Cushing’s Disease Summary

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This page summarizes the complex disease know as Cushing’s disease, also know as hyperadrencorticism. It is a disease that occurs from the overproduction of cortisone by the adrenal glands

Anatomy

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

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.

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

  • Cortex

    This is the section that produces the glucocorticoid cortisol. Cortisol has large effects on carbohydrate and protein metabolism.

  • Medulla

    This consists of the very center of the adrenal gland. It secretes hormones commonly known as epinephrine or adrenaline.

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 a profound effect on the body. They also 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 a summary of adrenal hormone physiology is presented.

The adrenal glands secrete several important hormones, most of which originate from cholesterol. The most important hormone secreted in relation to Cushing’s is called cortisol.

Cortisol, also commonly known by the slang term “steroids”, 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 kidney system.

Stress will increase the level of this hormone in the bloodstream. This includes surgery, infection, fever, and hypoglycemia (low blood sugar). The level of this hormone continually fluctuates in the bloodstream depending on physiologic needs. This continual fluctuation adds to the difficulty of diagnosing Cushing’s, which you will learn about soon.

To control the level of these hormones, the hypothalamus and pituitary gland in the brain secrete chemicals into the bloodstream. One of these chemicals is called adrenocorticotrophic hormone (ACTH). It is the amount of ACTH circulating in the blood stream that tells the adrenal glands 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 ACTH secreted. This allows the body to precisely refine the levels of cortisol, and change cortisol levels rapidly due to changing physiologic needs.

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 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.

  • Non-Pituitary Dependent (aT)

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

    The benign version of this tumor occurs 50% of the time, and is called an adenoma. The malignant version, which occurs the other 50% or the time, is called an adenocarcinoma. It can spread from the adrenal gland to the liver, lung, kidney, and lymph nodes.

  • Iatrogenic

    Long term use of supplemental cortisone, in oral, injectable, or even topical form, might cause an animal to have the symptoms of Cushing’s disease. A common supplemental cortisone is called prednisone. The blood level of cortisone that results from this supplemental use will cause the adrenal glands to shrink in size. This is because 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 it is being introduced into its body, not because the adrenal glands are overproducing it.

Symptoms

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

  • Polyphagia- excess appetite.
  • Polyuria/polydypsia (PU/PD)- This is excess urinating and excess drinking of water. Several other important diseases cause these symptoms also, notably liver disease,kidney disease pyometra, and diabetes mellitus (sugar diabetes).

  • Pot bellied abdomen.
  • Thin skin and usually symmetrical hair loss along the trunk. The hair might grow in lighter in color or even be hyperpigmented. Secondary skin infections are common.
  • Other symptoms could include lethargy, muscle wasting, poor appetite, weakness, and behavioral changes.

Diagnosis

Cushing’s disease has a large effect on the skin. Many skin conditions have similar symptoms, so numerous diseases have to be kept in mind when making a diagnosis. These include hypothyroidism,skin allergiessarcoptic mangedemodectic mange, and Ringworm.

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 so that we do not overlook some of the diseases that are also encountered in pets as they age.

  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.

    Other findings include skin infections that recur after antibiotic therapy is stopped. Some dogs might be itchy if a skin infection is present.

  3. Physical Exam

    Routine physical exam findings might include:

    • Pot bellied abdomen

    • An enlarged liver (hepatomegaly) might be palpated, along with smaller muscle mass in general.
    • Bruising might be seen under the skin or when a blood sample is obtained.
    • Hair loss that is symmetrical and calcium deposits under the skin.
    • Blood pressure might be elevated.
  4. Diagnostic Tests

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

    • Blood Panel

      A CBC (complete blood cell) 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 increased WBC (white blood cell count). The biochemistry panel might show an elevated alkaline phosphatase (Alk Phos). This is an enzyme that is located in the bile production area of the liver. The excess cortisol influences this enzyme, although other diseases can cause this elevation also.Cholesterol, red blood cells, blood glucose, and liver enzyme tests might also be elevated. If a thyroid test is run also, it might be low or borderline normal.

      This dog has a high Alk Phos. Some dogs 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. BUN is usually low, not high, in Cushing’s Disease, so this pet might also be dehydrated or have kidney disease at the same time.

    • Urinalysis

      This test is not as important in Cushing’s disease as it is in other diseases, especially kidney disease. 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 this Cushing’s dog shows a low specific gravity and excess protein, but the glucose in normal and there is no sign of an infection.

    • Radiography

      Radiography might be of value if the adrenal glands are calcified (might occur with an adrenal tumor), otherwise the adrenals do not show up on a radiograph. an enlarged liver 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.

      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 can not be seen since it is not calcified.

      The liver (L) might be enlarged, although this enlargement can be found in other diseases, especially liver cancer

    • Ultrasound

      This test can be highly beneficial in this diagnosis. The adrenal glands can be measured, and their internal architecture can be analyzed.

      This adrenal gland measures 1.9 cm by 0.9 cm, so it is a little enlarged. In this dog it was due to pituitary dependent Cushing’s

    • 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 know as the hypothalmic-pituitary-adrenal axis. The first goal is to determine if Cushing’s Disease exists. after this is achieved, the next step is to determine if it is pituitary dependent (PD) or an adrenal tumor (AT).

    • Urine cortisol:creatine ratio

      In this test the level of cortisol in the urine is measure, 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. It is used in a pet that has PU/PD, but not the other signs of Cushing’s. It works in both dogs and cats.

      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. If the test comes back normal, then it is unlikely that Cushing’s is present.

    • ACTH Stimulation

      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 dog

      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.

    • Low Dose Dexamethasone Suppression Test (LDDS)

      This is also a good test when the history, physical exam, and routine blood panel and urinalysis are consistent with Cushing’s. It only works in dogs because cats get a significant number of false positives.

      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.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.

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

      This test will catch most dogs that have the disease. 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.

Treatment

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. Skin infections and internal organ problems like kidney disease need treatment for a successful Cushing’s outcome. Urinary tract 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 drugs have been used over the years to treat this disease. The 3 most common and effective ones will be described.

Pituitary Dependent (PD)

L-Deprenyl (anipryl)

This drug should be considered first in the treatment of PD Cushing’s. 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 is given daily for 2 months, with the dose increased if the symptoms don’t diminish. Side effects are negligible. 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. This drug should not be used if your pet is being treated for Demodex with Mitaban, or with antidepressant medications or Prozac.

Mitotane (o,p’-DDD)

This drug, know by the trade name of Lysodren, selectively destroys part of the adrenal gland. This limits the amount of cortisol that the adrenal gland secrete can secrete. Pets that are on insulin for diabetes mellitus need to have their insulin dose adjusted downwards when given mitotane. It should be administered with meals to enhance its absorption.

Side effects can occur with this drug:

  • lethargy
  • vomiting
  • diarrhea
  • poor appetite
  • weakness
  • incoordination

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 the use of mitotane. We will give you cortisone pills to give at home if side effects are severe enough.

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. Dogs with this problem have to be put on supplemental prednisone for the rest of their lives.

  2. It is not uncommon for relapses of Cushing’s to occur within 12 months, even while on the maintenance therapy.

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.

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 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 give every 12 hours for the rest of the dogs life. This is a more expensive proposition than mitotane.

Iatrogenic

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 cortisone 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.

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. The disease follow a similar pattern in cats and dogs with a few notable exceptions:

  • 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.

  • 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.

They do not routinely show any changes on a regular blood panel or urinalysis. If the alkaline phosphatase is high it is usually due to liver changes from unregulated diabetes mellitus.

The ACTH stimulation test is used but 2 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.

The LDDS test is used but the dexamethasone that is injected needs to be given at a higher dose.

Medical therapy is generally unrewarding 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 for the rest of its life. 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.