Cushing’s disease describes a syndrome resulting from the overproduction of cortisol, a normal naturally occurring hormone in cats and dogs. This overproduction results in a constellation of clinical signs and is also known as hyperadrenocorticism. It is seen mostly in dogs; cats are rarely affected. Middle-aged and older dogs are most commonly diagnosed, and the disease is slightly skewed toward females.
Overproduction of cortisol can result from either excess activity of the adrenal glands themselves or from excess stimulation of the adrenal glands to make cortisol caused by the release of the hormone ACTH by the pituitary gland in the brain. The most common form of Cushing’s disease is caused by the over production of ACTH by a pituitary gland tumor in the brain that in turn controls the volume of cortisol produced by the adrenal glands. This is called pituitary-dependent Cushing’s disease and is responsible for approximately 85% of the cases observed. A smaller percentage of dogs (15%) with Cushing’s disease have a tumor of one of the adrenal glands, which is responsible for the over production of endogenous cortisol. This disease state is known as adrenal-dependent Cushing’s. A small percentage of cases are caused by the over administration of glucocorticoids (iatrogenic Cushing disease) also known as steroids, while the pet is being treated for a steroid responsive disease process.
Cortisol affects the function of many organs in the body, so the signs of Cushing’s disease may be varied. The most common symptoms by far are excess hunger, excess urination, and excess thirst. Less common symptoms include an increase in panting, a pendulous abdomen (“sway belly”), exercise intolerance, weight gain, physical changes to the sexual organs, and symmetrical hair loss. Hair loss caused by Cushing’s disease occurs primarily on the body, sparing the head and legs. The skin is not usually itchy as it is with other skin diseases. If you pick up a fold of skin on a dog with Cushing’s disease, you may notice that the skin is thinner than normal. The pet may have fragile blood vessels and may bruise easily. A veterinarian may also note skin masses called comedones, an enlarged liver, an oily coat, and muscle wasting.
As previously mentioned, approximately 85% of Cushingoid dogs exhibit pituitary dependent Cushing’s syndrome. Most cases are caused by a benign tumor of the pituitary gland. The excessive ACTH produced by the pituitary gland tumor stimulates the adrenal glands to produce disproportionately high amounts of cortisol. Cushing’s syndrome results when the pituitary gland is unable to slow down its stimulatory messages when enough cortisol is present because of the presence of this particular type of brain tumor. As a result, the pituitary gland keeps encouraging the adrenal glands to make cortisol, a vicious cycle ensues, and Cushingoid symptoms result. The normal part of the pituitary gland shuts down, and the abnormal cells now function autonomously. In cases of adrenal dependent Cushing’s disease (15%), an adrenal tumor is responsible for the excess production of cortisol. In these cases, the normal pituitary gland senses the excessive production of cortisol and decreases its production of ACTH in an attempt to limit the amount of cortisol produced. Unfortunately, these adrenal tumors function independently of the levels of ACTH produced by the pituitary gland. While the causative mechanism is different, the result is the same, the over production of circulating cortisol.
Excess cortisol causes a host of problems. It acts on water balance, causing excess thirst and urination. It causes protein breakdown, so patients become weak and lack muscle mass while feeling very hungry. Normal skin function is disturbed and thinning, fragility, and changes to the skin and coat ensue. These patients are more susceptible to skin infections, hypertension, and the formation of blood clots.
Cushing’s disease is successfully diagnosed through a number of well-choreographed diagnostic tests. A normal blood panel and urinalysis often yields the first clues by reflecting changes in certain liver values as well as the presence of dilute urine. Radiographs may indicate an enlarged liver, thinning bones, and/or changes to lung tissue. Many of these animals will have high blood pressure. If the disease is suspected, one of two paths can be pursued. Most commonly, veterinarians will begin with what is known as an ACTH stimulation test. In this test, an analog of the pituitary hormone (cosyntropin) is given intravenously to stimulate cortisol release into the bloodstream from the adrenal glands. Cortisol levels are measured immediately before and 1 hour after administration of the cosyntropin. A normal animal will have low levels of cortisol before the cosyntropin is administered and moderately higher levels afterwards. Animals with Cushing’s disease will have higher levels before administration and very high levels afterward. This test is approximately 85% effective at identifying the disease, but less effective at identifying pituitary dependent versus adrenal gland dependent disease. The ACTH stimulation test is the gold standard of tests for the diagnosis of iatrogenic Cushing’s disease. For this reason, a dexamethasone suppression test is often performed after Cushing’s syndrome has been diagnosed by the pre and post ACTH stimulation test. The low dose dexamethasone suppression test is considered an excellent test with an estimated 90-95% ability to diagnose Cushing’s disease. A fasted dog has a blood sample taken as a baseline in the morning. A small amount of dexamethasone, a synthetic glucocorticoid, is injected, and follow-up blood samples are taken 4 hours and 8 hours later. In a normal patient, this steroid injection will signal the pituitary gland to decrease its production of ACTH and the adrenal glands will cease their production of cortisol. It essentially tells the brain and the adrenal glands that enough steroids are present in the body, so there is no need to be active at that time. Cushingoid dogs will not suppress blood cortisol in response to the dexamethasone injection because their feedback mechanisms are not working properly as explained above. This test does not differentiate between forms of Cushing’s disease (adrenal vs. pituitary), although it may be suggestive. Dogs that suppress at 4 hours and rebound at 8 hours usually have pituitary tumors. Once a dog has been diagnosed as Cushingoid, the high dose dexamethasone suppression test can be used to differentiate between forms of Cushing’s. Similar to the low dose dexamethasone test, a fasted dog has a baseline blood sample taken in the morning. The dog is then given a larger dose of dexamethasone. Blood samples are taken 4 hours and 8 hours later. A dog with an adrenal tumor will not suppress at all. The adrenal tumor simply doesn’t “care” about the level of blood cortisol; it keeps manufacturing cortisol. A dog with a pituitary tumor still has some limited ability to respond to feedback and thus should respond to a high dose of dexamethasone with a suppressed cortisol level. Approximately 15%-20% of dogs with pituitary tumors will not suppress on a high dose dexamethasone test; these dogs generally have large pituitary macroadenomas.
In this way, a dexamethasone suppression test is best for differentiating between pituitary-dependent and adrenal-dependent hyperadrenocorticism. Additional testing may be necessary to distinguish the cause of excessive cortisol production and include but are not limited to tests measuring baseline cortisol values, urinary cortisol:creatinine ratios, abdominal ultrasound to examine the adrenal glands, and computed tomography (CT) or MRI evaluation to examine the pituitary gland and/or adrenal glands. Because no one individual test yields all the necessary information about a patient with Cushing’s disease, most doctors will perform more than one test to accurately diagnose a case of pituitary dependent versus adrenal dependent Cushing’s disease.
As previously mentioned, there is no one single test to diagnose Cushing’s disease. The history, physical exam, and results of initial blood and urine tests often provide a strong suspicion for the presence of Cushing’s disease. Laboratory tests that are most commonly altered by Cushing’s disease are an increase in white blood cell count, increase in the liver enzyme ALP (also called SAP or serum alkaline phosphatase), increased blood sugar (although not as high as the blood sugar levels of diabetic patients), increased cholesterol, and dilute urine.
Radiographs of the abdomen often indicate a larger than normal liver. Occasionally, the x-ray will indicate dystrophic calcification in the area of one of the adrenal glands that is suggestive of an adrenal tumor. Ultrasound of the abdomen may reveal enlargement of both adrenal glands in pets with pituitary-dependent Cushing’s or enlargement of just one of the adrenal glands in pets with an adrenal tumor. The adrenal glands are NOT always seen during an ultrasound exam in pets with Cushing’s. In some pets with an adrenal tumor, the ultrasound or CT/MRI evaluation may indicate the tumor infiltrating into large blood vessels close to the affected adrenal gland or metastatic spread of the tumor into the liver.
Once a diagnosis has been made, there are several treatment options. Treatment depends on the type of Cushing’s disease, as well as on the overall health of the canine patient. As many dogs with Cushing’s are elderly and may have concurrent health problems, treatment can be complicated. In some cases, the owner may elect to wait to treat until symptoms are severe enough that they interfere with a patient’s quality of life. For example, a dog with hair loss and no other symptoms may not be candidate for aggressive treatment, but will be if he develops additional clinical signs. Thus, a decision to treat Cushing’s disease is made with the owner and the veterinarian and takes substantial labwork as well as the patients’ current status and quality of life into consideration. Many veterinary internal medical specialists believe that no dog should be treated unless it has obvious and worrisome clinical signs.
If Cushing’s disease is caused by an adrenal tumor, the logical approach is to surgically remove the tumor and the affected adrenal gland. These tumors tend not to recur on the remaining adrenal gland. In theory, this can cure adrenal-based Cushing’s disease, and the prognosis is very good for dogs with benign adrenal tumors. Dogs may be treated with ketoconazole or trilostane for 8-16 weeks prior to surgery to try to minimize the symptoms of Cushing’s disease, as one significant symptom of Cushing’s is delayed wound healing. There are high risks associated with adrenalectomies, and given that patients are often elderly dogs, this may deter an owner from pursuing this treatment route. Unfortunately, approximately 50% of adrenal tumors are malignant and may have already metastasized to the liver or lungs or invaded the major arteries and veins in the immediate region by the time they are discovered.
Pituitary tumors are not removed surgically in veterinary medicine. These tumors tend to be very small and slow-growing and cause little or no damage on their own, aside from overstimulating the adrenal glands. With these canine patients, the symptoms themselves are treated and not the root cause. Pituitary macroadenomas may be treated with radiation in an attempt to shrink them and thus relieve the neurological symptoms caused by their presence and the pressure they place on brain tissue.
The current treatment of choice in most cases is administration of a drug called trilostane (brand name Vetoryl). Trilostane acts by inhibiting cortisol production, so that levels in the blood are lower. Trilostane is generally given at a tapering dose as the patients’ symptoms subside. Vomiting and diarrhea are the most common side effects, but are seen far less frequently than with other drugs used in this disease. Trilostane, however, is the only drug associated with necrosis, adrenal rupture, acute bleeding, related illness, and/or death.
Lysodren (Mitotane, o.p’DDD) was, until the advent of trilostane, the most commonly used drug for pituitary-dependent hyperadrenocorticism. It is also used, albeit with less effectiveness, in treating adrenal-based Cushing’s. Lysodren selectively destroys adrenal cortex tissue, the cells that produce glucocorticoid hormones. An initial week or so of daily lysodren (a loading or induction phase) damages the adrenals enough to bring cortisol blood levels within normal ranges and make Cushingoid symptoms begin to abate. Thus, even though the pituitary gland may be secreting surplus ACTH and excessively stimulating the adrenals to release more cortisol, the adrenal glands simply cannot respond. Dogs are then be maintained on once or twice a week lysodren dosages for the remainder of their life. Half of dogs will relapse and need another round of daily lysodren. Sometimes dogs fail to respond to lysodren either from the start or after having been on it for some time. Lysodren is effective, yet it carries a great potential for serious side effects. If too much adrenal tissue is destroyed, a dog can be given permanent Addison’s disease, hypoadrenocorticism (the opposite of Cushing’s). This occurs inadvertently in approximately 5% of dogs given lysodren. More typically, a dog will experience a lysodren reaction in which cortisol levels are acutely too low. This occurs in approximately one third of canine patients and can be reflected in inappetence, vomiting, diarrhea, muscle weakness, wobbliness, lethargy, or even collapse and death. As with trilostane, mitotane has been associated with adrenal necrosis but has not been linked to adrenal rupture. Less than 1% of dogs experience fatal complications. Owners must carefully monitor dogs taking lysodren and respond to such adverse reactions by stopping the lysodren and administering prednisone. Also, dogs on lysodren must receive periodic ACTH stimulation tests to monitor their blood cortisol levels. Thus, treating with lysodren requires a greater than average owner commitment to monitoring their dog.
Ketoconazole is an antifungal drug, which is less commonly used than either trilostane or mitotane. While it controls the disease by inhibiting the synthesis of cortisol, it is only effective in approximately 50-75% of cases. It also commonly causes nausea, lethargy, and diarrhea. This is considered in the treatment of dogs with either pituitary-dependent or adrenal-based hyperadrenocorticism who cannot tolerate trilostene or lysodren or who do not respond to either of these two drugs. Ketaconazole is an oral anti-fungal medication with the unusual side-effect of suppressing hormone production. That side-effect is sought-after when using Ketaconazole for treating Cushing’s disease. This drug is given daily, and it can be prohibitively expensive to use. It has the advantage of being safer than lysodren, as it does not cause permanent adrenal tissue damage. Any effects it has on hormone production are fully reversible.
L- Deprenyl (Anipryl, selegiline) acts via a different pathway, known as the hypothalamic-pituitary axis, but its’ efficacy has been questioned. This is the most controversial of the drugs to treat Cushing’s disease. Anipryl does not affect the adrenal glands directly. First marketed for dogs as a psychotropic medication to help senile dogs think more clearly (canine Alzheimer’s), Anipryl allegedly stabilizes the balance of brain chemicals. It reduces ACTH production by functionally increasing dopamine levels. Approximately 70-80% of Cushingoid dogs responded favorably to the drug in clinical trials, yet actual practicing veterinarians are skeptical of its effectiveness. One endocrinologist claimed that it is very effective for only about 15% of dogs with pituitary-dependent Cushing’s. Others report a response rate closer to 40%. The effectiveness seems to be related to the specific location of the pituitary tumor itself. Anipryl is expensive and takes 1-3 months to evidence effects. Nonetheless, Anipryl is extremely safe and cannot cause Addison’s disease. Anipryl has no effectiveness at all in treating adrenal-based tumors.
All treatment options require a strong relationship and excellent communication between the owner and the veterinarian. For most treatment choices, potential side effects can be monitored at home, but patients must come in to the clinical setting for periodic ACTH stimulation tests to monitor their response much more accurately. Clients should be educated so that they are able to recognize if a patients’ dosage is too high or too low. It is important to note that dogs and cats rarely die of Cushing’s disease. Rather, the disease is treated because its manifestations can severely affect a patients’ quality of life. The goal in treating the disease is not cure, but rather control of symptoms. Patients with Cushing’s disease can lead long happy lives with prompt detection, proper care and appropriate monitoring. The goal of treatment, therefore, is to improve quality of life and perhaps lengthen life, except in situations where an adrenal tumor can be completely removed or where a dog can be weaned off external sources of cortisone. Again, as many Cushing’s patients are elderly and have concurrent health issues, hyperadrenocorticism is a serious condition, and maintaining a dog with Cushing’s disease requires vigilance and commitment on the part of the owner. In summary, Cushing’s disease is a common condition in older dogs and is often mistaken for signs of normal aging. Although most dogs with Cushing’s disease cannot be cured, their quality of life (as well as the owner’s quality of life) can be improved, and their lives may be extended with early intervention. It is often possible to successfully manage this disease for years. It thus behooves the pet owner to become familiar with the typical signs of Cushing’s and the treatments available.
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