Steroids

Glucocorticosteroids can contribute to a significant reduction in serum iCa concentration in hypercalcemic animals with lymphoma, apocrine gland adenocarcinoma of the anal sac, multiple myeloma, thymoma, hypoadrenocorticism, hypervitaminosis D, hypervitaminosis A, or granulomatous disease, but they have little effect on serum iCa concentration in animals with other causes of hypercalcemia (Box 6-4). Some cats with IHC also have a substantial decrease in serum iCa concentration after glucocorticoid treatment. Steroids exert their effects mainly by reducing bone resorption, decreasing intestinal calcium absorption, and increasing renal calcium excretion.328

Box 6-4 Steroid-Sensitive Causes of Hypercalcemia

Lymphoma or Leukemia

Multiple myeloma

Thymoma

Vitamin D toxicity

Vitamin A toxicity

Granulomatous disease

Hypoadrenocorticism

Idiopathic hypercalcemia in cats

Cytotoxicity against neoplastic lymphocytes after glucocorticoids can result in a dramatic and rapid reduction in serum calcium concentration in dogs with lymphoma. Whenever possible, however, glucocorticoids should be withheld from animals for which a diagnosis has not yet been established because lymphocytolysis can make a definitive histopathologic diagnosis of lymphoma much more difficult or impossible. A challenge test for the diagnosis of occult lymphoma has been proposed using L-asparaginase at 20,000 IU/m2 intravenously in an effort to disturb tumor cell metabolism but not cause cytolysis. Calcium concentrations are measured at baseline and then every 12 to 24 hours for 72 hours. A complete return of serum calcium concentration to normal suggests occult lymphoma.178 Once a diagnosis of lymphoma has been made, prednisone is usually administered at 1 to 2 mg/kg twice daily concomitant with chemotherapy.

Decreased bone resorption after administration of glucocorticoids may be the result of impaired osteoclast maturation and decreased numbers of calcitriol receptors in bone.545 Cortisol antagonizes the effects of vitamin D on the intestine in rats.235 In dogs, chronic oral administration of prednisone (1.2 to 1.5 mg/kg/day) resulted in decreased serum calcitriol concentrations but caused no change in the number of calcitriol receptors or calcium-binding proteins in enterocytes.307 Granulomatous diseases associated with increased calcitriol synthesis and hypercalcemia are often sensitive to the effects of glucocorticoids in reducing the serum calcium concentration.467,528 However, caution is advised because the underlying disease (e.g., systemic mycosis) may be worsened. Hypercalcemia associated with hypervitaminosis A can also be steroid responsive.41

Calcitonin

Calcitonin treatment may be useful in animals with severe hypercalcemia. Calcitonin should be considered instead of prednisone for the treatment of animals without a definitive diagnosis. Calcitonin rapidly decreases the magnitude of hypercalcemia primarily by reducing the activity and formation of osteoclasts. A maximal decrement in serum tCa concentration of approximately 3 mg/dL can be expected.115 The only known adverse effects of calcitonin are anorexia and vomiting, but relatively few treated dogs and cats have been evaluated. Calcitonin treatment is expensive; the magnitude of its effect is unpredictable; its effects may be short-lived (hours); and resistance often develops in a few days. Receptor down-regulation is believed to be responsible for development of resistance, a phenomenon that may be delayed by concurrent glucocorticoid treatment. The effectiveness of calcitonin may be restored after discontinuing treatment for 24 to 48 hours.354 Despite these limitations, calcitonin in combination with pamidronate is considered the best therapy for severe malignancy-associated hypercalcemia in humans.123,525

The dosage of calcitonin in animals has been extrapolated from that used in humans (4 IU/kg intravenously, followed by 4 to 8 IU/kg subcutaneously once or twice daily).315 Calcitonin is listed as an antidote on packages of cholecalciferol-containing (vitamin D) rat poison, and treatment with calcitonin has been reported in dogs with hypercalcemia resulting from cholecalciferol toxicity. The dosage of calcitonin used in these dogs was 8 IU/kg subcutaneously every 24 hours,194 5 IU/kg subcutaneously every 6 hours,206 and 4 to 7 IU/kg subcutaneously every 6 to 8 hours.149 Short-term calcitonin treatment (6 U/kg subcutaneously every 8 hours for 2 days) was not effective in controlling hypercalcemia in dogs when measured 4 days after ingestion of cholecalciferol.500 Vomiting was common within 2 hours of calcitonin administration. Calcitonin (4 U/kg every 4 hours for the first day and then 8 mg/kg twice daily for the next 3 days) decreased serum tCa from nearly 18 mg/dL to 13 to 15 mg/dL, but the effect only lasted 4 to 8 hours.248 Calcitonin has also been used as part of combination therapy for treatment of hypercalcemia in a cat with granulomatous disease.368

Bisphosphonates

Bisphosphonates (formerly misnamed diphosphonates) are drugs (pyrophosphate analogues) that have been developed to inhibit bone resorption.58,474 The hypocalcemic effects of bisphosphonates during malignancy are bone related because there is no effect on tumor mass. Bisphosphonates decrease osteoclast activity and function, despite increased numbers of osteoclastspresent as a result of local or humoral mechanisms of osteolysis. Their presence in bone interferes with hydroxyapatite dissolution and exerts direct effects that reduce osteoclastic function. Induction of osteoclast apoptosis appears to be the main effect of bisphosphonates.58 Inhibition of resorption requires 1 to 2 days. Long-term bisphosphonate administration can lead to decreased osteoclast numbers through lethal injury of osteoclasts and decreased recruitment of new osteoclasts. The magnitude of effect in lowering circulating calcium concentrations is related to the initial level of hypercalcemia, the dose, route administered, and the specific bisphosphonate administered. The duration of initial beneficial effect following IV administration of bisphosphonates may last 1 to 4 weeks.

Etidronate was the first bisphosphonate to be used clinically, and the activity of newer bisphosphonates is often compared with that of etidronate. Bisphosphonates that contain a nitrogen side chain have enhanced antiresorptive activity and are called aminobisphosphonates (pamidronate, zolendronate, ibandronate). Early generation bisphosphonates, such as etidronate and clodronate, are lacking in nitrogen side chains and so are less active. The greatest potency to date has been obtained in those compounds containing a tertiary amine (zoledronate).384 Clodronate, pamidronate, alendronate, and residronate have potencies 10, 100, 1000, and 5000 times as great as that of etidronate, respectively.191 Ibandronate is approximately 5000 times and zoledronate is more than 10,000 times the potency of etidronate.410,412 Zoledronate is 100 to 850 times more active than pamidronate.59

Inhibition of bone resorption by pamidronate occurs earlier and is maintained longer than that induced by etidronate. Intravenous infusion of pamidronate has been the treatment of choice for severe hypercalcemia associated with malignancy in humans,60,123 controlling cancer-induced hypercalcemia in more than 70%510 to 90% of human patients.60 Intravenous administration of bisphosphonates is preferred over oral administration for treatment of severe hypercalcemia because some patients will be vomiting and cannot tolerate oral medication. The use of intravenous zoledronate is the new treatment of choice because of its increased potency over pamidronate, as well as the more convenient infusion protocol of only 15 minutes.* Serum tCa decreases more rapidly, and maintenance of normocalcemia is nearly twice as long when treated with zoledronate compared with pamidronate.611

Acute renal injury and renal failure attributed to precipitation of insoluble calcium-bisphosphonate salts in the renal tubules was reported in the early days of IV bisphosphonate treatment in humans, often after multiple doses and some with preexisting chronic kidney disease.25,341,352,439 Renal toxicity in dogs may be more likely when doses of 10 mg/kg or more of pamidronate are given.499 The rate of infusion and the particular bisphosphonate chosen influence the possibilities for nephrotoxicity.4,384 Dehydration should be corrected before bisphosphonates are administered to lessen the chances of renal injury. Depending on the bisphosphonate used, several hours of 0.9% saline infusion may be required to attenuate potential adverse effects. Acute renal failure is very uncommon today due to efforts to ensure hydration before, during, and after bisphosphonate infusion. People with relatively severe azotemia can be safely given IV infusions of bisphosphonates when given slowly and adequate hydration is maintained.39,341,585 Acute intrinsic renal failure can occur in dogs given greater than or equal to a dose of 10 mg/kg, according to the package insert for pamidronate. Hypocalcemia can occur following treatment with bisphosphonates but this is not usually a clinical problem.

IV pamidronate infusions at 1.0 to 2.0 mg/kg have been safely and effectively used to treat hypercalcemia in dogs and cats with malignancy, calcipotriene toxicity, granulomatous disease, and idiopathic hypercalcemia of cats.262 Beneficial effects were seen in these animals despite the presence of initial azotemia in more than 40% of these cases. It is important to deliver the pamidronate as an infusion over at least 2 hours during mild volume expansion after dehydration has been corrected.

IV pamidronate at 1.3 to 2.0 mg/kg was highly effective in lowering serum calcium in dogs with experimental cholecalciferol intoxication.499,500 Dogs treated with pamidronate (1.3 mg/kg in 150 mL saline administered intravenously over 2 hours), starting 1 day following ingestion, lost less weight and had significantly lower serum concentrations of phosphorus, tCa, and iCa than those treated with saline or calcitonin. Mean serum tCa decreased to within the reference range, and values for iCa decreased but not to the same degree as that for tCa following pamidronate treatment.500 In a subsequent study, three different doses of pamidronate were given to dogs after a single dose of cholecalciferol.499 Clinical signs were fewest in dogs given the two higher doses of pamidronate. All dogs given any dosage of pamidronate were alert and lost less weight compared with saline treatment. The decreases in serum tCa were dose dependent. Pamidronate lessened the reduction in the GFR in a dose-dependent manner, but the GFR was still reduced by 20% to 25% on day 14 (end of study). Minimal histopathologic lesions were seen in dogs treated with the low and intermediate doses of pamidronate; no lesions were detected in dogs treated with the high dose of pamidronate. It appears that doses of pamidronate at 2.0 mg/kg are most effective in dogs with cholecalciferol toxicity. Alhough not specifically reported, we have used this dose range to treat dogs with primary hyperparathyroidism before surgical correction in an effort to reduce crisis-level hypercalcemia and to reduce postoperative “hungry-bone” syndrome.

Clodronate was used clinically to treat hypercalcemia of malignancy in one dog and hypervitaminosis D in another dog.448 Serum iCa and tCa concentrations were normal at 36 and 48 hours after a 4-hour infusion of clodronate (20 to 25 mg/kg), but long-term results were not reported. In a dog with severe hypercalcemia associated with adenocarcinoma of the anal sac, a single 2-hour infusion of pamidronate rapidly reduced serum tCa and iCa that had not previously responded to intravenous fluids, calcitonin, and furosemide.283 In seven dogs with clinical calcipotriene toxicity, pamidronate (1.3 to 2.0 mg/kg intravenously) resulted in a decrease in tCa, phosphorus, and creatinine.230 In another clinical report, seven dogs and two cats were given pamidronate (1.05 to 2.0 mg/kg intravenously) for a variety of disease processes, and treatment rapidly decreased serum calcium without evidence of toxicosis.262 In dogs with bone tumors, intravenous pamidronate (1 mg/kg given over 2 hours as a constant rate infusion) was administered every 28 days depending on progression of the bone tumor.171 One hundred thirty-three doses of intravenous pamidronate were given to this group of 33 dogs. Only one dog developed renal toxicity 16 days following the second pamidronate treatment; this dog also had paraneoplastic hypercalcemia. Based on these findings, pamidronate at multiple doses may safely and effectively lower both serum total and iCa concentrations in patients with hypercalcemia resulting from various disease processes.

There is limited information about the use of oral bisphosphonates in general, and none for control of hypercalcemia specifically reported in dogs or cats. Oral bisphosphonate therapy is generally designed for maintenance treatment after a course of intravenous bisphosphonates has been effective in the control of hypercalcemia. Less than 5% of orally administered bisphosphonate is absorbed from the gastrointestinal tract,192 which limits the usefulness of oral forms of etidronate, clodronate, and alendronate.224 Food in the stomach markedly reduces the oral absorption of some bisphosphonates.211 Increasing the dose can slightly increase the oral absorption of bisphosphonates.384 High-dose oral bisphosphonate treatment can achieve similar results as the IV route in some instances in people.436 Etidronate is generally administered orally to dogs at 10 to 40 mg/kg/day in divided doses, and it has had some effectiveness in reduction of hypercalcemia associated with lymphoma, myeloma, primary hyperparathyroidism, and hypervitaminosis D in dogs (Drs. Dennis Chew and Guillermo Couto, unpublished observations). A puppy with hypercalcemia and primary hyperparathyroidism was also successfully treated using etidronate.568 There is concern about the oral administration of some bisphosphonates to humans because nausea, vomiting, abdominal pain, dyspepsia, esophagitis, and esophageal reflux can be the adverse effects.52 Both clodronate and alendronate have been used orally in humans.37,269 A small number of cats with odontoclastic resorptive dental lesions were treated with oral alendronate at 9 mg/kg twice weekly orally for 27 weeks without development of adverse effects.388 In a pilot study conducted at Ohio State University, once weekly oral alendronate reduced serum iCa concentration in most cats with idiopathic hypercalcemia (Dr. Brian Hardy, unpublished observations). No side effects were documented over the 6 months of the study with an average weekly dose of 10 mg alendronate per cat. Care should be taken to ensure that tablet medication does not stick in the esophagus, as this is a known risk for erosive esophagitis in humans. Tap water given PO following pilling is recommended to help lessen the possibility of esophagitis; “buttering” of the lips to encourage salivation, swallowing, and increased transit of pills into the stomach is also recommended. In cats that fail to return to normocalcemia with diet and prednisolone treatment, oral bisphosphonate therapy may restore normocalcemia. Some cats have required up to 30 mg weekly per cat to achieve normocalcemia. In a small number of cats with idiopathic hypercalcemia, oral bisphosphonate treatment has failed to achieve normocalcemia. Several cats have been on alendronate treatment for years without known adverse effects; one cat with idiopathic hypercalcemia did develop hypocalcemia and clinical signs. The salutary response during bisphosphonate treatment indicates that blunting of osteoclastic bone resorption can be effective in decreasing serum iCa, but it does not prove that accelerated bone resorption is the underlying cause of idiopathic hypercalcemia. The long-term safety and effectiveness of this treatment remain to be proven.120

Both clodronate and pamidronate have safely and effectively been given subcutaneously for the control of hypercalcemia in people.158,475 Use of subcutaneous clodronate was better tolerated than subcutaneous pamidronate.593,594 The subcutaneous route has not yet been investigated for use in dogs or cats with hypercalcemia.

Other Miscellaneous Treatments

Mithramycin is a potent inhibitor of osteoclastic bone resorption.483,486 Significant toxicity, including thrombocytopenia, hepatic necrosis, renal necrosis, and hypocalcemia, unfortunately has been reported with the use of this drug.115,184,314 Mithramycin was safe when two doses of 0.1 mg/kg were administered intravenously 1 week apart to eight normal beagle dogs. Mithramycin decreased serum iCa concentration in these normal dogs without adverse side effects such as hepatotoxicity, nephrotoxicity, or bone marrow hypoplasia, but some shivering occurred during the infusion. Osteoclastic bone resorption was significantly reduced.486 Mithramycin was used to treat cancer-associated hypercalcemia in client-owned dogs.487 A single infusion of 0.1 mg/kg to two dogs resulted in normal serum tCa concentration within 24 hours, but severe hepatocellular necrosis associated with marked vomiting, diarrhea, and fever resulted in death shortly thereafter. To decrease additional episodes of toxicity, the dosage of mithramycin was decreased to 25 μg/kg for the remaining dogs in this study. Serum calcium concentration returned to the normal range in six of nine dogs within 24 to 48 hours of treatment. Toxicity at this dosage was minimal, but the calcium-lowering effect lasted only 24 to 72 hours in three dogs. PTHrP concentrations and tumor size remained unchanged after treatment, and the lowering of serum calcium concentration was attributed to decreased osteoclastic bone resorption. Mithramycin is seldom prescribed because of its toxicity in hypercalcemic dogs at higher dosages and the short-lived effect at lower dosages.

During a hypercalcemic crisis, EDTA can be infused at a dosage of 25 to 75 mg/kg/hr. Administered EDTA combines with circulating calcium to form a soluble complex that then is excreted by the kidneys.115 This treatment is considered a rescue method designed to allow other modalities time to take effect. Use of EDTA should be reserved for crisis situations because EDTA is nephrotoxic at higher dosages. A 2-hour infusion of EDTA in normal dogs at 25 mg/kg/hr did not have detrimental effects on the kidneys.578

Hemodialysis or peritoneal dialysis with calcium-free dialysate may be used to lower serum calcium concentration when other methods fail.98,306 Dialysis may be particularly helpful in animals with severe intrinsic renal failure caused by hypercalcemia. Clinical experience with this method of treatment in animals is limited.

Future Considerations

Calcimimetics are a new class of compounds that are able to activate the calcium receptor, stopping PTH secretion.170,588 Cinacalcet (Sensipar) has been marketed for use in human renal secondary hyperparathyroidism.55,198,407 This drug is expensive, and it is available only as a solid tablet, making its use in small animals problematic because creating smaller doses is very difficult. Despite their action on calcium receptors throughout the body rather than exclusively on the calcium receptors of the parathyroid glands, calcimimetics may have promise in treating hypercalcemia of most types, including idiopathic hypercalcemia of cats. However, the calcimimetic cinacalcet is contraindicated if renal disease is present due to hyperphosphatemic consequences.131,284 In the future, calcimimetics for veterinary use may be developed.

The calcium channel blocker diltiazem reduces the magnitude of hypercalcemia and soft tissue mineralization in vitamin D toxicosis in chicks162 and may be effective in hypercalcemia of other causes. The toxic effects of hypercalcemia on the cardiovascular system of dogs can be blunted by verapamil,33,637,639 and this drug may prove useful for stabilizing dogs and cats with severe hypercalcemia until other measures to decrease serum calcium concentration become effective.

Most treatments for HHM have focused on counteracting the effects of excess PTHrP rather than inhibiting PTHrP secretion. Somatostatin congeners inhibit secretion of certain hormones, and one congener, lanreotide, successfully reduced serum calcium and PTHrP concentrations in a human patient with HHM.14 Similar results were observed in other tumors in humans treated with octreotide.383,395,450,584

Nonhypercalcemic analogues of calcitriol have been reported to inhibit cell proliferation and PTHrP production by neoplastic tissue in vitro.366,634 These new modalities for treating hypercalcemia in conditions associated with increased PTHrP appear to be safe, are easy to use, and are effective.314

Gallium nitrate is an antineoplastic, radioprotectant drug that has hypocalcemic properties related to its ability to reduce the solubility of hydroxyapatite in bone and inhibit osteoclast function. Gallium nitrate has been considered for treatment of refractory hypercalcemia, but it requires constant infusion.48,315,420,599 Gallium nitrate was more effective in control of hypercalcemia for longer periods than etidronate or pamidronate in a recent study of humans. Treatment with gallium nitrate may be more effective than bisphosphonates in cancer-related hypercalcemia in those with the highest concentrations of PTHrP.327 The cytoprotectant amifostine (investigational drug WR-2721) inhibits PTH secretion and may have effectiveness in animals with hyperparathyroidism.604 Use of amifostine has been limited to humans, and its adverse effects include nausea, vomiting, somnolence, and hypotension.48

Additional Specific Treatments for Hypervitaminosis D

In hypervitaminosis D associated with cholecalciferol intoxication, treatment may be necessary for several weeks because of the long half-lives of cholecalciferol and vitamin D metabolites. Consequently, aggressive fluid therapy for 1 week or more may be required to correct the severe hypercalcemia that is often encountered. Prednisone and furosemide therapy should be continued as maintenance therapy for 1 month. In addition, a low-calcium diet is important to reduce intestinal absorption of calcium. The diet provided can be a commercially available veterinary food or a homemade diet consisting mostly of macaroni and lean ground beef. Dairy products should be strictly avoided. Non–calcium-containing intestinal phosphorus binders may also be beneficial to counteract the effects of hyperphosphatemia. This treatment may be particularly important because the magnitude of soft tissue mineralization is most severe in animals with hypercalcemia induced by vitamin D toxicosis. Aluminum hydroxide at 30 to 90 mg/kg/day in divided doses is recommended during the first 2 weeks, with dosage and duration of treatment adjusted based on serial measurements of serum phosphorus concentration. Other unproven methods for treatment include anticonvulsants to increase hepatic metabolism of cholecalciferol, intestinal calcium binders to reduce intestinal calcium absorption, and calcium channel blockers to decrease the toxic intracellular effects of persistent hypercalcemia.162

When hypervitaminosis D is caused by excess calcitriol in patients with granulomatous disease, chloroquine, hydroxychloroquine, and ketoconazole may be used as supplemental therapeutic agents or as substitutes for glucocorticoids because they impair conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by macrophages.164,478

Hypocalcemia

Introduction

Hypocalcemia based on serum tCa is a relatively common laboratory abnormality and was observed in 13.5% of serum biochemical profiles of dogs in one clinical study.115 Based on serum iCa measurement in 1633 sick dogs, the prevalence of hypocalcemia was 31%,519 and in 434 sick cats, the prevalence was 27%.204 On the basis of serum tCa concentration, hypocalcemia is usually defined as a concentration less than 8.0 mg/dL in dogs and less than 7.0 mg/dL in cats. When serum iCa concentration is used, hypocalcemia is generally defined as a concentration less than 5.0 mg/dL (1.25 mmol/L) in dogs and less than 4.5 mg/dL (1.1 mmol/L) in cats. The most likely reason for submission of samples to measure calcium regulatory hormones in animals with hypocalcemia is for those with persistent hypocalcemia that is moderate to severe in magnitude and for which a known cause cannot be identified; most will be submitted with suspicion for a diagnosis of primary hypoparathyroidism.

In human patients, large and unexplained differences between ionized and tCa concentrations have been found in hypocalcemic conditions.320 This discordance is also seen in dogs and cats and is not predictable. Based on serum tCa measurement in 1633 sick dogs, 27% were classified hypocalcemic, but when iCa was measured, 31% were hypocalcemic.519 Using serum tCa measurement in 434 sick cats, 49% were classified hypocalcemic, but when iCa was measured, only 27% were actually hypocalcemic. Thus, in dogs, tCa measurement underestimated ionized hypocalcemia, and in cats, hypocalcemia was overestimated when using serum tCa concentration to predict iCa status.

Consequences of hypocalcemia and clinical signs

Clinical signs related to hypocalcemia are identical regardless of the underlying cause (Box 6-5). Low serum iCa increases excitability of neuromuscular tissue, which accounts for many of the clinical signs of hypocalcemia. Animals with mild decreases in iCa concentration may display no obvious clinical signs. The duration and magnitude of ionized hypocalcemia and the rate of decline in iCa concentration interact to determine the severity of clinical signs. Clinical signs in dogs often are not obvious until serum tCa concentration is less than 6.5 mg/dL, and some dogs show surprisingly few signs despite severe hypocalcemia (serum tCa concentration, <5.0 mg/dL), especially if the underlying disease has been chronic and there has been sufficient time for physiologic adaptation. Acute development of hypocalcemia is usually associated with severe clinical signs. In its most severe forms, hypocalcemia can cause death as a result of circulatory effects (e.g., hypotension and decreased myocardial contractility) and respiratory arrest from paralysis of respiratory muscles. Serum tCa concentration less than 4.0 mg/dL can cause left-sided myocardial failure154 and death,179 especially if the decline in serum calcium concentration was rapid.

Box 6-5 Clinical Signs Associated with Hypocalcemia

Common

None

Muscle tremors or fasciculations

Facial rubbing (paresthesia?)

Muscle cramping

Stiff gait

Behavioral change

Restlessness or excitation
Aggression
Hypersensitivity to stimuli
Disorientation

Occasional

Panting

Pyrexia

Lethargy

Anorexia

Prolapse of the third eyelid (cats)

Posterior lenticular cataracts

Tachycardia or electrocardiographic alterations (prolonged QT–interval)

Uncommon

Polyuria or polydipsia

Hypotension

Respiratory arrest or death

Other electrolyte and acid-base abnormalities can either magnify or diminish the signs of hypocalcemia. Correction of hypokalemia in cats with concurrent hypocalcemia may precipitate the onset of clinical signs of hypocalcemia.145,408 Patients with chronic hypocalcemia often display intermittent clinical signs despite seemingly stable serum tCa concentrations. Although unpredictable, clinical signs often follow periods of exercise or excitement that may be associated with respiratory alkalosis and subsequent decreases in iCa concentration. Rapid infusion of alkali to correct metabolic acidosis can cause seizures in animals with marginal or previously compensated hypocalcemia through further reduction in iCa concentration.

Clinical signs in dogs with chronic hypocalcemia (primary hypoparathyroidism) include seizures, muscle tremors or fasciculations, muscle cramping, stiff gait, and behavioral changes (e.g., restlessness, excitation, aggression, hypersensitivity to stimuli, and disorientation).87,115,145,530 Seizures often begin as focal muscle tremors that become more widespread. Most dogs in one series had a seizure during the initial 24 to 48 hours of hospitalization, a much higher frequency than that encountered with idiopathic epilepsy.179 Seizure activity associated with hypocalcemia may not be similar to that in idiopathic epilepsy because affected dogs may remain partially conscious and retain urinary continence during the seizure.179,446 Seizures are often preceded by apprehension or nervousness. The seizures may be as short as 60 seconds or as long as 30 minutes in some dogs. Most seizures resolve without treatment but often recur despite treatment with anticonvulsants. Growling attributable to pain or behavior change occurred in approximately 40% of dogs, and intense rubbing of the face with the paws or on the ground was observed in more than 50% of dogs. These signs were attributed to either paresthesia or pain from facial muscle spasms.87,179

Pyrexia may be caused by increased muscular activity with or without seizures. Lethargy and weakness are seen in approximately 33%, and polyuria and polydipsia occur in about 25% of cases as a result of psychogenic mechanisms or renal injury (nephrocalcinosis) from hypercalciuria associated with PTH deficiency in animals with hypoparathyroidism.504,530 Anterior and posterior lenticular cataracts occurred in more than 33% of affected dogs87,308 and also in cats.179,444 Tachycardia and electrocardiographic abnormalities (increased QT–interval) may also be encountered. Both hypertension and hypotension have been reported during hypocalcemia in humans.97,154

Neuromuscular signs in cats with chronic hypocalcemia associated with primary hypoparathyroidism are similar to those in dogs (e.g., muscle tremors, weakness, and generalized seizures).444 Anorexia and lethargy appear to be more common in cats than in dogs with primary hypoparathyroidism, but seizures have not been reported to be induced by excitement, as occurs in dogs. Prolapse of the third eyelid is occasionally observed in cats with acute hypocalcemia but is not a prominent finding during chronic hypocalcemia.

Clinical signs associated with acute postoperative hypocalcemia are similar in dogs and cats and are related to neuromuscular excitability. Focal twitching of facial muscles and vibrissae may be noticed before more generalized muscle tremors or seizures develop. Tetany or facial twitching has not been observed in cats after thyroidectomy until serum tCa concentration is less than 6.9 mg/dL.179,444,446 Severe hypocalcemia (<6.5 mg/dL) is often associated with muscular twitching, tetany, or seizures. Anorexia and lethargy are not often considered primary signs of hypocalcemia, but both signs decrease in cats during calcium infusion after thyroidectomy, suggesting a relationship between hypocalcemia and these signs.

Approach to hypocalcemia

Hypocalcemia develops when bone mobilization of calcium is reduced, skeletal calcium accretion is enhanced, urinary losses of calcium are increased, gastrointestinal absorption of calcium is reduced, calcium is translocated intracellularly, or as a result of a combination of these mechanisms. Much like the initial approach to hypercalcemia, it is helpful to make the initial distinction as to whether hypocalcemia is parathyroid dependent or parathyroid independent. Ionized calcium concentration must be evaluated in conjunction with PTH concentration to determine whether PTH production is appropriate. Patients with low iCa and low PTH concentrations have absolute hypoparathyroidism (parathyroid dependent). A normal reference range PTH when iCa is low is inappropriate, because normal parathyroid glands should respond with increased PTH. Hypocalcemic patients with increased PTH are classified as having parathyroid-independent hypocalcemia. Normograms to determine the adequacy of the increased response of PTH to low iCa have not been established for dogs or cats. In cases of parathyroid-independent hypocalcemia, hypocalcemia exists from redistribution of calcium into other body spaces, excess phosphorus effects, or from deficiencies of vitamin D or dietary calcium. Patients with persistent moderate to severe hypocalcemia based on serum tCa should be evaluated for iCa and PTH concentrations; measurement of 25-hydroxyvitamin D and serum phosphorus is also helpful, and in rare circumstances, measurement of calcitriol may help provide a definitive diagnosis. The conditions associated with hypocalcemia in dogs and cats are listed in Box 6-6 according to their relative frequency, regardless of clinical signs or severity of decreased serum calcium concentration. The anticipated changes in calcium hormones and serum biochemistry in disorders causing hypocalcemia are noted in Table 6-4.

Box 6-6 Conditions Associated with Hypocalcemia

Common

Hypoalbuminemia

Chronic renal failure

Puerperal tetany (eclampsia)

Acute renal failure

Acute pancreatitis

Undefined cause (mild hypocalcemia)

Occasional

Soft tissue trauma or rhabdomyolysis

Hypoparathyroidism

Primary
Idiopathic or spontaneous
Postoperative bilateral thyroidectomy
After sudden reversal of chronic hypercalcemia
Secondary to magnesium depletion or excess

Ethylene glycol intoxication

Phosphate enema

After NaHCO3 administration

Uncommon

Laboratory error

Improper sample anticoagulant (EDTA)

Infarction of parathyroid gland adenoma

Rapid intravenous infusion of phosphates

Acute calcium-free intravenous infusion (dilutional)

Intestinal malabsorption or severe starvation

Hypovitaminosis D

Blood transfusion (citrated anticoagulant)

Hypomagnesemia

Nutritional secondary hyperparathyroidism

Tumor lysis syndrome

Human

Pseudohypoparathyroidism

Drug-induced

Hypercalcitonism

Osteoblastic bone neoplasia (prostate cancer)

Table 6-4 Anticipated Changes in Calcemic Hormones and Serum Biochemistry Associated with Disorders of Hypocalcemia

image

Differential diagnosis and mechanisms of hypocalcemia

Hypoalbuminemia

Hypoalbuminemia is the most common associated condition but perhaps the least important for clinical consequences, and it occurs in nearly one half of the dogs with hypocalcemia.115 Hypocalcemia associated with hypoalbuminemia is usually mild (serum tCa concentration, 7.5 to 9.0 mg/dL in dogs), and no signs referable to the functional effects of low serum calcium concentration are observed. Application of calcium correction formulas to serum tCa concentrations in dogs or cats with hypoproteinemia or hypoalbuminemia has been advocated in the past. However, these correction formulas do not improve the prediction of actual iCa concentration and in many cases increase the level of diagnostic discordance.519 Use of correction formulas to adjust serum tCa concentration to serum total protein or albumin concentration is not recommended.

Renal Failure

Renal failure is the second most common disorder associated with hypocalcemia in dogs.115 Decreased calcitriol synthesis by diseased kidneys and, to a lesser extent, mass law interactions of calcium with markedly increased serum phosphorus concentration are probable causes of the hypocalcemia observed in dogs and cats with CRF. To decrease iCa concentration by 0.1 mg/dL, serum phosphorus concentration must increase by 3.7 mg/dL.7 Calcitriol deficits are more important because hypocalcemia results from reduced intestinal calcium absorption and increased skeletal resistance to PTH.404 Animals with CRF and decreased serum tCa concentration are most often asymptomatic, possibly because of an increase in iCa concentration that accompanies metabolic acidosis.

Serum tCa concentration was 8.0 mg/dL or less in 10% of 268 dogs with clinical CRF, whereas low serum iCa concentrations were detected in 40% of affected dogs.118 In 23 dogs with CRF, iCa represented 40% of tCa as compared with 51% of tCa in normal dogs.303 Serum iCa was low in 56%, normal in 26%, and high in 17% of the dogs with CRF. Thus, iCa concentration was low in the majority of dogs despite the presence of metabolic acidosis in 83% of dogs, which would be expected to increase iCa.303 Hypocalcemia was diagnosed more frequently in a study of 489 dogs with CRF when determined by iCa measurement. Based on serum tCa measurement, hypocalcemia was noted in only 19% of dogs with CRF; when iCa concentration was measured, hypocalcemia was observed in 29% of dogs with CRF.519

In 74 cats with clinical CRF, 15% were hypocalcemic based on serum tCa.147 In cats with CRF, hypocalcemia was found more commonly with higher magnitudes of azotemia.27 In 73 cats with CRF, none had hypocalcemia based on tCa, but 3% of cats with moderate CRF and 23% of cats with advanced CRF did have hypocalcemia. In 47 cats with CRF, 14% with moderate CRF and 56% with advanced CRF had ionized hypocalcemia. Mean iCa for cats with advanced CRF was significantly lower than values from normal cats or cats with mild and moderate CRF. Hypocalcemia was underappreciated when based on results of tCa measurement, especially with advancing azotemia.

AIRF and postrenal failure can result in hypocalcemia that is more likely to be symptomatic because the degree of hyperphosphatemia is often greater than that observed in CRF. Dogs with AIRF had a mean serum tCa concentration of 9.8 ± 1.7 mg/dL, but iCa was not reported.589

Secondary hyperparathyroidism is common in association with renal failure, and is characterized by low or normal ionized calcium with elevated circulating concentration of serum PTH. In a study of 54 dogs with chronic kidney disease, secondary hyperparathyroidism was present in 76% of all dogs.130 In nonazotemic kidney disease (IRIS stage 1), 36% of dogs already had developed secondary hyperparathyroidism. With mild azotemia (IRIS stage 2), 50% of dogs had developed secondary hyperparathyroidism, and with moderate azotemia (IRIS state 3), 96% had secondary hyperparathyroidism. By the time severe azotemia was present (IRIS state 4), 100% of dogs had developed secondary hyperparathyroidism.

Emergency and Critical Care

Ionized hypocalcemia is common in critically ill humans in the intensive care setting and is more common in septic patients.106,333,644 The magnitude of hypocalcemia is correlated to severity of illness. Hypocalcemia with critical illness also occurs in veterinary patients.145,257 The causes of hypocalcemia in critical illness appear to be multifactorial because sepsis, systemic inflammatory response syndrome, hypomagnesemia, blood transfusions, and AIRF have been associated with hypocalcemia.145,332,636,644 In humans, hypocalcemia associated with critical illness involves decreased PTH secretion, hypercalcitonism, and altered calcium binding to proteins.465 The cause of the hypocalcemia is not related to enhanced urinary calcium excretion, decreased bone mobilization, or blunted secretion of PTH in septic patients.333 The presence of proinflammatory cytokines during sepsis is related to the development of hypocalcemia in septic patients.333 PTH is commonly elevated in this population even when normocalcemia exists.106,333 In a study of 141dogs admitted to an intensive care unit, 16% showed hypocalcemia based on iCa concentration.257 Hypocalcemia was associated with longer intensive care unit and hospital stays, but was not associated with decreased survival. Dogs with sepsis were more likely to exhibit hypocalcemia.

Up to 88% of hospitalized human patients had decreased iCa that correlated to severity of illness but not any specific diagnosis.644 The impact of hypocalcemia on patient survival has not yet been determined, although in one study, hypocalcemia and higher levels of PTH were more frequently associated with fatality.106

Ionized calcium concentration decreased in experimental dogs with hemorrhage-caused hypotension and continued to decline during replacement of blood volume with citrated whole blood.56 Hemorrhage also decreases iCa concentration in clinical dogs. Massive transfusions in 10 dogs resulted in significant ionized hypocalcemia.282

Cardiopulmonary resuscitation (CPR) may result in hypocalcemia. Dogs developed ionized hypocalcemia within 5 minutes of starting CPR in dogs with prolonged cardiac arrest and continued to decrease after 20 minutes.93,415 Serum tCa was not concordant with changes in iCa because mean serum tCa did not change, and iCa concentrations were negatively associated with lactate concentrations. Decreased iCa was most likely related to formation of complexes with lactate.

In horses with enterocolitis, decreased iCa was identified in nearly 80% of patients.575 Ionized hypocalcemia was associated with decreased iMg, increased serum phosphorus, decreased fractional urinary excretion of calcium, and increased PTH in 71% of cases. Hypocalcemia in 29% of these horses was a result of inadequate secretion of PTH, although impaired mobilization of calcium from bone and loss or sequestration of calcium within the gastrointestinal tract could not be excluded.

Acute pancreatitis may be associated with hypocalcemia. In 46 cats with acute pancreatitis, iCa concentration was low in 61% of cats.295 Suggested mechanisms that may account for low iCa in acute pancreatitis include sequestration of calcium into peripancreatic fat (saponification), increased free fatty acids, increased calcitonin secondary to hyperglucagonemia, and PTH resistance or deficit resulting from the effects of hypomagnesemia.45,145,277,505

In dogs with diabetes mellitus, 47% had ionized hypocalcemia.244 Normal iCa concentrations were noted in 49.4% of dogs from this study, and 3.5% had ionized hypercalcemia. Acute pancreatitis was diagnosed in 13% of these dogs, which could be the mechanism in some but not all of those with hypocalcemia. In a study of 127 dogs with diabetic ketoacidosis, 52% exhibited ionized hypocalcemia.286 Dogs that did not survive had lower iCa concentrations than those that did survive.

Puerperal tetany (eclampsia) typically occurs between 1 and 3 weeks postpartum in females of small dog breeds and is attributed to loss of calcium into milk during lactation, although parathyroid gland dysfunction has not been conclusively excluded.21,179 Proposed mechanisms for hypocalcemia include a poor dietary source of calcium, major loss of calcium during lactation, fetal skeletal ossification, and abnormal parathyroid gland function, including parathyroid gland atrophy. Hypophosphatemia may accompany the hypocalcemia, and clinical signs rarely occur before whelping.103 In 31 dogs with periparturient hypocalcemia, iCa was less than the reference range, and small breed dogs with large litters were typical.152 Median time from whelping to detection of clinical signs was 14 days, but variation was wide. Clinical signs most often included seizures, trembling, twitching, shaking, and stiffness. Nontypical signs included panting, behavioral changes, collapse, and whining; vomiting, diarrhea, and choking were rare. Rectal temperature was elevated, attributable to increased muscle activity. After treatment with intravenous calcium gluconate (mean dose, 115 mg/kg), iCa concentration normalized within 25 minutes in 90% of dogs. Most dogs received more than one injection of calcium gluconate, but the total calcium dose given did not correlate to initial iCa concentration. In one lactating bitch, severe hypocalcemia and hypomagnesemia occurred in association with acute onset of gastric and bladder atony, congestive heart failure, weakness, and paresis without muscle fasciculation or seizures.16

Puerperal tetany is rare in cats.602 Eclampsia was described in four cats in which hypocalcemia developed 3 to 17 days before parturition.174 Signs of depression, weakness, tachypnea, and mild muscle tremors were most common; vomiting and anorexia were less common, and prolapse of the third eyelid occurred in some cats. Hypothermia, instead of hyperthermia as seen in dogs, was observed. All cats responded to parenteral calcium gluconate initially and to oral calcium supplementation throughout gestation and lactation.

Ionized hypocalcemia is common in cats with urethral obstruction and is likely to develop in cats that also have hyperkalemia and metabolic acidosis. Cats with severe ionized hypocalcemia can exhibit compromised vital functions, although most survive with relief of urethral obstruction. In 199 cats with urethral obstruction, iCa was below the reference range in 34%, normal in 47%, and above the reference range in 19%.324 Of those with low iCa, 14% had moderate and 6% had severe hypocalcemia. In an earlier study, 75% of cats with urethral obstruction exhibited low iCa.153 Most of these cats had elevated tMg, probably from reduced renal function at the time of obstruction. Hypomagnesemia is not likely to account for the development of hypocalcemia in these cats, but iMg was not measured. Calcium regulatory hormones were not evaluated in either of these studies. Alkalinizing infusions designed to correct metabolic acidosis or for translocation of potassium into cells are often considered for treatment of cats with urethral obstruction, but these can decrease tCa and iCa concentrations.114

Rhabdomyolysis is sometimes associated with hypocalcemia, but clinical signs of hypocalcemia are rare. Mild hypocalcemia in dogs and cats with severe vehicular muscle trauma is occasionally observed (Chew, personal observations). Hypocalcemia likely occurs as a consequence of translocation of calcium into the damaged muscles. Symptomatic hypocalcemia resulting in death of three dystrophin-deficient cats occurred following anesthesia or mild exertion during restraint and subsequent acute rhabdomyolysis.208 Hypocalcemia was documented along with hyperphosphatemia, increased liver transaminases, and massive increases in creatine kinase. Hypocalcemia has been described in some dogs with fatal Vipera xanthina palestinae envenomation.17 The origin of the hypocalcemia may be multifactorial, including muscle necrosis. Renal transplantation in 14 cats resulted in decreased iCa in the 5-day postoperative period.624 All cats also had decreased serum iMg but normal tMg.

Small Intestinal Diseases

Hypocalcemia may occur in association with gastrointestinal disease. Ionized calcium concentration was below the reference range (mean, 0.99 ± 0.19 mmol/L; reference range, 1.13 to 1.33 mmol/L) in 12 dogs with intestinal lymphangiectasia.317 Ten of 13 dogs had hypoalbuminemia with a mean of 2.12 ± 0.70 g/dL, and “corrected” serum tCa was discordant with iCa measurement. Mechanisms for hypocalcemia could include calcium/fatty acid complexes in the intestinal lumen that could decrease intestinal calcium absorption. Hypovitaminosis D from malabsorption or hypomagnesemia may have contributed to hypocalcemia but was not evaluated. No dogs had clinical signs associated with hypocalcemia.

In five Yorkshire terriers and a shih tzu with protein-losing enteropathy, iCa and tMg concentrations were moderately to severely low.92,294 Concentration of PTH was increased (secondary hyperparathyroidism), and 25-hydroxyvitamin D concentration was below the reference range. It is not clear whether the apparent elevation in PTH was increased to an appropriate level in the face of low iCa, or whether maximum production was suppressed because of the effects of hypomagnesemia. Intravenous supplementation with fluids containing magnesium salts resulted in increases in PTH and iCa; 25-hydroxyvitamin D remained below the reference range.92 Following 8 weeks of treatment for inflammatory bowel disease, calcium homeostasis was normal based on normal iCa, PTH, tMg, and 25-hydroxyvitamin D concentrations. Magnesium repletion apparently resulted in resolution of hypocalcemia largely because of increased PTH secretion, whereas 25-hydroxyvitamin D concentration was still low. Resolution of weakness may have been the result of correction of hypocalcemia, hypomagnesemia, or both. Low iCa concentration with elevated PTH and low concentrations of both 25-hydroxyvitamin D and calcitriol were also noted in two dogs with protein-losing enteropathy.371 One dog was diagnosed with lymphangiectasia, and the other was diagnosed with chronic lymphocytic/plasmacytic enteritis.

Alkali Administration

The administration of alkaline agents may result in the development of hypocalcemia. Symptomatic hypocalcemia was documented in a cat treated for salicylate intoxication with sodium bicarbonate.2 Muscle fasciculation increased during treatment with sodium bicarbonate, and serum tCa was low. A single dose of intravenous sodium bicarbonate at 4 mEq/L to cats resulted in a maximal decrease of iCa 10 minutes following infusion; iCa remained below baseline for 3 hours.114 Part of the decrease in iCa was attributed to dilution and part to increased pH of serum, but most of the decrease was the result of unidentified factors. Similar findings were noted in dogs receiving sodium bicarbonate infusion.380 Twitching has been observed on rare occasion during or shortly after infusion of sodium bicarbonate solutions in cats with urethral obstruction and in dogs or cats with renal failure (Chew, personal observations) presumably because of decreases in serum iCa.

Acute Reversal of Chronic Hypercalcemia

The sudden correction of chronic hypercalcemia can result in hypocalcemia as a result of parathyroid gland atrophy and inadequate ability to synthesize and secrete PTH. This happens frequently in dogs with primary hyperparathyroidism caused by parathyroid gland adenoma following surgical excision of the affected parathyroid gland(s). The degree of parathyroid gland atrophy depends on the magnitude of hypercalcemia and its duration before correction. Two dogs with spontaneous infarction of a parathyroid gland adenoma have been reported with the development of hypocalcemia and clinical signs.485 Rapid correction of hypercalcemia following chemotherapy for lymphosarcoma or surgical excision of anal sac adenocarcinoma often results in mild hypocalcemia that is usually not associated with clinical signs, but clinical signs of hypocalcemia may occur.259 Persistent hypocalcemia has been observed in dogs following parathyroidectomy in association with hypomagnesemia. In three dogs, hypocalcemia resolved following supplementation with magnesium salts, but calcium regulatory hormones were not measured (Chew, unpublished observations).

Tumor Lysis Syndrome

Tumor lysis syndrome occurs when there is rapid destruction of sensitive tumor cells (usually lymphoid or bone marrow tumors) following chemotherapy.440 Release of intracellular products can result in hyperkalemia, hyperphosphatemia, and hyperuricemia. Hypocalcemia can develop as calcium-phosphate salts are deposited into soft tissues by mass-law effects from markedly increased serum phosphorus95,426,453 and may be associated with the development of AIRF. Tumor lysis syndrome is a rarely reported cause of symptomatic hypocalcemia in dogs,426,453 although it may be more common than previously reported because the Ohio State University oncology service has documented seven cases (Couto, personal communication, 2004).

Nutritional Secondary Hyperparathyroidism

Vitamin D deficiency and nutritional secondary hyperparathyroidism associated with low calcium and/or high phosphorus concentrations in the diet result in low serum iCa and phosphorus concentrations, with an increase in PTH secretion. Nutritional secondary hyperparathyroidism may also occur when severe gastrointestinal disease is present, limiting the absorption of calcium and vitamin D. Increased PTH secretion tends to return serum iCa concentration to normal, but decreases serum phosphorus concentration.623 The occurrence of nutritional secondary hyperparathyroidism has decreased dramatically since the advent of feeding commercially available, nutritionally complete and balanced pet food.286 Nutritional secondary hyperparathyroidism was induced in adult beagles by feeding a diet high in phosphorus and low in calcium, with a calcium to phosphorus ratio of 1:10.128 A significant increase in PTH production was seen at 10 weeks of feeding, and cancellous bone volume was reduced by 20% to 30%. Under experimental conditions, puppies fed a low-calcium, normal phosphorus content diet exhibited increased concentrations of PTH and calcitriol, with a decrease in 24,25-dihydroxyvitamin D concentration.239 In five German shepherd dog puppies fed a diet consisting of 80% steamed rice and 20% raw meat, nutritional secondary hyperparathyroidism was observed.289 This diet apparently had an adequate calcium concentration but contained an excess of phosphorus. All puppies showed moderate to marked fibrous osteodystrophy.

Serum iCa and phosphorus concentrations were below the reference range in six young cats with nutritional secondary hyperparathyroidism.573 Clinical signs referable to hypocalcemia (excitation, muscle twitching, seizures) and spontaneous fractures of bones were present in most cats. Renal secondary hyperparathyroidism preferentially affects the bones of the face (fibrous osteodystrophy), whereas nutritional secondary hyperparathyroidism tends to cause osteopenia of the long bones and vertebrae. Calcitriol concentration was mildly increased in three of four cats in which it was measured, whereas 25-hydroxyvitamin D was mildly decreased in three of three cats. PTH concentrations were increased in all cats and ranged from a minimal increase in one cat to a marked increase of 4 to 9.7 times the upper range in the remaining five cats. Cats had been fed meat only (three cats), meat combined with vegetables (two cats), or vegetables only (one cat). Dietary calcium intake was less than one tenth of the minimal nutritional requirement; dietary intake of phosphorus was mildly below the minimal requirements in five of six cats. An unfavorable calcium to phosphorus ratio existed for all diets.

A case of type 2 vitamin D-dependent rickets was described in a 5-month-old Pomeranian dog with intermittent lameness, and forelimb bowing and thickening.326 Vitamin D-dependent rickets type 2 is characterized by end-organ resistance to calcitriol. This puppy was fed a commercial puppy food and had persistent hypocalcemia with elevated PTH concentration. Despite high-dose calcitriol therapy, hypocalcemia persisted. A case of type 2 vitamin D-dependent rickets was described in a 4-month-old cat examined because of vomiting, diarrhea, muscle tremors, and mydriasis of acute onset.522 Serum tCa and tMg concentrations were decreased, and serum phosphorus, calcitriol, and PTH concentrations were increased, excluding hypoparathyroidism as the cause of hypocalcemia. Calcitriol and calcium salt supplementation resulted in the return to normocalcemia. Another case of vitamin D-dependent rickets type 2 was described in a 4-month-old kitten.556 In this kitten, serum iCa concentration was low, with elevations of both PTH and calcitriol. Serum concentration of 25-hydroxyvitamin D was within the reference range. The kitten was smaller than its littermates, had bilateral forelimb swelling, and a hunched appearance. Even with calcitriol therapy, the kitten failed to grow, had continual hypocalcemia, and died of unknown causes 7 months after diagnosis.

Vitamin D-dependent rickets type 1 has been described in a 5-month-old kitten.210 Vitamin D-dependent rickets type 1 is characterized by a deficiency of 1α-hydroxylase, which converts 25-hydroxyvitamin D to calcitriol. The kitten was examined because of generalized pain and reluctance to move. This kitten exhibited hypocalcemia, elevated serum PTH concentration, with low serum calcitriol concentration. The serum concentration of 25-hydroxyvitamin D was within the reference range. The kitten responded to calcitriol therapy.

Exotic animals may be at increased risk for the development of nutritional secondary hyperparathyroidism because nutritional requirements are not always known. Nutritional secondary hyperparathyroidism was documented in a 3-month-old tiger cub that was fed only beef with no calcium or vitamin supplementation.622 This tiger cub was reluctant to walk, exhibited osteodystrophy of the lumbosacral vertebrae, and had an elevated serum PTH concentration. Clinical signs improved after administration of vitamin D and calcium.

With the feeding of BARF (biologically appropriate raw food, or bones and raw food) and other homemade diets, the occurrence of nutritional secondary hyperparathyroidism is more likely. In a recent report, 6-week-old, large-breed puppies from two litters were fed a BARF diet on weaning.138 Puppies were weak, exhibited pain, and had abnormal-appearing joints, and some were unable to stand. In puppies that were radiographed, osteopenia was noted, with pathologic fractures apparent in multiple long bones. In euthanized puppies, the long bones were pliable, and cortices were thin. Parathyroid glands were prominent, and histologically, fibrous osteodystrophy was present in bones. Nutritional secondary hyperparathyroidism was attributable to a diet low in calcium and an inappropriate calcium to phosphorus ratio. Diffuse osteopenia and myelopathy occurred in a puppy fed a raw ground beef diet.557 This 8-month old puppy had been fed a commercially available organic premix mixed with ground beef for the previous 4 months. Vitamin D-dependent rickets Type I developed following the feeding of this nutritionally incomplete diet. While young animals may be more susceptible to nutritional secondary hyperparathyroidism, clinical signs can occur in adult dogs fed incomplete diets. Osteopenia occurred in a 6-year-old dog that had been fed a homemade diet for the previous year.136 This homemade diet did not include any vitamin or mineral supplements, and was deficient in both calcium and vitamin D. Plasma PTH concentration was elevated, and circulating 25-hydroxyvitamin D concentration was low. Severe osteopenia of the skull bones was present, with facial enlargement.

Secondary Hyperparathyroidism Associated with Hyperadrenocorticism

Hyperadrenocorticism has been associated with elevations in serum PTH concentration.461 In 68 dogs with hyperadrenocorticism, 92% had concentrations of serum PTH above the reference range. Ionized calcium was measured in 28 of these dogs, and was within or below the reference range in 20 dogs. However, the mean iCa concentration in dogs with hyperadrenocorticism was not significantly different from a group of 20 other hospital patients that did not have hyperadrenocorticism. Serum PTH concentration was significantly positively correlated to basal and post-ACTH cortisol concentrations, and to serum alkaline phosphatase concentration. The mechanism for the development of secondary hyperparathyroidism is unknown in these dogs, though glucocorticoids can decrease intestinal absorption of calcium and increase urinary calcium excretion. These effects may be sufficient to create a negative calcium balance, resulting in increased secretion of PTH.

The effect of trilostane treatment for hyperadrenocorticism on serum PTH and calcium concentrations was studied in 22 dogs.559 With treatment, serum PTH concentrations were significantly lower, and were not different from a control population that did not have hyperadrenocorticism. Serum calcium concentration increased significantly with trilostane therapy, even though there was no significant difference in calcium concentration between the pretreatment hyperadrenocorticism group and the control group. Serum phosphate concentrations also significantly decreased with trilostane therapy, but there was still a significant difference post-treatment between the dogs with hyperadrenocorticism and the control group.

Effects of drugs

Drug administration may cause a decrease in iCa. A significant decrease in iCa was observed in dogs administered enrofloxacin at 5 mg/kg intramuscularly once daily for 14 days.138 Mean iCa decreased to its nadir on day 3, remained below normal at day 10, and normalized by day 14 despite continued administration of enrofloxacin.

The administration of mithramycin or bisphosphonates can cause mild hypocalcemia as a side effect in humans, but symptomatic hypocalcemia is rare.570 The potential for development of hypocalcemia exists in dogs following mithramycin administration because normal dogs and those with malignancy-associated hypercalcemia undergo significant decreases in serum iCa and tCa.486,487 Use of mithramycin is reserved for emergency management of hypercalcemia refractory to other treatments because of severe toxicity in some dogs.

Phosphate enema administration can result in hypocalcemia after rapid absorption of phosphate, hyperphosphatemia, and subsequent mass law interaction with serum calcium. This is particularly a problem in cats and small dogs in which death can occur.18,281,512,574 Serum tCa decreased within 45 minutes of administration of a hypertonic phosphate enema to cats and persisted for 4 hours.18 Mean serum phosphorus was more than 14 mg/dL within 15 minutes, and increases persisted for 4 hours. Serum tCa concentrations were negatively correlated to serum phosphorus. Mild hypernatremia, severe hyperphosphatemia (mean, 37.6 mg/dL), and hypocalcemia were noted in five cats. Phosphate enemas should not be used in small dogs, cats, or in debilitated patients of any size.

Hypoparathyroidism

Hypoparathyroidism is an absolute or relative deficiency of PTH secretion that can be permanent or transient. Hypocalcemia and clinical signs referable to low iCa concentration are the hallmarks of advanced hypoparathyroidism. Hypoparathyroidism in dogs is most commonly idiopathic, whereas surgical removal of or injury to the parathyroid gland during thyroidectomy to correct hyperthyroidism is the most common cause in cats.

Idiopathic chronic inflammation of parathyroid tissue occurs sporadically in both dogs and cats but more commonly in dogs. It is presumed that parathyroiditis has an immune-mediated mechanism. Histopathologic study of affected parathyroid glands reveals inflammatory cell infiltration (lymphocytes, plasma cells, and neutrophils), fibrosis, and loss of secretory cells.87,179,444,446,530 Clinical signs occurred 1 to 26 weeks (mean, 7 weeks) before diagnosis of primary hypoparathyroidism in cats444 and 1 day to 25 weeks (mean, 3 weeks) before diagnosis in dogs.87 Primary hypoparathyroidism and parathyroiditis occur in dogs and cats of any age but more frequently in female dogs and male cats. In 735 dogs with primary hypoparathyroidism, 62% were female and 38% were male.466 Mean age was 7.0 ± 3.9 years, with 71% of diagnoses occurring in purebred dogs. The highest odds ratios for hypoparathyroidism correcting for breed popularity occurred in the standard schnauzer, Scottish terrier, miniature schnauzer, West Highland white terrier, and dachshund. Reduced risk was identified for the German shepherd dog, shih tzu, and Labrador retriever. In another study, 357 dogs were diagnosed with primary hypoparathyroidism over a 2-year period.521 Mixed-breed dogs accounted for 25% of the cases, with 13% schnauzers, 7% Labrador retrievers, 5% dachshunds, 4% Yorkshire terriers, 4% poodles, 3% golden retrievers, and 3% Scottish terriers without correction for breed popularity. There were 59 other dog breeds represented with an incidence of less than 3% each. In a study of 17 dogs, mixed-breed dogs, German Shepherd dogs, Saint Bernards, and terrier breeds were most commonly affected.503

Serum tCa concentration is usually less than 6.5 mg/dL (often 4.0 to 4.9 mg/dL) in dogs with primary hypoparathyroidism. Dogs that have episodes of tetany or seizures often have serum tCa concentrations less than 6.0 mg/dL. Serum phosphorus concentration is greater than serum calcium concentration in nearly all affected dogs and cats, and most have hyperphosphatemia. Parathyroid gland biopsy may confirm the diagnosis of lymphocytic parathyroiditis as the cause of primary hypoparathyroidism, but the parathyroid glands can be difficult or impossible to locate during surgical exploration because of atrophy and fibrosis. Parathyroid gland biopsy is not recommended to confirm hypoparathyroidism since the advent of validated PTH assays for use in the dog and cat.

Diagnosis of Hypoparathyroidism

Inappropriately low concentrations of PTH result in hypocalcemia, hyperphosphatemia, and decreased concentrations of 1,25-dihydroxyvitamin D (calcitriol). Hypocalcemia results from increased urinary loss of calcium (hypercalciuria), reduced bone resorption, and decreased intestinal absorption of calcium. Hyperphosphatemia results from decreased urinary loss of phosphorus (hypophosphaturia) that overrides the effects of decreased bone resorption and decreased intestinal absorption of phosphorus (secondary to calcitriol deficit) on serum phosphorus concentration. PTH is a potent stimulator and phosphorus is a potent inhibitor of the 25-hydroxyvitamin D-1α-hydroxylase enzyme system in renal tubules. Consequently, the absence of PTH and the presence of hyperphosphatemia act together to decrease renal synthesis of calcitriol. Decreased concentrations of calcitriol contribute to hypocalcemia via decreased intestinal calcium absorption. Hypocalcemia unrelated to low PTH concentrations may arise from increased uptake of calcium by bone after rapid correction of long-standing hyperparathyroidism or hyperthyroidism, both of which are associated with loss of bone calcium before treatment (“hungry bone” syndrome).548,567,617

Definitive diagnosis of primary hypoparathyroidism is based on the combination of clinical signs (see Box 6-5), low iCa concentration, and PTH concentration inappropriately low to the magnitude of ionized hypocalcemia. Hypoparathyroidism is the only possible diagnosis when low serum calcium concentration, high serum phosphorus concentration, normal renal function, and low PTH concentration are present in combination. Low serum calcium and high serum phosphorus concentrations can be encountered during nutritional and renal secondary hyperparathyroidism, after phosphate-containing enemas, and during tumor lysis syndrome, but PTH is increased in all of these conditions.

PTH should be measured in patients with chronic hypocalcemia of undetermined cause. Primary hypoparathyroidism requires lifelong treatment, and confirmation of the diagnosis with PTH measurement is recommended. It is not necessary to measure PTH routinely in patients with postsurgical hypocalcemia because this effect is usually transient and the cause obvious. PTH concentrations should be determined for patients in which hypocalcemia does not resolve. Absolute hypoparathyroidism is present if a PTH concentration below the reference range is detected simultaneously with hypocalcemia. Relative hypoparathyroidism is present if PTH concentration is inappropriately low but remains within the normal reference range. Increased serum phosphorus and decreased calcitriol concentrations provide further support for a diagnosis of hypoparathyroidism.232

Causes of Hypoparathyroidism

The causes of hypoparathyroidism can be divided into three categories: (1) suppressed secretion of PTH without parathyroid gland destruction,115,145 (2) sudden correction of chronic hypercalcemia, and (3) absence or destruction of the parathyroid glands. The most common category of hypoparathyroidism in dogs and cats is absence or destruction of the parathyroid glands.

Postoperative hypocalcemia developed 1 to 3 days after thyroidectomy in approximately 20% to 30% of cats.51,187,190,223,609 Some cats developed hypocalcemia as late as 1 to 2 weeks after surgery. The surgical technique used for thyroidectomy influences the chances that hypocalcemia will develop, and hypocalcemia occurred in more than 80% of cats when original extracapsular technique was used.187 When a modified intracapsular dissection technique was used, transient hypocalcemia developed in about 6% of cats postthyroidectomy.399 Hypocalcemia resolved in all cats within 6 days with therapy. Bilateral thyroidectomy results in loss of the two internal parathyroid glands, and hypoparathyroidism is permanent in patients in which the external parathyroid glands are completely removed during bilateral thyroidectomy. Hypocalcemia and hypoparathyroidism do not develop if the two external parathyroid glands are not excised or damaged during thyroidectomy. Normocalcemia can be maintained with one completely functional parathyroid gland.

Hypoparathyroidism is usually transient when the external parathyroid glands are retained but have their blood supply disrupted (parathyroid gland ischemia after physical trauma, vessel stretching, suture, cautery, or transection) during surgery. Permanent hypoparathyroidism is rare, but it may take as long as 3 months to be certain whether remaining parathyroid tissue can recover by hyperplasia.51,446,504 Similar injury to parathyroid glands can occur during any extensive surgery of the neck in dogs241,301 or cats or after exploration of the neck for unilateral parathyroid gland removal. Restored vascular supply to damaged parathyroid tissue seems unlikely as the mechanism for recovery from hypocalcemia. It is more likely that hyperplasia and hypertrophy of parathyroid gland remnants left behind during surgery or ectopic parathyroid tissue achieve sufficient mass to synthesize adequate amounts of PTH. Experimental cats subjected to parathyroidectomy predictably developed hypocalcemia and low serum PTH concentration, but, interestingly, the hypocalcemia resolved, although the PTH concentrations remained low.188 Autotransplantation of parathyroid tissue after bilateral thyroparathyroidectomy was associated with reduced morbidity and rapid return of serum calcium concentrations to normal in experimental cats.425

Long-standing ionized hypercalcemia causes normal parathyroid tissue to atrophy. If hypercalcemia is nonparathyroid in origin, PTH concentrations will already be low. Rapid correction of hypercalcemia results in hypocalcemia because the atrophic parathyroid glands cannot respond immediately to the need for increased PTH secretion. Surgical removal of a single parathyroid gland tumor (usually an adenoma) commonly causes postoperative hypocalcemia in this manner. Hypocalcemia severe enough to require treatment is likely to develop within 24 to 48 hours. Nearly 50% of dogs with primary hyperparathyroidism can be expected to develop clinical signs of hypocalcemia 3 to 6 days after surgical removal of a parathyroid gland tumor. Hypocalcemia is more likely to develop in dogs with higher presurgical iCa concentrations. More than one half of hyperparathyroid dogs exhibit a rapid decrease in serum iCa concentration that normalizes within 24 hours of surgery. Serum iCa concentrations in the remaining dogs usually normalize by 2 or 3 days after surgery, but some require as long as 5 days. Hypoparathyroidism resolves for most affected dogs in 8 to 12 weeks. Cats develop hypocalcemia less frequently than dogs after surgical correction of primary hyperparathyroidism.141,285

Hypoparathyroidism following spontaneous infarction of a parathyroid gland tumor previously causing hypercalcemia is a rare condition that can result in acute hypocalcemia in dogs.485 The rapid correction of cancer-associated hypercalcemia (e.g., with tumor excision and chemotherapy) can be associated with hypocalcemia and low PTH concentration, but hypocalcemia is usually minor and transient.

Both acute hypermagnesemia and severe magnesium depletion may suppress PTH secretion.63,465,572 As with hypocalcemia, mild acute hypomagnesemia stimulates PTH secretion, but severe magnesium depletion decreases PTH secretion, increases end-organ resistance to PTH, and may impair calcitriol synthesis. The end-organ resistance to PTH that develops during magnesium depletion may persist for days after magnesium repletion and resumption of normal PTH concentrations in humans. Until recently, hypomagnesemia has been reported rarely in dogs and cats with hypoparathyroidism. Normal serum tMg does not guarantee a normal iMg concentration because there is substantial discordance between these two measurements.

Magnesium depletion can cause functional hypoparathyroidism, and measurement of serum iMg concentration is recommended to exclude or identify this form of hypoparathyroidism. Serum tMg concentrations when measured in dogs and cats with primary hypoparathyroidism usually have been normal.87,179 In 357 dogs with primary hypoparathyroidism, mean iCa and mean PTH concentrations were below the reference range.521 The iMg concentration was below the reference range in 39%, within the reference range in 55%, and above the reference range in 6% of dogs with hypoparathyroidism. Of the 55% of dogs with iMg within the reference range, 69% had an iMg concentration within the lower half of the reference range, and only 31% had an iMg concentration within the upper half of the reference range.

Despite the relative paucity of published reports from cats, hypoparathyroidism was diagnosed in 27 cats during a 2-year period.521 Of cats with hypoparathyroidism, 59% were domestic shorthairs, 22% were an unspecified breed, and 15% were Siamese. Mean serum iCa concentration was below the reference range, and mean PTH concentration was in the lower half of the reference range. The iMg concentration was below the reference range in 37%, within the reference range in 59%, and above the reference range in 4%. Of the 59% of cats with iMg within the reference range, 88% had an iMg concentration within the lower half of the reference range, and only 12% had an iMg concentration within the upper half of the reference range. These results suggest that a large number of dogs and cats with hypoparathyroidism also exhibit subnormal or marginal iMg concentrations. The impact of magnesium supplementation in the treatment of hypoparathyroidism should be investigated. Although primary hypoparathyroidism is usually diagnosed in older cats, it has been reported in a 6-month-old kitten initially evaluated for lethargy, inappetence, muscle tremors, and seizures.34

Most causes of primary hypoparathyroidism have been attributed to immune destruction of parathyroid tissue. Early reports of hypoparathyroidism in dogs and cats did not consistently evaluate magnesium status and used tMg when it was reported. Based on discordance of magnesium status using iMg versus tMg, hypomagnesemia based on tMg assessments may have underestimated a role for hypomagnesemia in the genesis of hypoparathyroidism in animals. Hypomagnesemia may decrease cell membrane receptor sensitivity to iCa and PTH, as well as decrease PTH synthesis.325 Serum iMg concentration should be measured when iCa and PTH concentrations are determined.

The potential role of magnesium depletion in the development of post-thyroidectomy hypocalcemia in cats has not been explored. Magnesium depletion could play a role in the development of postoperative hypocalcemia in cats with hyperthyroidism, because hyperthyroidism can be associated with magnesium depletion.179

Canine distemper virus (CDV)-induced parathyroid hypofunction may contribute to development of hypocalcemia. Dogs infected with CDV had reduced serum tCa concentrations associated with ultrastructural evidence of parathyroid gland inactivity, degeneration, and viral inclusions.608

Miscellaneous Causes of Hypocalcemia

Metabolites of ethylene glycol can chelate calcium and become deposited in soft tissues, resulting in hypocalcemia. Both dogs and cats exhibit hypocalcemia after ethylene glycol ingestion.569 Seizures have been observed in dogs within hours of ingestion; renal function was normal at this time (Chew, personal observations). Hypocalcemia often develops later when renal function is severely reduced from acute renal failure and when hyperphosphatemia is severe.

Pansteatitis has been associated with severe hypocalcemia in a cat.641 A 13-year-old cat had a history of anorexia, lethargy, and abdominal enlargement; decreased serum iCa and tCa concentrations were observed with an elevation in PTH concentration (secondary hyperparathyroidism). No clinical signs of hypocalcemia were noted. Pansteatitis was confirmed on histopathology. The exact mechanism of hypocalcemia was not determined, although it was probably due to the formation of calcium soaps.

Acute decreases in iCa concentrations are most commonly caused by acute respiratory alkalosis in humans.465 It is likely that this phenomenon also occurs in dogs and cats subjected to the stresses of hypocalcemia and a visit to a veterinary clinic. This could explain the phenomenon of mild stress-induced seizures or tetany in dogs that have hypocalcemia, as the alkalosis shifts some calcium to the protein-bound state, causing more severe ionized hypocalcemia.

Treatment of hypocalcemia

Puerperal tetany is the condition most likely to require correction of hypocalcemia acutely, but chronic treatment is not needed. Hypoparathyroidism is the only condition requiring acute and chronic treatment to alleviate clinical signs of hypocalcemia. Other conditions associated with hypocalcemia are transient or result in minimal decreases in serum calcium concentration, do not cause obvious clinical signs, and only occasionally necessitate calcium replacement therapy. No treatment is indicated for hypocalcemia attributable entirely to hypoalbuminemia or hypoproteinemia, assuming that the iCa fraction is normal.

Treatment is individualized based on severity of clinical signs, magnitude of hypocalcemia, rapidity of decline in serum calcium concentration, and trend of serial serum calcium measurements (i.e., further decrease or stability). Aggressive treatment is prescribed for patients with severe clinical signs of hypocalcemia, patients with severe ionized hypocalcemia with or without signs, and patients in which serum calcium concentration is steadily or rapidly declining. Acute, subacute, and chronic rescue treatment regimens are available using supplementation with calcium salts and vitamin D metabolites. The goal of therapy is to increase serum calcium concentration to a level that alleviates the signs of hypocalcemia, minimizes the likelihood of the development of hypercalcemia, and reduces the magnitude of hypercalciuria (especially in patients with hypoparathyroidism). It is usually not necessary or desirable to return serum calcium concentration completely to normal because many clinical signs improve dramatically with slight increases in serum calcium concentration, and the consequences of overcorrection can be serious. For suspected temporary postsurgical hypoparathyroidism, it is desirable to keep the serum calcium concentration relatively low to maximize compensatory hypertrophy of remaining parathyroid glands.

In patients with hypoparathyroidism, no treatment regimen completely compensates for the full range of physiologic actions of the absent PTH. Vitamin D metabolite treatment corrects the low intestinal absorption of calcium but does not completely protect the kidneys from hypercalciuria as would occur in the presence of PTH. Similarly, vitamin D metabolites do not exert as powerful an effect on bone in the absence of PTH. Replacement therapy with once-daily subcutaneous injections of human PTH (1-34) in human subjects was highly effective in providing good 24-hour control of serum calcium concentration.616 Use of synthetic human amino-terminal PTH for the treatment of veterinary patients is possible because the amino-terminal portions of PTH are highly conserved, function in vivo in animals, and would be unlikely to elicit an immune response.

Hypocalcemia severe enough to cause clinical signs should be anticipated in dogs undergoing parathyroidectomy as treatment for hypercalcemia related to a parathyroid gland adenoma. Animals with very high concentrations of serum calcium, PTH, and serum ALP may be at greater risk of developing postoperative hypocalcemia. Postoperative hypocalcemia in this instance is the consequence of acute hypoparathyroidism resulting from chronic suppression of remaining parathyroid glands and calcium uptake into “hungry” bones. Hypocalcemia should be anticipated in cats that undergo bilateral thyroidectomy, because up to 30% of cats can be expected to have transiently lowered serum calcium concentrations.

Therapy should be instituted before the development of tetany. Preemptive therapy to increase serum calcium concentration may be a good choice for animals with marked hypocalcemia with no apparent clinical signs or for those in which serum calcium concentration is steadily or rapidly declining. Prophylactic therapy to prevent hypocalcemia in dogs undergoing surgery for hyperparathyroidism should be considered, especially in dogs with severe hypercalcemia. Active vitamin D metabolites should be started before surgery in these instances because there is a lag time until maximal effect is achieved. Vitamin D metabolites given at the time of surgery or just after surgery fail to prevent development of hypocalcemia.

Autotransplantation of normal parathyroid glands is a treatment option used to minimize postoperative hypocalcemia when it is obvious that damage has been done to the parathyroid glands during surgery (bilateral extracapsular thyroidectomy). Autotransplantation of normal parathyroid glands was studied in experimental cats following bilateral extracapsular thyroparathyroidectomy.425 External parathyroid glands were harvested and dissected from thyroid tissue, and small pieces of parathyroid tissue were embedded into the sternohyoideus muscle. Cats showed an average decrease of 44% in serum tCa with the nadir occurring 1.9 days following surgery. Hypocalcemia was present for a median of 14 days in cats having parathyroidectomy and autotransplantation in this study compared with a median of 71 days in cats of a previous report involving parathyroidectomy without autotransplantation.188 Seven of eight cats with autotransplantation of parathyroid glands regained normocalcemia within 20 days without oral calcium salt supplementation.425

Acute Management of Hypocalcemia Causing Tetany or Seizures

Tetany or seizures caused by hypocalcemia require treatment with intravenously administered calcium salts. Calcium is administered to effect, at a dosage of 5 to 15 mg/kg of elemental calcium (0.5 to 1.5 mL/kg of 10% calcium gluconate) over a 10- to 20-minute period.115,179,446,447 The calcium content of different calcium salts varies considerably (Table 6-5). There is no difference in effectiveness of calcium salts administered intravenously to correct hypocalcemia when the dose is based on elemental calcium content. Calcium gluconate is often the calcium salt of choice because it is nonirritating if the solution is inadvertently injected perivascularly. In contrast, calcium chloride is extremely irritating to tissues but provides more elemental calcium in each milliliter of solution (see Table 6-5).

Table 6-5 Treatment of Hypocalcemia

image

The heart rate and electrocardiogram should be monitored during acute infusions of calcium salts. Bradycardia may signal the onset of cardiotoxicity arising from excessively rapid infusion of calcium. Sudden elevation of the ST segment or shortening of the QT–interval also may indicate cardiotoxicity resulting from the calcium infusion. Not all clinical signs abate immediately after acute correction of hypocalcemia; some may persist for 30 to 60 minutes. Nervousness, panting, and behavioral changes may persist despite return of normocalcemia during this period, perhaps reflecting a lag in equilibration between cerebrospinal fluid and ECF calcium concentrations.179,297,504 Hyperthermia that resulted from increased muscle activity or seizures may also take time to dissipate.

Subacute Management of Hypocalcemia

The initial bolus injection of elemental calcium can be expected to decrease signs of hypocalcemia for as little as 1 hour to as long as 12 hours if the underlying cause of hypocalcemia has not been corrected. Vitamin D metabolites should be administered as soon as possible because some of them require a few days before intestinal calcium transport is maximized. Calcitriol exerts initial effects on the intestine within 3 to 4 hours.601 Additional parenteral calcium salt administration is necessary until therapy with vitamin D metabolites is effective at maintaining serum calcium concentration at an acceptable level.

Multiple intermittent intravenous injections of calcium salts can be administered to control clinical signs, but this method is not recommended because wide fluctuations in serum calcium concentration are observed. Instead, continuous intravenous infusion of calcium is recommended at 60 to 90 mg/kg/day elemental calcium (2.5 to 3.75 mg/kg/hr) until oral medications provide control of serum calcium concentration.87,179,446,447 Initial doses in the higher range are administered to patients with more severe hypocalcemia, and the dose decreased according to the serum calcium concentration achieved. The intravenous dose of calcium is further reduced as oral calcium salts and vitamin D metabolites become more effective.

Ten milliliters of 10% calcium gluconate provides 93 mg of elemental calcium. A convenient method for infusing calcium is available when intravenous fluids are given at a maintenance volume of 60 mL/kg/day (2.5 mL/kg/hr). Approximately 1, 2, or 3 mg/kg/hr elemental calcium is provided by adding 10, 20, or 30 mL of 10% calcium gluconate, respectively, to each 250-mL bag of fluids. Calcium salts should not be added to fluids that contain lactate, acetate, bicarbonate, or phosphates because calcium salt precipitates can occur. Alkalinizing fluids that contain or generate bicarbonate should be avoided because they can decrease iCa and may unmask the clinical signs of hypocalcemia in animals with borderline hypocalcemia.

Subcutaneous administration of calcium gluconate has been regarded as safe for use in dogs with hypocalcemia when diluted to a ratio of at least 1:1 by volume. The use of calcium chloride is too caustic to ever be given subcutaneously. However, a recent report raises concerns about the safety of calcium gluconate administration subcutaneously. A 6-month-old border collie with hypoparathyroidism was initially treated with intravenous calcium gluconate, followed by oral calcitriol and calcium carbonate.513 This dog then received subcutaneous calcium gluconate three times daily for 2 days, and calcium gluconate was diluted as previously recommended. Fever and pain, swelling, and erythema of the ventral abdomen were obvious after 2 days of subcutaneous calcium gluconate treatments. Initial skin biopsy revealed calcinosis cutis with pyogranulomatous dermatitis and dermoepidermal separation. The dog’s condition worsened; ulceration involving about 80% of the skin developed over the trunk; and the dog was euthanized. A second skin biopsy revealed severe pyogranulomatous panniculitis with mineralization of adipocytes.

Reports of this reaction to the subcutaneous administration of calcium gluconate had not previously been reported in dogs despite its extensive use by some institutions (Feldman, personal communication, 2005). Unfortunately, we are aware of at least three other dogs with similar severe reactions to the subcutaneous administration of properly diluted calcium gluconate as treatment for primary hypoparathyroidism, resulting in euthanasia for most (Chew, personal communications, 2003, 2004). Differences in an individual animal’s susceptibility to the effects of calcium salts on subcutaneous tissues could account for severe reactions in some dogs. All dogs with this severe tissue reaction were also receiving calcitriol, which may potentiate more local dramatic effects in the subcutaneous tissues as compared with less active vitamin D metabolites (cholecalciferol, ergocalciferol, and dihydrotachysterol) commonly used in the past.

There are only two reports of cats with primary hypoparathyroidism that were treated with subcutaneous administration of calcium gluconate. No adverse effects were noted in one report.195 Iatrogenic calcinosis cutis, skin necrosis, and scarring occurred at sites of diluted calcium gluconate injection and sites where injected fluids pooled in one cat.501 This cat survived. Because of the severity of adverse reactions that have recently been observed in dogs and a cat, the administration of subcutaneous fluids containing calcium gluconate is no longer recommended as a safe and predictable treatment.

Subacute and Chronic Maintenance

Supplemental elemental calcium is administered orally (see Table 6-5) to guarantee adequate calcium for intestinal absorption after treatment with vitamin D metabolites. Oral calcium administered by pill or slurry is most important during initial treatment, especially if the animal is not eating. Active intestinal transport of calcium is under the control of calcitriol when calcium intake is low, but vitamin D-independent (passive) intestinal absorption of calcium occurs when calcium intake is high. The passive mechanisms for intestinal calcium transport can be used therapeutically before the actions of vitamin D take effect in the intestine. In most patients, normal dietary intake of calcium is sufficient to maintain adequate serum calcium concentrations in the presence of vitamin D metabolite treatment. Consequently, oral calcium salt supplementation can be tapered and discontinued in many instances as vitamin D compounds reach maximal effect.

Calcium carbonate is the most widely used oral preparation of the calcium salts because it contains the greatest percentage of elemental calcium. This approach allows fewer pills to be administered. The degree of calcium ionization from its salt and its bioavailability for absorption vary for each calcium salt and with conditions in the intestine. Consequently, it is not a simple matter to determine the bioavailable elemental calcium content of a specific oral calcium salt. Oral calcium is usually administered at 25 to 50 mg/kg/day elemental calcium in divided doses. Oral calcium carbonate serves as an intestinal phosphate binder in addition to providing calcium for intestinal absorption. It is advisable to continue oral calcium carbonate therapy for its intestinal phosphate-binding effects if serum phosphorus concentration remains increased. Lower serum phosphorus concentrations may allow increased endogenous synthesis of calcitriol because phosphate inhibits renal synthesis of calcitriol.

Vitamin D preparations (see Table 6-5) include ergocalciferol, cholecalciferol, 25-hydroxycholecalciferol (calcidiol), 1α-hydroxycholecalciferol, and calcitriol. Ergocalciferol and calcitriol are the preparations most commonly used in veterinary medicine. Lifelong treatment with some form of vitamin D metabolite is necessary for patients with primary hypoparathyroidism or postoperative hypocalcemia that fails to resolve spontaneously.

Ergocalciferol is favored by some because of its low cost,465 but it has several features that make it the least attractive agent for the treatment of hypocalcemia. Ergocalciferol and its immediate metabolite, 25-hydroxyergocalciferol, have low VDR avidity; thus, high doses are necessary. Ergocalciferol is highly lipid soluble, and several weeks are required to saturate body stores and achieve a maximal effect. It also has a long half-life. Consequently, prolonged periods of hypercalcemia occur after overdose with ergocalciferol. In addition, there is extreme individual variation in the dose of ergocalciferol required to achieve a target serum calcium concentration. Use of loading doses reduces the time required to achieve a maximal effect (see Table 6-5).

Calcitriol is the vitamin D metabolite of choice to provide calcemic actions because it has the most rapid onset of maximal action and the shortest biologic half-life. Calcitriol is approximately 1000 times as effective as parent vitamin D and 500 times as effective as its precursor, calcidiol (25-hydroxyvitamin D), in binding to the VDR. The dose of calcitriol can be adjusted frequently because of its short half-life and rapid effects on serum calcium concentration. If hypercalcemia occurs, it abates quickly after dose reduction. The half-life of calcitriol in blood is 4 to 6 hours, whereas its biologic half-life is 2 to 4 days. Loading protocols for use of calcitriol in animals have not been reported, but it is logical to use a loading protocol when more rapid correction of serum calcium concentration is desirable. A calcitriol dosage of 30 to 60 ng/kg/day has been recommended.87,179 This dosage may be satisfactory as a loading dose, but in our experience it is too high for chronic maintenance therapy. Calcitriol dosages for chronic maintenance therapy in humans range from 10 to 40 ng/kg/day, and doses are divided and given twice daily.232,465,616 We have used loading dosages of 20 to 30 ng/kg/day for 3 to 4 days and maintenance dosages of 10 to 20 ng/kg/day in most patients. The dose of calcitriol is divided and given twice daily to ensure sustained priming effects on intestinal epithelium for calcium transport. Calcitriol is commercially available in 0.25- and 0.50-μg capsules (250 and 500 ng per capsule, respectively). It is likely that reformulation of calcitriol in doses suitable for a variety of animal sizes will be necessary. It may be useful to prescribe calcitriol in liquid formulation so that small adjustments in dosage can be made accurately. A number of specialty pharmacies reformulate human drugs for veterinary use and can create any calcitriol dose needed.

Clinical follow-up and potential complications

Periods of hypocalcemia and hypercalcemia occur sporadically in patients during initial efforts to manage serum calcium concentration. Daily measurement of serum tCa concentration during stabilization is necessary. Weekly serum calcium measurements should suffice during maintenance therapy until target serum calcium concentration has been achieved and maintained. Measurement of serum tCa concentration is recommended every 3 months thereafter in animals with permanent hypoparathyroidism. Serum calcium concentration should be adjusted to just below the reference range. This not only lessens the likelihood that hypercalcemia will develop but also reduces the magnitude of hypercalciuria that occurs in patients with PTH deficiency. Maintaining a mildly decreased serum calcium concentration also ensures a continued stimulus for hypertrophy of the remaining parathyroid tissue in patients with postoperative hypoparathyroidism.

A change in dosage of vitamin D metabolites should only occur after maximal effect has occurred and should be altered gradually. The time lag for maximal effect varies with the different vitamin D metabolites (see Table 6-5). Dosage increases of 10% to 25% are recommended when serum calcium concentration is still below the target level.446,447 Vitamin D metabolite and calcium salt supplementation should be discontinued temporarily in patients that develop hypercalcemia.

Hypercalcemia is a serious adverse effect of treatment that can result in death or renal damage causing acute or CRF.111,115,314 Early signs of hypercalcemia should be explained to owners, who should be instructed to seek veterinary attention immediately if clinical signs suggest hypercalcemia. Clinical signs of hypercalcemia that clients are likely to recognize include polydipsia, polyuria, anorexia, vomiting, and lethargy. Animals with severe hypercalcemia require hospitalization. Fluids, furosemide, corticosteroids, bisphosphonates, calcitonin, or some combination may be required. All patients with symptomatic, vitamin D metabolite-induced hypercalcemia should be given a calcium-restricted diet because increased intestinal absorption of calcium contributes substantially to the development of hypercalcemia in hypervitaminosis D.

Patients that maintain serum iCa concentrations in the target zone are often managed successfully for years. Twenty-four of 25 dogs with primary hypoparathyroidism were managed successfully for more than 5 years,179 and long-term management was successful in a small number of cats.444 Patients that develop episodic or prolonged hypercalcemia during treatment have a poor prognosis. Management with calcitriol is easier and more successful in inducing and maintaining serum iCa concentrations in the target zone than are older therapeutic approaches.

Hypercalciuria, nephrocalcinosis, urolithiasis, and reduced renal function have occurred in humans treated for chronic hypoparathyroidism.232,572,616 As many as 80% of human patients treated for 2 years or longer have decreased creatinine clearance.616 These abnormalities can be attributed to episodes of hypercalcemia and hyperphosphatemia and to hypercalciuria that occurs in the absence of the actions of PTH on the renal tubules. In the absence of PTH, hypercalciuria occurs more readily at all serum iCa concentrations and is especially severe as iCa concentrations approach the normal range, which increases the filtered load of calcium. Nephrocalcinosis, reduced renal function, and CRF have also been suspected in veterinary patients receiving long-term treatment for hypoparathyroidism, but the risk for these disorders has not been critically evaluated.446

Vitamin D metabolite treatment is gradually tapered and then discontinued in patients with postsurgical hypoparathyroidism because hypocalcemia is usually transient. Most cats are able to maintain normal serum iCa concentrations 2 weeks after thyroidectomy, although some may take as long as 3 months. Dogs with hypocalcemia usually require 6 to 12 weeks of treatment after removal of a parathyroid gland adenoma. A reduction in dose of vitamin D metabolites is usually begun 1 month after initiation of therapy. If serum iCa concentration declines substantially, the previous dose is resumed, and reduction is attempted again 1 or 2 months later. Permanent hypoparathyroidism is likely if failure to maintain acceptable serum iCa concentration occurs after reduction of the vitamin D metabolite dose at 3 months.

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