Cushing's Disease (hyperadrenocorticism)

Introduction
Anatomy
Physiology
Cause
Symptoms
Diagnosis
Treatment
Feline Cushing's

Introduction

Cushing's Disease (also know 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 the most common endocrinopathy (hormone disease) encountered in older dogs. This disease is the exact opposite of another endocrine problem in dogs called Addison's disease (hypoadrenocorticism).

This detailed page will emphasize Cushing's disease in dogs, with an explanation of how it differs from cats at the end. This is a complex disease that does not lend itself to a simple explanation or an easy diagnosis. You might want to go to the bathroom before attempting this page! 

We have a summary page on Cushing's if the explanation on this page is too detailed for your needs.

Several medical terms and abbreviations relate directly to Cushing's:

Anatomy

The adrenal glands are small paired glands buried in fat in the front of each kidney. Even though they are small, the cortisol they secrete, along with their other functions, have great significance to normal physiology.

The arrows point to the paired adrenal glands in front of each kidney. The extensive blood supply to the kidneys and adrenal glands is apparent.

This is a picture of an adrenal gland (arrow) that is buried in fat near the kidney (K). It is from a ferret that has an adrenal gland tumor, so the adrenal gland is inflamed and easily visualized. This is not necessarily the case in dogs and cats that have adrenal gland tumors.

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The internal architecture of the adrenal gland is made up of several distinct zones.

Cortex

The cortex of the adrenal gland is made up of 3 anatomical parts:

Zona Glomerulosa

This is the outer layer of the adrenal gland. This section secretes the mineralcorticoid aldosterone. Aldosterone is vital to proper sodium and potassium regulation.

Zona Fasciculata

This is the next layer as you go inward, and produces the glucocorticoid cortisol. The cells in this area are the ones that cause Cushing's.

Zona Reticularis

As we continue inward we come across this section that secretes the sex hormones known as androgens (male sex hormones), estrogen (female sex hormones), and sex steroids. These are usually secreted in such small amounts as to be of no major significance in healthy animals.

Medulla

This consists of the very center of the adrenal gland. It secretes hormones called catecholamines. The two important ones are epinephrine (adrenaline) and norepinephrine.

Physiology

These tiny organs have a profound influence on many internal organs. The hormones they secrete work in unison with other internal organs, particularly the liver, and have an enormous effect on physiology. These hormones interact with many other hormones that have the opposite effect, usually in some type of feedback mechanism that is monitored by the brain. This interaction is complex, so only a summary of adrenal hormone physiology is presented.

The adrenal glands secrete several important hormones, most of which are synthesized from cholesterol. We will explain 3 of them; cortisol, aldosterone, and epinephrine:

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 weight lifters 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. You can learn more about insulin by going to our diabetes mellitus page.

The level of cortisol in the bloodstream continually fluctuates as physiologic needs vary. Surgery, infection, fever, and hypoglycemia (low blood sugar). will cause cortisol to increase. This continual fluctuation adds to the difficulty of diagnosing Cushing's.

To control the level of cortisol the hypothalamus and pituitary gland in the brain secrete chemicals into the bloodstream called releasing factors. In the case of the adrenal glands , the hypothalamus secretes a hormone called corticotropin releasing hormone (CRH). It goes to the pituitary gland and stimulates it to release a hormone called adrenocorticotrophic hormone (ACTH). It is the amount of ACTH circulating in the blood stream that tells the adrenal glands (specifically, the cells at the zona fasciculata) how much cortisol to secrete. There is a negative feedback loop that allows the hypothalamus and pituitary gland to refine precisely how much cortisol circulates in the bloodstream. The more cortisol secreted by the adrenal glands, the less CRH and ACTH secreted. This allows the body to precisely refine the level of cortisol, and to change the level rapidly due to changing physiologic needs.

Numerous internal organs are affected by cortisol:

Muscles

Cortisol is needed for proper muscle action, yet too much can cause the muscles to atrophy (shrink). This is due to their catabolic effect. This means that they literally cause the body to use the amino acids in the muscle fibers 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 at the abdominal muscles the abdomen appears 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

It 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. In cats the skin changes can become severe, and are called the fragile skin syndrome.

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. Cortisol also increases the number of circulating red blood cells and helps maintain blood pressure.

Central Nervous System (CNS)

Cortisol is necessary for the normal maintenance of brain functions. It 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. You will be shown a picture of an enlarged liver on an x-ray in the diagnosis section.

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. Our kidney disease page has more details. This is one of the reasons why dogs with Cushing's drink and urinate excessively (PU/PD), and urinate a 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 more susceptible to infections, especially those caused by bacteria.

Mineralcorticoids

Aldosterone is the principal mineralcorticoid secreted by the adrenal glands. This hormone is secreted as a response from the kidneys when fluid volume in the bloodstream is decreasing. It involves other hormones called renin and angiotensin. The end result is an increase in sodium in the bloodstream, with a corresponding increase in blood volume and blood pressure. This hormone also interacts with and affects potassium levels. To further complicate the picture, ACTH also has an affect here, just like it does with cortisol.

This part of adrenal gland physiology is not significantly altered in Cushing's. Addison's disease, which is the production of too little cortisone, has a greater affect on aldosterone.

Epinephrine (Adrenaline)

This compound, technically called a neurotransmitter, also has hormone-like properties. It is a very powerful chemical that effects all organ systems. It acts very rapidly, with effects remaining only for a short period of time. It is the primary reason the body has the ability to respond to an emergency. This physiologic mechanism is also known as the "flight or fight" response.

Upon stimulation of the central nervous system (ex.-fear or pain), the adrenal medulla is stimulated to secrete epinephrine into the bloodstream. We are all familiar with what happens next. The pupils dilate, the heart rate and blood pressure increase, and the palms get sweaty. Internally, the body is increasing the blood glucose level, the breathing passages are opened up, more red blood cells are secreted into the circulation, blood is shunted away from the skin and other internal organs, and blood flow is increased to the brain and skeletal muscles. All of this has the effect of bringing the brain and skeletal muscles extra glucose and oxygen, and accounts for the extra boost of awareness and energy we all feel at this time.

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Cause

Pituitary Dependent (PD)

Up to 90% of all Cushing's cases in dogs fall into this category. The pituitary gland is invaded with a slow growing cancer called an adenoma. This causes it to secrete an excess amount of ACTH. The cells in the zona fasciculata area of the adrenal glands respond to this excess ACTH by hypertrophying (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 effect 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. Unfortunately, some of these neurologic symptoms mimic those seen as side effects to the medication used to treat Cushing's.

Brain tumors are best diagnosed using an MRI (magnetic resonance imaging). This boxer has a large white tumor in its brain.

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Non-Pituitary Dependent (AT)

In up to 15% percent of Cushing's there is an actual tumor of one of the adrenal glands (sometimes both are involved). The tumor enlarges and 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 will cause the other adrenal (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. The malignant version, which occurs the other 50% of the time, is called an adenocarcinoma. It can invade the primary vein returning blood back to the heart (called the vena cava), and spread from the adrenal gland to the liver, lung, kidney, and lymph nodes.

The white arrow points to a very small and normal adrenal gland in a ferret. A lobe of the liver has been pulled to the left (forward) so that you can see the adrenal gland. The dark blue structure running horizontally is the vena cava as it courses past the liver towards the heart. The close proximity of the adrenal to the vena cava and liver shows how easily a malignant tumor here can spread into the bloodstream and lodge elsewhere in the body.

This chest radiograph follows the vena cava (arrows) as it continues from the liver to the heart. Unfortunately, the heart unwittingly can now pump cancerous tissue to the rest of the body.

 

Adrenal tumors are a common problem in ferrets. The adrenal tumor in this case does not secrete excess cortisol, so technically the disease is not called Cushing's. The tumor causes an excess secretion of sex hormones, causing a different set of symptoms when compared to the dog and cat.

Iatrogenic

Exogenous (external or supplemental) use of cortisone is very common in medicine. It is a highly beneficial drug used to treat a wide variety of diseases. In some cases it is used as an emergency drug to literally save a life. Cortisone is beneficial in several disease categories:

• Inflammation
• Immune system
• Neoplasia (cancer)
• Cerebral edema (brain swelling)
• Shock

Long term use of cortisone, in oral, injectable, or even topical form, might cause an animal to have the 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. 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.

The level of cortisone that results from this exogenous use will cause the adrenal glands to atrophy. The negative feedback loop tells the brain there is plenty of cortisol in the bloodstream, so the pituitary secretes less ACTH. The pet has the symptoms of Cushing's because cortisone is being introduced into its body, not because the adrenal glands are producing it in excess amounts.

Exogenous cortisone goes by several names. 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:

Ectopic ACTH Syndrome

This is a rare version of Cushing's that does not fall into any of the above categories. It can be found in association with cancer in the dog.

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Symptoms

Some dogs with Cushing's disease show the classic symptoms, while other show only a few vague symptoms. The classic symptoms are:

Polyuria/polydipsia (PU/PD)- This 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 to the point a dog might look pregnant. It is due to hepatomegaly and abdominal muscle weakness.

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

Muscle wasting over the head, shoulders, thighs, and pelvis.

Polyphagia- excess appetite. This is often interpreted by clients as being healthy, since most people think of a sick pet as not eating well. In this case your pet is over-eating, which is consistent with Cushing's.

Other occasional symptoms include:

• Pruritis (itchy skin)- due to secondary bacterial, fungal, or parasitic infections
• Thin skin
  
• Lethargy
• Panting- due to affects on the lungs or the respiratory center in the brain
• Obesity
• Anorexia (poor appetite)
• Straining to urinate or blood in urine due to urinary tract infection or bladder stone
  
• Weakness
• Depression
• Aggression
• Lethargy
• Corneal plaques 
• Irregular heat cycles in female dogs
• Testicular atrophy in males and clitoral enlargement in females
• Emesis (vomiting) due to pancreatitis
• Ataxia (in coordination), blindness, circling, and seizures due to a large pituitary tumor or spread of a malignant adrenal tumor
• Lameness due to a ruptured cruciate ligament

Diagnosis

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

The best way to diagnose this disease is with history and physical exam. If your dog has PU/PD, polyphagia, alopecia, muscle weakness, and excessive panting, then it has Cushing's. The adrenal screening tests are used to verify the diagnosis.

Some dogs have the normal symptoms of Cushing's, but routine 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 abdominal ultrasound to look at the actual glands.

1. Signalment

Cushing's tends to be a problem that affects older dogs, usually greater than 10 years of age. The disease tends to have a slow and gradual onset, so the early symptoms are easily missed.

Several canine breeds are prone to getting Cushing's:

• Yorkshire Terrier
• Poodle
• Beagle
• Boston Terrier
• Boxer
• Dachshund

Females and males get it at about the same frequency, neutered pets might be at higher risk of Cushing's.

2. History

Cushing's disease is suspected in any pet that has some of the symptoms described above, particularly the skin symptoms and the PU/PD. It is important to remember that 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 and cats 8 years of age or more.

Since dogs with this disease do not have a poor appetite (they have the opposite as explained in the symptoms section above), owners wil delay in bringing their dog in for an exam. They assume a good appetite means their dog is doing fine. They misinterpret the excessive appetite (polyphagia) as being a good sign, when in reality is a sign of disease.

Most people wait until a dog, that is normally housebroken, is now urinating in the house. This delay can make it difficult to treat, and will frustrate some people to the point they are contemplating euthanasia.

Other historical findings include skin infections that recur after antibiotic therapy is stopped. Some dogs have a history of pruritis (itchiness) if pyoderma is present.

A history of poorly controlled diabetes mellitus might also clue us in to Cushing's.

3. Physical Exam

Routine physical exam findings might include:

Pot bellied abdomen

The abdomen of this dachshund is pot bellied due to Cushing's. It could also have been due to fluid buildup from cancer or heart disease. An enlarged liver from a disease other than Cushing's can cause this also.

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Enlarged lymph nodes due to secondary bacterial infections 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.

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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.

Heart disease, initially noted with the stethoscope as an increased heart rate, an irregular heart rate, or a murmur.

4. Diagnostic Tests

Several tests are used as an aid in making this diagnosis. Each test has its advantages and disadvantages.

Skin Scraping

Skin scrapings are usually negative in Cushing's, although demodex is possible as a secondary problem due to the immunosupression effect of cortisol.

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 (RBC's). 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 (neutrophilia), less lymphocytes (lymphopenia), and less eosinophils (eosinopenia). These white blood cell abnormalities can also be caused by the "stress response". It is due to excess epinephrine and cortisol secreted in response to the actual process of taking the blood sample (those people that have passed out when their blood was taken are an extreme example of this). The excess cortisol secreted by the adrenals in the stress response is temporary, and part of normal physiology. It is not caused by Cushing's disease.

Cholesterol, blood glucose, 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, drugs, pets with diabetes mellitus, and pets with cancer can all cause an elevated Alk Phos.A significantly increased Alk Phos alerts us to keep Cushing's in our tentative diagnosis list.

This dog has a mildly elevated liver enzyme test and mildly elevated Alk Phos. If the signalment, history, and physical exam do not make us suspect Cushing's we probably will not proceed to adrenal screening tests. This dog should be examined, and the blood should be checked every 3-6 months to see if these abnormalities are increasing.

  

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This dog has a normal liver test but a higher Alk Phos than the dog above. Some dogs even go much higher than this, especially if the disease has been present for a long period of time. This dog needs further diagnostic tests if there are any other Cushing's symptoms present also. Note the 3 arrows on the bottom that point to Cholesterol, Bun, and Creatinine. Cholesterol is usually high, but BUN is usually low, not high, in Cushing's Disease. The high BUN and creatinine could indicate that this pet might be dehydrated, or even have kidney disease in addition to Cushing's.

  

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Urinalysis

A normal specific gravity in a dog should be around 1.025, and there should be no or minimal protein, glucose, WBC's, or bacteria, as a general rule. In Cushing's the specific gravity of the urine might be low, the protein might be elevated, and a urinary tract infection might be present because of excess glucose in the urine.

This urinalysis of a Cushing's dog shows a low specific gravity and excess protein, but the glucose is normal and there is no sign of an infection.

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Skin Biopsy

This test can give us an idea that Cushing's is the cause of a skin problem. Many of the changes that are noted microscopically when evaluating the biopsy are also seen in other diseases, so it is not specific for Cushing's. In spite of this fact, skin biopsies give us a large amount of information in skin conditions.

Radiography

Radiography might be of value if the adrenal glands are calcified (happens in up to 50% of adrenal tumors), otherwise the adrenals do not show up on a radiograph. Hepatomegaly can be seen on the radiograph, along with problems associated with other diseases in pets this age, so a radiograph can be highly beneficial to help rule them out. Radiography might also show osteoporosis (poor bone density) and calcification of soft tissue, both of which could be due to excess cortisol.

In this lateral view (laying on its side) of the abdomen, the kidney (K) closest to the arrow is the right kidney. The arrow points to where the right adrenal gland is located, although it cannot be seen since it is not calcified. The whitish area between the K's is normal, and is caused by the effect of the 2 kidneys as they overlap.

This is a VD (ventral-dorsal, or laying on its back) view of a dog. The left kidney (K) is labeled, and the arrow points to where the left adrenal gland is located. There is some calcification in this radiograph, but it is not at the adrenal gland. Can you see it?

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The liver (L) might be enlarged (hepatomegaly), although this enlargement can be found in other diseases, especially liver cancer and diabetes mellitus.

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Ultrasound

This test can be highly beneficial in this diagnosis. The adrenal glands can be measured, and their internal architecture (called parenchyma) can be analyzed. It is not feasible to visualize all of the distinct different zones of the adrenal gland though. Other internal organs are also checked, giving us a substantial amount of information from just one test.

This adrenal gland measures 1.9 cm by 0.9 cm, so it is a little enlarged (hypertrophied).

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This dog also had an enlarged spleen (splenomegaly) with a mass in the center of the spleen

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The final report summarized the problems:

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Screening Tests

This is the most reliable way to confirm a diagnosis of Cushing's disease. 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 hypothalmic-pituitary-adrenal axis. The first goal is to determine if Cushing's disease exists. The next step is to determine if it is pituitary dependent (PD) or non-pituitary dependent (an adrenal tumor- AT). You might want to go back to the Cause Section above for a review before proceeding further.

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. Because of this there are inherent limitations with laboratory testing.

The normal values in animals calculated by a particular lab are called reference values. They reflect 95% of the population, statistically the same thing as the values that fall under the bell shaped curve. Not every animal falls perfectly into this range, so there is always a degree of interpretation needed in determining whether a value is abnormal or not. Eventually, it boils down to a determination of probabilities.

Two important concepts of laboratory testing relate directly to Cushing's:

Sensitivity

The sensitivity of a test refers to the ability of that test to detect diseased patients. A Cushing's test that is 95% sensitive will diagnose Cushing's in 95% of all dogs with Cushing's disease. 5% of the dogs in this scenario will have Cushing's, even though their screening test for Cushing's says they don't have the disease.

Specificity

The specificity of a test refers to the ability of the test to detect only diseased patients. A Cushing's test that is 95% specific means that 95% of the time if the test is positive for Cushing's, the animal really does have Cushing's. This means that 5% of the time the test will say an animal has Cushing's disease when in reality it does not.

Animals that do not have Cushing's disease might show up positive on these tests, while others that have the disease might be negative on these tests. Many times we have to play the odds based on probabilities. Due to this limitation in testing we recommend using these tests in combination, and repeating them if they do not give clear cut answers.

These tests sometimes come back as positive for Cushing's when in reality other diseases are affecting the cortisol level. Some of these diseases (called non adrenal illness) include liver disease, chronic kidney disease, urinary tract infection, skin diseases, and uncontrolled diabetes mellitus. Also, cortisone and anticonvulsants can give false positives.

The most common screening tests are as follows. If you make it through this next section then you should give yourself a pat on the back. You might just want to go right to a summary of these tests.

Urine cortisol:creatine ratio

In this test the level of cortisol in the urine is measured and used as an indication of the cortisol level in the bloodstream. Creatinine is measured to adjust for different levels of urine dilution. Our kidney page has more information on creatinine.

This test is useful as a screening tool when our differential diagnosis (you know what that means because you read the Diagnostic Process page) does not put Cushing's on the top of the list. For example, we might use it in a pet that has PU/PD, but not the other signs of Cushing's. It works in both dogs and cats.

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This test is easy to perform because all that is needed is a urine sample. We recommend you obtain this sample at home in the morning just after your pet wakes up. Bring it to us immediately for analysis by our lab. Obtaining it at home will minimize the stress of a car ride and a visit to our hospital, both of which will normally increase the level of cortisol in the bloodstream (remember the stress response?), thus affecting this test.

A high level of cortisol in the sample is suggestive of Cushing's. Unfortunately, up to 80% of dogs that don't have Cushing's will also have an increased level. This means that the specificity is low. A cortisol:creatinine ratio test that is high needs one of the other screening tests to determine if Cushing's is indeed present. If the test comes back normal, then it is unlikely that Cushing's is present.

ACTH Stimulation

This test checks for Cushing's and Addison's disease. Some experts recommend this as the best general test for a diagnosis of Cushing's. It is also used to monitor therapy on pet that is on medication for Cushing's.

When a dog or cat is given ACTH by an injection the adrenal glands are stimulated to produce cortisol. By measuring this cortisol with a blood sample we can determine what reserve the adrenal glands have in the production of cortisol.

This is the ACTH we inject. It is given at a specific dose depending on the weight of the pet.

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This test is very specific for Cushing's, so false positives are rare compared to other screening tests. It is not as sensitive as other screening tests, particularly the LDDS test. For this reason it is sometimes used in combination with the LDDS test.

This is the only test that can distinguish between iatrogenic and naturally occurring Cushing's. It is the only test that gives reliable results for a dog that has been on cortisone recently. It does not distinguish between pituitary dependent (PD) and non-pituitary dependent (AT-adrenal tumor).

A blood sample is taken to measure the resting cortisol level before ACTH is given. Two hours after the ACTH injection is given a blood sample is taken again to measure the level of cortisol. This two hours gives the ACTH injection time to stimulate the adrenal glands to produce cortisol.

In the dog, if the second test of cortisol is much higher than the first, it is suggestive of Cushing's 80-95% of the time. It does not necessarily tell us if it is PD or AT, because this exaggerated response will occur in 85% of PD Cushing's, and also 50% of those with AT Cushing's. This test is not as reliable in cats, only 51% of cats with Cushing's will show an exaggerated response.

If there is a reduced level of cortisol on the second blood sample then either the dog has Addison's disease or iatrogenic Cushing's. This reduced response also occurs in dogs that are receiving Mitotane or Ketaconazole therapy for Cushing's.

Between 5% and 20% of dogs that have Cushing's (either PD or AT) will not show the exaggerated response expected with this disease. If we suspect Cushing's in these dogs then the test should be repeated at a later date or the LDDS test should be performed.

Low Dose Dexamethasone Suppression Test (LDDS)

This is probably the best test when the history, physical exam, and routine blood panel and urinalysis are consistent with Cushing's. It might also help differentiate between PDH and AT, but that is better determined by the HDDS test (High Dose Dexamethasone Suppression test). It only works in dogs because cats get a significant number of false positives.

It is sensitive for Cushing's because 85% to 100% of the time it finds a Cushing's disease that is present. Its specificity is low though, meaning it might come back as positive for Cushing's between 44% and 73% of the time when the dog does not have Cushing's.

This dose of dexamethasone (which is a version of cortisone) suppresses the adrenal gland from producing cortisol in normal dogs, but not those with Cushing's. It achieves this suppression by interfering with the negative feedback mechanism. The dexamethasone is monitored by the brain as an excess of cortisone in the bloodstream, so less ACTH is secreted, and therefore less cortisol is secreted by the adrenal gland.

In this test an injection of Dexamethasone is given and cortisol levels are measured at 4 hours and 8 hours after the injection. Like the ACTH stimulation test, a pre-injection blood sample is taken to measure the resting cortisol level.

In interpreting this test we look at the 8 hour sample first. At this time cortisol levels should be below the baseline level obtained before the injection. If not, then a diagnosis of PD or AT Cushing's is made, or there is a false positive result. If the 4 hour or 8 hour cortisol test result is less than 50% of the normal resting cortisol, then a diagnosis of PD Cushing's or false positive is made. If the 4 hour or 8 hour cortisol test result is greater than 50% of the normal resting cortisol, then a diagnosis of Cushing's is made or there is a false positive. In this last scenario it cannot be determined if the Cushing's is PD or AT.

If the 4 or 8 hour samples show suppression when compared to the normal resting cortisol level then there is no Cushing's disease, or else there is a false negative.

Here are the LDDS test results on a dog that we suspected of having Cushing's. What is your diagnosis in this case?

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High Dose Dexamethasone Suppression Test

This test is not used as a routine screening test. It comes into play when a dog already has Cushing's and you want to be certain that it is not that occasional case that is an adrenal tumor.

The protocol for this test is similar to the LDDS test, except of course, a higher dose of dexamethasone is injected. A dog with an adrenal tumor does not suppress cortisol levels from the baseline sample.

Summary of Cushing's Screening Tests

Urine cortisol:creatinine

In some dogs with Cushing's the excess cortisol that circulates in the blood stream will spill over into the urine. If this test is positive then a dog might have Cushing's. If it is negative, there is a good chance it does not have Cushing's.

ACTH Stimulation

A positive on this test gives a reasonably good chance that a dog has Cushing's. It will not catch all dogs with Cushing's, so a dog with a negative test might still have the disease.

LDDS

This test will catch most dogs that have the disease, and is the test of choice for Cushing's.  A negative on this test means that most likely the dog does not have Cushing's. A positive on this test indicates that a dog might have Cushing's. It is the most popular adrenal screening test.

See how easy that was! 

5. 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. You should note significantly less PU/PD, improved skin, and a more active pet if the treatment is successful.

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 b present also.

Treatment can be drawn out, and involves significant time and expense to monitor your pet after we treat it. Also, in some dogs, treatment can lead to side effects that are more serious than the symptoms of this disease. One of these side effects includes death, so we do not undertake treatment of this disease lightly.

This disease tends to occur in older dogs that commonly have other problems. Some dogs die of other diseases before the symptoms of Cushing's become a significant problem. Treating Cushing's does not necessarily give your pet a longer life. The goal of therapy is to give your pet a better quality of life.

Underlying problems need identification and treatment. If your dog is hypothyroid the problem needs to be corrected with supplemental soloxine. Internal organ problems like kidney disease need treatment for a successful Cushing's outcome. Urinary tract and skin infections need to be cleared up with the use of antibiotics, and underlying diabetes mellitus needs to be regulated with insulin.

Some dogs with large tumors of the pituitary gland might initially respond to medical therapy for pituitary dependent Cushing's. The Cushing's symptoms, especially neurologic, might recur as the tumor progresses.

Several different treatment modalities have been developed for Cushing's. Some are for Pituitary Dependent Cushing's, some are for Iatrogenic Cushing's, and some are for adrenal tumors. 

Pituitary Dependent (PD) Cushing's:

Mitotane (o,p'-DDD)

This drug has been used to treat this disease for 30 years, and is  know by the trade name 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:

• lethargy
• emesis (vomiting)
• diarrhea
• anorexia (poor appetite)
• weakness
• ataxia (in coordination)

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 you are to immediately stop medicating and call us. We will already have given you prednisone pills to give at home if side effects are significant.

After 7-10 days of loading dose the cortisol levels are assessed with the ACTH stimulation test. Do not give your pet any supplemental cortisone on the day of testing. 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:

1. The 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.

2. 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.

This drug controls the symptoms of Cushing's 80% of the time.

Trilostane

This is the newest treatment for this disease.  Trilostane is an inhibitor of an enzyme called 3-beta-hydroxysteroid dehydrogenase. This enzyme is involved in the production of several steroids including cortisol. Inhibiting this enzyme inhibits the production of cortisol. 

It has similar side effects as mitotane, usually when given once per day. A modified dose, given every 8-12 hours, works better for most dogs. It is significantly more expensive than mitotane. With this new treatment regimen it is the drug we recommend for Cushing's.

L-Deprenyl (Anipryl)

It works only for PD Cushing's, although it has been show to be ineffective treatment for this disease overall. It is used for Parkinson's disease in people and is also used to treat canine cognitive dysfunction (CD). This is helpful because one medication can be used to successfully treat 2 diseases that occur in older dogs.

It affects the hypothalamus and its interaction with the pituitary gland in relation to a chemical called dopamine. There are minimal side effects, especially when compared to the other drugs used to treat Cushing's. ACTH testing is of no value to monitor effectiveness since the drug does not act on either the pituitary or the adrenal gland.

It is given daily for 2 months, with the dose increased if the symptoms don't diminish. The majority of PD Cushing's dogs will show an improvement in symptoms within the first 2 months. If there is no improvement within one month after the dose is increased then concurrent illnesses need to be looked for. If they do not exist then therapy with mitotane should be instituted. Anipryl drug should not be used if your pet is being treated for Demodex with Mitaban, or with antidepressant medications or Prozac. 

Ketaconazole

This is a drug routinely used to control fungal infections. It has a different mechanism of action than mitotane. It inhibits cortisol production in dogs and humanoids by preventing enzyme pathways from functioning properly. Ketaconazole works for PD and AT Cushing's. It is not as common to use as the previous 2 drugs.

It needs to be given at a test dose initially to watch for anorexia or emesis. If tolerated well, a loading dose is given for 7-10 days. After an ACTH test to determine if the cortisol is in the normal range, the drug is given every 12 hours for the rest of the dogs life. This is a more expensive proposition than mitotane.

Surgery

Surgery to remove both adrenal glands can also be used. It is an involved endeavor performed at a specialized surgical hospital. Post operative complications are common, and these pets need lifetime prednisone replacement therapy. As a result, this treatment is not commonly utilized.

Radiation

Recurrence of the symptoms of PD Cushing's after initiation of therapy might be an indication of a large pituitary tumor. MRI is recommended to identify this type of tumor. Radiation therapy is recommended to prevent further progression of symptoms. Unfortunately, there are very few specialty radiation centers that can perform this procedure.

Iatrogenic Cushing's:

This form of Cushing's is the easiest to treat since we are not giving a medication but taking one away. In most cases the elimination of exogenous cortisone will return your pet to normal function, although this might take several months. Some of the skin changes might take longer, and may not even return completely to normal. In some cases we use a decreasing dose of supplemental prednisone for several weeks to give the adrenal glands time to resume normal production of cortisol.

Adrenal Tumor (AT):

The surgery to remove the cancerous adrenal gland is called an adrenalectomy. It is a specialized surgery that is not routinely performed. Post operative complications are common.

Because the remaining adrenal gland is atrophied the dog needs to be supplemented with prednisone until the gland returns to normal function. ACTH tests are done every few months to determine when the gland is functioning normally, which can take up to 12 months.

Adrenal tumors can also be treated with mitotane at high doses and for a long period of time. Side effects are common at this dose, and relapses can occur. These dogs will also need to be on supplemental prednisone for the rest of their lives.

Feline Cushing's

Cushing's in cats is rare compared to dogs. One reason is because they tend to be more resistant to higher levels of cortisol, especially if iatrogenic. Most feline Cushing's occurs in females. It can affect the ability to control the blood sugar level in cats with diabetes mellitus concurrently.

History

Cats do not show as much PU/PD as dogs do, unless they have diabetes mellitus concurrently. Most cats are presented in a more advanced state of Cushing's disease because the early symptom of PU/PD is not observed. They might also have hepatomegaly, weight gain, pot-bellied appearance, and muscle wasting.

Sometimes the skin is easily bruised and torn. This is called the fragile skin syndrome.

This picture is from an older cat that was at the groomer to be clipped. The skin literally peeled off like wet tissue paper when the groomer attempted to clip some mats.

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Diagnosis

Cats do not routinely show any changes on a regular blood panel or urinalysis. The most consistent finding on a blood panel is hyperglycemia. an elevated alkaline phosphatase occurs in only a minority of cases. Oftentimes the elevated alkaline phosphatase is due to liver changes from unregulated diabetes mellitus.

The urine cortisol:creatine ratio test is helpful in cats, especially since it is a relatively stress free test compared to blood sampling. If the test is normal then there is much less of a chance that Cushing's is present. It the test is elevated it might be Cushing's, but there are also other situations that cause this elevation.

The ACTH stimulation test is used, but two blood samples need to be analyzed at 30 and 60 minutes, instead of the 1 sample at 2 hours for the dog. This is because the increase in cortisol is variable in the cat. False negatives are common. False positives occur in stressed cats or those with non adrenal illness.

The LDDS test is used but the dexamethasone that is injected needs to be given at a higher dose. This test, when used in conjunction with the ACTH stimulation test, is one of the best ways to diagnose Cushing's in the cat.

The HDDS test to differentiate PD from AT has not been refined to the point that is of diagnostic value.

In general, results of these tests can be variable, and must be interpreted in conjunction with the history and clinical findings. In light of the fact that Cushing's is uncommon in cats, these tests need careful interpretation.

If the above tests suggest Cushing's then radiology can be helpful since up to 30% of feline adrenal tumors are mineralized. Other radiographic findings include hepatomegaly and obesity. Ultrasonic evidence of an enlarged adrenal gland (especially if unilateral) or changes in internal adrenal architecture is strong evidence of an adrenal tumor (AT).

Adrenal tumors occur in about 20% of feline Cushing's. They can be malignant or benign.

Treatment

Medical therapy is generally unrewarding. Ketaconazole can be used, but the effects are variable, and side effects can occur. Mitotane might help, along with metyrapone. Metyrapone may be more helpful as a presurgical stabilization prior to surgery. Anipryl has not been used in cats.

Surgery is needed to remove one of the adrenal glands if the gland has a tumor, and both glands if the problem is PD. If both glands are removed the cat has to be on supplemental cortisone and mineralcorticoids for the rest of its life. Some cats with concurrent diabetes mellitus will no longer have the disease when their adrenal tumor is removed.

Unfortunately, cats with Cushing's can be poor anesthetic risks due to diabetes mellitus and fragile skin. When this occurs we sometimes will use medical therapy to help control the problem and make our patient a better anesthetic risk.

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