Investigation and Management of Hypercalcaemia

Investigation and Management of Hypercalcaemia

The Webinar Vet

Thursday 19th April 2018

James WarlandMA VetMBDipECVIM-CA MRCVS

EBVS European Specialist & RCVS Recognised Specialist in Small Animal Internal Medicine

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Learning Objectives:

• Recognition of clinical signs associated with hypercalcaemia in dogs and cats
• Appropriate and logical investigation of the hypercalcaemic patient
• Interpretation of further testing results
• Emergency treatment of hypercalcaemia
• Medical management of common causes of hypercalcaemia

Introduction & Normal Homeostasis

Disorders of calcium homeostasis are an important presenting complaint for the small animal practitioner to be familiar with, both because of the frequent requirement for urgent treatment and the diagnostic leads that can be provided by the finding.

Calcium concentration is very tightly regulated in the circulation, and is found in 3 forms – ionised (~50%), protein bound (~40%) and chelated (complexed with bicarbonate, lactate, citrate) (~10%). The ionised calcium is the physiologically active form, and is the form tightly regulated by the body, but most measurements of calcium will be of a total concentration. Therefore, total & ionised calcium concentrations will be influenced by various factors, including protein concentrations (particularly albumin), acid-base status, and the presence of chelators.

Calcium is the most abundant mineral element in the body, owing to large quantities stored in bone. It is required for a diverse range of cellular processes, including nerve conduction, muscle contraction, blood coagulation and others. Skeletal bone acts as a reservoir for maintaining calcium homeostasis within the body; appropriate absorption of calcium is controlled in the small intestine and the amount of excretion is controlled via the kidney. These processes are carefully controlled via 3 hormones

• Parathyroid hormone (PTH) – produced by the parathyroid glands in response to low calcium concentration, this will increase calcium concentrations.
• Vitamin D – obtained through the diet and activated via the liver and kidneys to an active form, vitamin D increases calcium concentrations.
• Calcitonin – produced by the thyroid gland to decrease calcium concentration. Calcitonin excess/deficiency is rarely implicated in disease.

Clinical Features of Hypercalcaemia in Dogs & Cats

Clinical signs of hypercalcaemia relate to the diverse roles of calcium in the body, particularly the neuromuscular, renal and gastrointestinal systems.

In dogs the most common clinical sign is polyuria (and consequent polydipsia) due to the inhibition of antidiuretic hormone (ADH) in the kidney. Urolithiasis can develop as a consequence of the calcium dysregulation, and can be the primary presenting complaint. The neuromuscular effects lead to non-specific signs, including lethargy, exercise intolerance and weakness; some dogs will show muscle twitching. Inappetance/anorexia is a common feature, and some animals will show other GI signs, including vomiting and weight loss.

In cats, clinical signs are typically similar although often less specific, with PUPD being much less common, and most cats with hypercalcaemia presenting with non-specific lethargy, anorexia/inappetance and weakness.

Of course, many animals will present with clinical signs related to the primary cause of the hypercalcaemia, such as lymphadenopathy, dyspnoea/pleural effusion (mediastinal mass) or anal sac mass. These will be discussed further during discussion of differential diagnosis and investigation.

Diagnostic Approach to Hypercalcaemia

Ionised vs Total Hypercalcaemia

Ionised calcium is the biologically active form of calcium, and represents the form that is of concern when elevated. However, most biochemistry analysers will routinely measure total calcium. Ionized calcium requires careful handling and, if being performed at an external laboratory, it is important to discuss appropriate handling with the lab.

Calcium measurement must be performed on serum samples. Anticoagulants such as EDTA or citrate will chelate calcium and cause markedly inaccurate measurements.

Due to the effect of protein binding, total calcium measurement must always be interpreted alongside albumin/protein concentrations; in the circumstance of hypercalcaemia, only severe hyperproteinemia is likely to cause the recording of significant total hypercalcaemia, but clinicians should be mindful of severe hypoproteinemia masking hypercalcaemia.

Ideally ionised calcium should be measured in all cases to quantify the significance of hypercalcaemia. Correction formulas for estimating ionised calcium using the total calcium are unreliable.

Signalment & History

Age should be considered when investigating hypercalcaemia as it will affect the relative prevalence of different diseases. Mild hypercalcaemia is considered normal in young animals.

Breed predispositions exist to many conditions, although the author would advise caution about jumping to premature conclusions with regard to the cause of hypercalcaemia. Of particular note, the Keeshond has been reported to be at markedly increased risk of hyperparathyroidism. English cocker spaniels are at increased risk of anal sac adenocarcinoma.

History of toxicity should be investigated through careful questioning of owners. Occasional episodes of vitamin D contamination of commercial pet food are reported1, and should be considered, particularly if multiple cases are seen receiving the same diet.

Physical Examination

A detailed clinical examination is a vital part of investigation of hypercalcaemia, and the finding of this abnormality on a biochemistry profile should prompt the clinician to review their routine examination, with particular focus on lymph nodes, rectal examination (anal sacs) and the ventral neck (parathyroid mass). Fine needle aspirates should be considered from any abnormal masses, as many different neoplastic/granulomatous causes of hypercalcaemia have been reported.

Further Biochemical Testing

The results of routine biochemistry testing frequently provide clues to the cause of hypercalcaemia. Other electrolytes should be carefully examined; hyperkalaemia/hyponatraemia should increase suspicion of hypoadrenocorticism, but in some cases no electrolyte abnormalities are seen.

Parathyroid hormone causes the reduction of serum phosphate concentrations, so this is typically low/low-normal in dogs with hyperparathyroidism, or when hypercalcaemia is driven by a similar mechanism, such as PTH-rp (malignancy). On the other hand, in vitamin D toxicosis, phosphate will be elevated, and when renal disease is driving hypercalcaemia, phosphate is typically elevated due to reduced excretion. Hypercalcaemia in renal disease is complex and phosphate will not always be elevated, particularly in cats.

Azotaemia (elevated urea and creatinine) is also consistent with renal disease, but pre-renal azotaemia can be seen in many cases, given the polyuria and consequent dehydration that can occur. It is important to remember that the polyuria seen with hypercalcaemia will leadto low urine specific gravity (USG), meaning that this measure cannot be used to differentiate pre-renal from renal azotaemia. Typically USG will be <1.020 in hypercalcemic animals. This effect seems to be less clear in cats.

Primary Hyperparathyroidism / Malignancy / Hypervitaminosis D / Chronic Kidney Disease / Hypoadrenocorticism
Calcium / Increased / Increased / Increased / Increased, Decreased, Normal / Increased or Normal
Ionised Calcium / Increased / Increased / Increased / Increased (especially cats), Decreased, Normal / Increased or Normal
Phosphate / Decreased/Normal / Decreased/Normal / Increased / Increased or Normal / Increased or Normal
PTH / Increased/ Reference Range / Decreased/Lower Reference Range / Decreased / Increased or Normal / Normal or Decreased
PTH-rp / Normal / Normal or Increased / Normal / Normal / Normal

Hypoadrenocorticism should be ruled out if signs are consistent or an alternative diagnosis is not quickly established. Basal cortisol can be used to rule out (but not confirm) Addison’s disease; ACTH stimulation test will confirm the diagnosis. Hypercalcaemia is reported in about 30% of cases of hypoadrenocorticism, although is usually mild, and can occur in so called ‘atypical hypoadrenocorticism’, presenting with normal sodium and potassium concentrations2.

Diagnostic Imaging

In the absence of causes being identified from physical examination, the author would recommend pursuing diagnostic imaging of the thorax and abdomen, particularly looking for neoplasia. Mediastinal masses, including lymphoma and thymoma are frequent causes of hypercalcaemia, and many animals will not show respiratory signs. Ultrasound can be helpful to look for abdominal masses, adrenal size, gastrointestinal thickening and visualise the kidneys.

Parathyroid Hormone (PTH)

PTH is labile and therefore careful handling is required; the sample should be taken into EDTA, followed by including immediate separation and freezing of the plasma. It is vital that PTH is measured with a paired calcium measurement (preferably ionised) to aid interpretation. In the presence of hypercalcaemia, PTH should be suppressed, meaning that the finding of mid-normal to high PTH in the presence of hypercalcaemia confirms hyperparathyroidism. In a large cohort of dogs with hyperparathyroidism, 73% had a PTH measurement within the reference range, and many of these were in the lower half, although not necessarily paired with calcium measurement3

Hyperparathyroidism can occur as a primary condition, due to autonomous secretion from a parathyroid adenoma or carcinoma, or can be secondary to renal disease. Dietarydeficiencies (low vitamin D/calcium diet) and adrenal disease (hyperadrenocorticism)can also cause secondary hyperparathyroidism, although these will not typically cause an elevated calcium concentration.

Parathyroid Hormone - Related Peptide (PTH-rp)

Important in fetaldevelopment, PTH-rpconcentration is very low in normal adult animals. It is a major cause of hypercalcaemia in malignancy, with production by tumour cells essentially causing a similar effect to PTH. Elevated PTH-rp should prompt a detailed search for occult neoplasia. In some cases of hypercalcaemia related to malignancy, the PTH-rp will not be abnormal, so a normal PTH-rp cannot rule out neoplasia. Sample handling is as for PTH, and many laboratories will perform these tests together.

Vitamin D

Vitamin D measurement can be valuable in some cases where a diagnosis has not been reached via other testing. It is worth testing both 25(OH)D & 1,25(OH)2D as different forms will be elevated in different conditions. Unfortunately, due to the complex interactions of PTH and calcium on vitamin D concentrations, and endogenous production from, for example, macrophages in granulomatous disease, elevated vitamin D does not simply indicate toxicity and can be seen several conditions, includinghyperparathyroidism or malignancy.

Other Testing

Depending on the clinical picture, further testing may be indicated, including serum protein electrophoresis (multiple myeloma), biopsy of bone marrow or other organs, Angiostrongylus testing (serum ELISA; faecal testing) or ultrasound of the neck.

Treatment of Hypercalcaemia

Treatment of the underlying cause should always be considered the most effective way to treat hypercalcaemia. Prior to achieving a definitive diagnosis, or in some cases to lower hypercalcaemia of a known cause (e.g. toxicity, malignancy, idiopathic), treatment may be necessary to lower the risk of renal injury or improve the animal’s clinical picture.In cases of mild hypercalcaemia, with mild clinical signs, no specific treatment is necessary, but rather the focus should be on confirming that the finding is persistent, and then pursuing a diagnosis. A recent review of treatment options may be of interest to readers4.

Emergency Management of Hypercalcaemia

In cases that are severely clinically affected and/or the calcium is markedly elevated (>3.5-4.0 mmol/l; ref. tCa 2.0-3.0) then emergency treatment should be considered to reduce the calcium. This will improve the animal’s attitude and may assist with feeding, and reduce the risk of adverse renal effects from hypercalcaemia. Traditionally, calcium x phosphorus product has been used to assist in predicting animals requiring aggressive therapy, with the rationale that the product is predictive of soft tissue mineralisation. To the author’s knowledge, the evidence for this calculation is very limited, but animals with hyperphosphataemia and hypercalcaemiamay be more clinically affected. Where possible, erring on the side of caution with early intervention is likely to be beneficial, and predicting renal injury is difficult.

Generally, dogs with primary hyperparathyroidism present with insidious onset disease, and be systemically well, meaning that emergency therapy is not necessary unless the calcium is markedly elevated. On the other hand, dogs with malignancy or hypervitaminosis D are frequently much more severely affected and treatment will be necessary.

Fluid therapy is the mainstay of emergency treatment for hypercalcaemia, with the aim of inducing diuresis. 0.9% NaCl is the fluid of choice, and should be given with the aim to correct dehydration and then expand the extracellular fluid to increase glomerular filtration (typically 5-10 ml/kg/hr). Care should be taken not to rapidly alter sodium concentrations, and Hartmann’s (or similar) are also options if hyponatraemia is a concern (e.g. hypoadrenocorticism).

Loop diuretics (e.g. furosemide) can be used to reduce calcium concentrations, but only when the animal is adequately hydrated. Furosemide doses of 1-2mg/kg IV/IM/PO q8-12h are appropriate. Care must be taken to avoid dehydration and hypokalaemia.

Bisphosphonates, acting as osteoclast inhibitors & reducing bone resorption, can also be used to reduce hypercalcaemia. Oral treatment is an option for chronic treatment, but in the acute setting, IV infusions (e.g. pamidronate 1-2mg/kg IV infusion over 2h with 0.9% NaCl) are effective at reducing serum calcium concentrations, although have a delayed onset of activity (24-48h)5. Bisphosphonates are generally well tolerated, but side effects include GI upset, and they are reported to be nephrotoxic; however, use at standard doses appears to be safe.

Glucocorticoids will increase urinary excretion of calcium, decrease gastrointestinal uptake and decrease bone resorption, thus reducing hypercalcaemia. However, these will have profound effects on many neoplastic cells, particularly lymphoma, and can make diagnosis very challenging even after a single dose and a very short period of time. The author would not recommend the use of glucocorticoids until a diagnosis has been reached.

Selected Causes of Hypercalcaemia

It is beyond the scope of this webinar to discuss the management of all different causes of hypercalcaemia in detail, given the variety of different causes, particularly of malignancies. However, a few key considerations for treatment are discussed below.Readers are advised to consult specific texts about management of these cases, such as:

• Ettinger, Feldman & Cote “Textbook of Veterinary Internal Medicine”
• WithrowMacEwen’s“Small Animal Clinical Oncology”
• BSAVA Manuals of Small Animal Oncology or Endocrinology

Primary Hyperparathyroidism (PHPT)

Most dogs with primary hyperparathyroidism are systemically well, and show relatively mild clinical signs, which may be insidious in onset. The disease occurs due to autonomous secretion of PTH by a parathyroid adenoma (rarely carcinoma).Keeshonds are overrepresented and significantly predisposed. Total and ionised calcium are mildly to severely elevated and the diagnosis is confirmed by demonstrating concurrently elevated PTH, with no evidence of another cause. Imaging of the parathyroid glands, using ultrasound, will usually confirm the presence of one, or sometimes more than one, enlarged parathyroid gland(s).

In asymptomatic cases, monitoring is reasonable rather than embarking on definitive treatment, and the disease usually progresses slowly over many months. PHPT associated hypercalcaemia can lead to renal injury, although prediction of which cases will be affected is difficult; the risk generally appears to be low. Around 30% of cases will develop urinary calculi and a similar proportion have urinary tract infections.Treatment of choice is destruction or removal of the affected parathyroid gland(s). This can be achieved through surgical removal, or using ultrasound guided heat or alcohol ablation of the gland. Success depends on the skill of the operator, but is reported to be high (>90%), with a good prognosis. Recurrence can occur, particularly in Keeshonds.

Risks associatedwith treatment include post-operative hypocalcaemia, which can be severe; the author would consider it inappropriate to perform parathyroidectomy/parathyroid ablation techniques in PHPT cases in a hospital without 24 hour care and the ability to monitor calcium levels postoperatively. The nadir is typically at 3-7 days post-surgery and the author would recommend animals remain hospitalised during this time. Animals with high risk of developing hypocalcaemia should be started on vitamin D supplementation 24h before surgery to reduce this complication. There is evidence that animals with the highest pre-surgery ionised calcium values are at the highest risk of developing hypocalcaemia, and dogs with longer duration of disease prior to treatment may also be at higher risk of developing clinically significant hypocalcaemia6.

If instigated, treatment with vitamin D analogues may be required for several weeks after surgery. Treatment must be monitored carefully as over supplementation (and hypervitaminosis D) is possible and can be severe. After discharge, monitoring should be every few days until stable and every few weeks as treatment is gradually weaned.

Initial dosing of calcitriol is 20-40 ng/kg/day or alphacalcidol is 10-30 ng/kg/day. These reach maximum effect after a relatively short period (<4 days) and have a relatively short half-life, therefore making them easier to manage than other vitamin D analogues. Doses will need to be titrated to effect for the individual animal.

Calcium supplementation can also be used for short term stabilization, but is rarely required long term as vitamin D will allow sufficient absorption of dietary calcium. Intravenous calcium should be used with caution due to risks of extravasation, but is essential in hypocalcaemic crises; diluted calcium borogluconate (0.5-1.0 ml/kg over 20-30 minutes, diluted) is the author’s first choice treatment. Oral calcium can be used to avoid crises (alongside vitamin D); dosing should be on the basis of the elemental calcium within the product (25-50mg/kg/day, split into 2-3 doses). Hypercalcaemic crises are worsened by excitement, stress or activity and these should be avoided wherever possible.

Primary hyperparathyroidism is uncommon in cats, but has been reported and recently reviewed7. In cats a palpable cervical mass is present in the majority of cases, although it should be remembered that a thyroid mass is far more common than a parathyroid mass, if this is detected; hyperthyroidism should always be ruled out and has been reported as a cause of hypercalcaemia in cats.

Renal Disease

Hypercalcaemia associated with renal disease is typically mild, total hypercalcaemia. Ionised calcium is usually low or normal, at least in dogs. Historically this was also reported in cats, but a recent publication has suggested that most hypercalcaemic cats also have elevated ionised calcium8. In this study, around 30% of cats with CKD had elevated tCa.

The mechanism of hypercalcaemia in renal disease is complex, creating these different possible calcium outcomes, and is related to secondary hyperparathyroidism and acidosis;however, diuresis, phosphate retention and reduced vitamin D activation will counteract this effect leading towards hypocalcaemia. Secondary hyperparathyroidism develops secondarily to phosphate retention and hypocalcaemia. Typically, when present,hypercalcaemia in renal disease is mild. Of course, another complicating factor is the risk of inducing renal injury through hypercalcaemia; this may create difficulties in result interpretation.