Canine Addison’s disease: a new treatment option

Canine hypoadrenocorticism (Addison’s disease) is a well-recognised, immune-mediated endocrinopathy that can present with a wide variety of clinical signs, of varying severity.

None of the clinical signs are pathognomonic for the condition, so it needs to be confirmed using laboratory tests. A new formulation of desoxycortone pivalate (DOCP) has been authorised for use in dogs in the EU and this is set to change how this condition is managed in the UK.

The authors, having been involved in a clinical trial with DOCP for the past 10 months, will provide a brief overview of canine hypoadrenocorticism, followed by specific suggestions for managing these cases, based on their experiences to date.

Diagnosis

Clinical signs

Most cases of hypoadrenocorticism are presented with a chronic waxing and waning history of lethargy, failure to thrive and mild gastroenteric symptoms (more commonly vomiting than diarrhoea, but both can be seen). A poor appetite and weight loss are quite common as well.

Some cases – often with a chronic history that has not been investigated – will present as emergencies, with collapse, haemorrhagic gastroenteritis and, sometimes, bradycardia. These cases can, therefore, resemble inflammatory bowel disease, renal failure, parvovirus, obstructing intestinal foreign bodies and many other conditions. A few cases of hypoadrenocorticism will present with just one sign – for example, episodic collapse – which could be misleading for cardiac disease or neurological disease (for example, myasthenia gravis).

A detailed, clear clinical history is the most useful tool in raising awareness of canine hypoadrenocorticism in any given case. The dogs are usually young, more often female and often of a predisposed breed (which in the UK probably includes West Highland white terriers, Rottweilers, great Danes, bearded collies and, above all others, standard poodles (and now labradoodles). However, the condition can be seen in any dog of any age or breed. Some protected dog breeds may exist, such as Yorkshire terriers, golden retrievers and dachshunds.

The most common signs of hypoadrenocorticism are shown in Table 1 and the most common clinicopathological abnormalities in Panel 1, both in approximate order of frequency. It is important to note most cases of hypoadrenocorticism will have electrolyte abnormalities.

Diagnostic tests

As the clinical signs are so vague and many other conditions present with similar signs, diagnostic testing is essential to confirm the diagnosis.

Before considering the diagnosis of hypoadrenocorticism, it is important to know what therapy (including fluid therapy) the dog has recently received and, in particular, whether steroids have been administered. This is important as fluid therapy and steroids may mask expected changes on the routine biochemistry and steroids affect the performance of the adrenocorticotropic hormone (ACTH) stimulation test.

The only test that can be said to confirm the diagnosis of hypoadrenocorticism, and must be performed before starting any specific treatment for this condition, is the ACTH stimulation test. Basal cortisol measurements may be useful as screening tests if ACTH is not readily available; however, the use of basal cortisol measurement can increase the costs to clients and may delay the correct diagnosis if an ACTH stimulation test has to be performed subsequently.

Regardless of the test, it is important the cortisol is measured using a suitably sensitive, specific and reliable assay with which clinicians are familiar. Some variability exists even between reputable laboratories and using the same laboratory regularly is good practice. Once the ACTH stimulation test is completed, then emergency treatment with steroids can be started (whereas this is not possible with basal cortisol).

If a dog is receiving steroids then it is hard to confirm the diagnosis of hypoadrenocorticism, so this situation is best avoided if possible. The duration and dose of such therapy will determine the degree of suppression of the response. Sometimes clinicians are presented with patients with suspected hypoadrenocorticism that have been given a single dose of dexamethasone the previous evening.

In such circumstances, it is prudent to support the animal with fluid therapy for 24 hours before performing an ACTH stimulation test. It is highly unlikely the ACTH stimulation test will be sufficiently suppressed to give a false-positive result for hypoadrenocorticism 36 hours after a single dose of dexamethasone. Prednisolone should not be given during the 24 hours before an ACTH stimulation test as it may cross react with cortisol in the assay. One month of immunosuppressive doses of prednisolone can suppress the hypothalamic-pituitary axis in some dogs for up to one month after cessation of therapy.

Treatment

Emergency treatment

Acute and severe signs of hypoadrenocorticism represent a life-threatening emergency and dogs need to be treated as soon as possible. Therapy aims to correct the hypotension, hypovolaemia, electrolyte imbalances, acidosis and hypoglycaemia. Fluid therapy is the most important part of treatment at this stage. Once the dog is clinically stable, rehydrated and the diagnosis confirmed – but not before – then DOCP and prednisolone may be given.

Before starting therapy

Before starting the DOCP/prednisolone combination, it is important long-term management of hypoadrenocorticism is discussed with owners. It may take several visits and multiple monitoring blood tests to find the right dose of DOCP and a glucocorticoid for each dog.

Furthermore, although properly treated dogs should be happy with a normal appetite, it is important to remember they are not normal dogs. They have a chronic disease and will need lifelong medication and monitoring. Owners should understand the dose of DOCP is adjusted by assessing electrolytes and clinical signs, whereas the glucocorticoid (mainly in the form of prednisolone) dose is adjusted according to the clinical history (they need to be aware their observations matter).

Every dog being treated with DOCP also needs to be given glucocorticoids – prednisolone is the most common and is licensed in dogs. One of the main advantages of using DOCP and prednisolone is the dose of each can be titrated to effect (unlike fludrocortisone, which provides a fixed mineralocorticoid to glucocorticoid ratio) allowing individual treatment regimens for each and every treated dog.

Titrating glucocorticoid treatment

The starting prednisolone dose rate is 0.2mg/kg to 0.4mg/kg every 24 hours by mouth, with larger dogs tending to use the lower end of the dose range. The final dose varies between individual animals and many dogs will ultimately be stable at 0.05mg/kg to 0.1mg/kg every 24 hours by mouth.

For dogs requiring particularly small doses of glucocorticoid, cortisone acetate could be considered as an alternative. Glucocorticoid dose adjustments should be 25% to 50% of the previous dose. Try to wait two weeks to assess the effect.

Glucocorticoid deficiency causes lethargy (which can be severe), inappetence, weakness and gastrointestinal signs. Equally, too much glucocorticoid causes polyuria/polydipsia, poor hair regrowth and increased bodyweight. Too much DOCP can also cause polyuria/polydipsia, so it is important to check electrolytes as well before reducing the dose of prednisolone.

At times of metabolic stress or illness – for example, surgery or other systemic illnesses – the glucocorticoid dose should be increased (two to four times) for the duration of that stress. Psychological stress (such as kennelling) does not normally require increases in glucocorticoid, but where such stress leads to metabolic effects (for example, a dog not eating when in kennels) then small supplements to the normal steroid dose may be beneficial.

Titrating DOCP treatment

The starting dose of DOCP is 2.2mg/kg SC every 25 to 31 days. No adjustment is made for larger dogs. For convenience, the authors prefer to inject cases every 28 days and will adjust the dose to achieve control within that time frame. Most dogs will require dose reductions over time as published evidence would suggest the final dose will lie between 2.5mg/kg and 1mg/kg, with a median dose of about 1.5mg/kg. It is important to resuspend the product properly and inject straight away.

The aim of DOCP treatment should be to maintain the electrolytes within their respective reference ranges (it is important to use the reference range appropriate for the specific assay). Sodium:potassium ratios are of lesser importance and no published evidence suggests dogs with electrolyte concentrations within the reference ranges need a dose adjustment, regardless of their sodium:potassium ratios.

The dose of DOCP is adjusted in 10% to 20% steps, with the aim of achieving electrolytes within their reference ranges at days 10 and 28. The authors regard a dog as stable once the electrolytes are within their reference ranges on days 10 and 28 after two injections of the same dose of DOCP (that is, four electrolyte measurements over a two-month period). Once this has been achieved, the electrolytes are monitored every four to six months as further dose adjustments may be needed as the disease develops in the individual animal.

At a routine check, when DOCP is due to be injected, if the potassium is below and/or sodium is above their respective reference range then DOCP should not be injected and the electrolytes should be reassessed every seven days until they are within their reference ranges, and then the DOCP re-injected at a lower (approximately 20%) dose. The authors recommend a 10-day test after each dose adjustment.

Obviously, if potassium is above and/or sodium is below their respective reference range on a day of injection then DOCP must be injected at a higher dose and, if this happens more than once, consideration should be given to reducing the dosing interval (Panel 2).

Dealing with problems – top tips

As with all newly introduced drugs to a veterinary market, a few problems have been seen. These are listed below for information, but it is important to be aware in countries that have been using DOCP for many years, it is regarded as a safe, flexible and relatively problem-free drug.

• Occasionally, laboratory results do not agree with the clinical picture. It is important to recognise low-level EDTA contamination can have a profound impact on electrolyte results. Over-reliance on one set of electrolyte results to make significant changes in the management should be avoided in favour of repeated electrolyte measurements.
• The new formulation of DOCP is a suspension. It settles quicker than many other suspensions used for injection. It is important to make sure the bottle of DOCP is resuspended properly each and every time.
• If a dog is on a DOCP and prednisolone combination and arrives at an emergency clinic then it is rarely wrong to give steroids.
• In cases of lack of expected efficacy, before increasing the DOCP dose, consider whether the dog was adequately hydrated at injection, the product was adequately resuspended and whether the injection was successfully administered.
• Consider potassium supplementation if the dog is symptomatic and potassium is less than 3mmol/L. The use of an aldosterone antagonist, such as spironolactone, could also be considered – especially if potassium supplementation alone is not effective.
• If dogs are currently being treated with fludrocortisone then see Panel 3 for the protocol for transferring them to the DOCP and prednisolone combinations.

Clinicians can contact Dechra Technical Services or the authors ([email protected]) for support regarding individual cases.