Cushing's disease: Something new, something blue (Proceedings)

Hyperadrenocorticism remains one of the most common endocrine disorders diagnosed in the geriatric dog population. It is a disease that is seen in almost every veterinary practice. Unfortunately, the disease tends to be frustrating to deal with, a definitive diagnosis is at times elusive and therapy can have major adverse side effects. Knowing how to diagnose, what problems hyperadrenocorticism can cause in a patient that justify aggressive therapy, and the advantages and disadvantages of the various treatment modalities can be helpful in determining an appropriate diagnostic and therapeutic plan.

Clinical Signs

The most common clinical signs of Cushing's disease are quite familiar to practicing veterinarians. Commonly PU/PD, pot-bellied appearance, lethargy, polyphagia, obesity, and panting. In addition, many dermatologic manifestations are seen including alopecia (of the trunk), comedones, thin skin, calcinosis cutis, bruising, hyperpigmentation, pyoderma and seborrhea. Less commonly identified signs include muscle weakness or pseudo-myotonia ("frozen" muscles), polyneuropathies, or rupture of the cranial cruciate ligament. Hypertension is relatively common (50% or greater) though with the lack of blood pressure monitoring devices in many practices it often goes undiagnosed. Pulmonary thromboembolism, recurrent (often asymptomatic) urinary tract infections, proteinuria, pancreatitis, pulmonary mineralization, and calcium oxalate urolithiasis are also often frequently seen with Cushing's disease. Recently it has been noted that many dogs with hyperadrenocortism are hypoxic, whether or not they have mineralization of the lung parenchyma. This can be a serious consequence, leading to distress as well as excess strain on the right side of the heart. Some of the clinical problems caused by Cushing's disease are more bothersome than dangerous. Other clinical problems are life threatening such as thromboembolism or pancreatitis. Still other clinical problems can aggravate other disorders that the patient may have, such as is the case if hypertension is present in a dog with underlying heart disease. This is not an uncommon scenario since older dogs tend to have Cushing's as well as valvular heart disease. Hypertension in a dog with valvular problems can be a factor that leads to more rapid progression of the heart problem as well as difficulties in treating heart failure if it occurs.

Diagnosis

One of the most frustrating parts of Cushing's disease is trying to establish a definitive diagnosis. Ideally of course clinical signs should be consistent with hyperadrenocorticism. Basically testing is still divided into screening tests and test to differentiate between pituitary dependent hyperadrenocorticism (PDH) and adrenal tumors (AT). There are differences between labs, so it is advisable to contact them if there are any questions regarding the outcome of testing.

A random cortisol level has no diagnostic value in regard to the diagnosis or exclusion of Cushing's disease. The simplest screening test is a urine cortisol to urine creatinine ratio. False positives occur frequently, however false negatives are rare. As such it is a good test to rule out Cushing's. Even the stress of a visit to the veterinarian will elevate the values and as such it is advisable to have the owner collect the urine prior to presentation at the clinic. Because there are so many false positives, a follow-up test such as a low dose dexamethasone suppression test (LDDS) or ACTH stimulation test should be run. These two tests have advantages and disadvantages. The LDDS has some false positives but few false negatives. It can also lead to differentiating between PDH and AT when 4 and 8-hour samples are taken, one of the reasons it is my preferred screening test. If the cortisol levels drop at 4 and escape to above normal range at 8 hours PDH is present. The ACTH stimulation test has few false positives, but false negatives do occur, especially with adrenal tumors. The combined ACTH stimulation /LDDS test is generally not recommended.

Differentiation tests also have their drawbacks. Not all dogs with PDH will suppress on a high dose dexamethasone suppression test. An endogenous ACTH level is a very good test, however the sample needs to be meticulously handled (contact your lab) which often makes it difficult to run. Abdominal ultrasound can be helpful to rule out tumors as well. At times it is not possible to completely rule out an adrenal tumor.

Therapy

There have been some changes in regard to what therapies to consider. Some will probably never become important methods. One method that is interesting but unlikely to be commonly used is surgery for PDH. It is possible to remove the pituitary tumor via transspenoidal surgery. This is of course more likely to be curative since it eliminates the underlying cause of the PDH. Obviously a learning curve exists and it is not widely practiced. The same applies for radiation therapy, which is used when there are indications that the pituitary tumor is actually a large macroadenoma, which would eventually cause neurologic signs. To diagnose this it is necessary to have imaging such as MRI or CT available. Medical therapy still remains the most commonly used form of therapy and will probably remain so long term.

There are 4 major medications to consider for medical therapy; ketoconazole, mitotane, L-deprenyl and trilostane. Each of these treatments has advantages and disadvantages. It is however important to know when to treat. Just because Cushing's has been diagnosed does not mean that therapy is necessary. If clinical signs are absent it is difficult to justify a potentially dangerous and/or expensive therapeutic plan. If problems such as pseudo-myotonia, hypertension, proteinuria, and others are present treatment is clearly indicated. The most efficacious therapy is mitotane, though side effects are common. Fortunately the side effects can usually be managed, however in rare instances life threatening problems can occur including making the patient a permanent Addisonian dog. Unfortunately, the adverse effects cannot be predicted. It has been helpful to give physiologic doses of prednisone (0.2 mg/kg SID) to dogs during induction; it seems to make this process smoother. ACTH stimulation testing is required to determine efficacy, the lack of response to ACTH is the goal of therapy. Maintenance therapy is needed, however in about 1 year 50% of dogs are Cushingoid again.

L-deprenyl was considered a good alternative to mitotane. It has however been shown that although the majority of dogs do better clinically, the objective effects on the Cushing's disease are only present in 20% of patients. It may well have a role in the management of early and less severe forms or Cushing's or where mitotane is not tolerated. If a response is not seen in 2 to 3 months, alternatives should be considered.

Ketoconazole is rarely used as a first line therapy, however in some cases it is a good alternative when other treatments have not been successful or tolerated. The initial dosage is 10 mg/kg BID for 14 days. An ACTH stimulation test is run and dosage is adjusted accordingly. Liver values need to be monitored as liver toxicity can occur.

Trilostane is a newer therapy that has much promise. It reversibly inhibits cortisone production. Getting a patient on a stable dose may take some time and control of Cushings is not as complete as with mitotane. It is a good alternative for dogs where the main reason to treat is that the clinical signs the patient has are not acceptable to the owner. It has been shown that survival in dogs treated with mitotane or trilostane is similar.

References

Available upon request from the author.