A diagnostic challenge...

01 February 2010, at 12:00am

Veterinary Practice reports from a seminar on canine hyperadrenocorticism

THE latest series of Dechra Academy CPD events proved to be a great attraction at five venues across the UK. Meeting rooms were filled to capacity as vets and vet nurses gathered to hear Grant Petrie tackle the subject of Canine hyperadrenocorticism (HAC) – a diagnostic challenge

Right from the start, Grant’s message was clear. “We are dealing with dogs that show some clinical signs but that are generally well,” he said. “There is no substitute for thorough history taking, observation and a proper physical examination, because there is no single diagnostic test for Cushing’s syndrome (HAC). We use different tests to confirm a diagnosis.”

In an innovative two-hour presentation, the speaker assumed the role of a dog owner and interacted with the audience as he visited their “practice” with Otto, his 12-year-old miniature Dachshund, each time developing the diagnosis a stage further.

He explained that the clinical signs exhibited by dogs with HAC are caused by the production of excessive amounts of cortisol; and that in 80-85% of cases this is the consequence of over- stimulation of the adrenal glands by a benign ACTH-secreting tumour situated in the pituitary gland. Less commonly – and mainly in larger breeds of dogs – there may be a tumour in the adrenal glands themselves.

Regardless of its cause, over time, a dog suffering from HAC will develop a combination of clinical signs which clients may initially simply associate with the ageing process. These signs are variable in extent and result from the effects of excessive cortisol on target organs leading to gluconeogenesis, lipolysis, protein catabolism, anti- inflammatory responses and immunosuppressive activity. There may also be signs resulting from the physical presence of the tumours themselves. 

Certainly age is a factor and dogs over nine years old are prime candidates for HAC. Some breeds are predisposed to the condition too, including Bichon Frise, Dachshunds, Miniature Poodles and 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, it is often discovered when dogs are presented for other reasons or for routine vaccination.

Presenting signs

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 (owners will worry if their dog stops eating but are generally quite happy if it has what they consider to be a “healthy” appetite). HAC dogs rarely have a poor appetite or vomiting and diarrhoea; panting and muscle weakness are put down as being part of the ageing process.

Polyuria/polydipsia is common in HAC 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 may also report that their dogs are showing signs of poor exercise tolerance, panting, weakness and lethargy. 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 and coat in HAC cases will invariably show classic changes too – non-pruritic alopecia, poor hair re- growth, hyperpigmentation, skin thinning, more prominent blood vessels, and the appearance of keratin plugs, or comedomes. There may be some areas of calcium deposition in the skin too and this so-called “calcinosis cutis” is almost pathognomic for the syndrome. Indeed, calcium deposition can occur in other soft tissues including the kidneys, tracheobronchial tree and the “great” blood vessels.

Initial screening tests

Turning to the question of the routine work-up in suspected cases of HAC, 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 as sick dogs will already have increased “stress hormone” levels anyway.

So in uncomplicated HAC cases, the classic haematologic changes are a “stress leukogram” with a mature neutrophilia, eosinopaenia, lymphopaenia and monocytosis. The red blood cell count is usually normal and there may be 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 ALKP, 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 5% of cases glucosuria may feature. Up to half of HAC 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.

Putting imaging procedures into diagnostic context, Grant Petrie suggested that radiology had modest but limited value, in that the adrenals are usually invisible unless calcified, although generalised osteopaenia and signs of dystrophic calcification could be useful indicators.

Abdominal ultrasound can be useful to help differentiate between pituitary and adrenal forms of HAC. The normal left adrenal gland is peanut-shaped and typically <7.5mm in width, whereas the right adrenal is oval-shaped. 

Confirming the diagnosis

In summary so far then, dogs suspected of having HAC should have an appropriate history, with some compatible physical findings and suspicious clinico-pathologic results. Confirming the diagnosis requires the application of screening adrenocortical function tests and these tests would ideally be both sensitive and specific.

The speaker explained that sensitivity is defined as the proportion of cushingoid dogs with a positive test result (i.e. a highly sensitive test that correctly 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 highly specific test correctly identifies a high proportion of dogs that do not have the disease). However, such an ideal test (with high sensitivity and specificity) does not exist.

“There is no single gold standard test for the diagnosis of hyperadrenocorticism,” he said. “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 likely rule out HAC.

The ACTH response test assesses 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 <450nmol/litre whereas HAC cases stimulate to >600nmol/litre.

It is a useful screening test although a significant number have false negative results. It is the only test to distinguish iatrogenic from spontaneous HAC and it is useful as a baseline test for monitoring responses to medical therapy. However, it does not differentiate pituitary-dependent hyperadrenocorticism (PDH) from a functional adrenal tumour (FAT).

The low dose dexamethasone (DXM) suppression test is based upon the principle that, in normal dogs, administration of a low dose of DXM 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 DXM does not suppress pituitary ACTH. FATs secrete cortisone autonomously, independent of pituitary ACTH, and DXM will, therefore, not suppress cortisol production.

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

The speaker said that the low dose DXM supression test was his preferred initial screening test in that it gives him great confidence in a negative test result and is extremely sensitive if used in appropriate candidates. It is, however, poorly specific and one should not test “sick” patients until the associated illness has been resolved.

Having made a positive diagnosis of HAC, it is sometimes useful when considering the alternatives of medical management or surgery, to differentiate between HAC resulting from PDH and that arising from a FAT.

Adrenal gland ultrasonography is one option. Measurement of endogenous ACTH (eACTH) can be useful but eACTH is labile and the protocol needs to be strictly followed. 

The high dose DXM suppression test is another alternative. 

Management of HAC

At many points during his presentation, Grant stressed the importance of communicating clearly and openly with the owners of potential HAC 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.

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 thrombo-embolism, calcium oxalate urolithiasis and systemic hypertension.

Although surgical management is possible (adrenalectomy for FAT or trans-sphenoidal hypophysectomy for PDH), the majority of cases are managed medically. The veterinary licensed product in the UK is trilostane (Vetoryl, Dechra).

Trilostane competitively inhibits steroid synthesis by blocking 3β- hydroxysteroid dehydrogenase. “The aim is to control serum cortisol levels, not stop cortisol production,” said Grant Petrie.

Starting with a low dose initially, administered with food, the trilostane dose is increased if necessary until a good clinical and biochemical response is achieved.

Normally, metabolic signs of HAC resolve within a month and dermatologic signs improve after about four months, but each case must be assessed on an individual basis.

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