernatremia; the condition is referred to as "phosphate enema toxicosis" (3).

• Ethylene glycol toxicity: formation of calcium oxalate crystals and acute renal failure may lead to hypocalcemia in some cases (1,3).

Treatment

Emergency therapy:

If the history and clinical signs imply hypocalcemia, administer 5-15mg/kg IV 10% calcium gluconate slowly to effect over a 10-30 minute period. The IV infusion should be discontinued if bradycardia or ECG abnormalities develop. 10% calcium chloride, which is three times more potent than calcium gluconate, is also an effective treatment but can cause severe tissue irritation if administered extravascularlt - herefore, calcium gluconate is used most commonly.

Tetanic patients often present with an elevated body temperature due to muscle contraction. Once the tetany is resolved, the temperature should return to normal. If the acute hypocalcemic crisis is truly due to eclampsia most likely further treatment will not be necessary (3).

Maintenance therapy:

If the hypocalcemia is due to eclampsia, the puppies should be removed from the bitch and hand nursed until weaned (4). No further treatment should be required for the bitch other than a well balanced diet and close monitoring.

For other diseases, management will depend upon the specific cause of the hypocalcemia and the degree of the hypocalcemia and the rate of decline in serum calcium levels. The calcium concentration trend needs to be determined since treatment will vary whether the levels are fluctuating, stable, or quickly dropping. Serum calcium levels should be measured monthly for the first six months, and then every 2-4 months (4). The overall goal of treatment is to smoothly bring the patient's serum calcium level above the threshold at which clinical signs develop, which is 6-7.0 mg/dL. Throughout treatment the attending veterinarian needs to take care not to induce hypercalcemia (3).

• Short term Maintenance therapy options:
• Repeat IV boluses: not recommended
• Subcutaneous calcium: easy and inexpensive- can be used while waiting for oral vitamin D and oral calcium to take effect or while allowing atrophied parathyroid glands to regain function
• Administer 60-90 mg/kg/day divided to be given every 6-8 hours. Dilute the calcium gluconate to 1 part to 2-4 parts saline.
• Dose can be tapered every 48-72 hours as long as serum calcium levels are > 8 mg/dL/
• Calcium constant rate infusion:
• Do not add calcium to a bicarbonate containing solution for IV infusion as it will result in precipitation!!
• Long term Maintenance therapy for hypoparathyroid patients:
• Treat with oral Vitamin D therapy for life
• Initially administer oral calcium, but dose can be tapered and eventually stopped as commercial pet foods contain adequate calcium to meet the needs of dogs and cats.

Conclusion

Calcium is an important ion in a variety of intra- and extracellular activities. Disruption of serum calcium levels can occur due to hormonal, dietary, and renal diseases. Measurement and correction of systemic hypocalcemia can be done in private practice settings, but one must take care not to induce hypercalcemia.

References

1. Latimer KS, Mahaffey EA, Prasse KW: Veterinary Laboratory Medicine: Clinical Pathology, 4th edition, Iowa State Press, 2003, pp. 270- 278

2. Ettinger, SJ, Feldman, E.C: Textbook of Veterinary Internal Medicine, 6th edition, Elsevier Saunders, 2005, pp.1529-1535.

3. Feldman E.C., Nelson R.W: Canine and Feline Endocrinology and Reproduction, 3rd edition, Saunders, 2004, pp. 716-741.

4. Tilly, L , Smith, F: The 5-minute veterinary Consult- Canine and Feline, 3rd edition, Lippincott Williams & Wilkins, 2003 pp. 567-569.

5. Byrnes, et.al: A comparison of corrected serum calcium levels to ionized calcium levels among critically ill surgical patients. American Journal of Surgery; Vol.189 Issue 3, p310-314, 2005.

6. Schenck P, Chew D: Prediction of serum ionized calcium concentration by use of serum total calcium concentration in dogs. American Journal of Veterinary Research, Vol. 68 Issue 8, p 1330-1336, 2005.

Acknowledgement

"Trip the Dog" (c) Douglas Blair 1999 is from the artist's website Doug's Cosmic Art Gallery and is used with permission.

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