Calcium is an important electrolyte in the body and performs two main functions: maintenance of tooth and bone structure and as an important intracellular second messenger. In the latter role, Ca²⁺ controls many cellular processes including muscle contraction, nerve function, blood coagulation, enzyme activity, cell secretion and cell adhesion. The serum calcium concentration is normally maintained within narrow limits primarily by the combined effects of parathyroid hormone (PTH) and vitamin D. Disruption of normal homeostatic control mechanisms results in the development of hypocalcaemia or hypercalcaemia. This presentation will review normal calcium homeostasis and, using a case-based approach, will discuss the diagnosis and management of patients with calcium disorders.

Calcium Homeostasis

The majority of the calcium contained in the body is in the bone (99%). Most of the non-skeletal calcium resides in the extracellular space. Serum calcium exists in three forms: 50% is ionised (physiologically active form), 45% is protein bound (primarily albumin and to a lesser extent globulin) and 5% is complexed to anions (citrate, bicarbonate, phosphate or lactate).

Serum ionised calcium is regulated within a narrow range that is controlled by two principal hormones: PTH and the active form of vitamin D, calcitriol. PTH, synthesised by the chief cells of the parathyroid gland, acts on the bone to increase resorption and calcium mobilisation. It also works on the kidney to increase calcium reabsorption and decrease phosphorus resorption, and to increase the formation of calcitriol. The net result of PTH secretion is to increase calcium and decrease phosphorus in the serum. Vitamin D is formed from cholesterol precursors in the skin by the action of sunlight. The active form, calcitriol, is formed in the kidney. Vitamin D works primarily on the intestine to increase calcium and phosphorus absorption. The net effect of vitamin D is to increase plasma calcium and phosphorus.

Hypocalcaemia

Hypocalcaemia, defined as a concentration of <2.0 mmol/l in dogs and <1.75 mmol/l in cats, occurs when calcium is lost from the extracellular fluid (ECF) faster than can be replaced by absorption from the intestine or mobilised from the bone. It is the ionised fraction of calcium that is physiologically active, homeostatically regulated and best correlated with clinical signs. Formulas have been proposed to mathematically correct total calcium values for alterations in serum albumin levels. However, they have been shown to be poor predictors of measured ionised calcium. When hypocalcaemia is suspected based on measurement of a total calcium level and/or clinical signs, an ionised calcium level should be measured. Causes of ionised hypocalcaemia (<1.25 mmol/l in dogs and <1.12 mmol/l in cats) are listed in Figure 1.

Figure 1. Causes of hypocalcaemia (ionised).

Clinical signs of hypocalcaemia generally relate to the magnitude and rapidity of the decrease in calcium. Clinical signs are generally related to neuronal irritability and include behavioural changes, abnormal/stiff gait, panting, facial rubbing, muscle spasm/fasciculation, tetany and seizures. Hyperthermia (secondary to increased muscle activity), anorexia, vomiting and diarrhoea have also been reported. In human patients, laryngospasm or bronchospasm have been reported with hypocalcaemia. Severe hypocalcaemia causes cardiac changes including hypotension, bradycardia, arrhythmias and failure to respond to drugs that act through calcium-related mechanisms.

Treatment consists of emergency management of hypocalcaemic tetany as well as diagnosis and management of the underlying disease process. If ionised hypocalcaemia is identified, check serum magnesium and phosphorus levels. Additionally samples should be saved for plasma PTH and vitamin D levels. Acute, symptomatic hypocalcaemia necessitates intravenous calcium therapy. Calcium gluconate is most commonly used at a dose of 0.5-1.5 ml/kg slowly i.v. to effect. Excessively rapid administration can cause bradycardia; therefore an electrocardiogram (ECG) should be monitored during administration.

It is important to remember that serum magnesium levels influence both PTH secretion and action. Mild hypomagnesaemia stimulates PTH secretion, whereas severe hypomagnesaemia and hypermagnesaemia inhibit PTH secretion. Hypomagnesaemia also impairs PTH action at its receptor and causes vitamin D resistance. Hypomagnesaemic hypocalcaemia responds poorly to calcium therapy alone but does respond to magnesium ion repletion.

Hyperphosphataemia may cause hypocalcaemia as a result of calcium precipitation, inhibiting bone resorption and suppression of renal 1-hydroxylation of vitamin D. The phosphorus level should be measured in all hypocalcaemic patients, since administration of calcium to hyperphosphataemic patients may increase calcium precipitation and cause further harm. The hypocalcaemia in hyperphosphataemic patients is treated by lowering the serum phosphorus level.

Hypercalcaemia

Hypercalcaemia occurs when calcium enters the vascular space faster than it can be excreted or sequestered. The normal range of serum calcium levels will vary slightly between laboratories, but hypercalcaemia is commonly defined as a serum total calcium concentration greater than 3.0 mmol/l for dogs and above 2.75 mmol/l for cats. Ionised serum calcium concentrations greater than or equal to 1.5 mmol/l in dogs and greater than or equal to 1.4 mmol/l in cats are considered abnormal.

The most common cause of hypercalcaemia is malignant neoplasia. Neoplastic cells can produce a PTH-related protein (PTHrP) that binds with PTH receptors to cause hypercalcaemia. Neoplasias most commonly associated with hypercalcaemia include lymphosarcoma, apocrine gland adenocarcinoma, thyroid carcinoma, gastrointestinal (GI) or vaginal squamous cell carcinoma. Other causes of hypercalcaemia are listed in Figure 2. The clinical presentation of a hypercalcaemic patient will often reflect the underlying disease process and not the hypercalcaemia itself. Common clinical signs of hypercalcaemia include polyuria, polydipsia, anorexia, dehydration, lethargy, weakness, hypertension, seizures and acute renal failure.

Figure 2. Causes of hypercalcaemia (ionised).

Definitive therapy of hypercalcaemia is correction of the underlying cause. However, many patients will require symptomatic/supportive therapy while the underlying cause is diagnosed and treated. Emergency supportive therapy is indicated if the patient exhibits signs of dehydration, azotaemia, cardiac arrhythmia, weakness or other neurological dysfunction. Intravenous fluid diuresis to correct dehydration and promote calcium excretion should be the initial therapy. Following rehydration, loop diuretics such as furosemide may be added to inhibit calcium reabsorption at the thick ascending loop of Henle. Thiazide diuretics should not be used since they decrease renal calcium excretion.

If fluid diuresis and the administration of loop diuretics fail to control the elevated serum calcium, glucocorticoids may be considered. Glucocorticoids decrease osteoclastic bone resorption, inhibit osteoclast-activating factor, block prostaglandin synthesis and antagonise vitamin D action. However, their effect at lowering calcium is often by inducing remission of lymphosarcoma. Once remission has been achieved, it becomes extremely difficult to definitively diagnose lymphosarcoma. Therefore, avoid glucocorticoid administration until a diagnosis has been made. Bisphosphonates may also be considered for refractory, or non-curable causes of hypercalcaemia. Bisphosphonates lower serum calcium by reducing osteoclast activity and function. Pamidronate has been used in dogs to treat hypercalcaemia secondary to cholecalciferol rodenticide ingestion, congenital hyperparathyroidism and humeral hypercalcaemia of malignancy.