Cushings Disease (hyperadrenocorticism)
by Roger Ross DVM
Like Diabetes, Cushings Disease is a major metabolic disorder,
and like Diabetes, is a common disease in dogs.
Cushings, unlike Diabetes is not very common in Cats, so
this article pertains mostly to Dogs.
Introduction and general comments:
The adrenal glands produce the different types of steroidal hormones that help regulate metabolism and keep electrolytes in balance. These hormones affect the health and function of every organ in our body as well as our moods and reactions.
One of the most potent of the hormones that the adrenal glands produce is called cortisol or cortisone. Cortisone is critical to life, strength, and vitality ...too little and mammals die or become very sick; a disease we call Addison's disease or hypoadrenocorticism.
But too much cortisone causes a lot of trouble too. There are several reasons why the adrenal glands might produce too much cortisone and that's what this article is all about:
When the adrenal glands produce too much cortisone, disease occurs, and we call this disease Cushings Disease ... or in the new, more descriptive terminology: Hyperadrenalcortisim
A quick aside: The different sex hormones such as estrogen and testosterone, including all the variants that athletes, body builders, and other people "abuse", are cortisone based. In other words, the cortisone molecule is the main building block used by the body to make hormones. It's a very potent molecule. You've heard that taking steroids is dangerous; well you're about to find out what those dangers are because taking too much will cause the same problems that occur with Cushings Disease.
Here's a short list of the organs and tissues adversely affected by too much cortisone:
I mention the muscles first, because it's the desire for increased muscle mass and strength that most people abuse steroids.
And it's true, certain steroids known as anabolic steroids will increase muscle mass and strength, but remember that anabolic steroids contain the cortisol molecule and too much can cause the muscles to actually shrink. This is a little complex, but this is because one of the roles of cortisol is to regulate blood glucose levels by stealing amino acids from muscle cells for conversion to sugar in the liver. This process makes the muscles smaller! And weaker. In dogs (and humans), when the abdominal muscles become weak it makes the dog look "pot-bellied" : one of the big clues that vets look for on exam.
In people, the most noticeable sign of excessive steroids use is unhealthy skin: it causes changes in the elastic tissue, sebaceous gland disease and acne.
In cats and dogs, the most obvious sign is skin that is very thin or fragile. And hair loss. And we often find calcium nodules in the skin.
Excess cortisol causes the walls of the blood vessels to become too thin which can lead to easy bruising, hematoma's, and so forth.
Cortisol plays an important role in maintaining blood pressure, but too much can lead to excessive blood pressure.
Cortisone affects the calcium balance in bones, and too much causes the bones to lose calcium making the bones smaller and weaker. This process also leads to excess calcium loss through the kidneys.
Cortisone affects your mood, behavior, and even your sleep patterns. This is true in animals too, and the observant pet owner may notice this.
Cortisone stimulates the kidneys to go into overdrive; important when the body is in fight and flight mode, but hard on the kidneys if in constant overdrive. One of the big clues that a patient might have Cushings Disease is that the patient is drinking and urinating a lot more than normal and that the urine is not very concentrated. "It looks like water, Doc".
The Immune System:
This is a big deal. Steroids work better, as a rule, than any other medications at reducing severe itching, asthma, allergies, inflammation, and most other immune related diseases. That's why they are so often used for legitimate medical reasons. It does this, in general, by suppressing the immune system. It prevents the immune system cells from releasing all the chemicals that are needed to fight off allergens, germs, and repair damaged tissue. This is great if you're treating an over-active immune system...
But, too much immune suppression and you lose the ability to fight off infections making the patient susceptible to the zillions of organisms that invade the body on a daily basis. Remember that the body is at constant war with the microscopic world.
Because cortisone stimulates the liver to work harder than normal at making glycogen, over time the liver becomes larger. Your vet might notice an enlarged liver on palpation or on radiographs.
Dr Harvey Cushing, the most famous of neuro surgeons working on diseases caused by the pituitary gland would draw detailed sketches after each surgery
A Little Bit More About The Adrenal Glands
The adrenal glands are composed of two different types of tissue known as the cortex and the medulla. This is worth knowing because the cortex (or outer part) is the part of the adrenal glands that manufactures cortisone and it is this part of the adrenal gland that has gone haywire in Cushings disease.
The Medulla (or middle part) of the adrenal glands make the hormones and neuro-transmitters known as mineral-corticoids (including epineprhine and aldosterone) that are so important in regulating blood pressure, electrolyte balance, and the famous fight or flight response. Luckily, Cushings disease doesn't affect the medulla much.
(Addison's disease is the other major disease of the adrenal glands and it affects both the cortex and the medulla leading to too little hormone production...more or less the opposite problem that Cushing's causes.)
The Different Possible Causes Of Cushings Disease:
Too much ACTH : This is the most common cause of Cushings Disease and is known as Pituitary Dependent Cushings Disease.
This isn't too complicated, but the amount of cortisol in the body is regulated by the pituitary gland in the brain. Whenever the brain thinks more cortisol is needed, the pituitary gland in the brain releases a chemical (hormone) called ACTH into the blood stream. ACTH is an acronym for adrenalcorticotrophic hormone and it stimulates the cortex of the adrenal gland to manufacture and release cortisol (cortisone).
Well, unfortunately, the pituitary gland is prone to cancer; a benign, slow growing cancer called an adenoma. Not too big a deal as far as cancers go, but it makes the pituitary release more than normal amounts of ACTH and that makes the adrenal glands get bigger and stimulated to produce more than normal amounts of cortisone.
As an aside, this adenoma tumor in the brain sometimes gets big enough to cause other problems too, such as severe headaches and severe neurologic dysfunction. This is interesting from a medical standpoint because the medications used to treat Cushings can cause severe headaches and neurological dysfunction too, so it complicates things. If we notice trouble, is it the drugs or is it the tumor?
Pituitary Dependent Cushings Disease is the most common type by far, but there are several other possible causes and guess what? They're all lumped into a category called Non-Pituitary Dependent Cushings Disease.
Other Possible Causes of Cushings:
Tumors of the adrenal gland:
The other major cause of Cushings Disease is from tumors of the adrenal Cortex. About half the time the tumor is benign (Adenoma), the main problem being that it leads to excess cortisone production. The other half of the time the tumor is malignant (Adeno-carcinoma) and in addition to causing the adrenal gland to produce way too much cortisone, it will often invade and cause severe disease of the nearby liver, major veins, and lypmh nodes.
Another aside: Adrenal tumors are a common problem in ferrets. In ferrets, though, the tumor causes an excess secretion of sex hormones, not cortisone, causing a different set of symptoms when compared to the dog and cat.
The other big cause of Cushings-Like Symptoms is from taking cortisone based medications, either legitimately to treat another disease or not so legitimately because you want to be superman.
This is called iatrogenic Cushings. Iatrogenic is a fancy medical term for self induced.
Steroids are very useful in treating a lot of serious diseases, but it's because they can cause Cushings disease if given long term that Doctor's try to wean their patients off the drugs and/or find alternative treatments once the major symptoms of the disease are under control. The reason we usually wean patients off steroids slowly is because as long as there are synthetic steroids in the blood, the sensors in the brain (pituitary gland) assume the body doesn't need any more cortisone, so the brain tells the adrenal glands to take a rest; don't produce any more...and over time the adrenal glands shrink. It may take several weeks for them to get back into adequate production once you stop the synthetic cortisones.
There is one other possible cause of Cushings and it's pretty rare. It's called Ectopic ACTH Syndrome. Basically it means that some cancer somewhere other than the pituitary or adrenal gland happens to start producing ACTH. ACTH, you will probably remember is the hormone that stimulates the adrenal gland to produce cortisone, and in normal patients, is only made in significant quantities by the pituitary gland.
Dr Cushing performing an early brain surgery
Okay, enough introduction. Here's what might be happening to your dog if it has Cushings: Remember that some dogs with Cushing will show many of these symptoms and others may not.
1. Drinking and urinating a lot. This is usually the first sign. We also see this symptom with pets on steroids, and for those pets with other metabolic diseases such as diabetes, kidney disease, and liver diseases.
2. A distended abdomen or pot-belly.
3. Thin skin and poor coat, often with very wispy hairs and hair loss along the back.
4. Little calcium deposits under the skin. Black pigmentation of the skin.
5. Excess appetite (but sometimes poor appetite) often way overweight
6. Muscle wasting and shrunken testicles in intact males. (Big clitoris in females)
7. Other, more vague symptoms such as no energy, poor disease resistance and therefore multiple problems and infections, & mood or behavior changes.
What To Expect When You Go To The Vet
(Of course, your vet may do things differently)
Exam: Especially meticulous when you come in for any of the above complaints. Metabolic diseases can be tough to pin down and one can be confused with another. And we know from experience that so often multiple problems are going on at once. We will probably present you with quite a list of suspected problems which we will then try to narrow down by doing lab tests and deductive reasoning. We will ask a lot of "history" questions.
We will palpate for an enlarged liver. Also enlarged lymph nodes due to the secondary chronic infections, especially of the skin, that often occur in Cushings patients
Some dogs have both Cushings and Diabetes
Because blood pressure is affected we will be looking for symptoms such as bruising and vascular changes in the eye.
Detached retinas are sometimes seen with Cushings patients because of the higher blood pressure
We will listen for heart murmurs and slow weak pulses; these are sometimes associated with Cushings disease
Certain breeds of dogs are more prone to Cushings than others:
Beagles, Boston Terriers, Boxers, Dachshunds, Poodles, and Yorkies.
This is generally a disease of middle aged and older pets. Gender doesn't seem to be a big factor.
Diagnostic Tests That Might Help:
Routine Blood Panel
A CBC (complete blood count) and biochemistry panel should ideally be run on every dog 8 years of age or more as a geriatric screening test for all kinds of problems, but especially if they have any of the symptoms such as those described above. We often pick up Cushings disease on routine blood work as a "surprise"...before many overt symptoms appear while doing blood work for other reasons.
Typical Cushings patients have elevated red blood cells, alkaline phosphatase, cholesterol, glucose, and liver enzymes. BUN and Thyroid are often lower than normal. Remember that we run these tests not only to confirm our suspicions of Cushings, but also to rule out similar or additional problems.
More Specific Blood tests for cortisol levels:
Routine blood panels help us to rule out diseases such as diabetes which have similar symptoms and tell us whether or not Cushings disease is likely or not ... but routine blood panels don't prove the existence of the disease... nor do they tell us whether the suspected disease is due to an adrenal tumor or a brain tumor. So expect your vet to also recommend one of several types of cortisol testing. One of the easiest available, least expensive and informative tests is called a low dose dexamethasone suppression test and involves taking a blood sample from your dog 3 times over an 8 hour period. I do it at 0 hours, 3 hours, and 8 hours. Each time we will be testing for cortisol levels. Right after drawing the blood the first time, we inject a tiny amount of dexamethasone into your dog's vein. Dexamethasone is a common, inexpensive, synthetic cortisone that all vet's typically have in their practice. In a normal patient, this synthetic cortisone would fool the brain into thinking that there is too much cortisol in the blood and the brain would stop releasing ACTH and natural cortisol levels would become reduced by 50% after 3 hours and remain low at the 8 hour check too.
But in the dog with PDH or pituitary dependent hyperadrenalcortism ... or Cushings disease due to a tumor of the pituitary gland... natural cortisol is usually depressed at 3 hours but back to high levels at 8 hours.
And in dogs with Cushings disease due to adrenal tumors, the cortisol level is not depressed at all.
So this test tells us not only if our patient does, in fact, have Cushings disease (excessively high levels of cortisol on the first blood sample) but also tells us with fair accuracy whether or not the problem is due to a brain tumor or an adrenal tumor. Knowing which is important for deciding on treatment.
We often seen elevations of glucose, protein, and infection in the urine of dogs with Cushings, we often don't. But we do expect to find a low specific gravity: The urine is almost water like with this disease. Once we get a urine sample, getting a specific gravity reading is a standard and easy procedure.
This test will probably not be done to confirm suspected Cushings disease...but... I mention this test here because we sometimes do a skin biopsy to help figure out why a pet's skin is unhealthy and the biopsy results indicate the possibility of Cushings.
We usually can't see the adrenal glands on x-rays, but x-rays are still a useful tool with suspected Cushings Patients because they can show:
Calcified Adrenal Glands which occurs in many adrenal tumors.
Calcification of other tissues
Enlarged livers which can be associated with Cushings
Poor bone density which can be associated with Cushings
Hey, I don't pretend to know about MRI's, but if your vet or veterinary specialist has this available, it can identify and measure pituitary gland tumors. As of this writing, very few veterinary practices have an MRI machine available.
Step One: Treatment of the several problems that usually accompany Cushings Disease such as skin and bladder infections. Hypothryoidism. Kidney Disease. Diabetes.
Step Two: Understanding that there is not likely going to be a cure; our goal is usually to make the pet as comfortable as possible.
Step Three: Treatment of the Disease:
Up until recently, veterinarians have used ketoconazole, and Anipryl as treatments for Cushings disease but these older treatments are now considered inferior or maybe even useless.
Much superior is a chemo medication called Lysodren (Mitotane) which selectively kills the parts of the adrenal gland that produces cortisol. This helps, but it complicates other things; your vet will carefully go over all the ups, downs, and adjustments that will be needed. Also, side effects are fairly common such as diarrhea, vomiting, loss of appetite etc. Mitotane is fairly expensive and in addition to the expense of the medication, the dose should be monitored with lab tests costing about $100 a pop.
You may also have to supplement your pet with cortisone medications such as prednisone. You may also have to give your dog other medications to help control the side effects (GI upset) of Lysodren.
All this expense and nuisance may well be worth it, though...I've seen a lot of sick, miserable dogs become happy and healthier within weeks of treatment. And treatment is less expensive than the latest medication available:
Trilostane: I haven't had any experience using this medication yet but I understand it is now available in the U.S., and while more expensive than Lysodren, it has been quite successful and has fewer side effects.
Surgical Removal of the Adrenal Glands:
About 85% of Cushings disease cases are due to pituitary tumors in the brain and as far as I know, surgical treatment of these brain tumors is not available.
About 15% of Cushings disease cases are due to tumors of the adrenal gland and surgical removal is possible but not commonly done. (I did a very successful adrenal gland removal in a ferret this year but have never done the procedure in a dog) It's very difficult to manage electrolyte levels, blood pressure, and all the other roles associated with the adrenal glands synthetically. Sometimes just one adrenal gland will be removed...the one with the tumor...but the problem is that the other gland is often atrophied and not working.
This is yet another specialty that I know almost nothing about, but sometimes radiation therapy is used in treating Cushings. Learning more about the best options available for treating your dog ... whether it be more information about the new medication Trilostane, the possibility of surgical correction and/or radiation therapy are good reasons to go to a specialist. Veterinary specialists are now available in most large cities and most local veterinarians are delighted to refer pets with complicated medical conditions like Cushings.
Treatment of Iatrogenic Cushings:
You will remember that Iatrogenic Cushings is caused by giving too much cortisone based steroid medication...usually for the treatment of allergy symptoms. Usually the treatment simply involves reducing the steroid treatment over several months until things hopefully go back to normal.