Carmel T. Mooney, MVB, MPhil, PhD, DECVIM-CA, MRCVS
Small Animal Clinical Studies, School of Veterinary Medicine, University College Dublin, Belfield, Dublin, Ireland
Hyperadrenocorticism is a relatively common endocrine disorder in dogs. It is typically associated with inappropriate secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland (pituitary dependent hyperadrenocorticism [PDH]) and less commonly with a primary adrenal disorder (adrenal dependent hyperadrenocorticism [ADH]). By now it has been well described both pathophysiologically and clinically. There are numerous tests that are recommended for diagnosis and differentiation of the site of the lesion and the limitations of test performance in both these areas is well recognised. More recently there has been increasing interest in atypical forms of hyperadrenocorticism and other forms of adrenal hyperfunction. Additionally, with the increasing use of abdominal ultrasound and CT, adrenal masses are often identified without clinical suspicion of hormone dysfunction. Atypical hyperadrenocorticism was a term first used to describe dogs with clinical and clinicopathological signs of hyperadrenocorticism in which both the traditional ACTH stimulation and low dose dexamethasone suppression tests were negative for the disease.1 Others have suggested that the term atypical be replaced by occult. However, this term may be less appropriate as, at least in humans, it is reserved for patients without obvious or typical signs of hyperadrenocorticism.2 Whatever term is used it has been suggested that in such cases there is diversion of the normal adrenocortical pathways for cortisol and aldosterone synthesis into overproduction of cortisol precursors and sex hormones. In support of this, many studies have demonstrated that dogs with both typical and atypical hyperadrenocorticism have elevated concentrations of 17 hydroxyprogesterone, progesterone, corticosterone, androstenedione, oestradiol, testosterone, 11-deoxycortisol and 21-deoxycortisol following ACTH administration. This is not surprising as ACTH stimulates all cortisol precursors in a linear manner and does not imply a role of these hormones in the development of clinical signs. Indeed, elevated concentrations of these hormones are also found in dogs with non-adrenal illness. Generally their increase parallels that seen with cortisol. Their measurement may increase the sensitivity of the ACTH stimulation test for diagnosing hyperadrenocorticism but this is associated with a reduction in specificity. Caution is therefore advised in assessing such hormones for diagnosing hyperadrenocorticism. It is notable that atypical hyperadrenocorticism is rare and only a small number of dogs with hyperadrenocorticism have been reported with both normal ACTH stimulation and low dose dexamethasone suppression test results. If clinical signs are mild, retesting if they progress is recommended. Alternatively other diagnostic tests such as advanced imaging and the urine cortisol:creatinine ratio (UCCR) should be considered.
There are other forms of hyperadrenocorticism that better fit the term atypical disease and include combined PDH and ADH, bilateral adrenal tumours, non-cortisol producing adrenal tumours, food induced hyperadrenocorticism and ectopic ACTH production. Functional pituitary and adrenal tumours have been diagnosed in a small number of dogs.3 Whilst clinical signs of hyperadrenocorticism are typical, the results of tests used to distinguish between PDH and ADH may be confounding. Bilateral adrenal tumours, whilst described in dogs are rare.
It is well known that dogs with classical clinical signs of hyperadrenocorticism caused by adrenal tumours may have unexpectedly low basal and/or minimally stimulated cortisol after ACTH administration occasionally with values at or below the cut-offs traditionally used in the low dose dexamethasone suppression test.4,5 It is in these dogs that measurement of cortisol precursors is most valuable as they remain elevated after ACTH administration in the face of minimal change in cortisol. It is presumed that the cortisol pathway in these animals is no longer intact because of partial or complete deficiencies in the enzymes necessary for cortisol production. Why such dogs maintain clinical signs of cortisol excess is controversial. Most cortisol precursors have limited glucocorticoid effect and other disorders or physiological states associated with elevated concentrations do not give rise to the same clinical signs. It is possible in some animals that total daily production of cortisol is inappropriately high despite a lack of cortisol stimulation after ACTH administration. It is also possible that high circulating concentrations of these hormones displace cortisol from its binding proteins elevating the free and active portion.
Ectopic production of ACTH by a non-pituitary tumour is a well-recognised phenomenon in humans and accounts for up to 15% of all cases of hyperadrenocorticism. It is generally associated with small cell carcinoma of the lungs and less frequently other tumours such as neuroendocrine tumours of pancreatic or gastrointestinal origin and C cell carcinomas of the thyroid gland. Often associated with extreme elevations in cortisol and pronounced clinical signs, administration of corticotropin releasing hormone (CRH) generally does not increase ACTH concentrations. The tumours may be very small and advanced imaging techniques may be necessary for their location. There has been a recent report of probable ectopic ACTH production in a dog.6 Aberrant expression of functional hormone receptors in the adrenal gland may also give rise to hyperadrenocorticism. A recent case report described a dog with clinical signs of hyperadrenocorticism and potential food induced hyperadrenocorticism.7 Based on these two case reports it has now been suggested that hyperadrenocorticism be viewed as being ACTH dependent (PDH and ectopic ACTH production) and ACTH independent (adrenal tumours and food induced).
Hyperfunction of the adrenal gland may also involve mineralocorticoids or catecholamines. Hyperaldosteronism associated with adrenal neoplasia (Conn’s syndrome) in humans is usually associated with hypokalaemia, hypertension and metabolic alkalosis. Conn’s syndrome is more commonly recognised in cats but has occasionally been diagnosed in dogs. It may be related to excess aldosterone production or its precursors and diagnosis requires depiction of their elevation together with reduced renin activity.
Phaeochromocytomas are increasingly recognised in dogs. The majority are unilateral and they are commonly malignant. Clinical signs relate to catecholamine excess but as catecholamine secretion is variable, these signs may be sporadic, unpredictable, intermittent or paroxysmal. Signs typically involve the cardiovascular and neuromuscular systems. Whilst hypertension is considered the cardinal sign, it is only present in approximately 50% of cases. There may be many non-specific signs such as polyuria/polydipsia or signs related to tumour growth. Diagnosis is best made using measurement of urinary free normetanephrine concentration or urinary normetanephrine:creatinine ratio.8 Many case reports have suggested that dogs with phaeochromocytoma potentially have disorders akin to multiple endocrine neoplasia syndromes in humans. However, few have included all the typical manifestations noted in humans and the concurrent involvement of tumours in several endocrine glands simultaneously may be purely coincidental in dogs. Increasingly adrenal masses are found during either abdominal ultrasonography or CT where other non-endocrine diseases are being investigated. Overall the prevalence is between 4 and 9% and they are typically found in older animals.9,10 Tumours >2 cm in size are more likely to be malignant. When found diagnostic investigation should centre on determining whether functional or not.
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