Cushing's Disease in Dogs, by Long Beach Animal Hospital

Article by Long Beach Animal Hospital in Long Beach, CA

Cushing’s Disease (also known as hyperadrenocorticism-Cushing’s is easier to pronounce, so stick with that word) results when the adrenal glands secrete an excess amount of cortisone. It is named Cushing’s because that is the name of the doctor that discovered this disease.

It is the most common endocrinopathy (hormone disease) encountered in older canines. This disease is the exact opposite of another endocrine problem in canines called Addison’s disease (hypoadrenocorticism).

This is a complex hormonal disease that does not lend itself to a simple explanation or an easy diagnosis. Some pets have symptoms, yet the tests for Cushing’s are negative. Other pets have positive test results, but minimal symptoms. Test results can change when repeated a short time later. Everything can be vague and in a continual state of flux.

This complexity will be explained in this page, so get comfy and get ready to get your brain stimulated. Take a break, if needed, and come back to it when you are ready to learn more.

About Cortisol

Cortisol is a hormone that is essential for life. Cortisol maintains a normal blood glucose level, facilitates metabolism of fat, and supports the vascular and nervous systems. It affects the skeletal muscles, the red blood cell production system, the immune system, and the kidneys.

It is considered a “catabolic steroid.” This means it takes amino acids from the skeletal muscles and, with help from the liver, converts them to glycogen, the storage form of glucose. These functions are the exact opposite of “anabolic steroids,” the drugs that weightlifters take to increase muscle mass. The end result of this is an increase in the level of glucose in the bloodstream. The hormone called insulin has the opposite effect on blood glucose, adding to the complexity of this system.

The level of cortisol in the bloodstream continually fluctuates as physiologic needs vary. Surgery, infection, stress, fever, and hypoglycemia (low blood sugar) will cause cortisol to increase. This continual fluctuation adds to the difficulty of diagnosing Cushing’s, because the amount of cortisol in the bloodstream is so variable. A test taken at one moment in time might have different results if taken later.

Numerous internal organs are affected by cortisol:

Muscles

Cortisol is needed for proper muscle action, yet too much can cause muscles to atrophy (shrink). This is due to their catabolic effect. This means that they literally cause the body to break down the amino acids in the muscle fibers in order to increase the blood glucose (sugar) level. Cortisol does this in a complex mechanism that involves the liver. The end result is the muscles become smaller. When this occurs, the abdominal muscles and the abdomen appear pot-bellied.

Bone

Bone is made up of a protein matrix and calcium, both of which are affected by cortisol. Excess cortisol affects the protein matrix, decreases calcium absorption from the intestines, and increases calcium excretion by the kidneys. Skeletal mass decreases and bones become weaker.

Skin

Too much cortisol causes atrophy of hair follicles and sebaceous glands, which leads to alopecia (hair loss). Elastic tissue under the skin is also affected, leading to thinner skin and adding to the pendulous abdomen. The disruption in the elastic tissue of the skin can also cause calcium changes in the skin. This might lead to areas where calcium builds up in small nodules.

Vascular system

Cortisol is required for maintaining the integrity of the lining of blood vessels. An excess will lead to thinning of these walls and the potential for rupture. The end result is a hematoma.

Central Nervous System

Cortisol is necessary for the normal maintenance of brain functions. Excessive cortisol can interfere with sleep and change the mood. You might notice these effects if your dog has Cushing’s or is given supplemental cortisone for treatment of a disease.

Liver

Excess cortisol will increase the workload on the liver, as it converts amino acids to glycogen. Pets with Cushing’s will commonly have an enlarged liver, known as hepatomegaly.

Kidney

An increase of cortisol increases the blood flow (also called GFR-glomerular filtration rate) to the kidneys. This will result in an increase in the amount of water and waste products filtered by the kidneys. This is one of the reasons why canines with Cushing’s drink and urinate excessively (PU/PD) and produce dilute urine.

Immune System

This is one of the more profound functions of cortisol. It decreases the inflammatory process and helps minimize an over-reaction of the immune system to foreign bodies or infections. Unfortunately, it also suppresses the immune system to the point that the body has a hard time mounting a proper response. The body is now more susceptible to infections, especially those caused by bacteria.

Pituitary Dependent Cushing’s

Up to 85% of all Cushing’s cases in canines fall into this category. The pituitary gland is invaded with a slow growing tumor, called an adenoma. This causes it to secrete an excess amount of ACTH. The adrenal glands respond to this excess ACTH by enlarging and secreting excess cortisol. It is this excess of cortisol that is circulating in the bloodstream that causes the symptoms we see in this disease.

This pituitary gland tumor can remain slow growing and not affect the pet any more than inducing Cushing’s disease. In 10-20% of these tumors they enlarge to the point that they will cause significant neurologic symptoms.

Adrenal Dependent Cushing’s

In up to 15% percent of Cushing’s cases there is an actual tumor of one of the adrenal glands (sometimes both are involved). The tumor secretes excess cortisol in the bloodstream.

This excess cortisol is monitored by the hypothalamus and pituitary in the negative feedback mechanism, causing them to secrete less ACTH. Less ACTH in the bloodstream can cause the other adrenal gland (if it does not also have a tumor) to atrophy (shrink).

The benign version of this tumor occurs 50% of the time and is called an adenoma. Canines with these usually live a normal life. The malignant (cancerous) version, which occurs the other 50% of the time, is called an adenocarcinoma. It can invade the primary vein that returns blood back to the heart (called the vena cava), and spread from the adrenal gland to the liver, lung, kidney, and lymph nodes. Dogs with adenocarcinoma usually do not live more than a year.

Iatrogenic Cushing’s

Long term use of cortisone, in oral, injectable, or even topical form, might cause an animal to have symptoms of Cushing’s disease. It all depends on the type of cortisone used, the dose it is used at, and the duration of use. The pet has symptoms of Cushing’s because cortisone is being introduced into its body, not because the adrenal glands are producing it in excess amounts.

As a general rule, once the original symptoms of the disease are treated with cortisone, we recommend decreasing its use, stopping its use, or finding an alternative drug. Sometimes this is not feasible though, especially in immune system diseases. The symptoms of these diseases far outweigh the potential side effects from this exogenous use of cortisone. An example is Inflammatory Bowel Disease (IBD).

Exogenous cortisone goes by several names. It is a highly beneficial drug used to treat a wide variety of diseases. They come in injectable, oral, and topical forms, and tend to be more potent than the cortisol that is naturally produced by the adrenal glands. Some of the more common ones are Prednisone, Depo-Medrol, and Dexamethasone.

Cushing's Symptoms

Some dogs with Cushing’s disease show the classic symptoms, others show only a few vague symptoms. These symptoms are variable, and in a state of constant flux, which is consistent with endocrine (hormonal) disease.

The classic symptoms are:

• Polyuria/polydipsia (PU/PD), which is excess urinating and excess drinking of water. It is one of the first signs of the disease and usually precedes the other symptoms by a significant period of time. Several other important diseases cause these symptoms also, notably liver disease, kidney disease, pyometra, and diabetes mellitus (sugar diabetes).

• Pot-bellied abdomen due to enlarged liver and abdominal muscle weakness.

• Thin skin and usually symmetrical hair loss along the trunk - the hair might grow lighter in color or lose its luster. It might not grow well at all. Calcium deposits under the skin, called calcinosis cutis, occur on occasion. Secondary skin infections called pyoderma are common also. The skin might also be hyper-pigmented.

• Excess appetite and over-eating.

Other symptoms might include:

• Panting

• Obesity

• Straining to urinate or blood in the urine due to urinary tract infection or bladder stones, which dogs with Cushing’s are prone to.

• Ataxia (incoordination), blindness, circling, and seizures due to a large pituitary tumor

• Lameness due to a ruptured cruciate ligament, which dogs with Cushing’s are prone to

Cushing's Diagnosis

Cushing’s disease is suspected in any pet that has some of the symptoms described above, particularly the skin symptoms and excessively urinating and drinking water. Other common findings with Cushing’s include skin infections that keep recurring after antibiotic therapy is stopped. A history of poorly controlled diabetes mellitus might also clue us in to Cushing’s.

Some dogs do not show any symptoms early in the course of the disease. This is another reason for yearly exams and blood and urine samples in dogs 8 years of age or more.

A thorough approach is needed for a correct diagnosis of Cushing’s. In every disease we encounter, we follow the tenets of the diagnostic approach to ensure that we make an accurate diagnosis, and also so that we do not overlook some of the other diseases that are common in pets as they age.

Nature works in complex ways, and just because you have one disease does not mean you cannot get another one to complicate the matter. These co-morbidities are common in older pets, another reason we need to be thorough in our diagnosis, so as not to miss them.

Some dogs have the normal symptoms of Cushing’s, but blood sampling does not bear this out. In these cases, we will repeat the adrenal screening tests at some time in the future or even perform abdominal ultrasound to look at the adrenal glands. These glands are small, and a veterinary radiologist is needed oftentimes to find them and determine if they are diseased.

Physical Exam

Physical exam findings in dogs with Cushing's might include:

• Pot-bellied abdomen

• Enlarged lymph nodes due to secondary bacterial infection or spread of an adrenal tumor

• An enlarged liver (hepatomegaly) might be palpated, along with smaller muscle mass (atrophy) in general.

• Bruising (hematoma) might be observed under the skin, or when a blood sample is obtained.

• Skin infections and wounds that do not heal or recur after antibiotics are stopped.

• Hair loss (alopecia) that is symmetrical, along with thin skin, poor hair coat, and calcium deposits under the skin. Many skin conditions have similar symptoms, so numerous diseases have to be kept in mind. They include hypothyroidism, skin allergies, sarcoptic mange, demodectic mange, and Ringworm.

• Blood pressure might be elevated. This might cause a detached retina, picked up by an ophthalmic exam.

Blood Panel

A CBC (complete blood count) and biochemistry panel should be run on every dog 8 years of age or more, especially if they have any of the symptoms of Cushing’s.

The CBC might show an increase in the number of red blood cells and/or an increase in platelets. It might also show an increased WBC (white blood cell count), called leukocytosis. When these white blood cells are broken down, there are usually more neutrophils, less lymphocytes, and less eosinophils.

Cholesterol, blood glucose. triglycerides, and liver enzyme tests (ALT) might be elevated in Cushing’s. If a thyroid test is run it might be low or borderline normal.

An elevated alkaline phosphatase (Alk Phos) is a consistent finding in Cushing’s. This is an enzyme that is located in the bile production area of the liver. The excess cortisol influences this enzyme, although growing animals, fractures, obstructions of the bile ducts, liver disease, certain medications, and diabetes mellitus can all cause an elevated Alk Phos. A significantly increased Alk Phos alerts us to keep Cushing’s in our tentative diagnosis list.

Urinalysis

A normal specific gravity in a dog should be at least 1.025, and there should be no or minimal protein, glucose, white blood cells, or bacteria, as a general rule. With Cushing’s, the specific gravity of the urine might be low, the protein might be elevated, and a urinary tract infection might be present.

Ultrasound

Abdominal ultrasound can be highly beneficial in this diagnosis. The adrenal glands can be measured, and their internal architecture (called parenchyma) can be analyzed.

Screening Tests

The first goal is to determine if Cushing’s disease exists. The next step is to determine if it is pituitary dependent (caused by a pituitary tumor) or adrenal dependent (caused by an adrenal tumor).

Screening tests are the most reliable way to confirm a diagnosis of Cushing’s disease, and also where results get muddy sometimes. These tests evaluate the interactions that are occurring between the hypothalamus, the pituitary gland, and the adrenal gland. The interaction between these glands is known as the hypothalamic-pituitary-adrenal axis.

Testing this axis is not as easy as it sounds. The mammalian body is a dynamic system with thousands of chemical reactions and interactions occurring simultaneously. Also, levels of cortisol are in a continual state of flux, depending on the time of day, the season, medications, diet, and stress levels.

Underlying diseases like Urinary Tract Infections can affect these screening tests and need to be controlled first. Because of all this variability, interpreting these tests can be problematic, and it is not uncommon to repeat them in the future to look for consistent findings and monitor trends.

We prefer to perform these tests when the stress level is not high. It might be worth it to take your dog for a short walk after you park the car to let it settle down.

Sometimes the test results are borderline for the disease. In these cases, we use other tests like ultrasounds, or we repeat the tests 1-3 months down the road.

Response to Therapy

One of the tenets of the diagnostic process is whether or not a treatment that is instituted actually corrects the problem. This usually applies to Cushing’s. Then again, we might have the correct diagnosis and treatment, yet your animal does not get better because there are other diseases (co-morbidities), like causing the lack of response to treatment. Nobody ever said nature does things in simple ways.

Treatment

Before we discuss treatment, we need to keep things in perspective. This is a chronic disease, and most dogs do not die from this disease. We tend to treat when the symptoms described previously are affecting a dog’s quality of life or are a major nuisance to a pet owner. We do not routinely treat just because the tests say your dog has Cushing’s - the symptoms of the disease need to be present also.

It might be years before this dog shows signs, if any, of Cushing’s. At the same time, we want to start treatment at the optimal time just as the symptoms of Cushing’s starts. Any dog diagnosed with Cushing’s should have follow-up tests performed periodically to look for changes to help in this decision.

Dogs that have significant symptoms of Cushing’s and have been diagnosed by screening tests need to be treated to prevent potentially serious diseases secondary to Cushing’s, including Diabetes Mellitus, Urinary Tract Infection, pancreatitis and High Blood Pressure.

Vetoryl (trilostane)

This is the newest treatment for this disease, and the one we recommend in most cases. The active ingredient in Vetoryl is trilostane, an inhibitor of an enzyme called 3-beta-hydroxysteroiddehydrogenase. This enzyme is involved in the production of several steroids including cortisol. Inhibiting this enzyme inhibits the production of cortisol.

It can be given once or twice per day. In some dogs, especially those with Diabetes Mellitus, the Cushing’s symptoms might not diminish with once daily dosing, and the medication needs to be given twice per day (every 12 hours). It always needs to be given with food for proper absorption.

When using this drug to treat your dog’s Cushing’s, the ACTH stimulation test is used for monitoring purposes. Do not fast your dog on the day of this test and give Vetoryl as you always do. If your dog’s symptoms do not improve and the ACTH stimulation test indicates inadequate adrenal suppression, the dose or frequency of administration might need to be changed.

Lysodren (mitotane)

Mitotane has been used to treat Cushing’s disease for 30 years and is known by the tradename of Lysodren. It selectively destroys the zona fasciculata and reticularis, effectively limiting the amount of cortisol that these areas of the adrenal gland can secrete.

Pets that are on insulin for diabetes mellitus need to have their mitotane and insulin doses adjusted downwards. It should be administered with meals to enhance its absorption. This drug is first administered at a loading dose for 7-10 days.

Side effects are not uncommon with Lysodren (mitotane):

lethargy

vomiting

diarrhea

poor appetite

weakness

ataxia (incoordination)

Side effects are due to the cortisol level being reduced below normal levels. Even if the cortisol level does not go below normal levels, a rapid decrease in elevated cortisol levels to the normal range can still cause these symptoms.

You need to closely observe your pet when it is on mitotane for any of the above side effects. If they occur, immediately stop medicating and contact your veterinarian.

After 7-10 days of loading dose with Lysodren (mitotane), the cortisol levels are assessed with the ACTH stimulation test. The pre and post cortisol levels should be normal. If they are, then we will continue to use mitotane at a weekly maintenance dose to prevent the problem from recurring again. Once your pet gets to this point it is rare to need any supplemental cortisone pills.

Two long term effects can occur while on mitotane maintenance therapy:

• Mitotane can be so effective that the adrenal glands do not produce enough cortisol for normal physiology. This is called iatrogenic hypoadrenocorticism. In these dogs we stop all mitotane therapy and use supplemental prednisone. Sometimes this side effect is permanent, and your dog needs to be on supplemental prednisone the rest of its life.

• It is not uncommon for relapses of Cushing’s to occur within 12 months, even while on the maintenance therapy. These dogs are again given a loading dose of mitotane, then converted to maintenance dose when cortisol levels are normal. Both of these effects emphasize the need for continual monitoring of your pet. This means close observation at home and ACTH stimulation tests every 3-6 months.