Hypercalcaemia Refresher

 (From http://www.chem4kids.com/files/elements/020_shells.html

(From http://www.chem4kids.com/files/elements/020_shells.html

Basic physiology:

Hypercalcaemia is a common electrolyte disturbance in both cats and dogs. The differential diagnosis list is vast for both species with several options for both acute and chronic causes. 

Three forms of circulating calcium exist:

  • Ionised/free (biologically active)
  • Protein-bound
  • Complexed (to phosphate, bicarbonate, lactate, citrate and oxalate)

From a clinical standpoint, the ionised form is the most useful. Ideally it should be used to help guide treatment in these patients as it is considered to indicate functional calcium levels. 

Calcium regulation is complex and divided into both short-term/minute-to-minute control and long-term control. Parathyroid hormone (PTH) is synthesised in and secreted from the parathyroid glands in response to hypocalcaemia or low levels of calcitriol. PTH is secreted constantly to help maintain tight calcium control. It acts to increase calcium via increased tubular resorption in the kidneys; increased osteoclastic bone resorption; and increased calcitriol. 

Unlike humans, dogs and cats cannot synthesise vitamin D and require it in their diet. Vitamin D levels are inherently tied to calcium levels. Small animal veterinarians are seeing more frequent cases of vitamin D toxicosis related to ingestion of multivitamin supplements. Once ingested, vitamin D is converted to calcidiol in the liver and further converted to calcitriol in the kidneys. Calcitriol acts to:

  • Increase absorption of calcium in the intestines
  • Increase healthy bone formation
  • Promote renal calcium and phosphorus resorption
  • Inhibit PTH synthesis in the parathyroid gland 

As previously discussed, ionised calcium is the preferred parameter for interpretation in animals suspected of being hypo- or hypercalcaemic. Total calcium is often more available for many veterinarians. However in a sick patient, this parameter is often a sub-optimal indicator of ionised calcium. Formulae to convert total calcium into ionised calcium have been recommended in the past. However they are no longer considered valid and reliable. 

Clinical signs:

Common clinical signs of hypercalcaemia include polyuria/polydipsia (more common in dogs), anorexia, constipation, lethargy and weakness.
In severely affected animals, neurological signs including obtundation, twitching and seizures are possible but rare.
Cardiac abnormalities including certain bradydysrhythmias (especially atrioventricular block) are possible but also not commonly seen.

Clinical hypercalcaemia is diagnosed by measured ionised hypercalcaemia (> 5-6 mg/dl or 1.4-1.5 mmol/l) in the face of suitable clinical signs.

Causes:

Hypercalcaemia causes table.png

The most common cause of hypercalcaemia in dogs is neoplasia with lymphoma being the most common followed by apocrine anal gland adenocarcinoma.

In cats the idiopathic form is most common followed by renal failure and neoplasia.

Lymphoma is believed to cause hypercalcaemia due to release of PTHrp which acts in a similar way to PTH. There is an assay which can be used to measured PTH and PTHrp levels in dogs to help differentiate hypercalcaemia of malignancy from non-neoplastic causes.

Treatment:

Acute therapy for hypercalcaemia usually includes:

  • Diuresis with intravenous fluids and diuretics
  • Glucocorticoids
  • Bisphosphonates
  • Calcitonin

The fluid of choice is 0.9% sodium chloride (NaCl, ‘normal’saline). Sodium competes with calcium in the renal tubules allowing increased calcium loss into the urine. A typical fluid rate would be 1.5-2 times the patient’s maintenance fluid rate.

In additional to fluids, loop diuretics like furosemide can be used although they may need to be used cautiously in azotaemic animals. Furosemide given as a continuous rate infusion may promote more rapid diuresis and less potassium loss versus intermittent bolus administration. Thiazide diuretics are contraindicated as they promote calcium retention.

Glucocorticoids reduce bone resorption and intestinal calcium resorption and increase renal excretion. They need to be used cautiously in the absence of a definitive diagnosis as they may impede accurate diagnosis of certain types of neoplasia, especially lymphoma and multiple myeloma.

Calcitonin can act rapidly to reduce calcium levels, sometimes causing a profound hypocalcaemia. In certain countries the cost of this agent is preclusively expensive. Furthermore, the patient can grow tolerant to its affects reducing its utility for long-term calcium control.

In contrast to calcitonin, bisphosphonates take longer to reduce calcium levels (typically 2-3 days) but can have long-lasting effects (1-3 weeks). Pamidronate is the most common bisphosphonate used in veterinary medicine. It does need to be used carefully in dehydrated patients or those who are azotaemic as there are reports of nephrotoxicity in people – although this is usually seen when the drug is administered rapidly over a 1-2 hour period. Oral forms of bisphosphonate (alendronate) offer another long-term solution albeit it can cause gastrointestinal side-effects in some patients.

Hypercalcaemia treatment table.png