Hyperadrenocorticism

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Cushing's syndrome, characterised by pot-bellied appearance, polydipsia and symmetrical alopecia[1]

Canine hyperadrenocorticism (Cushing's syndrome) is a relatively common disease of older dogs characterised by overproduction of cortisol due to underlying neoplasia of the pituitary or adrenal glands[2][3].

There are three dominant causes of canine hyperadrenocorticism, in order of importance:

Differentiating between a pituitary and adrenal tumour is critical at times in order to determine prognosis and response to therapy.

A breed predisposition has been noted in the Miniature Poodle, Dachshund, Boxer, Boston Terrier and Beagle. A familial predisposition is particularly noted in the Dachshund[7].

In rare cases, multiple endocrine diseases may occur, with hyperadrenocorticism coexisting with thyroid carcinoma, pheochromocytoma[8], lymphoma and interstitial cell testicular adenomas[9][10], highlighting the need for vigilance in proper workup of potentially complex multi-organ dysfunction.

The primary hormonal aberration associated with this disease is hypercortisolism[11], but other adrenal-derived hormones are also affected, including progesterone and 17-hydroxyprogesterone[12][13]. The excess production of these hormones has a negative feedback effect on healthy adrenal tissue, resulting in adrenal atrophy of nonneoplastic tissue[14]. Concomitant with these changes are increased insulin resistance[15] and reduced levels of growth hormone and vitamin D levels[16].

It is through this constellation of hormonal aberrations that the majority of subsequent clinical symptoms appear, generally referred to as paraneoplastic syndrome. However, some cases are more perplexing where clinical symptoms are present but diagnostic tests (ACTH stimulation and low-dose dexamethasone suppression test) are normal. These atypical cases (occult hyperadrenocorticism), where sex hormone aberrations are suggested as playing a role in clinical etiology, must be approached more carefully[17].

Hyperadrenocorticism usually presents in dogs as a long history of polyuria, polydipsia, polyphagia, proteinuria[18], hypertension, hepatomegaly, prostatomegaly, clitoral hypertrophy, hormone-responsive dermatosis (alopecia, pyoderma[19], skin atrophy, phlebectasias, comedones, bruising, calcinosis cutis and hyperpigmentation), generalised muscle loss, excessive panting, truncal obesity ('pot-belly' appearance), insulin resistance and secondary diabetes mellitus, recurrent cystitis and a greater risk of thromboembolism (due to platelet hypercoagulability and increased levels of antiphospholipid antibodies and lupus anticoagulants)[20][21] and blindness[22].

A presumptive diagnosis is initially based on clinical signs and supported by blood tests which usually show varying degrees of hypokalemia, hyperphosphatemia[23], hypercholesterolemia, hyponatremia and elevations in fructosamine and liver enzymes such as ALT[24].

Further testing involves adrenal ultrasonography which has some inter-observer variability[25]. However, adrenal gland diameter < 7.4 mm in small dogs and > 10mm in large dogs is usually suspicious[26][27]).

Following these tests, an ACTH stimulation test, a low-dose dexamethasone suppression test and urine cortisol:creatinine ratio[28] are usually performed.

The specificity of the ACTH stimulation test is reasonably high but a negative result should not be used to rule out the diagnosis[29]. The low-dose dexamethasone suppression test is more sensitive but less specific and is useful in differentiating pituitary-dependent from adrenal-dependent hyperadrenocortism in about two thirds of all dogs with hyperadrenocorticism. A positive result on the urine cortisol:creatinine ratio does not help to differentiate hyperadrenocorticism from other diseases although a negative result indicates that hyperadrenocorticism is unlikely[30].

Urine cortisol:creatinine levels are usually significantly elevated in affected dogs. In dogs with pheochromocytoma, there is elevations in urinary catecholamines and metanephrines[31].

Pituitary tumors require CT or MRI imaging to confirm their presence[32], verified by an increase in pituitary height to area of the brain > 0.31[33]. Definitive diagnosis of pituitary tumors requires histological examination of tissue biopsies, which are often performed post-operatively.

A differential diagnosis would include other causes of hormone-responsive dermatoses, diabetes mellitus, hypothyroidism, chronic renal disease and Carney syndrome.

A number of medical options exist for treatment of canine hyperadrenocorticism. These are pharmacological therapies aimed at reducing secretion of glucocorticoids from the adrenal gland or pituitary gland by reducing the activity of these glands. However, the presence of metastatic disease considerably decreases survival time regardless of the choice of medical treatment[34].

  • Mitotane (Lysodren, o,p'-DDD) - is the mainstay drug in many countries[35]. It is cytotoxic drug which causes necrosis of the zona fasciculata and zona reticularis of the adrenal glands[36]. Mitotane is given initially at 50 mg/kg orally once daily. This drug has a narrow therapeutic index and accurate dosing is critical. Treatment is normally stopped when the patient's polydipsia and polyuria abate. Most courses last 5-10 days, and maintenance doses are then given at 25 mg/kg every 7 days. Repeat ACTH-stimulation tests are recommended every 3 months.
  • Trilostane - is a synthetic steroid that inhibits steroid synthesis by blocking 3-beta-hydroxysteroid dehydrogenase. It appears to be well tolerated by dogs with pituitary-dependent hyperadrenocorticism, although sub-clinical hypokalemia is a common side effect of therapy[37]. Commonly given once[38] or twice[39] daily, initially at 2 - 5 mg/kg orally and clinical signs usually abate after about 4 weeks, after which once weekly dosing may be instituted.
  • Ketaconazole - has been used with some efficacy at 5 mg/kg twice daily for 7 days, but has more side effects than teh above two drugs, particularly hepatotoxicity.
  • Bromocriptine[40]

In adrenal-dependent hyperadrenocorticism due to adrenal adenocarcinoma or carcinoma, adrenalectomy is the preferred treatment, but requires surgical expertise[41]. With worsening pituitary dependent hyperadrenocorticism, hypophysectomy may be indicated

Systemic hypertension, hepatobiliary disease[42] and glomerulosclerosis[43] are frequent long-term complications and do not always resolve after treatment of hyperadrenocorticism, resulting in a greater risk of chronic renal disease[44].

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