David Watson reports on a Dechra Academy CPD event, held in Bristol for vets and veterinary nurses on the topic of Canine Cushing's disease. The speaker was Grant Petrie, MA VetMB CertSAC CertSAM MRCVS, principal at the Portman and Bayswater Referral Clinics in London.

The speaker explained that the clinical signs exhibited by dogs with Cushing’s syndrome are caused by the production of excessive amounts of cortisol; and that in 80 to 85 per cent of cases this is the consequence of over-stimulation of the adrenal glands by a benign ACTH- secreting tumour situated in the pituitary gland(Figures 1 and 2). Less commonly – and mainly in larger breeds of dogs – there may be a tumour in the adrenal glands themselves (Figure 3).

Difficult to spot

There is often a low level of owner concern because progressive external signs – such as changes to coat texture – are slow, and polyuria/polydipsia and polyphagia are sometimes perceived as being positive things (Figure 4).

Furthermore, dogs with hyperadreno- corticism (HAC) rarely have a poor appetite or vomiting and diarrhoea; and panting and muscle weakness are put down as being part of the ageing process.

Polyuria/polydipsia is common in Cushing’s cases and often it is the marked increase in the frequency of urination that owners first mention. In nine out of 10 cases, polyphagia is observed, together with scavenging without any other gastro-intestinal disease. The reason for this is unclear, but it may represent a direct effect of the increased glucocorticoid levels.

Owners will also report that their dogs are showing signs of poor exercise tolerance, panting, weakness and lethargy. All these are linked to the underlying protein catabolism which, in turn, leads to muscle wasting. Thus panting is a consequence of weakened respiratory muscles; the increased frequency of ruptured cruciate ligaments, seen in smaller breeds, is the result of reduced joint stability and ligament weakness; and a combination of heavier abdominal contents and weakened abdominal muscles manifests itself as the classical ‘pot’ belly. There may also be some redistribution of fat.

The skin in Cushing’s cases will invariably show classic changes too – non-pruritic alopecia, poor hair re-growth, hyper-pigmentation, thinning, especially of the subcutaneous fat layer, more ‘prominent’ blood vessels, and the appearance of keratin plugs, called comedomes. There may be some areas of calcium deposition in the skin too and this is called ‘calcinosis cutis’. Calcium deposition can occur in other soft tissues including the kidneys, tracheobronchial tree and the ‘great’ blood vessels.

Age and breed factors

Age is a factor and dogs over the age of nine years are prime candidates for HAC. Some breeds are predisposed to the condition too, including Bichon Frise, dachshunds, miniature poodles, Yorkshire terriers and West Highland terriers. Of the larger breeds, boxers and German shepherd dogs feature strongly.

Throughout his talk, Grant emphasised that definitive diagnosis of the syndrome is a real challenge and that to all intents and purposes, certainly in its early stages, one is dealing with a “clinically-well dog”. Indeed HAC is often discovered when dogs are presented for other reasons or for routine vaccination.

Initial screening tests

Turning to the question of the ‘routine work-up’ in suspected cases of Cushing’s syndrome, the speaker reminded his audience that they would be looking for elevated levels of ‘stress hormones’ in clinically normal dogs. Therefore, any concomitant disease should be ruled out first because sick dogs will already have increased ‘stress hormone’ levels anyway.

So in uncomplicated HAC cases, the haematology results reflect a ‘stress leukogram’ with a normal red blood cell count, mature neutrophils, eosinopaenia, lymphopaenia, monocytosis and an increase in the number of platelets.

Serum biochemistry may show mild hyperglycaemia, decreased blood urea, mild increases in ALT. Moderate to marked increases in ALK-P, elevated cholesterol/triglycerides and a mild hypophosphataemia. Electrolyte levels are usually normal.

Urine is usually dilute (SG <1.020) with proteinuria (UPC ratio <5) and in about five per cent of cases glucosuria may feature. Up to half of Cushing’s syndrome cases will have urinary tract infection; so although the sediment may appear to be inactive, this is often the anti-inflammatory effect of the increased steroid levels and it is advisable to culture the urine anyway.

Many dogs with HAC will exhibit some degree of hypertension. Abdominal ultrasound can be useful to help differentiate between pituitary and adrenal forms of HAC. The normal left adrenal gland is peanut-shaped and < 7.5mm in width, whereas the right adrenal is oval.

Confirming the diagnosis

Confirming the diagnosis requires the application of screening adrenocortical function tests and these tests would ideally be both sensitive and specific. Sensitivity is defined as the proportion of Cushingoid dogs with a positive test result (i.e. a test that identifies a high proportion of dogs with the disease) and specificity relates to the number of normal dogs with a negative result (i.e. a test that identifies a high proportion of dogs that do not have the disease). However, such an ideal test does not exist.

“There is no single gold standard test for the diagnosis of hyperadrenocorticism,” said Grant. “But combining tests of differing sensitivities and specificities will improve accuracy. Establish normal ranges for your usual laboratory and never base the diagnosis of HAC solely on endocrine tests.”

The first test – which has good sensitivity but poor specificity – is to determine the urine cortisol:creatinine ratio (UCCR). In order to reduce the effects of stress, this should be performed on home- collected, morning, ‘free-catch’ urine. Levels of >10 x 10-6 are indicative of HAC, while levels below this figure suggest a normal UCCR and likely rule out the condition.

The ACTH response test assesses the adrenal gland reserve in response to a pharmacological dose of ACTH. It is a simple and quick test and, in general, normal dogs stimulate to < 450 nmol/litre whereas HAC cases stimulate to > 600 nmol/litre.

It is a useful screening test but a significant number have false negative results and, although it distinguishes iatrogenic from spontaneous HAC, it does not diffe
rentiate pituitary-dependent hyperadrenocorticism (PDH) from a functional adrenal tumour (FAT).

Perhaps its greatest use is as a baseline test for monitoring responses to medical therapy (Figure 5).

Figure 5: Bichon Frise showing typical signs of Cushing's syndrome

The Low Dose DXM screening test is based upon the principle that in normal dogs administration of a low dose of dexathasone inhibits pituitary ACTH and suppresses cortisol production. Pituitary tumours, however, are resistant to the feedback effects of cortisol – otherwise PDH would not develop – and exogenous dexamethasone does not suppress pituitary ACTH. FATs secrete cortisone autonomously, independent of pituitary ACTH, and dexamethasone will, therefore, not suppress cortisol.

Normal dogs suppress to < 40nmol/litre at three and eight hours. Cortisol levels > 40nmol/litre at eight hours is consistent with Cushing’s syndrome.

The speaker said that the Low Dose DXM test was his preferred initial screening test in that it gives him great confidence in a negative test and is extremely sensitive if used in appropriate candidates. It is, however, poorly specific and should not be used in ‘sick’ patients until the predominating illness has been treated and resolved.

Having made a positive diagnosis of HAC, it is sometimes useful when considering the alternatives of medical management or surgery, to differentiate between Cushing’s syndrome resulting from PDH and that arising from a FAT. This is not easy and involves the use of the Endogenous ACTH test. This is difficult to perform and involves adherence to a very strict and sensitive protocol. The High Dose DXM suppression test may be a better alternative.

Management of Cushing’s syndrome

At many points during his presentation, Grant stressed the importance of communicating clearly and openly with the owners of Cushing’s syndrome dogs. This is particularly important once a positive diagnosis has been made and treatment options are under consideration. All options should be discussed with the owner and dialogue established. There is a wealth of appropriate information to be found online at www.canine-cushings.co.uk.

The decision may be affected by the bias of the clinician, financial considerations, factors in the owner’s lifestyle and a consideration of the benefits versus the risks. If there are no clinical signs, should we treat? Or are there benefits from treating sooner? What are the consequences of not treating the patient? Certainly, HAC has been associated with conditions such as diabetes mellitus, pulmonary thromboembolism, calcium oxalate urolithiasis and systemic hypertension.

Although on the surgical front, adrenalectomy represents a high risk but potential cure for FAT, the only realistic treatment option in the majority of cases is the use of medical therapy. One such approach is the use of trilostane (Vetoryl – Dechra Animal Health).

Trilostane competitively inhibits steroid synthesis by blocking 3β-hydroxysteroid dehydrogenase. “It controls cortisol levels, but does not stop cortisol production" said Grant Petrie. The aim is to use a low dose initially, administered with food, and gradually to build up to an effective therapeutic level.

Normally metabolic signs of Cushing’s syndrome resolve within a month and dermatologic signs improve after about four months, but each case must be assessed on an individual basis (Figure 6).

Figure 6: The same patient following successful medical therapy

It is recommended that the ACTH response test is performed 10-14, 30 and 90 days after initial therapy; and then, once the patient is stable, every three to six months thereafter!

Author

Grant Petrie

MA VetMB CertSAC CertSAM MRCVS

• VOL 25 • No2 • February 2010 • Veterinary Nursing Journal