Hyperadrenocorticism is associated with excessive production or administration of glucocorticoids and is one of the most commonly diagnosed endocrinopathies in the dog.

Aetiology

Hyperadrenocorticism can be spontaneous or iatrogenic. Spontaneously occurring hyperadrenocorticism may be associated with inappropriate secretion of ACTH by the pituitary (pituitary-dependent hyperadrenocorticism) or associated with a primary adrenal disorder (adrenal-dependent hyperadrenocorticism).

Pathophysiology

Pituitary-dependent hyperadrenocorticism accounts for over 80% of dogs with naturally occurring hyperadrenocorticism. Excessive ACTH secretion results in bilateral adrenocortical hyperplasia and increased cortisol secretion.

Adrenal-dependent hyperadrenocorticism accounts for the remaining 15–20% of spontaneous cases of hyperadrenocorticism in dogs and may be caused by unilateral or bilateral adrenocortical tumours, which can be benign or malignant.

Clinical Signs

Any breed of dog can develop hyperadrenocorticism but Poodles, Dachshunds and small terriers appear more at risk at developing pituitary-dependent hyperadrenocorticism. Adrenocortical tumours occur more frequently in larger breeds of dog.

Pituitary-dependent hyperadrenocorticism is usually a disease of the middle-aged to older dog, with a median age of 7–9 years. Dogs with adrenal-dependent hyperadrenocorticism tend to be older, with a median age of 10–11 years. There is no significant difference in sex distribution in pituitary-dependent hyperadrenocorticism; however, female dogs are three times more likely to develop adrenal tumours than males.

Affected dogs usually develop a classic combination of clinical signs associated with increased glucocorticoid levels. Larger breeds of dogs, however, may not show all the classic signs. Hyperadrenocorticism has an insidious onset and is slowly progressive over many months.

Laboratory Findings

The most consistent haematological finding is a stress leucogram with a lymphopenia and eosinopenia. A mild to moderate neutrophilia and monocytosis may be present.

Glucocorticoids, either endogenous or exogenous, induce a specific hepatic isoenzyme of alkaline phosphatase in the dog. The increase in serum alkaline phosphatase is commonly 5–40 times the normal level and is perhaps one of the most reliable indicators of hyperadrenocorticism. Alanine aminotransferase (ALT) is commonly elevated in hyperadrenocorticism, but the increase is usually only mild.

Blood glucose is usually in the high normal range, but about 10% of canine cases will develop overt diabetes mellitus.

Cholesterol and lipid concentrations are usually increased due to glucocorticoid stimulation of lipolysis. Lipaemia is important as it can interfere with the accurate assessment of a number of laboratory parameters.

The specific gravity of the urine is usually < 1.015 and is often hyposthenuric (< 1.010), provided water has not been withheld. Dogs with hyperadrenocorticism can concentrate their urine if water is deprived, but their concentrating ability is usually reduced. Glycosuria is present in the 10% of cases with diabetes mellitus. Urinary tract infection is common and occurs in about half the cases of hyperadrenocorticism. Proteinuria is also common.

Basal thyroxine concentrations are decreased in about 70% of dogs with hyperadrenocorticism. This is, in part, due to inhibition of thyrotrophin-releasing hormone (TRH) and reduced pituitary secretion of thyroid-stimulating hormone (TSH).

Diagnostic Imaging

Radiography. Radiographic examination of the thorax and abdomen is advisable in all cases of suspected or proven hyperadrenocorticism. Although positive diagnostic information is only obtained in the small number of cases in which adrenal enlargement can be detected, radiographs may reveal significant concurrent disease.

Ultrasonography. Abdominal ultrasonography is commonly used to examine the adrenal glands. It is a challenge for the ultrasonographer to consistently distinguish between normal and hyperplastic adrenal glands. However, if both adrenal glands are of similar size and normal shape in a dog with known hyperadrenocorticism, it suggests the disease is pituitary dependent.

Abdominal ultrasonography can also detect adrenocortical tumours. Adrenal masses are diagnosed by the location of the mass and clinical signs exhibited by the animal. There is a propensity for adrenal tumours to invade nearby vessels and surrounding tissues, therefore a thorough ultrasonographic examination of adjacent vessels and tissues should be performed.

CT and MR imaging. Computed tomography (CT) and magnetic resonance (MR) imaging have also proved helpful in the diagnosis of adrenal tumours, adrenal hyperplasia and large pituitary tumours but these techniques are more expensive.

Endocrine Screening Tests

A presumptive diagnosis of hyperadrenocorticism can be made from clinical signs, physical examination, routine laboratory tests, and radiographic findings, but the diagnosis must be confirmed by either ACTH stimulation test or a low-dose dexamethasone suppression test.

Urinary corticoid:creatinine ratio. Evaluation of urinary corticoid:creatinine ratio rather than the more laborious 24-h urinary corticoid excretion has been shown to be a simple and valuable screening test, but lacks specificity.

ACTH stimulation test. The ACTH stimulation test is the best screening test for distinguishing spontaneous from iatrogenic hyperadrenocorticism and reliably identifies more than 50% of dogs with adrenal-dependent hyperadrenocorticism and about 85% of dogs with pituitary-dependent hyperadrenocorticism. It is a simple test to perform and the only one that documents excessive production of glucocorticoids by the adrenal cortex. The information gained also provides a baseline for monitoring therapy.

However, the ACTH stimulation test does not reliably differentiate adrenal-dependent from pituitary-dependent hyperadrenocorticism. It is less sensitive, but more specific than the low-dose dexamethasone test. A diagnosis of hyperadrenocorticism should not by excluded on the basis of a normal ACTH response if the clinical signs are compatible with the disease. Occasionally, an animal under chronic stress may produce an abnormal or equivocal ACTH response result.

Low-Dose Dexamethasone Suppression Test

The low-dose dexamethasone suppression test is more reliable than the ACTH stimulation test in confirming hyperadrenocorticism, since the results are diagnostic in all adrenal-dependent cases and in 90–95% of dogs with pituitary-dependent hyperadrenocorticism. However, it is not as useful as the ACTH stimulation test for the detection of iatrogenic hyperadrenocorticism. It is also affected by more variables, takes eight hours to complete, and does not provide pretreatment information that may aid in monitoring therapy. The low-dose dexamethasone suppression test is more sensitive, but less specific than the ACTH stimulation test. Like the ACTH stimulation, the low-dose dexamethasone test does not reliably differentiate pituitary-dependent from adrenal-dependent hyperadrenocorticism.

Endocrine Tests to Differentiate the Cause of Hyperadrenocorticism

The ability to differentiate between pituitary- and adrenal-dependent hyperadrenocorticism is important in order to provide the most effective treatment for the disease.

Plasma ACTH concentration. The determination of plasma ACTH concentrations in the dog provides a reliable test for differentiating pituitary and adrenal causes of hyperadrenocorticism providing sample handling is meticulous.

Diagnostic imaging. Diagnostic imaging techniques, particularly abdominal ultrasonography, have also proved sensitive in distinguishing animals with pituitary-dependent hyperadrenocorticism from those with adrenocortical tumours.

High-dose dexamethasone suppression test. The high-dose dexamethasone suppression test was the most commonly used test for differentiating the cause of hyperadrenocorticism, but is less accurate than abdominal ultrasonography or plasma ACTH measurements, as approximately 20–30% of pituitary-dependent cases will not suppress with this test.

Treatment of Pituitary-Dependent Hyperadrenocorticism

Trilostane is a synthetic steroid analogue. It is a competitive inhibitor of 3 β-hydroxysteroid dehydrogenase enzyme system and thus interferes with adrenal steroid biosynthesis. Following oral administration in dogs, peak trilostane concentrations are seen in 1.5 h and decrease to baseline values in about 18 h. However, there is considerable individual variability in trilostane concentrations following oral administration due in part to its low water solubility.

Dose: 2 mg/kg daily per os, dosage can be adjusted according to response. Treatment should be monitored using the ACTH stimulation test trying to get the post stimulation cortisol down to below 120 nmol/l starting 2 to 4 after oral administration. In some individuals trilostane may need to be given twice daily.

Trilostane is nearly as effective as mitotane in resolving the signs of hyperadrenocorticism in cases of PDH, however up to 10 per cent of cases with PDH may not respond adequately. Mean survival time is 662 to 900 days.

The prevalence of side-effects with trilostane is generally considered to be lower than with mitotane. In various studies, only 16 per cent of dogs treated with trilostane developed adverse effects that may have been attributable to the drug. This figure compares favourably to those reported with mitotane (25 to 42 per cent).

If failure to respond is regarded as an adverse effect then it is probably the most common adverse effect of trilostane administration. In these cases, an increase in the dose (and/or frequency) or a change to an alternative medication (such as mitotane) is indicated.

Another common side effect is an increase in the size of the adrenal glands and a change in the echotexture. The most serious side effect of trilostane that has been identified to date is acute adrenal necrosis. The development of adrenal necrosis could be due to the hypersecretion of ACTH, which, as well as increasing the size of the adrenals, may also, paradoxically, result in necrosis and haemorrhage of the adrenal glands.

Overdosing with trilostane will result in hypoadrenocorticism. Most cases of hypoadrenocorticism associated with trilostane recover rapidly following temporary cessation of the drug.

Mitotane (op'-DDD; Lysodren) selectively destroys the zona fasciculata and zona reticularis while tending to preserve the zona glomerulosa.

Mitotane therapy should only be considered once the diagnosis of hyperadrenocorticism has been confirmed. Because of its powerful effects, it should never be used empirically.

Initial treatment. Mitotane is given orally at a dose rate of 50 mg/kg/day and should be administered with food. Concomitant glucocorticoid treatment is not advised, although if the dog is being treated at home, the owner should be given a small supply of prednisolone tablets. Daily mitotane therapy should be continued until any adverse effects are noted. The initial course of mitotane is then stopped and the dog put on maintenance therapy (see below). Close monitoring of the patient during this period cannot be over-emphasised.

Mitotane therapy is comparatively safe and the side-effects which commonly occur, for example, anorexia, vomiting, or diarrhoea, are rarely serious providing they are noticed early so that the mitotane can be withheld. The majority of dogs with pituitary-dependent hyperadrenocorticism require between seven and 14 days treatment. In adequately treated cases, the basal and ACTH stimulated serum cortisol concentrations should be below 120 nmol/l.

Maintenance therapy. Having produced sufficient adrenocortical damage with daily mitotane treatment, it is important to continue therapy, albeit at a lower dose. Mitotane is given at a dose of 50 mg/kg/week with food.

Reexamination. Treated dogs should be reexamined 6–8 weeks after completion of the initial therapy, unless there are any problems. Reexamination every 3–6 months thereafter is recommended for the remainder of the animal's life. Relapses and episodes of overdosage do occur, and reassessment of adrenal reserve by ACTH stimulation testing is indicated. The mean survival time of treated dogs is 30 months with a range of a few days to over seven years.

Hypophysectomy has been successfully used for the treatment of pituitary-dependent hyperadrenocorticism in the dog, but the operation is technically difficult.

Treatment of Adrenal-Dependent Hyperadrenocorticism

Dogs diagnosed as having adrenal dependent hyperadrenocorticism carry the best prognosis if the tumour can be removed surgically, although mitotane and trilostane therapy is also recommended.

Unilateral adrenalectomy requires considerable experience and expertise because of the complex anatomy and should only be performed by an experienced surgeon, as perioperative morbidity and mortality is high. Postoperative support is important as the contralateral adrenal cortex will be atrophic. Replacement glucocorticoid therapy may be required for 7–10 days postoperatively. The median survival time is around two years with some dogs surviving for longer than four years.

Mitotane therapy is effective and relatively safe in dogs with adrenal-dependent hyperadrenocorticism. Dogs with adrenal tumours however, tend to be more resistant to mitotane than dogs with pituitary-dependent hyperadrenocorticism. Those dogs requiring higher dose rates tend to be more prone to adverse effects. The median survival time is 11 months with a range of a few weeks to more than five years.

Trilostane therapy has also been shown to be effective in controlling the signs in adrenal-dependent hyperadrenocorticism.