Cushing's Disease — A Case Study

from the AMCA Newsletter, Volume 45, No 12. December 1997 — Health Column written by Jocelynn Jacobs-Knoll, DVM

Molly was an eight year old female AKC Alaskan Malamute who had a successful show career as a young and middle aged dog. She had been bred three times and always produced healthy litters. Her last litter was whelped at seven years of age after which she was spayed. Throughout her life, she had consistently been a healthy bitch with visits to her veterinarian only for routine vaccinations and heartworm tests. Recently, however, her owners noticed she was drinking more water and would ask to go outside to urinate more often. Her owners also noticed that her abdomen appeared distended even though her diet had not been changed nor had the amount of food consumed varied. Molly also seemed to pant more even with the house cooled to 60° to 65°F. Everything else appeared to be normal, but because of her age and lack of past medical problems, Molly was taken to her veterinarian for a physical examination and possible blood work.

During Molly's physical examination, her veterinarian concluded that she did seem to have a pot-bellied appearance, her hair coat appeared to be thinning especially along her sides, and her coat felt drier to the touch than normal. She also was doing quite a bit of panting, but that was normal for her in the clinic due to nervousness. Overall, her signs and history were nonspecific, but with a history of excessive drinking and urinating (medically referred to as polydipsia and polyuria), a routine work-up was in order. Her urine was collected for a urinalysis and blood was collected for a routine CBC (complete blood count) and chemistry profile. The signs of polydipsia and polyuria can be seen in multiple disease processes. Some of these diseases include:

1. Diabetes (both mellitus and insipidus),

2. Renal disease,

3. Liver disease,

4. Cushing's disease,

5. Hypercalcemic nephropathy (a type of kidney problem),

6. Pyometra,

7. Psychogenic polydipsia, and

8. Idiopathic polydipsia caused by the use of certain medications (such as cortisones, diuretics, phenytoin, etc.). Because of this long list of differential diseases that can be seen with the non-specific signs of polydipsia and polyuria, both blood work and urine tests can help determine which disease is present.

In Molly's case, pyometra could be totally eliminated from the possible diseases since she was already spayed, as well as idiopathic polydipsia since she was not on any medications.

Molly's urinalysis results were done immediately (while her blood work was sent to the local lab), and it demonstrated no evidence of a urinary tract infection, no glucose or ketones, nor blood or protein in the urine. Molly's urine's specific gravity was basically the only thing abnormal. That value was low which indicated that she was not concentrating her urine like she should. The next day she was scheduled for a water deprivation test to determine if she could concentrate her urine if deprived of water over a certain time frame. Subsequently, Molly concentrated her urine well at her stay at the clinic the next day. Disease like kidney disease (the two types listed) and primary diabetes now were less likely her problem. However, the blood results give ancillary information as to whether these disease processes could be eliminated from the list of differential diagnoses.

Molly's blood test results came back after a few days. Basically everything was normal except for an elevation in her liver enzymes, alkaline phosphate levels and cholesterol levels. Molly did not have an elevation in her blood glucose (but some dogs with her condition may demonstration an elevation in the blood sugar level due to a secondary diabetic state caused by the disease). Now diseases like primary kidney disease (the two types listed), primary diabetes, and polydipsia due to a psychogenic problem could be eliminated from the causes of Molly's signs. Cushing's disease and primary liver disease were now the two processes being considered as primary rule-outs based on her signs and blood work. To differentiate between Cushing's and primary liver disease, other blood tests can be performed to specifically identify a Cushing's disease case. Molly had those tests run, and she was positively diagnosed as a case with Cushing's disease.

Pathophysiology and Diagnosis

Cushing's disease is NOT a rare condition in canines. It can be seen in any breed of dog, but a larger number of poodles, dachshunds (especially the long haired variety), Boston terriers and boxers are particularly at risk. Usually it is a disease that occurs around eight to twelve years of age with females at a slightly higher risk than males. It has a high potential for misdiagnosis based on its ability to alter other organ functions to mask the disease as a primary diagnosis.

Cushing's disease is also known as canine hyperadrenocorticism. This is a long medical term which means enlargement of the adrenal gland producing excessive cortisone. The adrenal gland is a small organ that sits on top of the kidney. There are two of them corresponding with each kidney. The adrenal's function is to produce various hormones and glucocorticoids (naturally produced steroids or cortisone). The pituitary gland in the brain tells the adrenal gland how much and when it should release its hormones and glucocorticoids so that various other organs can function properly. ACTH is the chemical that the pituitary gland releases that directly affects the adrenal gland to secrete its steroids.

Cushing's disease is seen when there is excess glucocorticoids being produced and released by the adrenal gland. There are two major reasons why the adrenal gland may produce excessive steroids:

1. A tumor (benign or malignant) may exist within the adrenal gland causing excessive production of cortisones to occur or

2. The pituitary gland may have some abnormality and produce more ACTH which in turn over stimulates the adrenal gland telling it to produce more hormones even though the body does not need it (again this may be due to a tumor or abnormal growth in the pituitary gland itself).

Cushing's disease can be tested for using a variety of tests. The ACTH stimulation test is the most commonly used. Like its name suggests, it is run by injecting exogenous ACTH into the body to see how it affects the adrenal gland. If ACTH is injected into an animal with Cushing's disease, the enlarged and abnormal adrenal glands will release an exaggerated amount of cortisone into the bloodstream (plasma cortisol to be specific) because it has large reserves of this chemical due to its size. If ACTH is injected into a normal animal, a normal level of cortisol will be released. The only disadvantage to this test is that it cannot help determine whether the abnormality lies with the pituitary gland or the adrenal gland.

Two other tests that can be done are a low dose dexamethasone suppression test (LDDST) and a high dose dexamethasone suppression test (HDDST). These tests' theory is based on the fact that if there are glucocorticoids already circulating in the body, that the pituitary gland should tell the adrenal gland NOT to produce any more cortisones (because there already is plenty in the system). The interpretation of these tests can be complicated, but they can help to demonstrate whether the Cushing's condition is caused by a pituitary problem or an adrenal one.

Treatment

Treatment of Cushing's disease depends on which of the two organs (the pituitary or the adrenal gland) has the abnormality. If there is an adrenal tumor, surgical treatment through removal of the tumor is the treatment of choice. This surgery can be difficult and post-operative care can be critical. Medical therapy of adrenal tumors does not produce significant results.

In contract, pituitary-dependent Cushing's cases are most successfully treated with medication. Since the pituitary gland is located in the center of the brain, it is difficult to surgically remove it. Therefore, medical therapy is the treatment of choice. A few years ago, only one type of medication was available to treat this type of Cushing's disease. Lysodren (o,p-DDD) was the initial drug available. It causes selective destruction of sections of the adrenal gland so excessive glucocorticoids are not produced. Some of the side effects that can be seen with treatment include anorexia, vomiting, lethargy and diarrhea. Lysodren is a medication that must be given for the rest of the dog's life, but may only need to be given once weekly for maintenance therapy. An ACTH response test may be done periodically to make adjustments to the Lysodren dosage.

In the past year or so, another drug has been introduced to treat pituitary dependent Cushing's disease. This drug is called Anipryl {selegiline HCL (L-deprenyl HCL)}. This drug does not cause destruction to tissues of the adrenal gland, but rather it helps restore function of a normal chemical in the brain (dopamine) which inhibits excessive ACTH production. This drug not only helps eliminate or significantly decrease clinical signs of Cushing's disease, but also there are behavioral signs which also increase with usage of the drug. Dogs who are on Anipryl have a tendency for increased activity (less sleepiness or lethargy), they appear more energetic and interact with the family more like they used to when they were younger. Owners of dogs who have been suffering from Cushing's disease are very excited about the advent of this drug. Many believe it has given their dog a “second wind.”

In Molly's case, it was determined that she had pituitary-dependent Cushing's disease. Although she was initially treated with Lysodren, she now is being successfully maintained on Anipryl.

Post script: A “pseudo-Cushing's disease” can also exist for those animals put on long term, high does of exogenous cortisones (i.e., Vetalog, azium, prednisone, etc.) This was listed on the list of differentials for polydipsia/polyuria as item #8). With a gradual weaning from these medications, the pseudo-Cushing's disease can be eliminated. This type of Cushing's disease is probably more common than the cases caused by naturally occurring adrenal or pituitary enlargement.