Faculty of Universidade Guarulhos, Pompeia Veterinary Hospital Endocrinologist, São Paulo
Hyperadrenocorticism (Cushing's syndrome) is one of the commonest canine endocrinopathies. It's a constellation of clinical findings and biochemical abnormalities caused by chronic overproduction of cortisol by the adrenal cortices. The syndrome can be caused by oversecretion of corticotrophin (ACTH) by a pituitary gland tumor (pituitary-dependent hyperadrenocorticism), cortisol-secreting adrenocortical neoplasia (adrenal-dependent hyperadrenocorticism) and iatrogenic administration of glucocorticoids. Pituitary-dependent hyperadrenocorticism accounts for 80-85% of cases. The excessive secretion of ACTH from pituitary micro or macroadenoma results in bilateral adrenocortical hyperplasia.
Chronic exposure to excess cortisol often results in the development of a classic combination of clinical signs and lesions that can be subtle or dramatic. Among the common signs are: polyphagia, polydipsia, polyuria, abdominal enlargement, alopecia, pyoderma, panting, muscle weakness and lethargy. However, not all dogs with hyperadrenocorticism develop the same signs.
A presumptive diagnosis of hyperadrenocorticism in dogs can be made from clinical signs, physical examination, routine laboratory tests, and diagnostic imaging findings, but the diagnosis must be confirmed by use of pituitary-adrenal function tests. The most common laboratory abnormalities observed in association with HAC include increased serum alkaline phosphatase activity, high serum alanine transferase activity, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, hyposthenuria, mild erythrocytosis and thrombocytosis, as well as a classic stress leukogram.
Screening tests designed to diagnose hyperadrenocorticism include the corticotropin (ACTH) stimulation test, low-dose dexamethasone suppression test, and the urinary cortisol: creatinine ratio. None of these screening tests are perfect, and all are capable of giving false-negative and false-positive test results. Because of the limitation of these diagnostic tests, screening for hyperadrenocorticism must be reserved for dogs in which the disease is strongly suspected on the basis of historical and clinical findings.
The predictive value of a positive screening test result for HAC increases in direct proportion to the number and severity of clinical signs and biochemical changes that develop in this disease.
The primary reason for treating a dog for Cushing's syndrome is to resolve clinical signs. If a dog has no clinical signs, regardless of biochemical test results, Cushing's syndrome does not exist. However, some laboratory abnormalities associated with PDH may pose severe physiologic consequences, and if found, would indicate that treatment is essential. These parameters include systemic hypertension, severe hyperlipidemia, recurrent urinary tract infection, Diabetes mellitus, severe muscular weakness or myotonia, hypercoagulable state.
Current medical treatment of PDH in dogs includes administration of mitotane (o,p'DDD) that destroys the adrenal cortex and administration of corticosteroid synthesis inhibitors such as trilostane, ketoconazole and metyrapone. For surgical treatment, bilateral adrenalectomy and hypophysectomy are performed. However, medical treatment with mitotane and trilostane are more commonly used than surgical therapy because of difficulties in securing adequate equipment and personnel and postoperative treatment.
Mitotane is a useful drug that suppresses excess secretion of cortisol by selective destruction of the cortisol-producing zona fasciculata and reticularis of the adrenal cortex, resulting in resolution of various signs of Hyperadrenocorticism. It has been reported that adverse effects were found in 25% and 31% of dogs during the mitotane induction period and maintenance period, respectively, including anorexia, vomiting, diarrhea, lethargy and ataxia. Iatrogenic adrenocortical insufficiency has also been reported. It's important to know, however, that side effects associated with mitotane should be divided into two categories: those associated to drug intolerance or those secondary to hypocortisolism.
Trilostane in an orally active steroid analogue that acts as a competitive inhibitor of 3 β-hydroxysteroid dehydrogenase, interrupting the synthesis of several steroids, including cortisol. Though there have been many studies documenting the safety and effectiveness of trilostane, there is a lack of consistent dosing protocol and treatment monitoring.
Although there are differences in treatment protocols, side effects and treatment monitoring between mitotane and trilostane, both are effective. It has been reported that there are no significant differences between the survival times for animals treated with mitotane or trilostane.
The choice in treating hyperadrenocorticism with trilostane or mitotane should be based on healthy conditions of the animal, as hepatopathy and phenobarbital therapy impairs mitotane effectiveness; on individual drug tolerance; financial conditions and also, in owner comprehension and education.
Also, medical complications associated to hypercortisolism should be identified and treated together, like hypertension, hyperlipidemia, urinary tract infection and Diabetes mellitus to get a good survive and drug tolerance.
Either mitotane and trilostane could be a safe and effective method of treatment for pituitary-dependent hyperadrenocorticism when the practitioner and client are well educated regarding their use and an appropriate monitoring protocol is used. Frequent clinical, biochemical, hematologic and hormonal monitoring are essential parameters to successful treatment.
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