Ep 20 - Why Cushing's Dogs Look the Way They Do: Understanding the Physiology Behind the Disease

A practical guide to hyperadrenocorticism for first-opinion vets

There are some diseases that most of us feel reasonably comfortable recognising in practice.

A middle-aged or older dog walks into the consult room with a pot belly, symmetrical alopecia, a ravenous appetite and an owner who's fed up of refilling the water bowl every five minutes.

Cushing's disease.

Easy, right?

Well, maybe.

And it turns out that understanding the physiology makes the disease much easier to diagnose, manage and remember.

And before you think you know everything you need to know... understanding why these dogs drink lots and have hypertension will help you understand so much more about emergency drugs and Addison's too!

What Actually Is Cushing's Disease?

Cushing's disease, or hyperadrenocorticism, occurs when the body is exposed to excessive cortisol for prolonged periods.

In most cases this is caused by:

• A pituitary tumour producing excess ACTH (around 80-85% of cases)

• An adrenal tumour producing excess cortisol

Either way, the result is the same:

Too much cortisol circulating around the body for too long.

The interesting part is that cortisol isn't a "bad" hormone.

In fact, it's one of the most important survival hormones we have.

Cortisol: The Ultimate Survival Hormone

Most people think of adrenaline when they think about stress.

Adrenaline is the immediate fight-or-flight hormone.

Cortisol is what helps you survive once the emergency lasts longer than a few minutes.

Its main job is surprisingly simple:

"keep glucose available for the brain"

The brain is incredibly demanding when it comes to energy requirements. If food becomes scarce, blood loss occurs or the body is under severe stress, cortisol ensures that glucose remains available where it matters most.

Many of the signs we see in Cushing's disease are simply the result of this survival system being switched on continuously.

Why Are Cushingoid Dogs Always Hungry?

One of the easiest clinical signs to understand is polyphagia.

If cortisol's job is to maintain glucose availability, the simplest solution is obvious:

Eat more food.

Dogs with Cushing's disease often develop an insatiable appetite because cortisol continually drives energy acquisition.

Unfortunately, they don't know they're not actually starving.

Why Do They Lose Muscle?

When food isn't available, cortisol activates Plan B. Eat yourself!

The body begins breaking down muscle tissue into amino acids.

These amino acids travel to the liver where they are converted into glucose through gluconeogenesis.

Over time this results in:

• Muscle wasting

• Reduced muscle mass over the spine and limbs

• Weakness

• Loss of abdominal muscle tone

This contributes significantly to the classic "pot-bellied" appearance.

Why The Pot Belly?

The Cushingoid abdomen is caused by several factors working together.

Firstly, muscle breakdown weakens the abdominal wall.

Secondly, the liver becomes enlarged due to glycogen accumulation from all that (now) excessive glucose production.

Thirdly, though fat is broken down to release glycerol for glucose production and fatty acids as a store of energy for muscles, because the system is on "always on" in Cushing's and there is no starvation or major emergency, all this production is wasted and needs to be stored again. So, hypercholesterolemia and hypertriglyceridemia are seen as the fat is packaged up and transported back to be stored as fat again!

The result is the classic pendulous abdomen that most of us immediately associate with Cushing's disease.

Why Do These Dogs Become Diabetic?

Cortisol doesn't just increase glucose production.

It also makes tissues less responsive to insulin.

This insulin resistance helps preserve glucose for the brain during times of stress. The lack of insulin around peripheries, means other organs are now unable to utilise the glucose and are forced to switch to the fatty acids release from fat lipolysis.

Unfortunately, when cortisol remains elevated for months or years, insulin resistance can become clinically significant.

This is why:

• Cushing's disease can predispose to diabetes mellitus

• Diabetic dogs can be difficult to stabilise if concurrent Cushing's disease is present

• Persistent insulin resistance should always prompt consideration of hyperadrenocorticism

Why Do They Drink And Wee So Much?

Polyuria and polydipsia are among the most common presenting complaints.

One reason for this is cortisol's effect on antidiuretic hormone (ADH).

ADH normally helps the kidneys retain water.

Excess cortisol antagonises this effect, reducing water reabsorption and leading to increased urine production.

The dog then compensates by drinking more.

For many owners, this is actually the first clinical sign they notice.

When discussing water intake, it can be helpful to ask questions such as:

• Are you filling the water bowl more often?

• Is your dog waking up overnight to urinate?

• Have there been any accidents in the house?

These questions often reveal clinically significant PU/PD that owners hadn't initially recognised.

Why would nature create cortisol to antagonise ADH? Well, one explanation may be that ADH is a potent vasoconstrictor and helps maintain blood pressure, and also hanging onto lots of fluid that would otherwise be urinated out. So, over time, this could lead to dangerous vascular overload, so cortisol provides the brakes, and ensure there is not deleterious hypertension.

Why Do They Get Hair Loss And Thin Skin?

If cortisol is trying to conserve energy, maintaining a luxurious hair coat becomes a low priority.

Hair follicles become less active.

Skin turnover slows resulting in thinning skin, which is often cited as a adverse effect from too much topical steroid. Obviously, another great way to save energy, preserving it for the major organs like the brain.

The result is:

• Symmetrical alopecia

• Thin skin

• Poor coat quality

• Delayed wound healing

  
  

The Classic Stress Leucogram

Routine blood work often provides valuable clues.

Many Cushingoid dogs develop a stress leucogram consisting of:

• Neutrophilia

• Monocytosis

• Lymphopenia

• Eosinopenia

One useful veterinary mnemonic is:

"Not Much Eats Leopards"

• Neutrophils ↑

• Monocytes ↑

• Eosinophils ↓

• Lymphocytes ↓

Understanding why this occurs is actually fascinating.

Cortisol suppresses energy-intensive adaptive immunity while preserving simpler innate immune responses.

The body is essentially prioritising survival over sophistication.

Why Do They Get Infections?

Because cortisol alters immune function, dilutes urine and weakens the hair follicles and skin, these dogs become predisposed to several infections.

Common examples include:

• Recurrent skin infections

• Demodicosis

• Urinary tract infections

What About Blood Pressure And Blood Clots?

Cortisol also increases vascular responsiveness and contributes to hypertension.

This is a feature of cortisol that few of us know... without cortisol, adrenaline and noradrenaline cannot do their vital job of constricting arterioles and maintaining blood pressure! This is why Addisonian dogs have floppy vessels and hypotension!

So it is perfectly understandable now that many Cushingoid dogs are hypertensive. And this extends to the glomeruli of the kidneys. The glomeruli can be rather damaged by this hypertension, leading to leakage of the larger proteins into the urine, increasing UPC and potentially the loss of anti-thrombin III too, which can increase risk of thrombosis.

Diagnosing Cushing's Disease

No single test is perfect.

Common diagnostic approaches include:

Urine Cortisol:Creatinine Ratio (UCCR)

Useful as a screening test.

A normal result makes Cushing's disease unlikely.

A positive result does not confirm the diagnosis but may justify further investigation. I would look at this test as a useful way to motivate your client into further tests, when you are suspicious of Cushing's and need a low stress option.

ACTH Stimulation Test

Widely used in practice.

Particularly useful for monitoring treatment.

Not my favourite due to borderline results and the need for extra tests.

Low Dose Dexamethasone Suppression Test (LDDST)

Often considered the most sensitive screening test.

Can sometimes provide additional clues regarding pituitary versus adrenal disease.

Do not run this test on poorly dogs.

Imaging: Don't Forget The Adrenal Glands

Abdominal ultrasound can be an extremely useful part of the Cushing's work-up, but is not essential as it often does not change the outcome decisively. I would discuss pursuing imaging, such as CT or ultrasound if I were suspicious of an adrenal tumour because of 4 and 8 hour escape on my LDDST, a large breed dog or poor medical management with trilostane.

Allow plenty of time and ensure fasting and good sedation with medetomidine. Make sure the patient is clipped well, and has plenty of good skin prep and time for the gel to soak in.

While it cannot diagnose hyperadrenocorticism on its own, it can provide valuable information about adrenal gland size, shape and symmetry, as well as identify concurrent disease. But, remember, adrenal gland sizes and masses can be misleading. Cushingoid dogs can have normal adrenal glands and some adrenal masses are simply incidental findings.

In general:

• Pituitary-dependent hyperadrenocorticism (PDH) often (but not always) results in bilaterally enlarged adrenal glands

• Adrenal-dependent hyperadrenocorticism (ADH) can result in one enlarged adrenal gland with atrophy of the contralateral gland

• Adrenal masses, mineralisation or local invasion may occasionally be identified

Starting out with adrenal gland ultrasound

However, adrenal ultrasonography is rarely straightforward. I would suggest anybody new to abdominal scanning practices this on every one of their abdo scans - finding the aorta and vena cava - two black tubes - dorsal or "north" to the bladder and practices tracing cranially from there to the kidneys. Also, keep an eye for the curved left adrenal artery as it hooks its way to the left kidney. These are all relatively easy to do. But this gives you the first part of finding adrenal glands.

Preparing The Patient

Adrenal imaging is one of those situations where preparation can make a huge difference.

Helpful considerations include:

• Fasting where possible

• Allowing adequate scanning time

• Good patient positioning

• Sedation almost essential unless you have epic-level skills

Finding The Left Adrenal

The left adrenal gland is usually the easier of the two to identify.

It is commonly located:

• Craniomedial to the left kidney

• Adjacent to the aorta

• Near the origin of the left renal artery

Many ultrasonographers will start by locating the left kidney before tracing cranially towards the adrenal gland, fanning between the cranial kidney and the aorta, and just cranial to the curved "hook" of the renal artery which is very distinctive and easy to find.

Importantly, the left adrenal gland is dark and peanut-shaped. The phrenicoabdominal vessels are another really good landmark for this adrenal gland. The vein is right next to the gland.

Finding The Right Adrenal

The right adrenal gland is often the more challenging structure.

It lies:

• Dorsal to the caudal vena cava

• Cranial to the right kidney

  
  

Gas-filled gastrointestinal contents and patient conformation can make visualisation difficult, particularly in larger dogs.

Treating Cushing's Disease

For most first-opinion clinicians, treatment means trilostane.

The goal isn't necessarily to normalise every laboratory value.

The goal is to improve the patient's quality of life while avoiding over-suppression of cortisol production.

This is where monitoring becomes crucial.

The Most Important Monitoring Tool: The Patient

Before discussing blood tests, it's worth remembering that the most useful information often comes from the owner.

We want to know:

• Is the dog drinking less?

• Is the appetite becoming more normal?

• Has the dog become more active?

• Are accidents in the house improving?

• Is the owner happier with their pet's quality of life?

Many clinicians ask owners to record daily water intake over 24 hours once or twice weekly, particularly during the early stages of treatment. Ask them to record the values and show you them on the follow up. This can be motivating for the client.

Improving clinical signs are often more informative than chasing specific cortisol numbers.

ACTH Stimulation Testing

Historically, ACTH stimulation testing has been widely used for monitoring trilostane therapy.

Advantages include:

• Extensive historical use

• Familiarity amongst clinicians

• Ability to assess adrenal reserve

Disadvantages include:

• Additional cost

• Requirement for synthetic ACTH

• Time-consuming for owners and practices

• Variable interpretation between patients

Whilst still commonly used, ACTH stimulation testing has become less popular in some practices over recent years.

Pre-Trilostane Cortisol Monitoring

An alternative approach is measurement of a pre-trilostane cortisol concentration, typically obtained immediately before the next scheduled trilostane dose.

Advantages include:

• Simpler to perform

• Less expensive

• No ACTH administration required

• Convenient for owners

Disadvantages include:

• Results must always be interpreted alongside clinical signs

• Less information regarding adrenal reserve

• Not appropriate as a standalone decision-making tool

Many clinicians now use a combination of clinical assessment and pre-trilostane cortisol monitoring for routine follow-up.

How Often Should We Monitor?

Protocols vary slightly between practices, but a common approach is:

• Initial recheck approximately 10-14 days after starting treatment

• Further reassessment at around 4 weeks

• Recheck again at approximately 12 weeks

• Ongoing monitoring every 3-6 months once stable

More frequent assessments may be required if:

• Dose changes are made

• Clinical signs recur

• Concurrent disease develops

• There is concern regarding over-treatment

Watch For Over-Treatment

One of the most important owner discussions involves recognising signs of excessive cortisol suppression.

Owners should be advised to stop medication and contact the practice if they notice:

• Reduced appetite

• Vomiting

• Diarrhoea

• Marked lethargy

• Weakness or collapse

Although uncommon, iatrogenic hypoadrenocorticism can occur and should always remain on the radar.

The Take-Home Message

Most of us recognise a Cushingoid dog when we see one.

The real trick is understanding why.

Once you realise that cortisol is fundamentally a survival hormone designed to preserve energy and maintain glucose delivery to the brain, many of the disease's seemingly unrelated signs suddenly make sense.

The pot belly.

The muscle loss.

The polyphagia.

The PU/PD.

The skin changes.

They're all part of the same story. And understanding that story makes Cushing's disease a lot easier to remember the next time one walks through your consult room.