Cushing's and Addison's disease: Testing and management (Proceedings)

Addison's disease and Cushing's syndrome are opposite sides of the same coin. Both are manifestations of dysfunction of the adrenal glands. The adrenals, located right next t o the kidneys (ad-renal), are a pair of glands that secrete several hormones. There are three layers of the adrenals: the zona glomerulosa, zona fasciculata, and zona reticulosa, from exterior to interior. Characteristic hormones from these layers are aldosterone (glomerulosa), which controls sodium balance in the body, cortisol (fasciculate), a major steroid in the body, and sex hormones (reticulosa). The adrenal glands are stimulated to secrete their products by the pituitary via signaling with ACTH.

Addison's disease

The overwhelming majority of cases of Addison's disease (hypoadrenocorticism) are due to a primary failure of the adrenals. While a deficiency of sex hormones aren't often clinically significant in our patients, a deficiency of aldosterone, the product of the zona glomerulosa, and cortisol, a product of the zona fasciculata, can be significant and life threatening. In the absence of aldosterone, sodium and potassium become disregulated, causing hyponatremia and hyperkalemia. In addition to the direct life threatening effects of these electrolyte disorders, volume depletion associated the electrolyte imbalances can cause hypovolemic shock. Absence of cortisol can initially be more subtle: causing malaise, inappetance, and failure to thrive. However, with prolonged cortisol deficiency and stress, weakness, significant gastrointestinal ulceration, and anorexia can result.

Diagnosis

After recognizing the possibility of Addison's disease, diagnosis is straightforward. A basal cortisol level can first be evaluated. If cortisol is greater than 2 ug/dL, it is extremely unlikely Addison's disease is present. Normal dogs can have low basal cortisols as well, therefore, if basal cortisol is low, a supraphysiologic dose of ACTH must be administered and cortisol levels are measured afterwards. If the adrenals are within normal limits, they will respond to the stimulation of the ACTH and the post cortisol level will be increased. In an Addison's patient, the adrenals are incapable of responding to even a supraphysiologic dose and post ACTH cortisol levels will be flat as with the pre level. Salient points of the ACTH stimulation test are listed in table 1.

Table 1: ACTH stimulation test protocol.

Note that synthetic ACTH is preferred product due to variability in ACTH gel products. Dexamethasone administered during a crisis situation will not cross react with the assay. However, long term administration of ANY steroid will blunt the adrenal response.

Treatment

Replacement of glucocorticoids is the hallmark of the management of Addison's disease. Additionally, mineralocorticoid deficiency must be addressed in all dogs with typical Addison's. The most common treatment options for Addison's disease are listed in table 2, along with pro's and con's of each. It should be noted, that a very small minority of dogs treated with DOCP may not need prednisone as listed, however, this is uncommon.

Table 2: Common options for treatment of typical Addison‘s disease.

Prognosis for dogs with typical Addison's disease is excellent if they have committed owners willing to deal with the initial titration phase and vigiliantly monitor their pets.

Cushing's syndrome

Cushing's syndrome is the opposite of Addison's: it is an excess of cortisol. However, other levels of the adrenal cortex are usually not significantly affected, therefore, electrolytes are normal. The excess cortisol is either the result of a functional adrenal tumor (primary Cushing's) or a functional pituitary tumor (secondary Cushing's: pituitaty dependant, or PDH) resulting in an excess of ACTH. This causes bilateral adrenal enlargement in contrast to primary Cushing's syndrome, when only the affected adrenal is enlarged.

Diagnosis

Several options are available for diagnosis of Cushing's syndrome. As with all tests, it is important to test only a suspect population or many false positives will emerge. Normal dogs can have abnormal tests for Cushing's, therefore, only animals showing clinical signs associated with Cushing's should be tested. Clinical signs associated with Cushing's syndrome are: PU/PD, pendulous abdomen, thin skin, "endocrine alopecia", hypertension, polyphagia, and weight gain. The natural response of the body to stress is to increase secretion of cortisol, therefore, in animals with poorly controlled or undiagnosed concurrent illnesses, false positives are common. This also has an impact on the performance of tests: any additional stress such as caging, interaction with other animals, or simply presence at the veterinary facility may cause cortisol secretion, confusing the interpretation of the results. It is for this reason that animals undergoing testing for Cushing's syndrome be as comfortable and stress free as possible.

Table 3: Testing options for diagnosis of Cushing‘s syndrome.

Tests are listed in order of increasing sensitivity, but decreasing specificity.

Treatment

Adrenal tumors

Preferred treatment of adrenal tumors is resection. However, some masses are intimately associated with major vessels and can be difficult to remove. Additionally, postoperative care can be difficult depending on the patient's pre-operative status.

Pituitary dependant hyperadrenocorticism

In the human population, pituitary tumors of acceptable size and location are removed surgically through the nasal cavity. This is performed at some institutions in Europe and is being investigated via endoscopic removal at some institutions in the United States. However, medical therapy is much more widely available.

Historically, mitotane (Lysodren) has been the mainstay of treatment. This drug is a chemotherapeutic agent that selectively destroys zona fasciculate and zona reticulosa of the adrenal cortex. This would seem to be an ideal treatment as loss of sex hormones (product of zona reticulosa) is not usually clinically significant in our patients. This would mean only the excessively functioning layer is affected. However, at increased doses, the zona glomerulosa is affected as well, leading to the production of a dog with Addison's disease and all the physiologic disturbances associated with that disease. It is therefore vital that daily communication between the veterinary staff and owner regarding the dog's well being occur during induction and the initial stages of treatment with this drug. Once adequate control is achieved, maintenance therapy is instituted. Continued monitoring with ACTH stimulation assays is essential.

More recently, the use of trilostane (Vetoryl) has been introduced to the United States. In contrast to mitotane, the adrenal cortical tissue is spared during treatment with trilostane. Trilostane inhibits synthesis of cortisol, therefore, while the adrenal tissue is still functional, a "blockade" is formed in the synthesis pathway and functional product is not secreted. It is more attractive in that it is more difficult to induce an Addisonian state, though it has been reported, and the effects are more rapidly reversed in the event of an overdose.

Monitoring of clinical signs and objective criteria are imperative during treatment with both of these options. Specific protocols for treatment as well as monitoring parameters will be discussed during the presentation. The technician is a key component to successful management of Cushing's syndrome in dogs.