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HYPERADRENOCORTICISM (CUSHINGS DISEASE)

Note for Pet Owners:

This information is provided by Provet for educational purposes only.

You should seek the advice of your veterinarian if your pet is ill as only he or she can correctly advise on the diagnosis and recommend the treatment that is most appropriate for your pet.

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Description
Hyperadrenocorticism is common in older dogs and it causes a wide range of clinical signs including a pot-bellied appearance and  hairloss, with an increase in thirst and urination. It is rare in cats but when it occurs it is often associated with over diabetes mellitus..

Cause
 The naturally occurring disease is caused by excess production of a hormone, cortisol, by the adrenal gland. Cortisol is produced by cells located in the outer cortex region of the adrenal gland and overproduction may be due to :

  • Disease of the adrenal gland itself - usually a tumour in one of the adrenal glands (may be a benign adenoma, or a malignant carcinoma). Accounts for about 10-15%of all cases in dogs.
  • Disease of the pituitary gland in the brain- usually a small (less than 1 cm diameter) benign neoplasm (adenoma)- resulting in increased secretion of the hormone adrenocorticotrophic hormone (ACTH) which causes bilateral hyperplasia of the adrenal glands, and increased cortisol secretion. So-called pituitary-dependent hyperadrenocorticism accounts for over 85% of all reported cases in dogs and most cases in cats.
  • Rarely there is a failure of feedback mechanisms to the brain to reduce ACTH production. The precise cause of this is not known.

Hyperadrenocorticism is also seen as a clinically-induced problem :

  • Iatrogenic hyperadrenocorticism is due to the direct effect of prolonged treatment with high doses of corticosteroid drugs. These drugs are widely used in veterinary medicine for the management of a variety of conditions. In this case the adrenal glands atrophy, and hypoadrenocorticism (Addison's Disease) can occur if drug administration is stopped.

Breed Occurrence
Cushings disease is most commonly seen in Boxers, Dachshunds, Lhasa Apso, Poodles (Miniature and Toy) and small Terrier breeds including Jack Russells and Staffordshire Bull Terriers..

It usually occurs in dogs over 4 years of age, and is particularly common in dogs over 8 years of age, and adrenal-dependent hyperadrenocorticism occurs in older animals - usually over 10 years of age.

For pituitary dependent Cushings disease slightly more females are affected than males, but for adrenal tumours females are almost three times as likely to be affected. 

Signs
Common clinical signs of hyperadrenocorticism  include :

  • Pot-bellied appearance - due to increased fat deposition, weakness of the abdominal muscles, and an enlarged liver
  • Increased thirst - affected dogs drink over 100 ml/kg body weight/day. This is secondary to increased urine losses, and due to a direct effect of glucocorticoids on the thirst centre in the brain. In cats polydipsia is a late sign associated with hyperglycaemia and overt diabetes.
  • Increased urine loss - passes over 50ml/kg body weight/day . Due to affects of glucocorticoids on antidiuretic hormone. In cats polyuria is a late sign associated with glycosuria and over diabetes.
  • Increased appetite - direct affect of corticosteroids on the brain
  • Hair loss - bilaterally symmetrical - particularly along the back, ventral abdomen and the flanks. It  is not itchy and is caused by the effect of corticosteroids which inhibit the anagen phase of hair growth.
  • Thinning of the skin
  • Large macules (circular pigmented areas) form on the skin
  • Calcium deposits in the skin (called calcinosis cutis)
  • Depression
  • Generalised muscle weakness - sometimes with obvious muscle wastage (eg temporal muscles) - due to increased protein catabolism caused by the high concentrations of corticosteroids.
  • Abnormal muscle contractions and rigidity (called myotonia) is sometimes present, creating a stiff gait when walking.
  • Lethargy and poor exercise tolerance - often mistaken for normal ageing 
  • Panting at rest
  • Sometimes behaviour changes - urinating in the house at night due to increased urine production; pacing, head pressing ...neurological signs due to the presence of a large (over 1 cm diameter) brain tumour (uncommon).
  • Sometimes apparent blindness due to pressure from a large brain tumour (uncommon)
  • Siezures due to secondary spread of a brain tumour (uncommon)
  • Atrophy of the testicles occurs in males, and there is inhibition of the oestrus cycle in bitches. These effects are both due to the enhanced feedback mechanism of high cortisol concentrations on the pituitary which inhibits the secretion of gonadotrophic hormones from the pituitary.

Complications
Hyperadrenocorticism may occur in conjunction with other endocrine disorders such as diabetes mellitus (c10% of canine cases)

Diagnosis

General laboratory findings in hyperadrenocorticism include :

  • Blood biochemistry
    • Greatly increased alkaline phosphatase concentrations - glucocorticoid isoenzyme. This is rarely noticed in cats as they can clear alkaline phosphatase rapidly.
    • Increased Alanine aminotransferase (ALT) concentrations - liver damage due glycogen storage
    • Increased blood glucose - insulin resistance due corticosteroids. In cats hyperglycaemia is a common finding 
    • Increased cholesterol and lipid concentrations - corticosteroid stimulation of lipolysis
    • Bromsulphthalein retention - increased due to liver damage
    • Bile acids - increased 
    • Low blood urea and creatinine concentrations - due to diuresis
  • Haematology
    • Low lymphocyte and eosinophil counts
    • Increased neutrophil, monocyte and erythrocyte counts
  • Hormones
    • T4 (thyroxine) concentrations are low in 70% of canine cases of hyperadrenocorticism. Due negative feedback of cortisol on the secretion of Thyrotropin-releasing hormone from the pituitary gland, and possibly increased rate of metabolic breakdown.
  • Urine test
    • Specific gravity less than 1.010 in dogs. They can concentrate urine if deprived of water.
    • Glycosuria - present in 10% with diabetes mellitus. It is common in cats.
    • 50% of cases of canine hyperadrenocorticism have a urinary tract infection

Specific laboratory tests :

1. Elevated basal plasma cortisol concentrations:

  • Above 330 nmol/l - highly suggestive
  • Above 410 nmol/l - definite

2. ACTH Stimulation test 

2 hours post-ACTH administration (0.25mg tetracosactrin intramuscularly) collect 5ml blood in heparin - 

  • Plasma cortisol concentrations over 550nmol/l indicate hyperadrenocorticism
  • 470 nmol/l - 550 nmol/l = borderline - repeat in 3 months
  • Less than 470 nmol/l - suggest negative but a few pituitary-dependent and almost 50% adrenal-dependent hyperadrenocorticism cases have values below this !

3. Low dose dexamethasone suppression test (most reliable test)

8 hours after administration of 0.01mg dexamethasone / kg body weight collect blood:

  • Less than 40 nmol/l cortisol - normal
  • Greater than 40 nmol/l cortisol - hyperadrenocorticism*

(* prior treatment with anticonvulsive therapy, glucocorticoids and some clinical cases do not show suppression ) 

4. High dose dexamethasone suppression test

Collect blood pre-dexamethasone treatment and at 3 and 8 hours post-administration of 0.1mg dexamethasone / kg bdy weight :

  • If plasma cortisol concentrations are less than 50% of the basal concentration after 3 or 8 hours pituitary-dependent hyperadrenocorticism is suggested
  • If following both tests plasma concentrations are greater  than 50% of the basal concentration adrenal neoplasia is suggested, although 15% of pituitary-dependent cases may cause poor suppression with this test.

 

Treatment
Thus far treatments except for adrenalectomy have not been very successful in cats, whereas they have in dogs.

Treatment depends upon the primary cause :

  • Iatrogenic hyperadrenocorticism

Gradually reduce the administered dose of corticosteroid therapy.

  • Pituitary-dependent hyperadrenocorticism

Chemotherapy

(NB care is needed to avoid overdosage and collapse due to hypoadrenocorticism. Manage such an incident with injectable glucocorticoid treatment and stop mitotane treatment until polyuria recurs) 

1. Mitotane (op'DDD) which destroys the adrenal cortex is very successful :

  • Method 1  50mg/kg body weight/day with food in the evening  for 10 days, then weekly doses for 2 weeks , then 25mg/kg/week for life
  • Method 2  50mg/kg body weight/day. Measure daily water intake. When water intake is less than 60ml/kg body weight/day , or one of the following side-effects occur :  the dog stops eating, develops vomiting, diarrhoea, or depression, reduce the dose to a maintenance of 25mg/kg body weight/week

If the side-effects become severe a small amount of cortisol can be administered by mouth.(1.5mg/kg body weight per day for up to 2 weeks), or prednisolone at 2mg/kg body weight can be given for 2 days then gradually reduced.

If there is no response to mitotane the most likely cause is adrenal neoplasia or misdiagnosis. Occasionally much higher doses of mitotane are needed in some individuals If dogs have a relapse after stabilisation repeat ACTH stimulation tests should be performed.

2. Ketoconazole - inhibits glucocorticoid synthesis, reduces circulating cortisol concentrations and reduces the response to ACTH. Dose 5mg/kg body weight/ twice daily for 7 days then 10mg/kg body weight/ twice daily, An ACTH stimulation test should be performed after 10 days on 10mg/kg body weight twice daily and the dose can be increased to15mg/kg twice daily if the cortisol concentration is greater than 300 nmol/l following the ACTH stimulation test.  However, it is expensive and can cause hepatotoxicity, as well as anorexia, vomiting and diarrhoea .

3. Trilostane (Vetoryl  - Dechra is a licensed veterinary product for use in dogs. It does not cure Cushing's syndrome but it reduces production of cortisol by the adrenals and so can help control the disease. 

Surgical removal

This procedure (called hypophysectomy) is technically difficult although the reported success rate (45%) is good.

Radiation Treatment

Has been used successfully to treat large pituitary tumours. CT or MRI imaging are needed pre-operatively to plan the radiation dose.

  • Adrenal-dependent hyperadrenocorticism

Adrenalectomy is the treatment of choice for unilateral adrenal tumours provided there is no evidence of metastatic spread to vital organs such as the lungs. The affected gland is usually much larger than the other (which has atrophied), and the affected gland may appear to be calcified on radiographs.

Post-operatively both mineralocorticoids and glucocorticoids must be given until the atrophied gland has returned to normal function. Wound healing is poor in dogs with hyperadrenocorticism. 

Mitotane - see above

Ketoconazole - may be used in older dogs, but it is potentially hepatotoxic. Dose 30mg/kg body weight/day.

 

Monitoring Improvement

The success of treatment is monitored by a return to normal appetite, drinking and urination and regrowth of hair. The success of treatment can be remarkable in some cases. By 8 weeks after the start of treatment significant improvement should be recognised.

Prognosis
It is reported that about 80% of pituitary-dependent cases respond well, though neurological signs will occur in some cases later as the tumour gets bigger.

Life-expectancy following diagnosis and treatment is over 2 years with many patients surviving over 7 years.

Long term problems

Patients should be re-examined every 6 months as relapses and transient overdoses do occur. Some individuals develop resistance to the mitotane.

 

To be Updated November 2013