Felipedia

Hypercalcaemia in cats

Aetiology and pathogenesis

Calcium is a second messenger required for many cellular biochemical functions including blood coagulation, muscle contraction, muscle tone, membrane stability, bone formation, liver function, cell cycle functions and nerve conduction. Normal serum calcium is maintained by close regulation of intestinal calcium absorption, renal calcium absorption, and turnover of skeletal calcium through the combined effects of parathyroid hormone (PTH) and cholecalciferol (vitamin D₃).

In cats, hypercalcaemia is defined ass fasting serum total calcium greater than 11.0 mg/dL, or ionised calcium greater than 1.4 nmol/L. In dogs, total calcium levels often are corrected by calculation to adjust for extensive binding to albumin. Similar calculated adjustments are not valid in cats.

Humoral hypercalcaemia of malignancy (HHM) is a common cause of persistent pathological hypercalcaemia in cats. The principle source of calcium in HHM is osteoclastic bone resorption, although increased renal tubular resorption and intestinal absorption can also contribute. The majority of cases result from the production of humoral factors by tumour cells that stimulate bone resorption at sites distant from the primary tumour. These humoral factors include PTH, a PTH-related peptide (PTH-rp), 1,25-dihydroxyvitamin D, prostaglandins, osteoclast activating factors, transforming growth factors, and a series of cytokines (IL-1, IL-4, IL-6, TNF-alpha and TNF-ß), also called osteoclast activating factos. Cytokine mediated direct stimulation of bone resorption adjacent to bone metastases is a less common mechanism of HHM.

Recent validation of an assay to measure PTH-rp in cats demonstrates that PTH-rp is a cause of HHM in cats. PTH-rp binds to the N-terminus of PTH receptors in bone and kidneys, and through mimicking the action of PTH, causes bone resorption and increased renal reabsorption of calcium. The most common cause of HHM is synthesis of PTH-rp by tumour cells. Cytokines cause hypercalcaemia by several different mechanisms including their synergistic/additive properties to the actions of PTH-rp on osteoclast function, and through induction of local bone resorption by haematopoietic neoplasia such as multiple myeloma or metastatic carcinoma.

Pathophysiology and clinical signs

Prolonged hypercalcaemia can affect many organ systems adversely. Mechanisms for development of these clinical signs are related to the function of calcium as a messenger necessary for multiple cellular functions. Clinical signs can vary greatly from patient to patient, from the asymptomatic patient diagnosed incidentally on routine biochemistry screening to the patient experiencing dysfunction or even failure of multiple organ systems.

Abnormal renal function accompanies hypercalcaemia frequently as a result of functional and structural renal changes. The functional effects usually are reversible, but the structural changes may be permanent. Defective urine concentrating ability and clinical signs of polyuria develop as a result of acquired, but reversible, inability of renal tubular cells and collecting ducts to respond to antidiuretic hormone (ADH), and secondary reduction in cyclic adenosine monophosphate (cAMP). These changes contribute to the development of compensatory polydipsia. Basement membrane, tubular, interstitial and even mitochondrial, renal tissue mineralisation are structural changes that may occur and contribute to impaired concentrating ability and progression to renal cell death. Azotemia results from a combination of prerenal and renal factors. Vomiting and polyuria cause volume contraction and the development of prerenal azotemia. Renal azotemia results from hypercalcaemia-induced renal vasoconstriction and decreased glomerular filtration rate. Sustained renal vasoconstriction and progressive nephrocalcinosis may lead to ischaemic tubular injury promoting the development of structural changes that further worsen renal function. Sustained hypercalcaemia ultimately can lead to irreversible kidney damage.

Hypercalcaemia also has adverse effects on other body tissues including the peripheral and central nervous systems and all muscle tissues, including skeletal, smooth, and cardiac. Decreased cell membrane permeability and excitability in nervous and muscle tissue can result in listlessness, depression, weakness, inappetence and decreased activity. Involuntary movements such as twitching, shivering and even seizures are a result of possible cerebral microthrombi, cerebral vasospasm, and interference with protective mechanisms within the brain to prevent seizures.

The effects of hypercalcaemia on gastrointestinal smooth muscle, parietal cells, and the pancreas can result in inappetence, vomiting, constipation, gastroduodenal ulceration, and pancreatitis. Calcium is an important regulator of the excitation-contraction coupling of heart and of smooth muscle tone in peripheral vessels. Cardiac arrhythmias can develop from direct effects of calcium resulting from rapid mineralisation of cardiac tissue and elevated catecholamine levels. Hypertension is recognised in human beings but has not been recognised in small animal patients.

Differential diagnosis

The most common differential diagnosis of hypercalcaemia in cats is HHM, primary hyperparathyroidism, and chronic kidney disease. Other reported causes that are less common include granulomatous disease, vitamin D intoxication, hypoadrenocorticism, rodenticide ingestion or plant ingestion (Cestrus diurnum [day blooming jessamine]; Solanum malacoxylon, and Trisetum flavescens). Interestingly, a significant number of cats have been diagnosed with mild to moderate hypercalcaemia for which no underlying cause apparently exists and subsequently is called idiopathic hypercalcaemia.

Hypercalcaemia of malignancy in cats has been reported with lymphoma, multiple myeloma, SCC, undifferentiated carcinoma, thyroid carcinoma, parathyroid adenoma/adenocarcinoma, bronchogenic carcinoma, myeloproliferative disease, myelosiderosis, erythroleukemia, aleukemic leukemia, osteosarcoma, fibrosarcoma, and lymphocytic leukemia.

Laboratory error is also a common cause of hypercalcaemia. In patients without clinical or physical examination findings consistent with hypercalcaemia, repeated blood sampling for re-evaluation of calcium levels is recommended.

Diagnosis

A thorough physical examination including peripheral lymph node palpation, oral examination, mammary chain palpation, thyroid (ventral cervical) palpation, abdominal palpation and skeletal palpation is likely to provide valuable information to help determine the cause of hypercalcaemia.

Ionised calcium values may be helpful to differentiate renal hypercalcaemia from other causes of hypercalcaemia. Hypercalcaemia of malignancy most often is associated with increased ionised calcium, whereas ionised calcium typically is normal or decreased in cases of chronic kidney disease.

PTH levels and PTH-rp levels as determined by immunoassay can be valuable in determination of the cause of hypercalcaemia. These assays have been validated recently for use in cats and should be evaluated in concert with ionised calcium. Increased PTH-rp has been reported in animals with chronic kidney disease and no evidence of malignancy.

Treatment

Intravenous therapy is employed commonly. Calciuresis is promoted by expansion of extracellular fluid volume and increased glomerular filtration rate.

Furosemide (2 - 4 mg/kg PO, SQ or IV q 8-12 hrs) interferes with renal calcium reabsorption. This effect is related directly to the amount of sodium delivered to the kidney, which makes volume expansion with saline before treating with diuretics essential. Thiazide diuretics should never be used because they enhance calcium reabsorption in the distal tubule and may exacerbate hypercalcaemia.

Glucocorticoids reduce calcium by inhibiting osteoclast bone resorption and by inhibiting vitamin-D-mediated intestinal absorption of calcium while increasing renal excretion of calcium. Because glucocorticoids may cause rapid reduction of tumour volume in cases of lymphoma, they should be withheld until the diagnosis is confirmed.

Biphosphonates (etidronate 5-20 mg/kg/day SQ) inhibit osteoclastic bone resorption, retard deposition of hydroxyapatite in bone collagen, increase unmineralized osteoid, and inhibit formation of calcium phosphate crystals. Salmon calcitonin (4-6 IU/kg IM q 12hrs) inhibits osteoclastic bone resorption and increases renal calcium excretion. Other benefits of calcitonin include analgesic properties, rapidity of action, and low risk of toxicity (anorexia, vomiting and diarrhoea). Disadvantages of calcitonin use include cost, unpredictability of action, and drug resistance. Resistance can be delayed with co-administration of glucocorticoids or discontinuation for 24-48 hrs.

Plicamycin (mithramycin 25ug/kg IV in dextrose 5% in water over 2 - 4hrs) can be given as often as one or two times weekly. This drug inhibits osteoclastic bone resorption and decreases bone turnover. Response typically is seen within 24-48 hrs of administration and effects may last 3-7 days. The toxicity profile includes anorexia, vomiting, thrombocytopenia, hepatotoxicity and nephrotoxicity.