Hipercalcemia em gatos

Introduction

Calcium is an essential divalent cation that participates in many vital intracellular and extracellular functions, including neuromuscular transmission, enzymatic reactions, hemostatic coagulation, vasomotor tone, hormone secretion, and bone metabolism. Calcium exists in three forms within the body, namely ionized, protein-bound, and complexed with anion fractions. Ionized calcium (iCa) makes up about 50% of total serum calcium and serves as the principal biologically active form responsible for orchestrating diverse physiologic and cellular functions. Given its broad biologic roles, iCa concentrations are tightly regulated through the concerted actions of parathyroid hormone (PTH), 1,25-dihydroxyvitamin D₃ (calcitriol) and calcitonin 1,2,3. iCa levels directly affect PTH secretion and active vitamin D maturation to regulate calcium concentrations in the body. 

In addition to the different forms of calcium, its distribution within the body can be either intracellular or extracellular. Intracellular calcium is one of the primary regulators of cellular responses to many agonists mediated through G-protein coupled receptors and serves as a common secondary messenger to transmit signals from the cell surface to the nucleus, and is ultimately responsible for changes in gene transcription, associated cellular behaviors, and phenotype 4. Within cells, cytosolic calcium concentrations are low, however, within specific organelles, including the endoplasmic reticulum and mitochondria, intracellular calcium is enriched and required for physiologic cellular metabolism. Complementing the critical intracellular calcium roles, calcium concentration in the extracellular fluid regulates functions of organized tissues at the organ level, including the parathyroid gland, kidney, and thyroid 2. 

Calcium homeostasis

To maintain steady-state concentrations of ionized calcium, the principal endocrine mediators (i.e., PTH, calcitriol and calcitonin) have biologic activities on three target organs; the kidneys, intestines, and skeleton 2,5. PTH governs the minute-to-minute fluctuations of calcium levels; if serum levels are increased, then PTH secretion is downregulated, leading to a net calcium loss through the distal tubules in the kidneys, a reduction in intestinal absorption of calcium, and diminished resorption of osteoclastic bone 2,6. If calcium levels are decreased, increased PTH acts on the distal renal tubules to cause calcium reabsorption and phosphorus excretion, as well as indirectly working on the intestines to increase absorption of calcium and phosphorus. Additionally, PTH will act on skeletal tissues to stimulate the activity of existing osteoblast cells (an early effect), or by increasing the number of osteoclasts and their bone resorption activity (a late effect) 5,7. 

Calcitriol functions to stimulate intestinal calcium absorption, to inhibit PTH synthesis by decreasing PTH mRNA transcription, to promote osteoclastic bone resorption, and by negative feedback on its own synthesis in renal epithelial cells 5. Calcitonin is secreted when stimulated by hypercalcemia, or by ingestion of high calcium meals via enteric secretion of gastrin and cholecystokinin. While it is not a major factor in the minute-to-minute regulation of calcium, it serves as an emergency hormone to reduce serum calcium levels, and plays a vital counterregulatory role if there is rapid increase in concentration. Its primary function is to inhibit osteoclastic bone resorption 8.

Patient evaluation 

The signs of hypercalcemia in cats can be vague, intermittent and non-specific, and often not noted by owners. Overall, anorexia is the most common clinical sign, with vomiting, lethargy, weakness, constipation, polyuria, and polydipsia (PUPD) also often reported 9,10. Some cats may display signs of lower urinary tract disease associated with increased calciuresis and development of calcium oxalate stones 11, hence a possible presentation can be urinary obstruction due to urolithiasis. PUPD is less frequently described in cats than dogs with hypercalcemia, perhaps because the feline species can concentrate urine to a greater degree 3. 

To rule out known causes of hypercalcemia, a methodical clinical approach is necessary (Figure 1), and should include a thorough physical examination, complete blood count, serum biochemistry, urinalysis, measurement of iCa and PTH concentrations, and imaging of the thoracic and abdominal cavities by radiography and ultrasonography, respectively. Supplemental diagnostic tests to establish more comprehensive databases might include the quantification of serum 25-hydroxy-vitamin D, 24,25(OH)₂-vitamin D, calcitriol, and parathyroid hormone-related peptide (PTH-rp) concentrations, as well as more advanced imaging techniques including ultrasonography of the neck to identify suspicious parathyroid nodules or computed tomography (CT) to detect occult neoplasia.

Interpretation of diagnostic tests

• Biochemistry panel and iCa measurement: Elevation of total calcium can be identified on routine screening biochemistry panels, but cannot accurately ascribe contributions from the different forms of calcium. When clinical suspicion is high for dysregulated calcium homeostasis, measurement of iCa levels is indicated and will help confirm if there is true hypercalcemia. In most laboratories, feline hypercalcemia is defined as total calcium greater than 10.8 mg/dL (2.7 mmol/L), or an ionized calcium greater than 5.6 mg/dL (> 1.4 mmol/L) 9. The biochemistry panel is also useful to evaluate renal function and phosphate concentration 3; the latter can often help prioritize potential underlying causes for hypercalcemia, as concurrent elevations in phosphorus levels suggest intrinsic renal failure, vitamin D toxicosis or osteolytic disease 12. 
• Urinalysis: As noted above, cats can be predisposed to calcium oxalate urolith formation with hypercalcemia 11. While secondary nephrogenic diabetes insipidus manifested as primary polyuria with secondary polydipsia is common in hypercalcemic dogs, the urine specific gravity in cats is typically greater than 1.030 and many cats with hypercalcemia can still maximally concentrate their urine, especially if they do not have concurrent chronic kidney disease (CKD) 9. 
• Parathyroid hormone (PTH): Measurement of PTH will help determine if hypercalcemia is parathyroid-dependent or parathyroid-independent in origin, with the majority of cats presenting with the latter. Under normal homeostatic conditions, PTH production from the parathyroid glands will be suppressed in response to hypercalcemia, so if levels are in the upper two-thirds of the reference interval or increased, this supports a diagnosis of parathyroid-dependent hypercalcemia 3. 
• Parathyroid hormone-related peptide (PTH-rp): PTH-rp is an important PTH-like factor that plays a central role in the pathogenesis of humoral hypercalcemia of malignancy (HHM), but it is not strictly a calcium-regulating hormone 13. Measurement of PTH-rp is recommended if malignancy is suspected as the underlying cause of hypercalcemia, although values can be undetectable even if there is neoplasia. As such, this analyte should not be used exclusively to rule out neoplasia as a differential cause for elevated calcium concentrations 3.
• Vitamin D metabolites: Measurement of these metabolites, namely 1,25 dihydroxycholecalciferol (calcitriol) and 25-hydroxyvitamin D₃ (calcidiol) can aid in diagnosing an underlying cause for hypercalcemia across different companion animal populations, given that vitamin D metabolites are chemically identical in all species 14,15. Calcitriol is a measure of the metabolically active form of vitamin D, while calcidiol reflects cholecalciferol ingestion following hydroxylation, and is the major form of circulating vitamin D 3. Iatrogenic hypervitaminosis D toxicity leading to hypercalcemia can be caused by excessive intake of the vitamin via dietary supplements, improperly balanced diets, ingestion of toxic plants or indiscriminate consumption of commercial products containing cholecalciferol or calcitriol analogues. In cats with idiopathic hypercalcemia (IHC), calcidiol concentrations are usually within the reference range, so normal levels of calcitriol and/or calcidiol in a feline patient does not necessarily exclude participation of these metabolites in the pathophysiology of hypercalcemia 9.
• Diagnostic imaging: Imaging of the thoracic and abdominal cavities can help screen for neoplasia or granulomatous lesions; any abnormal mass identified should prompt additional diagnostics, including fine-needle aspirate cytology or biopsy to confirm underlying disease processes (Figure 2). High frequency ultrasound of the cervical region can evaluate for physical abnormalities (irregular shape or size) of the parathyroid glands 16, and can support a diagnosis of parathyroid-dependent hypercalcemia. Soft tissue calcification can occur when the calcium x phosphate product is > 60 mg/dL (3.3 mmol/L), with the kidneys and gastric mucosa the predominant organs to be affected; in such cases pathologic metastatic mineralization may be detected on conventional imaging methods 9. 

Specific causes of hypercalcemia

Feline hypercalcemia can be associated with a variety of pathologies, including cancerous malignancies, renal failure, endocrine imbalances and toxicosis. Interestingly, the broader use of prescription foods or supplements to promote urinary acidification for the prevention of urolithiasis has recently been recognized as an emerging cause of hypercalcemia in cats 11,17. Despite the myriad of causes and clinical symptoms (Figure 3), the most common cause remains idiopathic hypercalcemia (IHC) in many studies, and is the one differential diagnosis unique to cats. Large surveys have identified the top three causes of feline hypercalcemia as:

1. IHC, 
2. chronic kidney disease (CKD), and 
3. malignancy associated diseases. 

Other less common causes are primary hyperparathyroidism, granulomatous disease, hypervitaminosis D and hypoadrenocorticism 9. While the most common cause of hypercalcemia is IHC, this is a diagnosis of exclusion and ideally other differentials should be systematically excluded before accepting IHC as the principal cause of hypercalcemia. 

• Idiopathic hypercalcemia: although IHC is the most common diagnosis, the cause remains unknown. Clinical signs for IHC are often vague or absent, and the diagnosis is likely an incidental finding; some cats may have an increased calcium level for months without any signs noted 18. If signs do develop, these usually involve the gastrointestinal system, potentially manifesting as weight loss, diarrhea, constipation, vomiting, or anorexia. In these patients, the total calcium (biochemistry panel) and iCa levels are elevated, while phosphate, PTH-rp, and vitamin D metabolites levels are within normal reference ranges 3. 
• Chronic kidney disease (CKD): Hypercalcemia can cause kidney damage or develop as a consequence of CKD. As such, ascribing the cause of hypercalcemia as a “cause or effect” in cats with concurrent renal azotemia can be diagnostically challenging. For most cats with early and mid-stage CKD, iCa is normal or low, whilst total calcium is normal or increased 3. This is likely due to increased phosphate concentration along with reduced renal clearance, resulting in the formation of complexes with iCa 19. Serum PTH concentration is often increased in patients with hypercalcemia related to renal failure 2. 
• Malignancy-associated hypercalcemia: neoplasia-associated hypercalcemia is much more common in dogs than in cats; cancer is the underlying cause of calcium disturbances in 1 in 3 hypercalcemic cats, versus 2 in 3 dogs 20. Mechanistically, hypercalcemia is induced by humoral effects of PTH-rp or other resorptive cytokines acting upon bone, kidney, and possibly the intestines 2. Lymphoma and squamous cell carcinoma are the two most common neoplastic causes of feline hypercalcemia (Figure 4), but other tumor types, including multiple myeloma, bronchogenic carcinoma/adenocarcinoma, osteosarcoma, fibrosarcoma, undifferentiated sarcoma, undifferentiated renal carcinoma, anaplastic carcinoma of the lung and diaphragm, and thyroid carcinoma have also been reported 21.
• Hyperparathyroidism: primary hyperparathyroidism is rare in cats and is often associated with an increase in both total and iCa concentrations, increased PTH, decreased phosphate, and normal to increased calcitriol levels 16. Excessive and inappropriate secretion of PTH by the parathyroid glands relative to serum iCa concentration characterizes this condition. Pathologic elevations in calcium can also be associated with secondary hyperparathyroidism (nutritional or renal). The nutritional form is typically associated with a predominantly meat diet that is low in calcium but high in phosphate, resulting in PTH production 3. The renal form develops from decreased renal clearance of phosphate in patients with compromised glomerular filtration, with compensatory stimulation of PTH production. 
• Hypervitaminosis D: Hypervitaminosis D refers to toxicity resulting from excess cholecalciferol (vitamin D₃) and ergocalciferol (vitamin D₂), as well as calcidiol or calcitriol. Reported causes include iatrogenic from excessive dietary supplementation. Other causes include consumption of certain plants such as jessamine (containing glycosides of calcitriol), rodenticides containing cholecalciferol 3, or topical ointments containing vitamin D analogues for the treatment of psoriasis. Calcidiol levels can be normal to increased in hypervitaminosis D cases, depending on the form of vitamin D associated with the intoxication, and PTH concentration will be low due to the elevated calcium and the suppressive effects of calcitriol. In such cases the hypercalcemia can be reversible with early and aggressive therapy which allows time for the calcidiol to be eliminated from the body.
• Granulomatous disease: Although uncommon, granulomatous inflammation is a potential cause of hypercalcemia in cats, resulting from calcitriol synthesis by activated macrophages during inflammation 22. It is normal for macrophages to express 1α-hydroxylase following stimulation with lipopolysaccharide or interferons, and the enzyme is capable of converting 25-hydroxyvitamin D to calcitriol 22. With granulomatous inflammation, macrophage production of 1α-hydroxylase is upregulated, leading to a dysregulated pathologic generation of calcitriol. In cats with granulomatous inflammation 23, infectious organisms responsible for causing hypercalcemia include Cryptococcus neoformans, Blastomyces spp., Histoplasma spp., and atypical Mycobacterium or Actinomyces spp.
• Hypoadrenocorticism: Hypoadrenocorticism (Addison’s disease) is rare in cats and an unlikely cause of hypercalcemia in the species 24, but it is the second most common cause in dogs. Why the condition causes hypercalcemia is unknown, but it may be associated with increased renal reabsorption of calcium secondary to hypovolemia, the presence of a metabolic acidosis, or increased bone resorption. 

General management of hypercalcemia

Several factors should be considered when developing a treatment plan for affected cats (Table 1), including the degree of hypercalcemia, its rate of development and progressiveness, and the modifying effects of other electrolyte and acid-base disturbances. No single treatment is recommended for the management of all cases, so the underlying cause should be identified and treated accordingly. Supportive therapy is directed at enhancing renal excretion of calcium and preventing calcium resorption from bone. 

Table 1. Treatment options for hypercalcemia in cats.

• Promoting calciuresis: This can be done by vascular volume expansion using intravenous isotonic saline (as it does not contain calcium) along with furosemide (which helps inhibit calcium reabsorption in the loop of Henle). Together they enable safe promotion of calciuresis, but it is vital to ensure treatment does not exacerbate existing perfusion deficiencies, so ensure that the cat is well hydrated before furosemide administration to avoid compromising renal function. It is also important to match the increased volume of urine lost with an increase in fluid volume to prevent dehydration and to help enhance the calciuresis. 
• Glucocorticoids: Glucocorticoids work to reduce bone resorption, decrease intestinal absorption, and increase renal excretion of calcium 3. This is achieved via a myriad of mechanisms, including inhibiting the production of prostaglandins, osteoclast-activating factors and vitamin D. Glucocorticoids can contribute to significant reductions in serum iCa concentration in hypercalcemic patients with lymphoma, apocrine gland adenocarcinoma of the anal sac, multiple myeloma, thymoma, hypoadrenocorticism, hypervitaminosis D or granulomatous disease 2. However, indiscriminate use of glucocorticoids is discouraged in patients where the underlying cause of hypercalcemia remains unknown, as this could confound a definitive diagnosis (lymphoma) or be contraindicated (granulomatous inflammation). 
• Bisphosphonates: Bisphosphonates (e.g., pamidronate, alendronate) work to inhibit bone resorption, exerting their effects by reducing the number and activity of osteoclasts. They will function even where osteoclast numbers are increased as a result of local or humoral mechanisms of osteolysis 25. Oral bisphosphonates are generally used as maintenance therapy after a course of intravenous bisphosphonates, with alendronate reported to be well-tolerated in cats 26.
• Calcitonin: Calcitonin may be useful to treat severe hypercalcemia and should be preferred to glucocorticoids in cases where a diagnosis is not yet identified. Calcitonin can rapidly decrease the magnitude of hypercalcemia, primarily by decreasing the activity and formation of osteoclasts. Even though calcitonin is one of the normal regulators of calcium, its effects are short-lived and requires daily administration, and its use in managing hypercalcemia associated with CKD in cats is not strongly supported 27. However, given its rapid onset, its use in the emergency setting may be appropriate. 
• Dietary change: Dietary change is one of the most important aspects for the long-term management of hypercalcemia in cats. High fiber diets work to bind intestinal calcium, thus reducing its absorption, whilst wet diets can also be help promote diuresis; in addition, they tend to have lower calcium levels than kibble. Renal diets are low in calcium and phosphorus, in addition to being more alkalizing, which can help further promote calciuresis. However, renal diets can have higher calcium to phosphorus ratios due to phosphorus restriction, and recent recommendations have been made to select diets with a Ca:P ratio below 1.4 to 1. Therefore, care should be taken when selecting a renal formula to consider the Ca:P ratio 28. Diets formulated for the management of calcium oxalate urolithiasis may also be considered, since hypercalcemia can promote those types of stones. 

Conclusion

Calcium is an abundant element responsible for normal physiologic and metabolic processes. Biologically active ionized calcium concentrations are very tightly regulated within the body, and alterations can lead to significant and detrimental systemic multi-organ effects. Several pathologies are recognized that can cause dysregulation in feline calcium homeostasis, resulting in hypercalcemia and associated tissue/organ injury, but the most common cause is idiopathic. Although the majority of clinical signs are often non-specific, early detection of the underlying cause is important. Once identified, instituting definitive treatment and supportive management will minimize life-threatening complications and maximize the chances for achieving the most favorable outcome.