Cushing’s disease (hyperadrenocorticism)

Although Cushing’s disease is a severe disease the changes it causes can be quite subtle in the early stages. Many owners do not recognise the signs of Cushing’s disease in their pet, instead confusing the changes caused by the disease with ageing. It is important to get an early diagnosis for this disease because, with treatment, affected animals can lead a normal and full life.

Cushing’s disease is caused by prolonged exposure of the body’s tissues to high levels of the hormone cortisol. It is called Cushing’s disease because it was named after a famous neurosurgeon, Harvey Cushing, who first recognised it. It is also sometimes called“hyperadrenocorticism” or “hypercortisolemia”.

Cushing’s disease is caused by an excess of the steroid hormone, cortisol. In the normal dog cortisol is produced by the adrenal glands, (which are located just in front of the kidneys). Scientists think that cortisol has hundreds of possible effects in the body. Among its other vital tasks, cortisol helps to:

  • maintain blood pressure
  • slow the immune system’s inflammatory response
  • balance the effects of insulin in breaking down sugar for energy
  • regulate the use of proteins, carbohydrates and fats in the body

Because cortisol is so vital to health, the amount of cortisol produced by the adrenal glands is precisely balanced. Cortisol production is regulated by hormones produced in the brain (from the pituitary gland). The hormones produced by this gland stimulate the adrenal glands. When the adrenal glands receive the signal from the pituitary they respond by producing cortisol. In the normal animal cortisol is produced mainly at times of stress – in Cushing’s disease the levels of cortisol in the blood are always too high.

Nearly all cases of Cushing’s disease are caused by a tumour in the pituitary gland. Although this is, strictly speaking, a brain tumour the tumour is usually tiny and benign and causes no effects related to pressure in the brain. A few cases of Cushing’s disease are caused by a tumour in the adrenal gland.

The two forms of natural Cushing’s disease are:

Pituitary-dependent Cushing’s disease

A tumour in the pituitary causes excess production of the hormone, adrenocorticotropic hormone (ACTH) resulting in enlargement of both adrenal glands.

Adrenal-dependent Cushing’s disease

A tumour of the adrenal gland makes one gland grow bigger and it is therefore able to produce more cortisol.

Sometimes signs of Cushing’s disease are caused by steroids given by the vet to treat another disease e.g. allergic skin disease.

The signs of Cushing’s disease are extremely variable and can be subtle in the early stages. It is usually not possible to decide which form of the disease is present by the clinical signs. Cushing’s disease affects older pets (over 7 years of age).

Because the changes come on slowly it is sometimes easier to spot them if you do not see an animal every day. Often it will be your vet who examines your pet during its annual or bi-annual examination and points out that changes have occurred since your last visit. Many owners do not recognise the signs of Cushing’s disease in their pet, instead confusing the changes caused by the disease with signs of ageing.

The steroid hormones affect almost every tissue in the body and the signs of Cushing’s disease can be diverse. The most obvious sign of Cushing’s disease is increased thirst. If your dog is drinking more (or is suddenly needing to get up in the night to urinate) you should always take them to the vet for a check-up. However, not all dogs with Cushing’s disease have increased thirst.

An increased appetite (and weight gain) is also very common in Cushing’s disease but owners may not recognise this as a sign of illness.

Cushing’s disease causes changes to the skin and haircoat. The hair is lost in patches (particularly over the flanks) but there is no scratching. Other symptoms appear in the skin, which becomes fragile and thin. It bruises easily and heals poorly. Purplish pink stretch marks may appear on the abdomen. Female dogs may stop coming into season.

Steroid hormones cause muscle wasting and weak muscles may make it difficult for your pet to exercise. You may notice that your dog is panting a lot or they may develop joint problems. In Cushing’s disease, fat is deposited in the liver making it swell and this may be visible causing the abdomen to hang down with a pot-bellied appearance.

High levels of steroid hormone in the blood suppress the immune system and healing process; so animals with Cushing’s disease may have repeated infections or wounds that do not heal as quickly as expected.

In most cases of pituitary-dependent disease the tumour in the brain is tiny and causes no physical effects. However, in a few animals the brain tumour is sufficiently large such that it can cause neurological signs e.g. depression, blindness or seizures.

Cushing’s disease can be very difficult to confirm. Your vet may suspect the disease based on simple blood tests but specific blood tests are needed to confirm the diagnosis. These special tests measure the level of cortisol in the blood. However, because the levels of this hormone vary from hour to hour in a normal animal, the disease cannot be diagnosed on the basis of one blood test.

Your vet will need to take a number of blood samples before and after injection of hormones that affect the amount of cortisol produced by your dog. Some of these blood samples have to be handled very carefully and will need to be sent away to veterinary laboratories for analysis.

Ultrasound examination of the abdomen allows your vet to measure the size of each adrenal gland. If a tumour is present in the adrenal gland this should be visible on the ultrasound (and one adrenal gland will appear larger than the other). If the disease is caused by a tumour in the brain then both adrenal glands will be larger than normal.

X-rays may also be needed to show other potential problems caused by the disease.

There are a number of reasons why examination of a urine sample can be useful in a dog with Cushing’s disease:

  • When levels of hormone in the blood are very high, some hormone may spill over into the urine and this can be measured. If there is no cortisol in the urine it is unlikely that your dog has Cushing’s disease. Unfortunately, finding cortisol in the urine does not mean that your dog has Cushing’s disease as many other conditions can cause this change.
  • If your dog has Cushing’s disease it is likely that their immune system will not be working as well as it should. Your vet will want to test a urine sample to see if there is any evidence of an infection in the urine.
  • Additionally, the high levels of cortisol in the blood can cause diabetes mellitus and your vet will want to check for sugar in the urine to rule this out.

Three medications may be used to treat the pituitary form of the disease:

  • Mitotane (Lysodren) has been the traditional therapy. Mitotane is toxic to the part of the adrenal gland that produces cortisol. It destroys the adrenal gland so that is unable to produce so much hormone. Mitotane can also kill cells in adrenal tumours. Remember that most cases of Cushing’s disease are caused by a small tumour in the brain and so mitotane does not usually address the underlying cause of the disease.
    When treatment is started the drug is given once daily for around 7-10 days. This causes rapid destruction of the adrenal gland. Once levels of hormone have dropped, mitotane is given as a weekly maintenance dose, just enough to kill off any new cells that have grown that week.
    Routine blood tests are taken three or four times a year to ensure that treatment does not need to be altered.
  • Selegilene (Anipryl) is approved by the FDA in the USA for the treatment of pituitary dependent Cushing’s disease in the dog. Unlike mitotane, the drug works at the level of the pituitary to decrease ACTH levels and does not have a direct effect on the adrenal gland.
    Anipryl is given once a day, has very few side-effects, requires no additional blood tests to monitor treatment and works in about 50% of cases. It may take 1-2 months of daily treatment to control the signs so it usually is reserved for dogs with mild or moderate signs of Cushing’s disease. It cannot be used in dogs with an adrenal tumour.
  • Trilostane (Vetoryl) is a new treatment for Cushing’s disease. This is a drug that inhibits the adrenal glands’ ability to produce cortisol. Unlike mitotane it does not destroy adrenal tissue. It is important to realise that this drug does not do anything to treat the tumour (pituitary or adrenal) causing the disease but it can be used to control the signs of cortisol excess in dogs with both pituitary and adrenal dependent Cushing’s syndrome.
    The drug is given as a tablet once (or sometimes twice) daily and it must be given regularly or hormone levels will rapidly rise again. As is the case with mitotane, routine blood tests are taken three or four times a year to ensure that treatment does not need to be altered.

In a few cases, surgical removal of an adrenal tumour is possible. This surgery is difficult and should be performed by a specialist in veterinary surgery. In addition to the risks of surgery itself, it is very important that animals are closely monitored immediately after surgery and they may need to spend time in an intensive care facility. Your vet may want to start medical treatment before surgery to help decrease the side-effects of high cortisol levels during anaesthesia and surgery.

If your dog has signs associated with a mass in the brain they will need additional treatment; as the drugs available will not affect the size of this tumour. Radiotherapy is available at some specialist hospitals and this can help shrink the tumour and eventually decrease the levels of ACTH and cortisol in the blood. Unfortunately, because of its location, surgical removal of the tumour in the brain is usually not possible in Cushing’s disease.

Very few side-effects are reported with the use of selegilene. There are few reported side-effects from trilostane – provided that careful monitoring is performed. Mitotane is a more potent drug and can have significant side-effects if not used correctly. An overdose of mitotane can completely destroy the adrenal gland and result in a deficiency of the stress hormones. Close monitoring of dogs receiving treatment with mitotane or trilostane is very important, particularly in the early stages.

Most dogs with Cushing’s disease are middle-aged or elderly and owners sometimes ask if it is worth treating them. Once an animal with Cushing’s disease is stabilised on treatment they will usually live a normal life (simply taking their tablets on a regular basis).

The outcome for dogs with pituitary-dependent Cushing’s disease with treatment is very good. Some signs will disappear quickly and others more gradually. Appetite and water consumption usually return to normal in a few weeks; whereas full return of the fur may take several months. Many dogs go on to live a normal lifespan. Without treatment the complications can be significant and will seriously affect the quality of your pet’s life.