Hypercalcemia: Pathophysiology, Clinical Signs, and Emergent Treatment

Introduction

Ca functions as a structural component of skeletal bone and is a chief messenger and regulatory ion at the cellular level.¹ Ca is present in three forms in the body. Complexed hydroxyapatite represents approximately 99% of the body's supply, while the remaining 0.9% and 0.1% is present intracellularly and extracellularly, respectively. Fifty percent of the Ca found in the extracellular fluid is comprised of the ionized biologically active form.¹ The remainder of the extracellular Ca is either protein bound or complexed in the forms of bicarbonate, citrate, phosphate, lactate, or oxalate.^1,2

The actions of Ca are varied and numerous and include involvement in muscle contraction, coagulation, hormone secretion, enzymatic activity, vascular smooth muscle tone, glycogen metabolism, and regulation of cellular growth and division.^1–3 Furthermore, Ca facilitates the release of acetylcholine during neuromuscular transmission and stabilizes nerve cell membranes.⁴ Due to its pivotal role in numerous vital biologic processes, Ca is normally maintained within a very small range.

Hypercalcemia is defined as serum total Ca >12 mg/dL in dogs and >11 mg/dL in cats.² Ionized hypercalcemia is present at serum levels >1.45 mmol/L in dogs and >1.4 mmol/L in cats; however, variation exists between different laboratories and point-of-care analyzers.^2,3 See Table 1 for reference intervals for serum total and ionized normocalcemia and hypercalcemia. Ionized Ca levels are considered a more accurate measure of hypercalcemia because increases in total serum Ca may not reflect changes in ionized Ca. Clinical signs of hypercalcemia vary according to the severity, the nature of the development (acute versus chronic), and the underlying cause. There is no defined concentration of serum Ca that should prompt a clinician to initiate treatment; however, animals that have a serum total Ca of ≥15 mg/dL or an ionized Ca of >1.8mmol/L commonly demonstrate clinical signs.^2,5,6 Hypercalcemia should be considered life threatening when the serum total Ca reaches ≥18–20 mg/dL or ionized Ca is >2.2 mmol/L ^2,5,6

Table 1 Reference intervals for serum total and ionized normocalcemia and hypercalcemia

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Ca Homeostasis

Ca homeostasis is very tightly regulated in health. Control is governed by a number of hormones and other substances. The most important of these are parathyroid hormone (PTH) and 1,25- dihydroxycholecalciferol (calcitriol).

Minute to minute fluctuations in Ca are governed by PTH.² The chief cells of the parathyroid gland are responsible for both the synthesis and secretion of PTH. Healthy adult animals maintain a continuously low level of PTH as the half-life is merely 5 min.² In times of ionized hypocalcemia, PTH increases blood Ca by a number of different mechanisms. It has a direct effect on bone by enhancing osteoclastic activity and bone resorption. In the kidney, PTH increases tubular reabsorption of Ca, promotes urinary phosphorus excretion, and triggers the bioactivation of calcitriol.^1,2,7 Furthermore, it has an indirect effect on the intestines and increases the absorption of dietary Ca in concert with calcitriol.^1,2

The primary impetus for the secretion of PTH is extracellular ionized hypocalcemia; however, the level of circulating calcitriol exerts ultimate control over the production and secretion of PTH in the chief cells.^1,2,7 When levels of calcitriol are elevated beyond a critical threshold, a negative feedback loop is established that results in the inhibition of further PTH synthesis.² It is of clinical importance to note that even in states of severe hypercalcemia, PTH secretion cannot be completely inhibited.

Unlike humans, dogs and cats are unable to adequately synthesize vitamin D and possess a direct need for a dietary source. Vitamin D is absorbed directly from the intestine and transported to the liver to undergo hydroxylation. The result is the formation of calcidiol (25-hydroxycholecalciferol). Calcidiol is further hydroxylated to the biologically active form of vitamin D (calcitriol) in the renal proximal tubular cells.

Calcitriol is responsible for the daily fluctuations in serum Ca.² Enhanced absorption of dietary Ca and phosphorus occur secondary to calcitriol's effect on the enterocyte in the small intestine. Like PTH, calcitriol also promotes bone resorption to release Ca stores into circulation and further fuels renal reabsorption of Ca and phosphorus.^1,2 Hypophosphatemia, hypocalcemia, and low levels of circulating PTH provide a stimulus for calcitriol secretion.²

Recent discovery of the G protein-coupled Ca-sensing receptor lends further insight into the control of Ca homeostasis at the cellular level. The activity of the Ca-sensing receptor is governed by extracellular Ca levels and directly affects the secretion of PTH and urinary Ca excretion.⁸ That receptor is now a therapeutic target for studies in human medicine.⁹

Calcitonin is manufactured by the C cells of the thyroid gland either ingestion of a Ca-rich meal or in states of hypercalcemia. Calcitonin's main target organ is bone where it interferes with osteoclast-mediated bone resorption and therefore decreases blood Ca levels.^2,4 Circulating calcitonin enhances calciuresis to a certain degree and collaborates with PTH to sustain ionized normocalcemia.²

Control of phosphorus homeostasis is influenced by Ca regulation. PTH increases Ca levels and promotes urinary phosphorus excretion. It also inhibits renal reabsorption of phosphorus from the glomerulus during times of hyperphosphatemia. Alternatively, calcitriol increases both intestinal and renal reabsorption of phosphorus. When ionized hypercalcemia is present, serum phosphorus levels must be closely monitored because concomitant elevations in those minerals have been reported to cause soft-tissue mineralization. Multiplication of the total serum Ca by the serum phosphorus yields the Ca-phosphorus product. A Ca-phosphorus product of >60–70 has been reported to increase the risk of soft-tissue mineralization. It is reported that widespread mineralization of many tissues can occur secondary to an elevation in the Ca-phosphorus product; however, clinical signs usually become most evident when the kidneys or cardiac structures undergo mineralization.¹⁰ That number is only valid in adults because growing animals often have a Ca-phosphorus product that is >70.^7,11

Because serum phosphorus levels fluctuate more than ionized Ca, it can be argued that the Ca-phosphorus product may not be clinically relevant.¹² It is proposed that serial measurements of phosphorus may be more useful in identifying patients at risk of mineralization compared to Ca because increased levels of phosphorus are reported to directly cause vascular smooth muscle cell calcification.¹³

Parathyroid related peptide (PTHrP) is synthesized broadly by many tissues in both the fetus and adult.² PTHrP is produced in the fetal chief cells, causing intestinal Ca absorption, maintaining normal Ca homeostasis, and assisting in the differentiation of developing tissues.¹ The mammary glands, muscles, brain, kidneys, skin, and other tissues in the healthy adult can produce PTHrP.¹ Although its exact function may be unknown in some instances, PTHrP likely exhibits a combination of paracrine and autocrine activity depending on the tissue of origin.^1,2 Fetal PTHrP levels are high; however, normal levels in adult animals should be quite low. Abnormally high levels of PTHrP can be an indicator of disease, most often malignant neoplasia. PTHrP functions as PTH and is often upregulated in neoplastic disease processes where normal negative feedback mechanisms are either overridden or inhibited, leading to hypercalcemia.

Diagnosis

Because ionized Ca is the biologically active form, a diagnosis of hypercalcemia should be made based on an ionized Ca measurement. Detection of elevated total serum Ca should prompt the clinician to obtain an ionized Ca level as there are no equations that can accurately determine ionized Ca based on a serum total Ca level.^2,4,14 It is recommended that a serum ionized Ca level be sent to a laboratory for confirmation as many point-of-care analyzers often provide falsely low ionized Ca results as heparin binds and dilutes Ca.¹⁵ It is also important to note that overestimation of Ca levels can occur when serum is stored in a serum separator tube or when significant lipemia is present.⁵ Fasted samples acquired under anaerobic conditions are preferred to prevent false decreases in Ca secondary to enhanced protein binding.⁴ When there is strong clinical suspicion of hypercalcemia, it may be beneficial to submit PTH and PTHrP levels along with the serum ionized Ca sample to hasten the obtainment of a definitive diagnosis of the cause of hypercalcemia.

Etiologies

Although infrequently diagnosed, hypercalcemia can result from a wide range of disease processes. The severity of clinical signs, treatment required, and the overall prognosis are heavily influenced by the cause of the increased Ca. The presence of concurrent disease may also impact morbidity and mortality. Either nonpathological or transient causes of hypercalcemia have minimal impact on prognosis. The outcome for patients that experience hypercalcemia secondary to toxin ingestion varies widely and is largely governed by the amount ingested compared to body weight as well as the timing and nature of the treatment. Prognosis for patients with chronic renal failure and neoplasia is poor given the nature of the underlying illness.

Etiologies of hypercalcemia are broadly categorized as parathyroid-dependent and parathyroid-independent. Parathyroid-dependent causes include primary hyperparathyroidism and secondary nutritional or renal hyperparathyroidism. All other sources of hypercalcemia are considered parathyroid-independent. Parathyroid-independent causes include transient or inconsequential causes of hypercalcemia, hypercalcemia of malignancy and cancer-associated hypercalcemia, toxic, idiopathic, metabolic, skeletal, and granulomatous etiologies.

Adenoma of the parathyroid gland is the most common cause of primary hyperparathyroidism. It is most often diagnosed in older dogs (>10 yr) and demonstrates a breed predilection for the keeshond.⁷ Hyperplasia of the parathyroid glands is uncommon. Parathyroid gland adenocarcinoma is rarely diagnosed in veterinary patients.

The mechanism for development of renal secondary hyperparathyroidism is not completely understood. A global decrease in Ca occurs secondary to changes in renal 1-α-hydroxylase activity and decreased activity of calcitriol.⁷ Decreased circulating Ca levels stimulate PTH. Eventually, the normal negative feedback mechanisms are rendered nonfunctional and Ca levels no longer exert control over PTH secretion. The result is hypercalcemia and hyperphosphatemia.⁷

The most common cause of pathologic hypercalcemia in dogs is neoplasia, most notably lymphoma and apocrine gland anal sac adenocarcinoma. Lymphoma and squamous cell carcinoma are the most likely neoplasms to induce hypercalcemia in cats. Humoral hypercalcemia of malignancy implies that a blood-borne factor causes hypercalcemia distant to the tumor whereas bony metastases and hematopoietic bone marrow malignancies cause hypercalcemia through local osteolytic effects.³

Idiopathic hypercalcemia is the most common form of hypercalcemia in cats. This diagnosis of exclusion is made when increased ionized Ca levels are present and an extensive medical work-up cannot identify an underlying cause.¹⁶

Clinical Signs

Clinical signs in patients with hypercalcemia can be diverse, vague, and may arise from the effects of increased Ca on numerous body systems, the underlying disease process, or a combination of both. In general, the severity of clinical signs roughly corresponds to the degree of ionized hypercalcemia, but that theory does not always hold true. A retrospective study of 71 hypercalcemic cats demonstrated that the extent of ionized hypercalcemia did not correlate with the clinical signs in any of the cats.¹⁷ Clinical signs are often more severe when the hypercalcemia develops quickly such as in vitamin D toxicosis.² Because of the Ca ion's ubiquitous role in cellular homeostasis, derangements in ionized Ca can negatively impact all tissues of the body. The presence of central nervous system, cardiac, renal, and gastrointestinal tract aberrations are most likely to be life threatening and require immediate attention.²

Anorexia, weakness, lethargy, vomiting, constipation, polyuria, and polydipsia are commonly observed in hypercalcemic dogs.^3,16,17 Unlike dogs, cats infrequently display vomiting, polyuria, and polydipsia.^4,16,17 The presence of lower urinary tract signs can also be recognized in some cats and may be indicative of urolithiasis.^16,17 Less common, but potentially fatal, complications in both species include obtundation, seizures, coma, renal failure, and arrhythmias.²

Dehydration and prerenal azotemia occur secondary to gastrointestinal losses and polyuria.² Polyuria ensues through diminished renal tubular sensitivity to antidiuretic hormone.³ Renal vasoconstriction, tubular necrosis, and interstitial fibrosis can result in renal failure.^2,3 More severe gastrointestinal effects include a reduction in intestinal smooth muscle contractility and gastric ulceration via direct stimulation of the parietal cells to produce gastrin. Although uncommonly reported, arrhythmias are thought to be a direct consequence of dystrophic mineralization of the myocardium.^2,3

Primary Treatment Options

Definitive treatment of hypercalcemia is achieved by identification and correction of the primary cause, but the etiology is not always readily apparent. The lack of a definitive diagnosis should not delay therapy, and measures should be taken to stabilize the patient and reduce ionized Ca levels as quickly as possible. Initial treatment considerations for hypercalcemia include IV fluid diuresis primarily to restore hydration if clinically indicated and secondarily to promote calciuresis, inhibition of osteoclastic bone resorption, promotion of extravascular Ca shift, and deposition and reduction of intestinal Ca absorption.^2,18

Restoration of euhydration is paramount in the treatment of all patients with pathological hypercalcemia. Hemoconcentration through means of decreased glomerular filtration decreases urinary Ca excretion.^1,2 Aggressive diuresis with 0.9% Na chloride is recommended for many reasons. Saline does not contain supplemental Ca and also provides the largest amount of Na/L compared to other isotonic replacement fluids. The effect of the increased Na ion concentration on the kidney is two-fold, resulting in an increased glomerular filtration rate as well as competitive inhibition of tubular Ca reabsorption.^1,2,4,18

Care must be taken to avoid hypervolemia, and serum Na levels must be monitored closely. Rapid volume expansion can result in the development of pulmonary edema. Severe hypernatremia causes cellular dehydration and hypertonic encephalopathy.¹⁸ Ideally, serial measurements of central venous pressure and serum Na level should be performed q 6–8 hr initially and then dictated by patient progress. Increases in serial central venous pressure measurements, clinical signs of overhydration, and a serum Na level >158 mEq/L indicate that the infusion rate should be lowered or adjustments in fluid choice should be made.^18,19 It is recommended that serum Na should not be increased faster than 0.5–1 mEq/L/hr or 10–12 mEq/L q 12 hr.¹⁸

The calciuretic effect of loop diuretics is well established. In well-hydrated patients, the use of furosemide to promote urinary Ca excretion and lessen the likelihood of hypervolemia can prove beneficial in hypercalcemic patients. Caution must be taken not to dehydrate the patient because hemoconcentration will negate calciuresis.

The use of glucocorticoids can prove beneficial in the treatment of certain causes of hypercalcemia. Corticosteroid administration results in decreased bone resorption via inhibition of osteoclast maturation. It also diminishes the number of calcitriol receptors present in bone. Glucocorticoids serve to impede intestinal Ca absorption and cause an increase in renal Ca excretion.^4,18 Vitamin D antagonism has also been observed with the use of glucocorticoids.⁴

Corticosteroids are best reserved for the treatment of hematologic neoplasia, granulomatous disease, idiopathic hypercalcemia, and hypervitaminosis. Their use is limited for the management of other neoplasms or primary hyperparathyroidism.¹⁸ A definitive diagnosis can be difficult to obtain once steroid therapy has been initiated because concentrations of PTHrP can be falsely decreased.^2,18,20

Secondary Treatment Options

The use of bisphosphonates for the treatment of hypercalcemia in veterinary patients has become more common within the last decade. Drugs such as pamidronate, clodronate, etidronate, alendronate, risedronate, and ibandronate are described for use in people with Ca disorders such as osteoporosis, hypercalcemia of malignancy, osteitis deformans, and heterotropic ossification.^21,22 Bisphosphonates decrease serum Ca levels by inhibition of osteoclastic activity and induction of apoptosis. Osteoclastic inhibition does not occur until 24–48 hr following parenteral administration; therefore, bisphosphonates are not considered initial drugs of choice for acute therapy unless prolonged hypercalcemia is expected or excess Ca is determined to from bony origin.⁴ Evidence exists that this particular class of drug may also interfere with absorption of Ca from the intestinal tract.²¹ Administration of osteoclast inhibitors has been documented in dogs and cats for the treatment of vitamin D toxicosis and humoral hypercalcemia of malignancy.^21–23 A study performed in 2000 individuals documented a dose-dependent decrease in soft-tissue mineralization following the administration of both low and high doses of pamidronate for vitamin D toxicosis in dogs.²³ The bone absorbs approximately 50–60% of pamidronate after IV administration. The drug is then slowly excreted unchanged via the kidneys. Pamidronate has been safely used in people with renal disease of varying severity, and previous veterinary studies have failed to document definitive adverse side effects of bisphosphonates when given doses within the accepted range.^21–23 Aledronate is available for oral administration. The bioavailability of oral bisphosphonates is approximately 5%. It is recommended that oral bisphosphonates be administered on an empty stomach. Oral bisphosphonates are only recommended for maintenance therapy.²

Calcitonin possesses the ability to most rapidly decrease serum Ca levels of all currently available treatments rendering its administration during extreme hypercalcemia potentially advantageous.¹⁸ Calcitonin directly reduces both the synthesis and biologic activity of osteoclasts, thereby inhibiting resorption of bone.⁴ Benefits are short-lived because resistance, likely secondary to receptor down regulation, is reached within 12–24 hr.^1,18 Simultaneous administration of glucocorticoids may delay development of resistance, and the efficacy of calcitonin may be re-established after discontinuing use for 1–2 days.² Expense and availability may limit its usefulness. Concurrent use of bisphosphonates and calcitonin is currently not recommended in veterinary medicine.²⁵ Documented side effects include vomiting, diarrhea, and possible allergic reaction; however, a thorough adverse effect profile has not yet been established for veterinary patients. ^1,2,24,25

Although infrequently used, Na bicarbonate can be administered in cases of life-threatening hypercalcemia. Its use is most efficacious when metabolic acidosis is present. When metabolic acidosis is corrected, ionized Ca is shifted to become protein bound or to form complexes with bicarbonate.² Treatment with Na bicarbonate is usually considered an ancillary therapy because the effects usually last no longer than 4 hr and the magnitude of reduction is only slight.² Acid-base status must be monitored carefully when administering Na bicarbonate.⁴

Hemodialysis and peritoneal dialysis are alternative forms of treatment for some causes of hypercalcemia, but the significant expense and the lack of availability pose limitations for its use. With the exception of acute intoxication, dialysis is often reserved for the treatment severe renal azotemia and hypercalcemia that is resistant to other forms of treatment. Benefits of dialysis are two-fold. Dialysis can be used to directly lower serum Ca levels to reduce the likelihood of acute kidney injury as well as treat severe renal azotemia secondary to hypercalcemia.²⁶ If the cause of hypercalcemia is amenable to dialysis, early consultation with a clinician who specializes in dialysis is recommended.

Tertiary Treatment Options

In cases of hypercalcemia that have not responded to primary or secondary treatment options, there are rescue therapies available. Refractory hypercalcemia can be treated with an infusion of ethylenediaminetetraacetic acid. Recommended dosages for administration range from 25 to 75 mg/kg/hr. Ethylenediaminetetraacetic acid forms complexes with Ca that undergo renal excretion and thus have the potential to be nephrotoxic. Use is reserved for life-threatening hypercalcemia, where other more efficacious treatments are unavailable, or in severe hypercalcemia that is unresponsive to other therapies.²⁰

Gallium nitrate, an antineoplastic agent that inhibits osteoclasts and decreases the solubility of hydroxyapatite, has been administered to both human and veterinary patients in the past. It is usually reserved for cases that appear refractory to bisphosphonate therapy; however, there is evidence to suggest that it may be superior to bisphosphonates for the treatment of humoral hypercalcemia of malignancy.²

Previously Documented Therapies

Mithramycin is a cytotoxic antibiotic agent that inhibits osteoclastic bone resorption. Its use in both human and veterinary medicine has fallen out of favor due to the potential to cause thrombocytopenia, renal and hepatic necrosis, and hypocalcemia.^18,27 Oral Na phosphate administration has been advocated in the past; however, the potential to exacerbate soft-tissue mineralization precludes it use.^2,28

Novel Therapies

Calcimimetics are a novel class of drugs used in human medicine that target the Ca receptor and inhibit the secretion of PTH.⁴ At the time this manuscript was prepared, the authors were unaware of any calcimimetics that have been used in veterinary species. The use of somatostatin congeners, Ca channel blockers and nonhypercalcemic calcitriol analogues have also shown promise either in laboratory settings or human medicine for the treatment of life-threatening hypercalcemia; however, use in veterinary species cannot be justified at this time.²

Cholestyramine is a bile acid sequestrant frequently used for the treatment of hypercholesterolemia and hypertriglyceridemia.²⁹ A previous report documents that use of this medication causes decreased intestinal Ca resorption and increased urinary excretion.³⁰ In the authors' experience [i.e., one of the author's (E. D.) participated in the successful treatment of a 7yr old castrated male pug that ingested an absolute maximum dose of 0.78 mg/kg of cholecalciferol, unpublished data], cholestyramine has been used in an isolated case of successful treatment of vitamin D toxicosis. It should be noted that cholestyramine was used in conjunction with other treatments including Na chloride diuresis, furosemide, glucocorticoids, and pamidronate.

Conclusion

Hypercalcemia is an uncommon condition in small animal veterinary patients. Clinical signs and prognosis are highly dependent on the cause and severity. A wide number of disease processes can result in hypercalcemia. When hypercalcemia is severe it must be treated aggressively and in a timely manner to avoid life-threatening complications. An overview of etiologies of hypercalcemia and potential treatments (see Table 2) and a summary of medical therapies for treatment of hypercalcemia are included for reference (see Table 3).

Table 2 Overview of the Etiologies of Hypercalcemia and Information Regarding Treatment for Each Disease

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Table 3 Documented Treatment Options for Hypercalcemia in Veterinary Patients

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