Cushing's Disease in the Dog: Prognosis, Diet, and Treatment of Cushing's Syndrome

Cushing's disease in a dog

CCushing's horror in a dog is a chronic disease that seriously affects the entire body of the animal.

If you've noticed your dog has been drinking a lot lately, has had a ravenous appetite for a while, and is weak and lacking in energy at the same time, it's time to see your vet.

These symptoms occur in most of the affected patients overactive adrenal cortex, but additional tests are required to confirm the diagnosis.

This article explains which dogs are most at risk Cushing's syndrome and how animals with this condition are treated.

I will also explain what the diet of a sick pooch should look like and what may be the consequences of ignoring the symptoms Cushing's disease in a dog.

• What is Cushing's disease in a dog?
• Cushing's syndrome of pituitary origin
• Cushing's syndrome of adrenal origin
• Iatrogenic cushing's syndrome in dogs
• Cushing's disease symptoms in dogs
  • General symptoms
  • Neurological and muscular symptoms
  • Skin symptoms
• Cushing's syndrome complications
• Cushing's syndrome: diagnosis
• Cushing's syndrome treatment
  • Treatment of cushing's syndrome of pituitary origin
  • Trilostane (Vetoryl) for the dog
  • Mitotane
  • Ketoconazole
  • L-DEPRENYL (monoamide oxidase inhibitor)
  • Pituitary excision
  • Radiotherapy
• Treatment of cushing's syndrome of adrenal origin
• Treatment of iatrogenic cushing's syndrome
• Treatment of coexisting diabetes mellitus
• Untreated overactive adrenal cortex
• Cushing's syndrome diet
• Prognosis of Cushing's syndrome

What is Cushing's disease in a dog?

What is Cushing's disease in a dog?

Overactive adrenal cortex in dogs (Hyperadrenocorticism / HAC), also called Cushing's disease or Cushing's syndrome / syndrome is a multi-system hormonal disorder, manifested by excessive production of cortisol by the adrenal glands and its long-term effects on the body.

Other common names for this disease are hypercortisolemia or hyperadrenocorticism.

To the state hypercortisolemia occurs as a result of:

• Malfunction of the pituitary gland - then we are talking about the pituitary gland Cushing's disease.
• Hyperfunction of the adrenal cortex caused by their malfunction - this is the adrenal form Cushing's syndrome.
• Human activities (administration of exogenous glucocorticosteroids) - we are talking then about the iatrogenic form Cushing's syndrome.

The terminology used to describe this unit is quite often problematic - some call it Cushing's disease, others use the name Cushing's syndrome or syndrome.

However, it should be known that these terms do not mean the same.

The main role plays an important role here the cause of hypercortisolemia.

So Fr Cushing's syndrome we say it is responsible for abnormal levels of glucocorticosteroids adrenal gland disease, while Fr Cushing's disease - when hypercortisolemia is induced abnormal function of the pituitary gland.

Due to the etiology, the following are distinguished:

1. Pituitary form of Cushing's disease.
2. Adrenal form of Cushing's syndrome.
3. Iatrogenic form of Cushing's syndrome.

To better understand the mechanism of action of hormones and their effect on the cells and tissues of the body, let's look at three important structures that make up the so-called. hypothalamic - adrenal axis. These are:

The adrenal glands

• The adrenal glands - a pair of endocrine glands overlapping the upper poles of the kidneys (hence the name - located just above the kidneys). Each gland has the cortex and the adrenal medulla.
  • The cortex of the adrenal glands secretes steroid hormones essential for life, which can be divided into 3 main types:
    • Mineralocorticosteroids (aldosterone),
    • Glucocorticosteroids (cortisol, corticosterone, cortisone),
    • Androgens.
  • Adrenal medulla produces catecholamines:
    • Dopamine,
    • Noradrenaline,
    • Adrenaline.

Action of glucocorticosteroids

In the course of Cushing's syndrome, the most important thing is cortisol, therefore, let's take a closer look at its effects.

They are numerous and very varied.

Cortisol is considered the so-called. stress hormone and it is he who is credited with reactions like "fight - or - flee ". Cortisol is a much needed chemical, especially in situations that require immediate reaction, but its long-term effect on the body wreaks havoc.

Simply put, the main physiological role of cortisol is wide impact on metabolism.

The most known metabolic reaction is very strong (sometimes even 5-10 times) enhancement of gluconeogenesis.

Glucocorticosteroids thus ensure that a sufficient fasting blood glucose is maintained, and also enable rapid energy production when the body is exposed.

This makes survival possible.

Unfortunately - with the long-term influence of cortisol, a "energy surplus " is created, which is not used and deviates into the paths of incorrect additional transformations (responsible for the appearance of symptoms of the disease).

The metabolism of simple sugars is somewhat doubled - on the one hand, their production increases (hepatic gluconeogenesis stimulated by cortisol), and on the other hand, their peripheral use is limited (glucocorticosteroids reduce glucose consumption by cells).

As a result, there is a strong tendency to occur hyperglycemia (increase in blood sugar) which leads to the development of diabetes mellitus of adrenal gland.

This is called the diabetogenic effect of cortisol.

Cortisol increases protein catabolism and the mobilization of amino acids in tissues, especially in muscles and bone tissue.

Protein is the second (after glucose) source of energy that is activated in emergency situations; additionally, it is an important building block for the reconstruction of any damage or wounds.

Many compounds resulting from protein catabolism are the starting products for the aforementioned gluconeogenesis.

No wonder that the increased breakdown of proteins due to the long-term action of steroids leads to skin disorders (atrophy, difficulties in wound healing, hair loss), bones (osteoperosis), muscles and fascia (soft, flabby abdominal shell).

Cortisol works lipolytic and ketogenic.

That is, it causes fatty acid mobilization from adipose tissue and intensifies their burning, and thus increases the concentration of free fatty acids in the blood.

Ketone bodies they are another (after glucose and proteins) source of energy.

A characteristic feature of steroids is the increased use of fatty acids for energy production, instead of glucose.

This may lead to an increase in ketone levels (the ketogenic effect of cortisol).

As a result of the long-term action of cortisol, the total body fat content increases (despite the lipolytic effect) at the expense of proteins and the distribution of adipose tissue changes, which accumulates mainly in the dorsal part of the torso.

In the limbs, muscle atrophy occurs (the characteristic silhouette of a sick dog - the so-called. "Fat ball on four matches ").

Cortisol blocks the action of the sex hormones.

As a result, it occurs in bitches up to extending the period of sexual rest (heat delay), in males up to testicular atrophy.

Cortisol increases the glomerular filtration rate in the kidneys and reduces the release of the antidiuretic hormone (vasopressin).

Effect - intensification of diuresis.

This is clinically apparent as polyuria (increased urination).

Cortisol enhances the effects of adrenaline and norepinephrine on blood vessels through increasing contractile reactivity (glucocorticosteroids somehow sensitize cells to the action of catecholamines).

In this way, they stimulate the contractility of the heart muscle and raise blood pressure.

Cortisol increases the release gastrin in the stomach, thereby leading to increasing the secretion of hydrochloric acid.

In the area of ​​the skeletal system, glucocorticosteroids induce demineralization and osteoperosis, while reducing the absorption of calcium ions and the reabsorption of phosphate from the intestines.

The mobilization of calcium from the bones in a stressful situation is related to the demand for this element on the part of muscles.

However, long-term high levels of calcium in the blood (hypercalcemia) can lead to cutaneous calcine (i.e. abnormal calcification foci in the skin). Cortisol and other glucocorticosteroids are potent anti-inflammatory, weakening the functions of the immune system.

They reduce the body's hypersensitivity to the action antigens, because they inhibit the release of histamine (this is the so-called. cortisol block).

In this way, they prevent the occurrence of most life-threatening allergic reactions, such as anaphylactic shock or serum sickness.

Through their long-term action, they induce atrophy of lymphoid tissue throughout the body, reducing production immunoglobulins.

This leads to weakening of the body's immunity.

Excessive hormonal activity of the adrenal cortex, and hence - a permanently elevated level of cortisol in the blood - leads to the development of a complex of multiple symptoms that make up the picture Cushing's syndrome.

The pituitary gland

The pituitary gland is a small gland lying in the hollow of the sphenoid bone - the so-called. turkish saddle at the base of the brain.

It secretes a number of different hormones, the most important of which is for us adrenocorticotropic hormone - ACTH (aka corticotropin).

This hormone stimulates the activity of the adrenal cortex, and thus stimulates them to synthesize and release glucocorticosteroids.

The hypothalamus

The hypothalamus produces a releasing hormone corticotropin (CRH - corticotropin - releasing hormone; otherwise known as corticoliberin) in response to a stressful situation (e.g. visiting a veterinarian or meeting a new dog).

CRH is designed to "tell" the pituitary gland that it needs to produce the hormone adrenocorticotropic (ACTH).

This hormone, in turn, travels to the adrenal glands, stimulating them to release cortisol.

For what?

This so-called. the stress hormone is supposed to "turn up" the metabolism and provide anti-inflammatory and immunosuppressive effects.

Such an action is very beneficial, and if everything is going well, it is highly advisable.

However, the secretion of hormones from the hypothalamus and pituitary gland should be stopped at some point in order for the body to return to a state of calm.

How secretion is blocked under normal conditions?

High levels of circulating cortisol at some point signal the hypothalamus to stop producing CRH anymore, preventing the cycle from restarting.

This is nicely called "negative feedback " and is a very important mechanism to check, control, and balance the body against the excessive release of cortisol.

However, this self-controlling cycle of releasing and inhibiting hormone production is much more complex.

There is an inhibitory effect of cortisol on both the pituitary gland and the hypothalamus - that is, there is negative feedback on both the secondary (pituitary) and tertiary (hypothalamus).

The problem with the excessive production of cortisol by the adrenal glands may therefore be caused by the adrenal gland itself (we are then talking about primary hyperactivity of the adrenal cortex), or in the pituitary gland, where ACTH is overproduced (this is referred to as secondary or secondary adrenal hyperfunction).

It is also likely in dogs tertiary adrenal hyperfunction, associated with dysfunction of the hypothalamus and overproduction corticoliberin (CRH).

Pituitary Cushing's Syndrome

Pituitary-Dependent Hyperadrenocorticism (PDH) is the dominant form of Cushing's syndrome, accounting for approx. 80-90% cases of spontaneous hypercortisolaemia, usually induced pituitary tumor (adenoma or adenocarcinoma).

The most common pituitary tumors are:

• distal adenomas,
• less often adenomas of the intermediate part,
• very rarely pituitary cancers.

PDH characterized by abnormal, elevated levels of cortisol and ACTH.

Simply put, it can be said that as a result of the disease of the pituitary gland, there is a dysregulation of the hypothalamic-pituitary-adrenal system and a kind of "vibrations " in the production of ACTH (despite the increased level of cortisol in the blood).

As a result, there is excess release by the pituitary gland corticotropins both in terms of frequency and intensity.

The causes of PDH are related to the occurrence of various pituitary tumors. And this is how we distinguish:

1. Pituitary Cushing's disease related to pituitary macrotumors.
   Macroadenomas pose 10-20% cases. These include large pituitary tumors larger than 1 cm, which tend to extend beyond the upper border of the organ, reaching the hypothalamus. Symptoms of these tumors may be slightly different from those of Cushing's syndrome. Often a variety of ophthalmic symptoms appear, as well as a change in the dog's behavior:
   • aggression,
   • sensory disturbance,
   • appetite disorders.
2. Pituitary adrenal hyperfunction associated with pituitary microbes (most cases).
   Most pituitary tumors are Non-pigmented microadenomas. Usually these tumors are strictly limited and clearly localized, small in size (less than 1 cm in diameter).

Regardless of the cause, the excessive secretion of ACTH by the pituitary gland stimulates the adrenal cortex, increasing the secretion of cortisol and leading to its bilateral hypertrophy.

In the case of pituitary adenoma, negative feedback becomes relatively ineffective - however, hypothalamic function and the action of CRH in controlling ACTH release are suppressed.

It is surprising that in many cases the levels of ACTH and cortisol are generally within physiological limits. The pituitary form of Cushing's disease most often affects middle-aged and older dogs (the average age is approx. 7-9 years). It can appear in all breeds of dogs, but they are predisposed dachshunds, poodles and small terriers.

Cushing's syndrome of adrenal origin

The second type of Cushing's syndrome is caused by functional (cortisol-producing) tumors of the adrenal glands.

They could be adenomas or crampons (with equal frequency of occurrence).

The cancers are usually larger, they can infiltrate the surrounding tissues and cause distant metastases (mainly to the liver and lungs).

Adrenal tumors are responsible for approx 15-20% cases of hypercortisolemia. A tumor of the adrenal gland it is usually one-sided.

It uncontrollably produces extra cortisol, independent of the pituitary gland and ACTH.

Simply put, it gets out of control and, even in the absence of stimulation from the pituitary gland, it produces an excess of cortisol, which in turn suppresses the secretion of ACTH by the pituitary gland.

As a result, healthy adrenal glands (not covered by the neoplastic process) reduce their activity, which leads to the atrophy of its cortex.

In turn, in the gland where the tumor grows, normal cells gradually disappear.

Due to the high level of cortisol, the secretion of CRH and ACTH is inhibited (based on negative feedback), but it does not matter in the case of adrenal gland tumors.

Here there are episodes of "random ", completely accidental release of cortisol by a tumor of the adrenal gland. Nevertheless, adrenal tumors may respond to ACTH stimulation.

It is worth noting that there are also adrenal tumors that do not release cortisol.

These are usually adenomas that produce adrenal steroids other than cortisol.

Their presence can produce symptoms very similar to Cushing's syndrome, but blood cortisol levels are low. However, the levels of other glucocorticosteroids are high. Adrenal tumors are more common in representatives of the larger races; about 50% patients weigh> 20 kg.

The pituitary and adrenal forms of Cushing's syndrome are classified as. idiopathic Cushing's syndrome.

The form caused by the administration of exogenous steroids is classified separately; it is referred to as iatrogenic Cushing's syndrome.

The occurrence of cushing's syndrome

Which dogs get Cushing's?

Hypercortisolemia (excess cortisol) is the most common in middle-aged dogs (okay. 6 years old), although there are also cases when the disease affects one-year-old dogs.

It is diagnosed in many breeds of dogs, but some breeds are strongly predisposed to its occurrence:

• poodles,
• dachshunds,
• terriers (yorkshire terrier, jack russell terrier, staffordshire bullterrier, fox terrier),
• German Shepherds,
• beagle,
• labradors,
• as well as boxers and boston terriers.

About 55-65% cases constitute females.

On Cushing's syndrome dogs get sick older than 9 years, with the mean per 11 years old.

Pituitary Cushing's disease appears to be more common in small dogs (75% cases has less than 20 kg) while approx 50% dogs with active adrenal tumors weigh more than 20 kg.

Iatrogenic cushing's syndrome in dogs

Iatrogenic hypercortisolemia is caused by long-term, uncontrolled use of glucocorticoids (also local, e.g. in eye and ear drops, etc.).

Chronic supply of exogenous steroids inhibits secretion ACTH through the pituitary gland and leads to the disappearance of the streak layer of the adrenal cortex and a decrease in the production of endogenous glucocorticoids. Iatrogenic Cushing's syndrome it occurs regardless of the age, race or sex of the animal.

Cushing's disease symptoms in dogs

Cushing's disease diagnosis

The clinical picture accompanying hyperadrenocorticism is one of the richest among all pathological conditions in veterinary medicine.

The multitude and differentiation of symptoms and their various severity result from the multi-organ influence of adrenal cortex hormones.

Cushing's syndrome is a systemic disease, where some symptoms are typical and occur in most patients, while others may be less pronounced or not appear at all.

Many of them are difficult for the owner to spot and develop over months or even years.

They can also gradually increase, or periodically withdraw and come back.

The more symptoms there are, the more likely you are to have hypercortisolemia.

General symptoms

Polyuria and polydipsia

Polyuria / polydipsia syndrome - polyuria syndrome and increased thirst (80-85% of cases).

This is the most common motive for consultation at a veterinary office and perhaps the most specific symptom in patients with hypercortisolemia.

In over 85% of dogs with an overactive adrenal cortex, it appears as the first symptom:

a concerned owner reports that the dog cannot stay all night without urinating.

Polyuria results from the action of cortisol:

on the one hand, it reduces the release of the antidiuretic hormone, and on the other hand, it increases glomerular filtration in the kidneys.

This leads to significant increase the frequency of urination.

He also shows up frequently urinary incontinence in a dog. Polyuria is the primary symptom, while increased water uptake appears secondarily as compensation for losses.

If the dog drinks more than 60 ml / kg m.c. water, we are talking about polydipsia.

The severity of thirst is comparable to that of diabetes - a dog's water consumption is increased 2-6 times and it can reach 100 ml / kg m.c. /day, and even more.

Polyphagia

Increased appetite is a common symptom of Cushing

Polyphagia - Increased Appetite (> 90% of cases).

Another very common symptom reported by the owner to the veterinarian.

Initially, it might suggest diabetes, moreover, it is very likely that the increased appetite is due to decreased activity insulin.

Polyphagia is also caused by the neurological effects of cortisol.

Weakness, apathy, drowsiness

Quite often, the dog becomes lethargic in the course of Cushing's syndrome.

This is not the first symptom but it is as common as the symptoms listed above.

Intense panting, wheezing

Change of silhouette

Change in body shape occurs in over 80% cases.

• In Cushing's syndrome, the so-called. Cushingow's silhouette:
  • abdominal enlargement and sagging (associated with liver enlargement, muscle weakness, accumulation of abdominal fat),
  • uneven degree of fatness (mainly on the trunk),
  • limb muscular atrophy.

The Cushing's silhouette is the result of the action of glucocorticosteroids, which increase the tendency to fat (there is a disturbance in the breakdown of fatty compounds, which tend to accumulate in the dorsal line) and the relaxation of the myofascial elements (reduction of abdominal wall tension, limb abduction in which the muscle mass occurs). gradually fades away).

As a result, the dog looks like a "ball on four matches".

Liver enlargement

With hypercortisolemia, the liver is enlarged, which "rests" on the already flabby abdominal integuments, which further intensifies their stretching.

Down hepatomegaly is due to the action of steroids and this complex hepatic overload is known as steroid hepatopathy.

Neurological and muscular symptoms

Neurological and muscular symptoms occur in 75-85% of dogs.

The problem is frequently reported apathy and muscle weakness. The dog seems to have no strength.

It may develop in the course of Cushing's disease myopathy, which is characterized by stiffness of the limbs (mainly pelvic). This entails mobility problems:

the dog moves bouncing, often without bending the knees.

This disorder is not painful, but as it progresses, it leads to severe muscle atrophy, and the animal becomes more and more helpless and incapacitated over time.

The not uncommon neurological symptoms should also be mentioned facial paralysis and pseudomyotonia.

• Heat intolerance (risk of overheating)
• Abdominal obesity.

Abdominal obesity appears with an increase in appetite and is often considered by the owner as a symptom of good health.

Obesity in a dog

Skin symptoms

Dermatological symptoms are very common and usually strongly suggest Cushing's disease (along with polyuria / polydipsia syndrome).

It is not uncommon for skin lesions to be the first symptom reported by the owner.

Alopecia

They may appear as the first symptoms and initially do not lead to suspicion of hypercortisolemia.

However, this symptom may not be present i lack of alopecia does not exclude an overactive adrenal cortex.

The reason for their occurrence is the influence of cortisol on the anagen phase of hair growth.

The remaining hair is dominated by dull and matted hair, as well as with changed color (this is the so-called. telogen phase of hair growth).

If they are generalized bilaterally and symmetrically, their location may be breed specific.

A typical location is torso, but sometimes they only occur on the bridge of the nose (the so-called. linear alopecia) or in the form of rat's tail.

AT poodles alopecia is usually the first alarming symptom. They appear early after the sides of the body and the base of the limbs, and the head, the peripheral parts of the body remain covered with hair longer.

AT dachshunds hair loss is more diffuse. They are predilection places belly, lateral surface of the auricles, base of the tail, but also sides of the body and limbs.

Thin skin with reduced elasticity

Under normal conditions, the skin of dogs is thickest on the dorsal surface of the neck and torso, and thinnest on the limbs, especially on the toes.

With Cushing's syndrome, the skin becomes thin, especially in those areas where there is maximum lesion.

This is as a rule abdominal area, where the umbilical veins and the inner surface of the thighs are clearly visible through the skin:

the skin in these places is as thin as blotting paper.

It is a result of the loss of connective tissue in the skin under the influence of cortisol.

Additionally, the skin loses its elasticity. After grasping it in a fold, it slowly returns to its original state (under normal conditions, the fold of the skin straightens out immediately after release).

The skin wrinkles as if there is too much of it in relation to the body size - it is clearly visible in the form of numerous folds, especially in the area of ​​the ankle joints.

Spots

Pigmentation discoloration containing melanin is especially common.

They are scattered throughout the animal's body.

The spots are not specific to Cushing's syndrome, but their presence may increase the suspicion of the disease.

• The tendency to varicose veins. Vein dilatations appear as small, bloody streaks.
• Tendency to bruise
• Skin stretch marks arising spontaneously or in places of scarring. Scars may spread in areas of previous surgery.
• Blackheads.

Black seborrheic nodules present on the skin of the abdomen, especially around the mammary glands and in the perianal area, are very characteristic of hyperfunction of the adrenal cortex.

Their presence additionally predisposes to secondary infections of the hair follicles.

Cutaneous calcinosis

It consists in the deposition of insoluble calcium salts in the skin and subcutaneous tissue (mineralization).

The changes are most often located on ridge, especially on neck and sacral area, in armpits and groin.

Generalized cutaneous calcinosis, accompanying hypercortisolemia is associated with too much calcium in the blood (hypercalcaemia).

It can manifest itself in various forms - from very fine deposits of calcium salts, visible only under a microscope, through single, small nodules to yellowish deposits of large size, convex and clearly demarcated from the adjacent tissues.

If calcinosis is accompanied by secondary infections, it also occurs itching and ache, and scabs, located in diseased areas around the back, neck and nose.

Difficulty healing wounds

They can cause chronic ulcerative conditions, and result from reducing the proliferation of fibroblasts and decrease in collagen synthesis.

Confusing dermatoses

Demodicosis in a dog

• Multiple skin diseases can complicate the course of Cushing's syndrome:
  • seborrheic syndrome,
  • bacterial infections,
  • fungal infections,
  • Demodex invasions.
    The response to treatment in these cases is poor, especially if hyperadrenocorticism is not being treated concomitantly.

Reproductive problems

You can observe:

• lack or delay in heat,
• testicular atrophy,
• enlargement of the clitoris, resulting from overproduction of adrenal androgens.

Neurological symptoms

Neurological symptoms associated with pituitary macroadenoma:

• apathy,
• stupor,
• decrease in appetite,
• wandering, aimless wandering,
• spinning in circles, pressing on obstacles,
• behavior changes,
• Horner's syndrome,
• seizures - rare.

Symptoms and conditions not specific to Cushing's syndrome

They can coexist:

• lack or loss of appetite,
• vomiting,
• diarrhea,
• sneezing,
• cough,
• jaundice,
• itching,
• ache,
• lameness as a result of inflammation,
• epileptic seizures,
• bleeding,
• kidney failure,
• inflammation of the pancreas,
• liver failure,
• immune diseases,
• ligament rupture,
• ophthalmic symptoms - protruding eyes, corneal ulceration, blindness.

You can see what the symptoms of Cushing's disease may look like in the video below

Carrot Cake Doxie w / Cushings Disease eats a treat
Watch this video on YouTube

Cushing's syndrome complications

Complications appear in some animals, the following are observed:

• arterial hypertension (occurs in about 50% of cases),
• urinary tract infections,
• pyelonephritis,
• cystitis (clinically silent),
• urolithiasis,
• stones containing calcium,
• struvites if associated with infections,
• congestive heart failure,
• inflammation of the pancreas,
• diabetes,
• impaired wound healing,
• recurring infections,
• flabbiness of the joints,
• hypercoagulability,
• pulmonary embolism,
• aortic embolism.

Cushing's Syndrome: Diagnosis

Cushing's syndrome is often a very frustrating unit in diagnostics, because many - even typical - symptoms may not appear, the results of laboratory tests are sometimes ambiguous, and the accompanying complicating processes blur the typical clinical picture. Sick dogs, as a rule, do not display a life-threatening condition.

The disease usually progresses slowly, with most patients having only one or more of the common symptoms of the disease.

Cushing's syndrome is a clinical syndrome that cannot be diagnosed without the presence of typical clinical symptoms.

Therefore, the diagnostic process can be arduous and long.

Cushing's syndrome should be suspected in the presence of the following abnormalities:

Always, when:

• The dog has polyuria / polydipsia syndrome.
• Symmetrical alopecia on both sides is present.
• The dog presents "Cushing's silhouette" (abdominal obesity and weakening of the tone of the integuments).
• With such symptoms - of course, after excluding other diseases (eg. diabetes, hypothyroidism, kidney failure etc.) - Cushing's syndrome should be included in the differential diagnosis.

Alternatively, when:

• There is hyperpigmentation (discoloration) of the skin.
• Cutaneous calcinosis occurs.

Accurate collection is always a very important diagnostic element intelligence (including information about the administration of steroids).

Once suspected, hypercortisolemia should be performed thorough laboratory evaluation.

Complete blood count

• In the course of Cushing's syndrome, a fairly typical white blood cell image occurs very often - the so-called. stress leukogram. This picture is visible in almost all animals:
  • Leukocytosis with neutrophilia,
  • Monocytosis,
  • Lymphopenia,
  • Eosinopenia.
• Similarly thrombocytosis - Almost all hypercortisolemic dogs have increased platelet counts.
• In some dogs, it may be mild erythrocytosis - that is, an increase in the number of red blood cells.

Blood serum biochemistry

• Increase in blood glucose - hyperglycemia.

Most often it is a moderate rise in blood sugar and - in most cases - without glucosuria. Around 50% cases are associated with a simultaneous increase in insulin levels.

This is the effect of intense gluconeogenesis and reduced peripheral glucose utilization due to insulin antagonism.

Cushing's disease should always be considered in a diabetic dog who has difficulty finding an effective insulin dose.

Hypercortisolemia causes insulin resistance and can lead to development diabetes.

Interestingly, dogs with coexisting diabetes do not have the usual symptoms that indicate too high levels of cortisol.

Nevertheless, Cushing's development should always be considered if a diabetic dog fails to achieve normoglycemia.

• Increase in ALP alkaline phosphatase activity (> 150 U / l, sometimes> 1000 U / l) occurs in u 90-95% dogs with hiercortisolemia.

The increase in the level of alkaline phosphatase is marked (usually around 5-10 times above physiological norms).

It is considered a constant, though not specific, criterion for the diagnosis of Cushing's disease.

• Increase in the level of alanine transaminase ALT - found in over 90% dogs with hypercortisolemia. The cause is overload of the liver glycogen.
• Increase in blood cholesterol (due to increased lipolysis).

About 50% The parameter is not specific to patients, but with the coexistence of other characteristic abnormalities, it may suggest Cushing's syndrome.

Level increase cholesterol and growth serum alkaline phosphatase are the most reliable indicators of hypercortisolemia at this diagnostic stage.

In some patients, ALP may remain normal.

• Urea it is usually normal or may be lowered.
• Increase in triglyceride levels (as a result of lipolysis induced by cortisol).
• Slightly elevated level fatty acids.
• Slightly raised level sodium.
• Slightly lowered level potassium.

Urine general examination

• Urine specific gravity < 1,020, często nawet 50% patients experience impaired or inability to concentrate urine (hypo - or isosthenuria).
• Proteinuria.
• Bacterial inflammation of the urinary tract - v 40-50% cases:
  • infection is usually latent, therefore it is necessary to perform a bacteriological examination of the urine sample obtained using the cystocentesis method,
  • is the result of incomplete emptying of the bladder, caused by muscle weakness, as well as immunosuppression related to the action of glucocorticosteroids.
• Slight increase in protein / creatinine ratio (UP / C) - usually less than 5.

Radiography overview of the abdominal cavity

• enlarged liver,
• quite large amount of abdominal fat, providing good radiological contrast,
• overstretched bladder,
• urolithiasis,
• calcification (calcification) within soft tissues,
• osteoperotic lesions of the vertebrae,
• adrenal calcification - rare; usually associated with adenoma or cancer of the adrenal glands.

Review X-ray examination chest

• calcifications in the respiratory tract,
• osteoperotic lesions of the vertebrae,
• lung metastases (rare),
• pulmonary embolism.

Ultrasound examination abdominal cavity

• enlargement of the adrenal glands (in pituitary Cushing's syndrome),
• a tumor of the adrenal gland with a simultaneous reduction in the size of the second gland (in the course of the adrenal form of Cushing's syndrome),
• adrenal calcification (near the tumor),
• the presence of metastases,
• enlarged liver,
• increasing the echogenicity of the liver,
• dilated, atonic bladder,
• urolithiasis,
• soft tissue calcification.

Advanced imaging

Both computed tomography, what magnetic resonance imaging are tests useful in the diagnosis of tumors or hyperplasia of the adrenal glands and large pituitary tumors, but due to the relatively high costs, they are still too rarely used.

• Computed tomography or MRI of the brain can reveal a pituitary tumor
  • Testing recommended to confirm the cause of neurological symptoms as well as when considering radiation therapy or surgery.
  • Abdominal computed tomography is recommended before the procedure adrenaletomy (removal of adrenal glands).
• Histopathological examination (for tumors).

As the likelihood of Cushing's syndrome or disease increases, the next step is to test your adrenal function.

Screening tests

Goal hormonal tests is the demonstration of an increased production of cortisol by the adrenal glands or a decreased sensitivity of the hypothalamic-adrenal axis to negative feedback related to the action of steroids.

They are performed only when they are present clinical signs of hypercortisolemia, because only then do they have diagnostic value.

Blood Cortisol Test - Baseline Determination.

The determination of cortisol levels is a major part of the laboratory diagnosis of Cushing's syndrome. This study has an exclusive value - if cortisol levels are normal, Cushing's syndrome is unlikely.

However, in the event of an increase in the level of this hormone, additional tests should be performed.

This is because even in healthy but stressed animals, cortisol levels may exceed reference levels.

Daily fluctuations in cortisol levels are quite wide, and basal levels tend to be higher under stress or other illnesses.

Therefore, a single measurement of cortisol levels is of little use in making a diagnosis and should be supplemented by additional tests.

Determination of the urine cortisol to creatinine ratio (UC / C).

Dogs with Cushing's syndrome have elevated serum cortisol levels and excrete more cortisol in their urine.

Due to the fact that the amount of cortisol in the blood can increase with a physiological increase in the metabolic rate, it is related to the value of creatinine in the urine.

There may be fluctuations in its concentration in urine samples collected at different times of the day.

A simple method, introduced due to the ease of implementation and the possibility of eliminating stress.

It is mainly suitable as a screening test.

Owner by 2 consecutive days collects the dog's morning urine sample and stores it in fridge.

Then it calculates ratio of free renal cortisol to creatinine.

Urine Test Protocol:

• Collection of morning urine on the first day - the first sample.
• Collection of morning urine on the second day - the second sample.
• Sometimes (to differentiate the pituitary from the adrenal Cushing's syndrome):
  • Oral administration of dexamethasone on the second day at a dose of 0.1 mg / kg m.c. 3 times per day,
  • Collection of morning urine on the third day.

Urine Test Interpretation:

• Urine cortisol (nmol / L) / urine creatinine (mmol / L) x 10-6:
  • Value ratio:
    • Day 1 : < 15x10-6 wynik negatywny. To nie jest zespół Cushinga
    • Day 1: between 15x10-6 and 25x10-6 - questionable result
    • Day 1:> 25x10-6 - Cushing's syndrome in> 93% of cases
  • With double determination: the average is calculated from the coefficient values ​​of the first 2 days and evaluated as above.
  • If the ratio is increased in samples 1 and 2 - evaluate UC / C with inhibition test. Value ratio:
    • Day 3. UC / C ratio> 50% of the mean of the first two samples may indicate adrenal form.
    • Day 3. UC / C ratio

During spontaneous Cushing's syndrome the level of renal cortisol is higher than in healthy animals.

The test is relatively sensitive, but unfortunately not specific to hyperadrenocorticism.

Similar values ​​are obtained for other causes of polyuria and polydipsia.

Additionally, there are many false-negative results. Not all dogs with Cushing's syndrome have abnormal concentrations. Is to good screening test for dogs suspected of having Cushing's syndrome that do not have severe clinical signs.

Determining the cortisol / creatinine ratio in the urine allows to exclude hypercortisolemia when the result is normal.

Unfortunately, the increased K / K ratio does not allow for a reliable diagnosis.

Abnormal urine cortisol / creatinine ratios may be found in the presence of other conditions, such as diabetes, diabetes insipidus, pyomyxia, hypercalcemia, kidney disease, liver.

Hence, this test is better used to monitor treatment than to establish a diagnosis.

It is also not a method of differentiating PDH from ADH, unless the cortisol / creatinine ratio is 100x10 -6 as suggested by PDH.

ACTH stimulation test

It consists in determining the level of cortisol in the tested dog before and after stimulation of the adrenal glands with ACTH injection.

Thanks to this, it is possible to test the maximum secretory capacity of the adrenal cortex.

This test takes advantage of the fact that overgrown adrenal glands are able to produce more cortisol when stimulated.

It also allows you to demonstrate hypocortisolemia, which occurs as a result of corticotherapy (suppression of adrenal function).

This is very important information because when combined with the clinical picture it allows to determine whether this lesion is associated with iatrogenic Cushing's syndrome.

In dogs ACTH stimulation test is the method of choice for:

• diagnosis of iatrogenic Cushing's syndrome,
• controlling the treatment of overactive adrenal cortex,
• follow-up of the patient after adrenalectomy,
• also for the diagnosis of adrenal insufficiency (Addison's disease).

Test protocol (dog on an empty stomach):

• First blood sampling to determine basal cortisol levels. ACTH injection intramuscularly or intravenously at a dose of 0.25 mg. In a healthy animal, the cortisol level before ACTH administration is between 20 and 250 nmol / L (0.7 - 9 µg / dL)
• Second blood sampling 1 hour after injection = determination of cortisol level after ACTH stimulation. In a healthy animal, the level should be between 200 and 450 nmol / l (9 - 16 µg / dl).

Interpretation of the result:

• Cortisol levels after ACTH stimulation:
  • > 22 µg / dl (> 607 nmol / l) - elevated level - Cushing's disease very likely
  • 17 -22 µg / dl (470 - 607 nmol / l) - inconclusive result ( "gray zone ") - probable Cushing's disease, but additional tests should be performed and the diagnosis should take into account clinical symptoms and their severity
• Cortisol levels before and after ACTH stimulation:
  • Both values

Interpretation of results varies from lab to lab, but there is usually a clear response to ACTH - concentrations after 1 hour are usually three times higher than the baseline levels.

Regardless of the initial cortisol concentration, however, when its level after ACTH administration is over 600 nmol / l, recognize hyperadrenocorticism.

It is a test of o highest specificity, however, Fr low sensitivity.

There are a lot of false-negative results, which is why we obtain the greatest certainty with a positive result.

Because dogs sick with the iatrogenic form of Cushing's syndrome show a very reduced response to ACTH stimulation, it is the test of choice when suspecting this disease entity.

However, it cannot determine the differences between the existing, possible causes of Cushing's syndrome and should be supplemented by another test (inhibition test).

Additionally, some dogs with adrenal tumors respond correctly to stimulation.

Low-dose dexamethasone inhibition test - LDDST (fasting patient!)

The purpose of this test is to assess the pituitary-adrenal axis, which is abnormally resistant to stimulation with exogenous steroids in cases of spontaneous Cushing's syndrome.

The method is more sensitive, than the ACTH stimulation test, however less specific (more false positives happen).

However, it gives a high degree of confidence in the case negative result.

The advantage of this test is that it can differentiate the cause of Cushing's syndrome and determine whether the disease is pituitary or adrenal.

Unfortunately, it is not a useful method for diagnosing iatrogenic Cushing's syndrome as well as hypoadrenocorticism.

The essence of this test is to determine the level of cortisol before and after the injection of a direct-acting glucocorticoid.

Generally for this purpose it is used dexamethasone.

The normal response to the supply of an exogenous steroid is a decrease in cortisol levels within a few hours, because dexamethasone inhibits its production (it reduces ACTH secretion through negative feedback).

After approx 2-3 hours ACTH secretion is suppressed, which lasts approx 24-48 hours.

The adrenal cortex produces less cortisol - its blood levels drop.

In the course of Cushing's syndrome, this inhibition is much less, especially in the presence of adrenal neoplastic tumors that autonomously produce cortisol (independent of ACTH).

Administration of dexamethasone will affect the secretion of ACTH, inhibiting it, but will not reduce the secretion of cortisol.

As a result, its level will not decrease or it will only slightly decrease.

Here the pituitary gland will react and the adrenal glands will not.

In pituitary Cushing's disease, dexamethasone has little or no effect on the pituitary gland.

After injecting the steroid, ACTH secretion is either not stopped at all, or it is temporarily inhibited, and then the pituitary gland releases the hormone again and stimulates the adrenal cortex to produce cortisol.

Effect:

the level of the latter drops very little or not at all and only for a short time.

This test is not suitable for the diagnosis of iatrogenic Cushing's syndrome or for monitoring treatment.

In practice, the doses of dexamethasone used have changed.

Two trials are currently underway:

inhibition with small (0.01-0.02 mg / kg m.c.) and large (0.1-1 mg / kg m.c.) doses of dexamethasone.

Study protocol:

• First blood sampling - determination of basal cortisol level (at. 0).
• Intravenous injection of dexamethasone at a dose of 0.01 mg / kg m.c.
• Second blood sampling 4 hours after steroid injection (at. 4). It gives an indication of the deposition of residues and allows the final form of Cushing's syndrome to be defined: pituitary or adrenal.
• The third blood sampling 8 hours after injection (at. 8) - determination of the suppressed value of cortisol.

Study interpretation:

When interpreting the test results, the first step is to take into account the concentration of cortisol in the sample taken 8 hours after the injection of dexamethasone.

• If the result is within the range of physiological norms, then:
  • or the dog does not have hyperadrenocorticism,
  • or (with a probability of the order of 5-10%) - there is hyperthyroidism of the pituitary gland. It happens that the dog has an early-stage pituitary disease that still reacts to the pharmacological dose of the steroid with reduced ACTH secretion, which leads to a decrease in blood cortisol. In such situations, please do ACTH stimulation test.
• If the cortisol level is above the upper end of the reference range, the dog is most likely to have an overactive adrenal cortex (possible false-positive results in non-adrenal conditions). The cortisol concentration in the starting sample and the 4-hour sample is then assessed to see how the cortisol secretion was inhibited throughout the test:
  • if a drop in blood cortisol levels is observed in the fourth or eighth hour by at least 50%, the final diagnosis is hyperadrenocorticism of pituitary origin and there is no need to perform further adrenal function tests.
• Healthy patient:
  • time. 0 - cortisol 1-5 µg / dl - normal or slightly elevated values ​​(due to stress),
  • time. 4 - cortisol
  • time. 8 - cortisol
• Hyperadrenocorticism of pituitary origin:
  • "Inhibition " occurs in 60-65% of dogs with PDH,
  • when the cortisol concentration in the sample after 4 hours is 1.4 µg / dl,
  • when the cortisol concentration in the sample after 4 hours is 1.4 µg / dl (> 40 nmol / l),
  • when the cortisol concentration is 1.4 µg / dl after 8 hours.
• Hyperadrenocorticism of pituitary or adrenal glands:
  • when the cortisol level> 1.4 µg / dl in the sample after 4 and 8 hours,
  • the lack of any effect suggests secretively active adrenal tumors.

Interpreting the results of a low-dose dexamethasone inhibition test is often difficult. Here are some examples:

Patient 1

Cortisol levels in a low-dose dexamethasone inhibition test:

• time. 0 - 10 µg / dL,
• time. 4 - 10 µg / dL,
• time. 8 - 10 µg / dL.

Interpretation:

We are definitely dealing with overactive adrenal cortex, because the cortisol concentration at 8 hours after steroid administration is> 1.4 µg / dL.

Due to the fact that cortisol levels were abnormally high in all samples, the results strongly suggest Cushing's syndrome of adrenal origin.

In adrenal tumors, inhibition is not noticed or it is very weak.

However, on the basis of such results, AT cannot be definitively diagnosed because even thirty% dogs with the pituitary form of the disease also did not respond by decreasing cortisol levels.

Therefore, the next differentiating test should be determination of endogenous ACTH.

Patient 2

Cortisol levels in a low-dose dexamethasone inhibition test:

• time. 0 - 10 µg / dL,
• time. 4 - 6 µg / dL,
• time. 8 - 4 µg / dL.

The 8 hour cortisol level is greater than 1.4 µg / dL - present hyperadrenocorticism.

Because dogs with adrenal tumors never experience suppression of cortisol in the test, the adrenal form of the disease cannot be recognized here.

At 8 hours after the administration of the steroid, the level of cortisol is 4 µg / dl, at least there is 50 percent inhibition of cortisol secretion, which allows for a diagnosis hyperactivity of the adrenal cortex of pituitary origin.

Patient 3

Cortisol levels in a low-dose dexamethasone inhibition test:

• time. 0 - 10 µg / dL,
• time. 4 - 4 µg / dL,
• time. 8 - 10 µg / dL.

Again - a cortisol level> 1.4 µg / dl proves overactive adrenal cortex.

Although the cortisol levels at 0 and 8 hours are the same, we are not dealing here with adrenal form of the disease, for it has happened at least 50% inhibition of secretion during the test (level at 4 hours - 4 µg / dl) .

The diagnosis is:

hyperfunction of the adrenal cortex of pituitary origin.

The increase in cortisol between 4 and 8 hours reflects the increased metabolism of dexamethasone during this time, which is often present in patients with hyperadrenocorticism.

Patient 4

Cortisol levels in a low dose dexamethasone inhibition test:

• time. 0 - 10 µg / dL,
• time. 4 - 6 µg / dL,
• time. 8 - 1 µg / dL.

Despite the high value of the basal level of cortisol (10 µg / dl), its concentration decreased after 8 hours to the reference values ​​(

Therefore, such a result should be approached very carefully.

On the one hand, it does not indicate an overactive adrenal cortex, but it should be remembered that even 10% dogs with pituitary disease may have normal test results.

In such a situation - in the case of patients with clinical symptoms of hyperadrenocorticism and normal results of the inhibition test - should be performed ACTH stimulation test or wait 4-6 weeks and try again.

High dose dexamethasone inhibition test (HDDST)

In the pituitary form of Cushing's syndrome, the negative feedback is not completely abolished, while in the adrenal form, the secretion of cortisol is not influenced by exogenous steroids.

High doses of dexamethasone (0.1 mg / kg m.c.) inhibit the release of ACTH by the pituitary gland, leading in the vast majority of cases to a clear suppression of cortisol levels in the pituitary Cushing's syndrome, while the secretion of this hormone is not inhibited (or it is small) in the adrenal form.

It is worth noting that approx 15-20% of dogs with pituitary Cushing's disease reacts with a small drop in cortisol levels also with a high dose of dexamethasone.

This test is used to make a more accurate diagnosis, as it allows you to find the cause of hypercortisolemia.

Study protocol:

• first blood sampling - basal cortisol level,
• intravenous injection of dexamethasone at a dose of 0.1 mg / kg m.c,
• the second blood sampling - 8 hours after the injection of dexamethasone - this is the suppressive level of cortisol.

Study interpretation:

• Suppressive level
• Suppression level> 50% of the baseline or> 1.4 µg / dl - adrenal Cushing's syndrome

Important note regarding both tests - inhibition of low and high doses of dexamethasone.

In the case of low dose inhibition in 35-40% there is no cortisol suppression (in the course of the pituitary Cushing's syndrome).

The high-dose inhibition test is not much more sensitive - it happens that in the course of the pituitary Cushing's form, a high-dose steroid will not cause suppression (even in 25% of cases).

Reflecting on the choice of further tests and bearing in mind the fact that the high dose dexamethasone inhibition test will "improve " the detection statistics only by approx. 10-15%, it is probably better to choose a different test for diagnosis. An adrenal tumor cannot be diagnosed with either LDDST or HDDST.

Determination of endogenous ACTH levels

Endogenous ACTH determination serves to differentiate between the pituitary and adrenal forms of Cushing's syndrome.

The essence of the test is that adrenal tumors (hormonally active) inhibit ACTH secretion due to negative feedback, while excessive ACTH secretion occurs in pituitary Cushing's syndrome.

Interpretation:

Due to uneven ACTH secretion and a large influence of stress factors on its level, the interpretation of the results may be difficult.

• ACTH level in the range of 9-67 (even 80) pg / ml - physiological value.
• Low ACTH concentrations
• High ACTH concentrations 45-450 pg / ml - Suspicion of pituitary Cushing's syndrome or primary adrenal insufficiency.
• Values ​​between 20 and 45 pg / ml - non-diagnostic result (test should be repeated).

Despite a fairly wide range of diagnostic methods, there is no test that is 100% accurate.

Each of these tests can be negative even in patients with symptomatic HAC.

If this is the case, select and run another test. If more than two tests are negative, a different diagnosis should be considered.

Sometimes the screening tests are not able to show a confirmatory result in a patient in the initial stage of hyperadrenocorticism.

Then it is advisable to repeat the tests after a few months, depending on the worsening of the disease symptoms.

A few years ago, there was a lot of controversy regarding HAC diagnostics.

In 2013, the "Journal of Veterinary Internal Medicine " published a statement providing some guidelines for the diagnosis of spontaneous hyperadrenocorticism. This opinion includes:.in.:

The likelihood of HAC occurrence should be determined at the stage of the interview with the owner and the clinical examination

Hormonal tests should be performed when there are clinical symptoms suggesting HAC. The more characteristic symptoms there are, the greater the indications for testing, but the presence of one or several symptoms specific to this individual is enough.

The results of laboratory tests (hematology, serum chemistry, urine tests, protein / creatinine ratio or blood pressure results) alone are not indications for hormonal tests.

Cushing's syndrome treatment

Cushing's syndrome treatment

Treatment of Cushing's syndrome is difficult and requires close cooperation between the veterinarian and the animal owner.

Discipline in administering medications, monitoring the condition of the dog, and relatively frequent check-ups are necessary.

The dog is doomed to taking medications most often for the rest of your life, and serious side effects quite often they accompany all forms of treatment.

How successful the treatment will be depends largely on the accuracy of the diagnosis, in tightness from identify the cause, but also from treatment of comorbidities (e.g. diabetes).

It would be a truism to say that you should always be sure of a diagnosis before starting treatment.

However, if a serious disease such as Cushing's syndrome is suspected, it is absolutely necessary to get rid of any doubts before introducing powerful and aggravating drugs.

The patient must have consistent clinical symptoms, test results consistent with the clinical course and results of laboratory tests confirming the suspicion of the disease.

Sometimes Cushing's syndrome is highly probable, but the test results do not confirm it.

Then the tests should be repeated after a few weeks or additional tests (eg. ACTH stimulation test with determination of the sex hormone panel).

It also happens that the dog has minimally severe clinical symptoms, and in turn the tests confirm the presence of the disease.

Make sure that the results are not false-positive (this happens when there is severe stress or there are competing, non-adrenal conditions).

There is no evidence that even with the onset of Cushing, early treatment is beneficial.

Certainly, however, the dog should be treated when the clinical signs affect the quality of life of the pet, owner, or there are symptoms that may indirectly indicate HAC, e.g.:

• hypertension,
• urinary tract infections,
• proteinuria.

Treatment of cushing's syndrome of pituitary origin

Trilostane (Vetoryl) for the dog

Trilostane is the only drug registered in Poland for use in dogs with hyperadrenocorticism, used as first-line drug.

Trilostane belongs to the group of reversible inhibitors of steroid synthesis.

In other words blocks the formation of glucocorticosteroids and - to a lesser extent - mineralocorticoids. In this way, it lowers the level of circulating cortisol, thanks to which the clinical symptoms disappear.

The blockade of steroid synthesis is reversible and its intensity depends on the dose.

Trilostane is a short-acting drug and requires a minimum administration 1 time a day with a meal.

Most dogs tolerate it well and very rarely show symptoms of hypoadrenocorticism when using it.

Often, however, there is a slight, asymptomatic increase in the level of potassium in the blood.

The drug is most effective in the pituitary form of hyperadrenocorticism (although not in all cases).

The manufacturer recommends administering trilostane in a dose 3-6 mg / kg m.c. orally every 24 hours. Capsules of various weights are available (10, 30, 60 and 120 mg).

It is best to give it with food as it is most effective.

The dose may be adjusted depending on your response to treatment and the results of the ACTH stimulation test.

The recommended doses are:

• 30 mg orally for dogs weighing
• 60 mg for dogs 5-30 kg
• 120 mg for dogs> 30 kg.

The effectiveness of the drug is assessed with the help of ACTH stimulation test, which should be done in 10-14, 30 and 90 days of treatment, and then regularly every 3 months.

Also, after each dose change, the test should be performed according to the protocol provided.

A blood sample should be taken on 4-6 hours after drug administration, when the cortisol concentration is at the highest level - if the test is performed at a different time, the cortisol concentration may have a completely different value.

• Cortisol levels after ACTH administration < 20 nmol/l (0,7μg/dl) – należy przerwać podawanie trilostanu i uważnie obserwować pacjenta pod kątem wystąpienia objawów hipokortyzolemii.
• Cortisol concentration after ACTH administration in the range of 0.7-1.5 μg / dL - trilostane should be withheld for 48 hours, then treatment should be resumed while reducing the dose by 50%.
• Cortisol concentration after administration of ACTH> 120 nmol / l (4.3 μg / dl) - the dose of the drug should be increased by 50-100%.
• The cortisol concentration after ACTH administration is between 20 and 120 nmol / l (0.7-4.3 μg / dl) and the patient feels well - the dose of trilostane should be unchanged.

In a situation where the animal feels unwell (despite normal cortisol values), trilostane should be administered 2 times a day.

The patient's clinical evaluation and the ACTH stimulation test are repeated over the course 2 weeks after dose change.

In a situation where, after the introduction of trilostane, stabilization of clinical symptoms is achieved, the patient feels well, and the cortisol values ​​are within the optimal range, control tests and the ACTH stimulation test should be repeated at least every 3-6 months, sometimes more often (e.g. in a situation where symptoms of hyperadrenocorticism appear, or on the contrary - hypocortisolemia).

Some patients have ACTH stimulation test results within the optimal range and still show symptoms of an overactive adrenal cortex.

In this situation, it is recommended to divide the dose of trilostane into 2 administrations every 12 hours, and then an ACTH stimulation test should be performed and possibly a dose adjustment made.

You should monitor kidney function while exercising serum biochemical test, and assessment of the level of electrolytes.

Many patients require trilostane doses to be adjusted during treatment.

Caution should be exercised if the patient is receiving other medications, such as.:

• spironolactone,
• angiotensin converting enzyme inhibitors.

In animals with heart or kidney disease, the drug should be used very carefully and the patient's condition should be monitored more frequently, despite the fact that it is less "harmful" than mitotane (another medicine used to treat Cushing's syndrome). Pregnant women should not come into direct contact with him.

After the introduction of the drug, on average after approx 2-4 days may appear harmless side effects, like for example.:

• decreased appetite,
• slight apathy.

They often go away on their own or with dose reduction.

In the event of more serious symptoms, the drug should be discontinued and given to the dog for 1-2 days prednisolone. Belong to them:

• diarrhea,
• vomiting,
• stupor.

Dangerous electrolyte disturbances appear rarely.

In such situations, patients require very low doses of trilostane for life.

Side effects of trilostane:

• moderate drowsiness,
• decrease in appetite for 2-4 days after starting treatment (most likely due to hypocortisolemia),
• moderate electrolyte imbalance (e.g. hyperkalemia),
• rarely - symptoms of pronounced adrenal insufficiency,
• sporadic cases of acute adrenal necrosis.

If any disturbing symptoms are noticed, the owner should contact a veterinarian as soon as possible.

In these situations, it may be necessary to stop dosing the medicine temporarily, perform a stimulation test, and perform supportive care.

Mitotane

The main drug that was used in the treatment of hyperadrenocorticism was Mitotan (Lysodren, o 'p ' DDD).

Now successfully replaced by Trilostan.

Mitotane is slightly more effective than vetoryl, but has more side effects. Currently, doctors use it when trilostane proves to be ineffective.

Mitotane was once used as insecticide (substitute DDT), however, it quickly showed adrenocorticolytic properties.

It has a cytotoxic effect on the adrenal cortex, which causes reduction in the production of glucocorticoids. Mitotane can cause necrosis of the entire adrenal cortex, especially its banded and reticular parts (the glomerular layer produces new cells in the adrenal cortex).

The effect of mitotane is most pronounced in overgrown adrenal glands, but its effect (change in the stimulation test) is also evident in normal adrenal glands.

Therefore, its use must be carried out with great care.

There are two options for mitotate treatment:

1. Traditional to control overactive adrenal glands in dogs without clinical signs of hypercortisolemia. It is recommended for the initial treatment of Cushing's syndrome.
2. Pharmacological adrenalectomy, the purpose of which is to destroy the adrenal cortex (i.e. transition from hyper - to hypocortisolemia). It is only considered in dogs that do not respond to conventional therapy or have stopped responding to mitotane therapy after prolonged use of mitotane.

Traditional mitotane treatment has two steps:

1. Induction (to achieve disease control).
2. Maintenance phase (lifetime treatment to prevent recurrence of clinical symptoms).

Induction phase

Before starting the administration of mitotane, the owner should determine the amount of water consumed per day and the amount of urination by the sick dog for several days.

This is very important as this information is the baseline criteria for assessing the effectiveness of the induction treatment and for entering the maintenance treatment phase.

Once this is established, mitotane therapy is started:

• Administration is initiated at a fairly high starting dose 50 mg / kg m.c. / day in two divided doses. Mitotane is more effective when given crushed, mixed with a small amount of vegetable oil, and given with food.
• Such treatment is continued at the recommended dose until the polyuria / polydipsia syndrome is clearly reduced. It is therefore important to monitor the amount of water you drink and your urine output very carefully, also after starting mitotane therapy.
• The owner should be in constant contact with the veterinarian . Since therapy is initiated at home, the caregiver's role in monitoring treatment is important to avoid the risk of developing profound hypocortisolemia and to move into the maintenance phase as soon as possible. The assessment covers:
  • dog activity,
  • state of consciousness,
  • appetite,
  • the amount of water consumed,
  • general condition of the dog.

• Immediate contact with a veterinarian required upon noticing symptoms such as drowsiness, vomiting, weakness, reduced water intake. If disturbing symptoms are found, a decision may even be made to discontinue mitotane administration.
• The average duration of this stage is 5-15 days, but significant and unpredictable individual differences mean that a response to treatment can be quick and delayed 3 day of treatment.
• The induction phase is complete when there is evidence of a decrease in appetite or when the dog's daily water consumption has dropped to a level At this point, mitotane therapy should be discontinued. This is confirmed by the result of the usual ACTH stimulation test 5-7 days after starting treatment. But it is on the shoulders of the pet's caregiver to "catch" the moment when the clinical symptoms of hypercortisolemia disappear. That is why close monitoring of the animal is of great importance.
• No therapeutic response within 30 days is rare. In such a situation, it is recommended to re-examine the patient thoroughly, together with repeating tests assessing adrenal function.
• The speed with which dogs respond to induction treatment may be an indication for a second phase prompt response to induction therapy suggests poor maintenance dose and vice versa.
  • The ACTH stimulation test should be performed when:
    • there will be a noticeable reduction in appetite and thirst after the introduction of mitotane,
    • the animal becomes apathetic, diarrhea or vomiting occurs,
    • or in 7 day of treatment.
  • The aim of the induction phase is a slight suppression of adrenal function, i.e. the cortisol level after ACTH should be in the range 1-5 µg / dl (27-138 nmol / l).
• The induction time is usually 5-10 days. Almost all dogs with pituitary hyperadrenocorticism respond within the first 14 days of treatment. At this point, you should switch to the mitotane maintenance dose and perform the ACTH stimulation test monthly initially and then monthly thereafter 3 months.

Maintenance phase

After the test, treatment is maintained at the same or half the dose one to two times a week, depending on the severity of symptoms.

During therapy, you should monitor the level of:

• urea,
• sodium,
• potassium in the blood.

The first effects of the therapy are usually visible as a reduction in the need for food (the dog clearly eats less and / or the time of his meal is longer).

At the same time, thirst is significantly reduced - the dog drinks less than 60 ml / kg / day.

During the first month of treatment, the patient becomes more alert and more resistant to exercise.

The skin symptoms disappear a little slower, but with time 3-6 months hair grows back properly.

However, the disappearance of alopecia is not linear and predictable - it largely depends on the initial degree of skin atrophy and the time elapsed from the appearance of the first dermatological symptoms and the start of treatment.

It should be remembered that during treatment, there may be a temporary deterioration in the condition of the skin after several weeks of treatment.

There is often development seborrheic syndrome and itching.

Many dogs experience a flare-up of symptoms over time and dose needs to be verified mitotane.

If the result of the ACTH stimulation test suggests that adrenal suppression has not been achieved (cortisol concentration after ACTH administration> 250 nmol / L (> 9 μg / dL), for 3 consecutive days continue dosing at the starting dose and check the effect by repeating the test.

It also happens that a patient develops an intolerance to mitotane.

Then, gastrointestinal symptoms appear, but without a simultaneous reduction in cortisol levels in the ACTH stimulation test.

These dogs should be treated with other medications to treat hyperadrenocorticism.

Side effects of mitotane

• Gastrointestinal disorders appear most often - vomiting and / or diarrhea, which forces immediate discontinuation of treatment or reduction of the frequency of drug administration (up to 1-2 times a week).
• Symptoms of acute adrenal insufficiencyy (general weakness, anorexia, vomiting, diarrhea or coma) may occur if the therapeutic effect does not appear quickly enough or if a reduced appetite or thirst is not noticed in time. It may then be necessary to administer exogenous glucocorticoids. Therefore, it is good if the pet owner has at home prednisolone (it is worth taking care of this before starting treatment) and can give it to the dog relatively quickly.
• Sometimes it comes to hyperkalemia and hyponatraemia (increase in potassium levels and decrease in sodium levels in the blood). In this case, an ACTH stimulation test should be performed. The cortisol concentration is then normal < 20nmol/l (

When switching from trilostane to mitotane (or vice versa) it is advisable to wait for the clinical signs of adrenal hyperfunction to return, thus confirming the absence of adrenal suppression.

However, you should not wait too long before changing your medication (e.g. until the ACTH test shows an overactive adrenal cortex again), as it sometimes takes months, and during this time you may develop severe symptoms of hypercortisolemia.

Ketoconazole

It can reduce the synthesis of steroid hormones, which is why it has been used to treat Cushing's syndrome in both animals and humans.

In dogs, the dose used is conventionally 30 mg / kg / day in two divided doses.

Improvement is usually visible after 2 months treatment.

Currently, ketoconazole has been replaced by trilostane and its use is controversial.

L-DEPRENYL (monoamide oxidase inhibitor)

The active substance - selegiline - used in some countries to treat the pituitary form of overactive adrenal cortex.

Selegiline is an inhibitor of monoamicoxidase type B (MAOBI).

Monoamine oxidase is an enzyme in the brain that breaks down dopamine, hence blocking it increases the level of dopamine in the brain. As a result, it indirectly leads to a decrease in the level of ACTH (dopamine released from the hypothalamus has an inhibitory effect on the pituitary gland).

The big advantage of this form of treatment is that selegiline does not interfere with adrenergic enzymes and is not adrenolytic, therefore monitoring is based only on clinical symptoms.

Hormonal monitoring is not recommended (no ACTH stimulation tests or electrolyte determination required).

It has a minimal effect on the functioning of the endocrine system, which to some extent improves the patient's clinical condition.

Due to its action, it only applies to medical treatment pituitary form of Cushing's syndrome.

It is administered in a dose 1 mg / kg m.c.

If clinical symptoms do not improve within one month, the dose is administered 2 mg / kg m.c./ day.

If there is no improvement within another month, treatment is stopped as the dose is increased further won't help the patient.

The efficacy of selegiline treatment in dogs with mild to moderate clinical picture of hypercortisolemia was estimated at 50-70%.

In dogs with more severe symptoms it is 20-30%.

Pituitary excision

A controversial procedure that requires great surgical skill and extensive experience.

It is recommended especially in the case of large adenomas, however, postoperative complications are very common:

frequent development diabetes as a corollary pancreatic necrosis if thyroid insufficiency.

Radiotherapy

It is effective in reducing the size of the tumor and reducing or eliminating neurological symptoms in dogs with symptoms of pituitary macroadenoma syndrome.

Treatment of cushing's syndrome of adrenal origin

A valid causative treatment for Cushing's syndrome of adrenal origin is surgical removal of the adrenal gland. The procedure makes sense only when we are dealing with benign, non-infiltrating and relatively small tumors.

The conditions for carrying out this type of surgery should be:

extensive experience of the surgeon and the ability to provide appropriate intensive postoperative care.

Controversy as to adrenalectomy it is primarily caused by the fact of the subsequent pharmacological treatment.

The adrenal glands secrete not only cortisol, but also other important hormones, which is why the state of the water and electrolyte balance is heavily disturbed.

The matter is further complicated by the fact that the second adrenal gland, as a rule, is atrophied, so it is not able to take over immediately after the adrenalectomy of the other side.

Proper preparation of the patient for surgery may increase the chances of its success.

It is worth introducing treatment before the procedure trilostane, as mitotane can cause the fragility of the tumor mass.

Animals that have not been treated pharmacologically before are difficult patients and may develop acute adrenal insufficiency after surgery.

It is also worth noting that even after a seemingly properly performed procedure, symptoms of adrenal cortex hyperfunction may return.

The main assumptions of the perioperative procedure in the case of adrenalectomy:

• There are no indications for administering glucocorticosteroids a few days before the procedure, because they facilitate the appearance of water and electrolyte disturbances and increase the risk of embolism.
• Initially, intravenous fluids (NaCL or Ringer's fluid), it is added to liquids just before the procedure dexamethasone in a dose from 0.02-0.04 mg / kg m.c. in such a way that the entire dose is given overnight 6 hours.
• Please reassure the patient minimum 24-hour intensive medical care after the procedure, because complications very often occur at this time.
• It is obligatory to control the level of electrolytes in the blood.
• After the procedure, mineralocorticoids (e.g. deoxycorticosterone acetate) in dose 0.1 mg / kg m.c.
• This is followed by an injection of dexamethasone until the dog begins to feed itself. When that happens, it passes prednisone orally: starting dose 1 mg / kg m.c. in the morning and in the evening for several days, then gradually reduced to stop them within 2 months.
• If the amount of sodium decreases and the amount of potassium increases to 5.5 mEq / L it is necessary to administer mineralocorticodes.

The adrenal form of hyperadrenocorticism is usually treated pharmacologically with the drugs mentioned in the treatment of the pituitary form of hypercortisolemia.

Trilostane is not cytotoxic, so it is likely to be less effective in preventing and combating metastasis compared to mitotane.

Treatment of iatrogenic cushing's syndrome

Prolonged and intensive administration of glucocorticoids causes inhibition of the anterior pituitary gland activity in the area of ​​ACTH secretion.

In such conditions, the adrenal cortex is not physiologically stimulated, which results in the secretion of less cortisol, and hence it is only a step to more or less advanced atrophy.

In such a situation, sudden discontinuation of the steroid becomes the cause of acute adrenal insufficiency (the so-called. adrenal crisis). Therefore, under no circumstances should you suddenly stop taking your current medications or quickly reduce their dose.

Symptoms of adrenal insufficiency include:

• excitement,
• disturbances of consciousness,
• poor pulse rate, low blood pressure,
• vomiting,
• involuntary urination and defecation,
• discoloration of the skin around the anus and vulva,
• impaired appetite,

Iatrogenic Cushing's syndrome requires a completely different treatment approach than spontaneous hypercortisolemia.

We are actually dealing with adrenal insufficiency, although clinical signs are indicative of overactive.

It is therefore imperative that corticosteroids be withdrawn slowly.

A slow reduction in steroid doses should occur over a period of several months (3-12 months), but the drug used so far should - if possible - be replaced with another drug from the same group, but with a weaker effect, e.g.:

• dexamethasone - prednisone / prednisolone,
• prednisolone - hydrocortisone.

Then, alternation therapy is introduced, consisting in administering drugs every other day.

At the onset of symptoms of adrenal insufficiency, the dose should be periodically increased or resumed daily.

If symptoms of adrenal insufficiency occur, the patient should be administered intravenously 0.9% NaCl plus glucose and hydrocortisone in dose 8-20 mg / kg m.c. in increments of every 4-6 hours until symptoms disappear. Be aware of a diet rich in full blown protein.

Supportively, the following are used:

• drugs to protect the gastric mucosa,
• drugs to reduce acidity,
• antisecretory drugs.

Blood potassium levels should be monitored and its deficiencies replaced if necessary.

Treatment of coexisting diabetes mellitus

Often times, hypercortisolemia is accompanied by diabetes, which is difficult to stabilize despite administration insulin.

Unfortunately, until we stabilize hypercortisolemia, proper glycemic control is not possible

…

Therefore, at the beginning of treatment, the most important goal is lowering cortisol levels.

Insulin treatment may be indicated initially, but not to achieve normoglycemia, or rather, to avoid a serious one ketoacidosis and serious hyperglycemia.

Therefore, classic doses are recommended (0.5-1 U / kg) intermediate-acting insulin.

Blood and urine sugar levels should be monitored, but modification of insulin doses and final glycemic control do not begin until hypercortisolemia is under control and maintenance therapy is initiated.

Regardless of the cause of Cushing's syndrome, before deciding to initiate treatment for hypercortisolaemia, it should be ascertained that the patient does not have any other conditions that may affect the clinical course.

Treatment of an overactive adrenal gland is not without its risks.

Drugs that are used to lower the concentration of cortisol circulating in the blood may cause various complications, as well as aggravate other symptoms of concurrent diseases, such as. osteoarthritis (osteoarthritis), atopy.

There is no one-size-fits-all treatment for an overactive adrenal cortex.

Given the complexity of the disease and the metabolic consequences of hypercortisolemia, each case should be carefully analyzed and treatment adjusted individually.

The pet owner should be able to make an informed decision about the treatment.

At the beginning of therapy, you should reach for the least toxic drugs, but if there is no improvement in the patient's clinical condition within three months, there should be no delay in changing the treatment regimen.

You should also not use drugs that have turned out to be ineffective.

Over time (months, years), the dose and frequency of administration may need to be increased.

Untreated overactive adrenal cortex

Untreated overactive adrenal cortex

What if treatment for an overactive adrenal gland is not treated??

Dangerous and - unfortunately - often fatal complications can occur, such as:

• diabetes,
• systemic hypertension,
• pancreatitis,
• glomerular damage,
• urolithiasis,
• thromboembolism.

Cushing's syndrome diet

Cushing's syndrome diet

In the course of this disease, there is a noticeable one increase in cholesterol and serum triglycerides.

Excessive stimulation of lipolysis by glucocorticosteroids and an increased tendency to accumulate fat significantly stresses the liver.

The occurrence of steroid hepatopathy can lead to stagnant bile, which may increase lipid disorders in the future.

Diet in the case of chronic hyperlipidaemia should include:

1. Give your dog a diet that is reduced in fat. (18% or 60g of protein / 1000 kcal).
2. Supplementation with omega-3 acids.
3. Addition of dietary fiber.
4. The addition of antioxidants.

However, it should always be taken into account accompanying diseases (e.g. diabetes), therefore the diet should be individually adapted to each patient.

Prognosis of Cushing's syndrome

Cushing's disease prognosis

The prognosis for survival in dogs with pituitary hyperadrenocorticism is dependent on century and general condition of the animal, and also from owner involvement.

The mean survival time from diagnosis is 30 months, in younger dogs it can be much longer (even 4 years). As a rule, the cause of death is complications of hypercortisolemia or other diseases of geriatric age.

After adrenalectomy, the average age of dogs is approx. 36 months.

In dogs with adrenocortical adenoma or non-metastatic cancer the prognosis is good. Dogs with metastatic cancer usually die during the year.

Pharmacological treatment of spontaneous hyperadrenocorticism helps to combat the symptoms of hypercortisolemia but does not cure the patient.

It must last for the rest of the animal's life, and keepers must come to terms with the prospect of regular check-ups.

All medications used have side effects and certain limitations that should be considered before introducing the therapy. It should be realized that the costs of treating and monitoring patients with hyperadrenocorticism are significant, especially during the first 6 months.

In most cases, Cushing's syndrome is not a life-threatening condition and is often more life-threatening than the dog's life.

Sometimes treatment is limited to treating complications related to this disease (e.g. urinary tract infections, skin diseases or diabetes), because the dog's guardian's financial resources are limited and he does not decide to incur fairly high costs.

Sometimes the course of the disease is so mild that it does not warrant treatment.

Immediate initiation of therapy is, in fact, only necessary in some cases where the clinical symptoms are severe (e.g. marked exercise intolerance, severe obesity, diabetes not responding to treatment or polydipsia / polyuria syndrome so severe that it is not accepted by the owner).

However, most dog handlers choose treatment to minimize clinical signs and the possibility of complications afterwards.

In this situation the prognosis is usually favorable.

Treatment effectiveness trilostane estimated at 67% - it allows you to reduce clinical symptoms over time 3-6 months.

Average survival time of dogs is from 664 to 900 days. For comparison, median survival for treated dogs mitotane totals 810-900 days.

Summary

Cushing's syndrome is a chronic disease

Finally, I would like to mention the concerns of owners of dogs with overactive adrenal cortex.

It is without a doubt chronic disease, and the diagnosis itself is often difficult to accept by the caregivers of animals suffering from it.

The vision of lifelong administration of drugs, very frequent checks and constant research fills you with fear, sadness, as well as a sense of reluctance and doubt.

In addition, the clinical picture of overt form of hypercortisolemia is often very difficult to be accepted by the owners.

There are situations when it is considered to donate the dog or even his euthanasia, because the pet urinates all over the house, moults intensively, he needs to refill his bowl with water every now and then, etc.

However, it is important to realize that this is a disorder chronic but treatable.

Symptoms usually disappear after the introduction of therapy, and caregivers get used to regular visits and administering medications fairly quickly.

The other side of the coin are costs, which unfortunately are quite high.

The diagnostic process itself is exhausting, both in terms of time and money, and it involves irritation, doubt and growing resistance from caregivers.

In this matter, a lot depends on the knowledge and experience of a doctor who can skillfully select diagnostic tests and tests and interpret them. Although even if the owner agrees to perform quite expensive tests, their results may be ambiguous and it will be necessary to extend the diagnostics.

This puts a lot of strain on the patience and pocket of the owner of a sick dog.

It is often very difficult to explain to caregivers that the diagnosis also takes place by eliminating other disease entities, which is very important from a medical point of view, but sometimes not acceptable to the owner.

However, the vast majority of dog keepers are capable of many sacrifices, which we - doctors - are fully aware of.

Because the most important thing in all this is to find the answer to the question "what is wrong with your dog" and to introduce appropriate treatment.

It will not significantly extend the survival time, but it will definitely improve the quality of life for both the animal and its owner.

Sources used >>

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