Cushing’s syndrome

So your pet has been diagnosed with Cushing’s syndrome (also known as hyperadrenocorticism)...

What is Cushing’s syndrome?

The normal pituitary-adrenal axis

Clinical signs/symptoms

Medical complications associated with Cushing’s disease

Diagnosis

Supportive findings Definitive diagnostic tests Differentiating tests

Therapy

Prognosis/survival

 

What is Cushing’s syndrome?

Cushing’s syndrome is a condition in which there is an excess of cortisol (cortisone).  This can be caused by drugs (e.g. prednisone, depo-medrol, dexamethasone, betamethasone) often prescribed for the treatment of many diseases; this syndrome is known as iatrogenic Cushing’s syndrome.  It can also be caused by an excess of the body’s own cortisol, caused by a pituitary tumor or adrenal tumor.

Iatrogenic Cushing’s syndrome is caused by administration of drugs that suppress the body’s own cortisol production.  Clinical signs and complications are similar to the naturally occuring disease.  The dog can become dependent upon the drugs with chronic use, and abrupt withdrawal can lead to signs related to lack of cortisol, such as lethargy, depression, vomiting, and diarrhea.  For these reasons, chronic steroid use is not recommended except in cases of life-threatening immune-mediated disease or chemotherapy protocols.  The lowest possible dose of steroids should be used for therapy.

Pituitary dependent Cushing’s disease is caused by a functional pituitary tumor that stimulates the adrenal glands to produce excess cortisol.  The tumor is usually microscopic and benign (a microadenoma).  Sometimes the tumor can be large enough to cause pressure on the nerves to the eyes and the part of the brain called the hypothalamus, causing behavior changes, lack of appetite, and blindness, in addition to the other signs of Cushing’s syndrome.  These tumors are known as macroadenomas.  Pituitary-dependent Cushing’s disease makes up about 85% of spontaneous Cushing’s disease cases.

Adrenal tumors can be benign, known as adenomas, or malignant, known as carcinomas.  They produce cortisol independent of the normal regulatory mechanisms of the body.
Adrenal-dependent Cushing’s syndrome makes up about 15% of spontaneous Cushing’s syndrome cases.

Clinical signs of Cushing’s disease

Medical complications associated with Cushing’s disease

Hypertension (high blood pressure) is associated with about half of the cases of Cushing’s disease.  It can cause blindness due to  detachment of the sight receptors in the eyes (retina) and bleeding. Kidney problems are related to protein loss due to damage of the filtering system by the high blood pressure.  Loss of the protein antithrombin III, which prevents clots, can cause thromboembolism (clots).  Heart problems are associated with hypertrophy (thickening of the heart muscle) and failure due to the pumping of the heart against the increased pressure.

Glomerulopathy is damage to the filtering system of the kidney, causing protein loss.  Up to 75% of dogs with Cushing’s have some protein loss, although most do not have severe complications. Proteins, especially albumin, are important in holding fluid within the blood vessels, and excessive loss can cause fluid accumulation in body cavities, underneath the skin, and the lungs.  There are other proteins, such as antithrombin III, which are important in helping the body to prevent clotting within the blood vessels.  Loss of this protein can predispose the animal to the development of thromboembolism (clots). A clot within an important organ, such as the lungs, can lead to the animal’s death.  Ultimately, progressive glomerulopathy can lead to kidney failure, and predisposes the animal to hypertension, further damaging the kidneys.  This vicious cycle can be the cause of the animal’s death.

Congestive heart failure is damage to the heart resulting in a decreased ability to pump blood forward through the blood vessels.  Eventually, fluid accumulates in the lungs, chest & abdominal cavities, and can lead to the animal’s death.  Excess fluid in the blood vessels due to too much fluid ingestion can lead to hypertension.  Hypertension causes the heart to pump too hard, resulting in failure.  Also, since many of these dogs are older animals, chronic valve disease may also be present, predisposing them to heart problems.  This is a rare complication.

Pancreatitis is inflammation of the pancreas, the organ that produces enzymes to help digest food.  With inflammation, the enzymes are excreted into the bloodstream and abdominal cavity instead of the gastrointestinal tract, resulting in a severe illness associated with vomiting, abdominal pain, peritonitis (inflammation of the abdominal cavity), and loss of protein into the abdominal cavity.  If the disease is severe enough, the animal can have fatal complications.  Controversy exists as to whether excess cortisol causes pancreatitis, since this complication is rare in dogs.

Thromboembolism is the formation of a clot within a blood vessel.  If the clot forms within an important organ, the animal requires intensive care, and can have fatal complications.  Cushing’s animals have thromboembolic disease due to glomerulopathy and antithrombin III loss, vascular stasis (blood pooling) due to an increase in blood cell numbers, damage to blood vessels due to hypertension, and an increase in clotting factors in the bloodstream.

Infections are common  in Cushing’s patients, since excess cortisol suppresses the immune system.  Urinary tract infections, skin infections, and rarely systemic infections (sepsis) can occur.  Since cortisol also decreases inflammation, often there are no clinical signs or elevations in white blood cells in the area of infection.

Decreased wound healing and slowed hair regrowth also occur in Cushing’s patients, since the excess cortisol inhibits the normal healing and growth processes.  For this reason, surgery in adrenal tumors is often postponed until the cortisol levels can be controlled, usually with ketoconazole.

Diagnosis of Cushing’s disease

Supportive findings:

Routine bloodwork and urinalysis:

                   -markedly increased serum alkaline phosphatase (SAP), which is induced by steroids
                   -mildly increased ALT, GGT due to liver "swelling"                    -elevated neutrophil count (the cells that fight infection)
                   -decreased lymphocyte count (the cells that make antibodies)
                   -decreased eosinophil count (the cells that cause allergies)

Urine cortisol: creatinine ratio

This is a test on a single urine sample that measures the amount of cortisol and creatinine (an enzyme filtered by the kidneys) and compares them.  The advantage is that a sample can be brought in by the owner and sent to the lab.  Unfortunately, many things can cause an elevation in cortisol, so an increased urine cortisol:creatinine ratio can be due to Cushing’s syndrome, stress, and other diseases. An elevation should prompt the performance of more definitive tests. A normal urine cortisol: creatinine ratio can be used to rule out Cushing’s syndrome.
 

 Definitive diagnosis:

ACTH stimulation test:

This is a 1-2 hour test in which a pre-ACTH blood sample is drawn, ACTH is given, and a post-ACTH sample is drawn.  This measures the adrenal’s response to ACTH, and determines if it responds appropriately.  A decreased response is indicative of Addison’s disease or iatrogenic Cushing’s syndrome,  An increased response is indicative of Cushing’s syndrome.  This test diagnoses Cushing’s disease 80-85% of the time.  If the test is normal, but Cushing’s syndrome is still suspected, a low-dose dexamethasone suppression test (LDDST) may be necessary, since about half of adrenal tumors will not respond to this test.

Low-dose dexamethasone suppression test (LDDST):

This is an 8 hour test in which a pre-dexamethasone blood sample is drawn, a low dose of dexamethasone is given, and 4-hour and 8-hour post-dexamethasone samples are drawn.  This test measures the adrenal gland’s responsiveness to the increased levels of steroid (dexamethasone) in the blood.  A normal dog’s adrenal gland will stop producing cortisol in response to increased amounts of steroid in the bloodstream.  A dog with Cushing’s syndrome will not suppress or will eventually "escape" suppression, since the adrenal gland is producing too much cortisol either due to an adrenal tumor or pituitary tumor, which don’t respond to normal physiologic processes.  This test diagnoses Cushing’s disease 90-95% of the time.  The adrenal’s response can also be indicative of pituitary-dependent vs. adrenal-dependent Cushing’s disease, since pituitary tumors are usually more responsive to physiologic stimuli than adrenal tumors are.
 

 Differentiating tests

Once Cushing’s syndrome has been diagnosed, treatment depends on the type of disease: pituitary vs. adrenal.  If the LDDST is not definitive, or if only an ACTH stimulation test was performed, further testing is necessary to decide which disease is present.
 

High-dose dexamethasone suppression test (HDDST):

This is an 8-hour test in which a pre-dexamethasone sample is drawn, a high dose of dexamethasone is given, and  4-hour and 8-hour post-dexamethasone samples are drawn.  Pituitary tumors are generally more responsive to normal physiologic stimuli, so if the Cushing’s syndrome is pituitary-dependent, the excess steroid (dexamethasone) will usually (about 80% of the time) cause the adrenals to stop producing cortisol, resulting in suppression.  Adrenal tumors usually are not controlled by normal physiologic stimuli, and will not suppress.
 
 

Endogenous ACTH

This is a one-time blood sample which must be processed in a special manner in order to measure the body’s own production of ACTH.  In a pituitary tumor, the problem is excess production of ACTH, so the levels will be high in the bloodstream.  In an adrenal tumor, normal pituitary production of ACTH is suppressed by the excess cortisol excreted by the adrenal gland, and levels should be low.
 

Abdominal ultrasound

In the hands of an experienced ultrasonogropher, the adrenal glands can be found in the dog and measured.  In pituitary tumors, the excess ACTH stimulates both glands, so they will both be enlarged.  In an adrenal tumor, the abnormal gland will be enlarged, and sometimes mineralized.  The normal gland is often suppressed through normal physiologic processes, and will be smaller.
 

Abdominal radiographs (x rays)

The normal adrenal glands are not seen on routine abdominal radiographs.  In adrenal tumors, a mineralized (bright white) area can sometimes be seen cranial to (in front of) the kidneys.  Usually the adrenal glands are not seen in pituitary-dependent hyperadrenocorticism.
 
 

CT scan

A CT scan is a "3-D" radiograph (x-ray). This procedure is currently only performed at referral centers, such as here at Auburn. A CT scan of the head to look at the pituitary gland is not usually performed, unless a macroadenoma is suspected. The animal is anesthetized for this procedure, because they must remain very still.

Treatment

Iatrogenic Cushing’s disease

Since iatrogenic Cushing’s disease is caused by giving steroids, often long-term, especially common in allergic dogs as "itch shots," withdrawal of the steroids is important in resolving the clinical signs.  Sometimes, the body’s own production of cortisol is suppressed by the drugs, and slow withdrawal of the drugs over weeks to months must be performed in order to allow the body time to recover its own production mechanisms.  An ACTH stimulation test helps to measure the body’s reserves for cortisol production.
 

Pituitary-dependent Cushing’s

Surgery to remove the abnormal pituitary has not been well-established in veterinary patients, although it is a commonly used modality in humans, because of the anatomy of the canine head.  Removal of the entire pituitary gland can result in permanent hypothyroidism and diabetes insipidus (lack of urine concentrating ability). Currently, researchers at Auburn are investigating techniques to make surgery more successful in dogs.

Medical therapy is currently the treatment of choice in dogs. The most commonly used drug is Lysodren (mitotane, o,p’-DDD).  This drug causes death of the adrenal cells that produce cortisol, eliminating the excessive production.  Since it does not actually treat the underlying pituitary gland problem, the therapy is lifelong. The initial phase is induction, in which a daily dose is given, usually for 5-14 days to bring the cortisol levels down into the normal range quickly, eliminating the clinical signs of disease.  The next phase is maintenance, in which the drug is given usually 1-2 times weekly to help keep the cortisol levels in the normal range.  Signs that the dog’s disease is being controlled include a decrease in water consumption, urination, and appetite.  Signs that an overdose has occurred include weakness, lethargy, lack of appetite, vomiting, diarrhea, and occasionally even death if left untreated (see Addison’s).  Fortunately, these complications are rare; prompt attention and supportive care with steroids will eliminate the danger of these problems. Constant communication with your veterinarian is a MUST in using this therapy, and frequent ACTH stimulation testing is necessary to establish the proper dose.  We usually recommend ACTH stimulation testing at the end of induction and every 1-2 months until the proper dose is established.  Periodic retesting every 4-6 months thereafter monitors the therapy safely.

Ketoconazole has also been used to treat Cushing’s disease.  This antifungal agent blocks the formation of the steroid hormones.  Daily therapy must be used, since cessation of therapy results in the continued production of cortisol.  This can become quite expensive.  Up to 25% of dogs will not respond to the drug.  Oftentimes, this drug is used to stabilize patients prior to surgery for an adrenal tumor.

L-Deprenyl is the newest drug to be licensed to treat pituitary-dependent Cushing’s disease.  It works to block the monoamine oxidase type B enzyme, and enhances dopamine levels.  In theory, a decrease in ACTH levels will occur and control the pituitary-dependent Cushing’s disease.  It has no effect on cortisol levels, however.  Many owners did report an increase in their pet’s activity levels and a decrease in excessive water consumption.  There are no serious side effects reported.  This is also a daily, lifelong therapy, and is relatively expensive.  At Auburn, we still recommend Lysodren therapy in the majority of cases.

Macroadenomas

Large pituitary tumors causing signs such as blindness, behavior change, and other neurologic signs are best treated with radiation therapy in order to shrink the tumor.  Fortunately, there are few side effects associated with this treatment.  Dogs do not experience nausea, vomiting, and malaise while undergoing therapy.  There may be some hair loss in the radiated site, and some skin irritation that resolves within a few weeks after treatment.  The dog usually receives 10-11 treatments over 3-4 weeks, and must be sedated for each treatment.  While the neurologic signs resolve, usually the Cushing’s disease persists, still requiring medical therapy.
 
 
MRI image showing contrast-enhanced 
pituitary macroadenoma 
 
 

Adrenal tumors

Surgery is the best recommended treatment for adrenal tumors.  Removal of a benign tumor, or even a small malignant tumor, often results in a cure.  However, some tumors can be invasive into surrounding tissues, and carcinomas (malignant tumors) can metastasize (spread) to other organs, especially the liver and lungs.  Prior to surgery, abdominal ultrasound and chest radiographs (x-rays) must be performed to determine the chance of tumor removal.  Since Cushing’s disease can also cause decreased wound healing, control of the excess cortisol levels prior to surgery is also recommended.  We routinely use ketoconazole to treat the effects of excess cortisol prior to surgery. There can be serious complications associated with surgery, including cortisol insufficiency, renal failure, thromboembolism (clots), pneumonia, pancreatitis, and cardiac arrest.  This necessitates intensive monitoring during and after surgery to prevent, recognize, and treat these potentially fatal problems. ACTH stimulation tests before and after surgery  determine the need for cortisol supplementation, and monitor for the presence of continued cortisol production, indicating incomplete removal of the tumor or metastasis.

Medical therapy for adrenal tumors can also be used, especially in animals with metastatic disease, or animals who are not good surgical candidates.  Increased dosages and length of treatment are often necessary to control an adrenal tumor with Lysodren, and not all tumors will respond.  There is also an increased risk of overdose and side effects with high-dose Lysodren therapy.  Ketoconazole has been used with some success to manage these tumors.

 Prognosis

Dogs usually respond very well to therapy and are able to lead normal lives. Relapses are quite common with pituitary-dependent Cushing’s syndrome, and occur in about 50% of dogs, requiring a change in the maintenance dose or reinduction therapy.  Overdose is also common, occuring in about 1/3 of treated dogs at some time during therapy.  Fortunately, the side effects are usually mild, and fatal complications from overdose occur in < 1% of dogs. Good owner observation and communication with the veterinarian are the most important factors that influence the success of treament.  Surgery will cure many benign adrenal tumors and small carcinomas.  If there are no post-operative complications, there can be prolonged survival even with invasive tumors or with metastatic disease.  Metastatic disease can be treated with medical therapy, often for greater than a year.

 

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