The Meowing Vet provides dog owners with an in-depth educational resource on the complex endocrine disorder of canine Hyperadrenocorticism, or Cushing’s Disease, a disorder in which the body produces an excessive amount of stress hormone.
Learn more about the potential multi-organ complications of this “stressful” endocrine disorder below…
*Note: the terms “hyperadrenocorticism” and “Cushing’s Disease” shall be used interchangeably.*
What Is Hyperadrenocorticism? (Pathophysiology)
Hyperadrenocorticism, more commonly called Cushing’s Disease, is an endocrine disorder that is overall rare in humans and in other animals, but it is more common in canine patients. Cushing’s Disease occurs when the body’s adrenal glands produce an excess amount of specific steroid hormones, predominately cortisol.
The body’s two adrenal glands lie beside each kidney. The inside of each adrenal gland consists of an innermost region called the medulla which is surrounded by another region termed the cortex. The medulla produces the catecholamine hormones epinephrine (or adrenaline) and norepinephrine. The cortex, on the other hand, produces various steroid hormone groups: glucocorticoids (such as cortisol), mineralocorticoids (such as aldosterone), and to a lesser extent, weak sex steroids (estrogen, etc.). The cortex functions as a member of the hypothalamic-pituitary-adrenal axis, a feedback network in which the brain and adrenal glands communicate during times of stress.
It is the adrenal cortex that is affected by hyperadrenocorticism (Cushing’s Disease). With the onset of a situation that the body perceives as either a physical or emotional threat (fear, disease, etc.), the hypothalamus (a region of the brain) produces corticotropin-releasing hormone (CRH). CRH then travels to the pituitary gland (known as the “master gland” of the body and residing at the base of the brain). The pituitary gland, in turn, releases adrenocorticotropin hormone (ACTH), which enters the bloodstream to travel to the adrenal glands. The adrenal cortex then produces the glucocorticoid hormone cortisol, the major stress hormone released during the “fight or flight” response. It tells the body the hop into action to deal with the stressful insult. For instance, it triggers the liver to release glucose (blood sugar) into the bloodstream, thereby offering the brain and muscles more energy to plan an escape, fight, or run away from danger. [Other hormones, such as aldosterone (a mineralocorticoid), are also released. Aldosterone, a component of the RAAS system (renin-angiotensin-aldosterone system) helps control fluid and electrolyte balance in the body as well as blood pressure.]
Normally, once the body detects a high cortisol level, the hypothalamus and pituitary gland then stop releasing CRH and ACTH, respectively, via negative feedback. Otherwise, they would keep sending signals to the adrenal glands to release more and more cortisol, which can have deleterious effects on the body over time (read more below). Well… this is exactly what happens during Cushing’s Disease: dysfunction at some stage of the hypothalamic-pituitary-adrenal axis occurs (either at the level of the pituitary gland or an adrenal gland), and the adrenal glands, therefore, don’t stop releasing cortisol into the bloodstream. Thus, the body persists in a constant state of stress.
Visit our site again on Friday, May 18th, for an upcoming article on what happens when the body produces too little cortisol, an adrenal gland disorder known as Hypoadrenocorticism, or Addison’s Disease.
Causes of Cushing’s Disease
Cushing’s Disease may be either pituitary-dependent hyperadrenocorticism (PDH), adrenal-dependent hyperadrenocorticism (ADH), or iatrogenic hyperadrenocorticism. PDH and ADH cases are termed “naturally-occurring” hyperadrenocorticism, whereas iatrogenic cases occur as a side effect to chronic steroid administration used to manage other medical disorders. Though these three sub-categories cause identical clinical signs, their respective treatments and prognosis differ.
PDH (pituitary-dependent hyperadrenocorticism) is the most common form of Cushing’s Diseae, comprising 80-85% of cases. PDH occurs when the pituitary gland near the brain (which controls the action of the adrenal glands) releases too much ACTH, thus stimulating the adrenal glands to produce an excess of cortisol. Thus, PDH type is also termed ACTH-dependent hyperadrenocorticism. PDH cases tend to lead to enlargement of both adrenal glands (a.k.a. bilateral hyperplasia of the adrenal cortices). The majority (85-90%) of PDH cases are caused by a tumor of the pituitary gland (typically a benign adenoma), while 10-15% do not have an attributable cause (i.e. are “idiopathic”). These idiopathic cases are theorized to caused by a failure of negative feedback in the hypothalamic-pituitary-adrenal axis, an undetectable microscopic tumor of the pituitary gland, or another tumor somewhere in the body that produces ACTH and has not been identified. Though regarded as rare, some cases of PDH are theorized to be food-induced. This occurs when errant receptors for particular peptides (proteins) arise within the adrenal gland that then release glucocorticoids after a meal that includes that peptide is consumed by the affected animal.
ADH (adrenal-dependent hyperadrenocorticism) cases are also termed ACTH-independent hyperadrenocorticism; they account for 15-20% of Cushing’s cases. A tumor arising from the cortex within one of the adrenal glands causes ADH cases, leading to an increased amount of cortisol released into the bloodstream. An enlargement of the affected adrenal gland will be detected; since this gland is producing an excess level of cortisol, the other adrenal gland will decrease in size (or atrophy) because it receives negative feedback from the pituitary gland that it need not produce any cortisol since there’s already an excess in the bloodstream. 40% of ADH cases are caused by a benign tumor called an adenoma while 60% of ADH cases occur due to a malignant (cancerous or neoplastic) tumor known as an adenocarcinoma.
Rather than occurring due to a natural disease process of the body, iatrogenic hyperadrenocorticism is a temporary Cushing’s-like state caused by chronic glucocorticoid/steroid use by pets, i.e. prednisone (“iatrogenic” meaning “caused by medical treatment”). It is one of the most common endocrine disorders seen in dogs. The cushinoid clinical signs are caused by side effects of excessive steroid use and are the same as those caused by naturally-occurring PDH or ADH. Oftentimes, the unintentional development of iatrogenic hyperadrenocorticism requires that steroid use be weaned off if possible.
Clinical Signs
Signs of Cushing’s Disease in dogs include:
- Increased urination and thirst (polyuria and polydipsia, respectively, or PU/PD): excessive cortisol levels affect function of the kidneys to regulate appropriate fluid levels in the body (How? Inhibits vasopressin/antidiuretic hormone secretion, increases atrial natriuretic factor, increases glomerular filtration rate/GFR.)
- Increased appetite (polyphagia): due to stimulation in centers of the brain that control appetite
- Panting
- Lethargy
- Poor muscling (muscle atrophy) and muscle weakness: excessive cortisol causes a metabolic breakdown (catabolism) of proteins that would otherwise be used to build up muscle mass
- A pendulous abdomen resembling a potbellied appearance: mostly occurs due to a propensity for fat to deposit in the abdomen rather than elsewhere because abdominal fat cells have a higher concentration of receptors for cortisol than in other regions of the body
- Skin and coat problems
- Thinning skin
- Hair loss (or alopecia) that typically occurs equally on both sides of the body
- Secondary skin infections (bacterial, fungal,and/or parasitic)
- Black heads (comedones)
- Hard and oftentimes painful red plaques caused by calcium deposits in the skin known as “calcinosis cutis” (often form at sites of injury)
- Areas of darkened skin (hyperpigmentation)
- Occasional enlargement of the vulva in spayed female dogs: most likely occurs because the adrenal glands also release weak sex hormones
Complications of Cushing’s Disease
When produced in excess chronically, cortisol can cause major systemic health effects, including:
- Impairment of the immune system by inhibiting protective inflammation, thus increasing the risk for urinary tract infections (UTIs) and secondary skin infections
- Liver disease: excessive cortisol levels cause an increased amount of glycogen storage, which thereby causes liver dysfunction
- Diabetes mellitus: excessive cortisol levels interfere with glucose (or blood sugar) metabolism by increasing hepatic gluconeogenesis (or sugar production by the liver) as well as by causing peripheral insulin resistance
- Systemic hypertension (high blood pressure)
- Hypercoagulability (the propensity for the body to form thromboemboli, or blood clots, which can lodge in great vessels in the limbs, lungs, and brain)
Due to these potential severe systemic complications, it is, therefore, important to properly diagnose and treat Cushing’s Disease in order to prevent severe multi-organ damage and potential fatality.
What PATIENTS Are Most Commonly Affected?
Cushing’s Disease is most common in older dogs, especially those between 7-9 years of age (though dogs between 4-14 years of age can also be affected). The majority of adrenal-dependent (ADH) cases are female (65%) while both male and females are affected equally by pituitary-dependent hyperadrenocorticism (PDH). While any dog breed may be affected by the ADH type, certain dog breeds are more susceptible to developing the PDH form. Dog breeds most affected by PDH are:
- Miniature poodles
- Dachshunds
- Boston terriers
- Silky terriers
What about Cats?
Naturally-occurring cases of feline hyperadrenocorticism are uncommon. However, these cats tend to have hyperaldosteronism in which aldosterone rather than cortisol level is increased. Diagnosis of hyperaldosteronism in cats is similar to that of hyperadrenocorticism in dogs (as described below). However, aldosterone levels rather than cortisol levels (as in dogs) are typically measured for diagnostic purposes. Some cats may also develop iatrogenic Cushing’s Disease, particularly those felines who receive chronic steroid medications such as prednisolone or Depo-Medrol® (methylprednisolone acetate). (Chronic steroid use also increases the risk of diabetes mellitus development.)
Diagnosis Status?: It’s Complicated
Unfortunately, no single perfect test exists to definitively diagnose Cushing’s Disease. Due to the complexities of the endocrine system, the variability of cortisol and other hormone levels based on the time of day and in the presence of other illnesses, and the stressful environment of a veterinary clinic where testing is performed, definitively attributing a high cortisol level to hyperadrenocorticism may be difficult. Instead, a combination of several different diagnostic tests may be performed. Each test has its own advantages and disadvantages, and your veterinarian will reach a diagnosis of Cushing’s Disease based on the cumulative results of these tests. Therefore, reaching a concrete diagnosis of Cushing’s Disease can be not only inconvenient, time-consuming, and expensive — not only to pet owners but to your vet as well.
However, please bear with your veterinarian as these tests are sequentially performed. Knowing whether or not your dog indeed has hyperadrenocorticism is vitally important to his or her overall health. A proper diagnosis and subsequent treatment is necessary to prevent potential health complications of untreated Cushing’s Disease. Below, we’ll run down the list of common tests for hyperadrenocorticism, describing their diagnostic strengths and weaknesses while discussing what value they add to determining a true diagnosis of Cushing’s Disease. Additionally, Today’s Veterinary Practice (Vol. 4 No. 1, January/February 2014) offers supplementary information on hyperadrenocorticism as well as a helpful algorithm used to help your vet determine which order of tests to perform.
In addition to a physical exam, your veterinarian will perform routine bloodwork, a urinalysis, abdominal x-rays and/or ultrasound, and blood pressure measurement. Additionally, a combo of special Cushing’s blood and urine tests to monitor adrenal and pituitary gland activity will be performed: basal cortisol level, the ACTH stimulation test, LDDS or HDDS, urinary cortisol to creatinine ratio, and endogenous ACTH measurement. These tests also help rule out other diseases (such as uncontrolled diabetes mellitus, liver disease, and renal failure) which can mimic some of the clinical signs of Cushing’s disease.
Specialized Adrenal Function Blood & Urine Tests
|
Test |
Description | Strengths |
Weaknesses |
| Basal plasma cortisol level | A blood sample is collected to measure the level of cortisol in the bloodstream. Cortisol should theoretically be increased in this sample if the patient has Cushing’s disease (read exceptions under ‘Disadvantages’). | Easy to perform. Inexpensive. | Not very accurate: cortisol levels fluctuate throughout the day, so a single measurement may not reflect the overall cortisol trend in the bloodstream (i.e. a patient with Cushing’s disease may not always have a high cortisol level at every moment of the day, while a patient withOUT Cushing’s disease may have a temporary increase in cortisol due to stress). |
| ACTH stimulation test | A basal cortisol level is taken via a blood sample, then synthetic ACTH is administered to the patient, and a second blood sample to measure a potential change in cortisol in the bloodstream is taken. This mimics how the body would respond to a natural release of ACTH by the pituitary gland: a slight increase in cortisol = normal; a great increase in cortisol = Cushing’s disease (ADH or PDH). | Fewer false positives. Good test to diagnose iatrogenic Cushing’s disease. Also useful for monitoring patients being treated for Cushing’s disease to ensure that they are receiving an appropriate drug dose for managing their disease. | Can be expensive. Better for diagnosing hypoadrenocorticism (Addison’s disease) rather than naturally-occurring Cushing’s disease. Does not differentiate between adrenal-dependent vs. pituitary-dependent hyperadrenocorticism. |
| LDDS (Low-dose dexamethasone suppression test) | A basal cortisol level is taken via a blood sample, then dexamethasone (a corticosteroid similar to cortisol) is administered to the patient; subsequent blood samples to monitor cortisol levels are then serially taken 4 hours and 8 hours later. This mimics how the body would respond to a natural release of corticosteroids (i.e. cortisol); normally, the body would detect that there are more than enough cortisol circulating in the bloodstream, so the adrenal glands do not need to product any more. However, with Cushing’s disease, this negative feedback regulation is amiss, and the adrenal glands will release cortisol anyway, causing the cortisol reading following dexamethasone administration to remain high. Normal if cortisol decreases at 4hr & remains decreased at 8hr. PDH if cortisol decreases at 4hr, but increases again at 8hr. Also PDH if cortisol is unchanged at 4hr, but increases at 8hr. Either ADH or PDH if cortisol remains the same at both readings or only slightly decreases. | Fewer false negatives (i.e. a negative test result means the patient does NOT have Cushing’s disease). May help differentiate adrenal-dependent (ADH) vs. pituitary-dependent (PDH) cases; however, ADH cases are more resistant to the effects of dexamethasone, so cortisol levels may remain unchanged in these cases (can therefore be difficult to differentiate from PDH since 25-50% of dogs with PDH also do not feature a decrease in cortisol). | Likelihood of a false positive result, especially if the patient has a concurrent disease (meaning a positive test result may not necessarily mean that the patient actually has Cushing’s disease, so it must be paired with another test to confirm). Time-consuming (takes 8 hours to perform). |
| HDDS (High-dose dexamethasone suppression test) | Very similar to the LDDS test, but a higher dose of dexamethasone is administered to the patient. Not used very often because not as advantageous as LDDS and other test. Normal, ADH, or PDH if cortisol decreases at 4h & 8hr. PDH if cortisol decreases at 4hr, but increases at 8hr. Also PDH if cortisol unchanged at 4hr, but increases at 8hr. Most likely ADH (but slight possibility of PDH) if cortisol remains the same at both readings or only slightly decreases. | More useful for detecting pituitary-dependent (PDH) cases. | Not as useful for detecting adrenal-dependent (ADH) cases; other testing required for these cases. |
| Urine cortisol : creatinine ratio | This test allows your vet to see the average level of cortisol in your pet’s body over the course of several hours. A sample of both blood and urine are collected. (Urine is typically collected at home by the owner where the dog is less likely to be stressed out, which could otherwise influence cortisol levels.) The cortisol level in the urine is compared to the creatinine level in the bloodstream. Increased cortisol : creatinine ratio = naturally-occurring Cushing’s disease (or stress). | Easy to perform. Inexpensive. Few false negatives (i.e. a negative test result means the patient does NOT have Cushing’s disease). Good screening test. | High likelihood of false positive result, especially in patients with a concurrent disease (meaning a positive test result may not necessarily mean that the patient actually has Cushing’s disease, so it must be paired with another test to confirm). |
| Endogenous ACTH concentration | A single blood sample is detected to measure the amount of ACTH in the bloodstream, as produced by the pituitary gland. PDH (and some normal dogs) = high ACTH. ADH = low ACTH. | Very reliable test according to many vets. Differentiates adrenal-dependent (ADH) cases from pituitary-dependent (PDH) cases. Relatively easy to perform (only 1 blood sample needed). Inexpensive. | Special laboratory handling required. Possibility for ACTH instability; ACTH is also released at specific times, not constantly, so its levels fluctuate and can interfere with test interpretation. Can be difficult to distinguish normal dogs from those with pituitary-dependent hyperadrenocorticism (PDH) in some cases. |
Other Diagnostic Tools
Though these tests do not specifically rule in or rule out Cushing’s Disease, certain abnormalities detected via these diagnostic tools help support a diagnosis of Cushing’s Disease. Abnormalities consistent with Cushing’s Disease include:
- Physical examination: Your vet will note many of the clinical signs of Cushing’s Disease as discussed previously: panting, a potbelly appearance (pendulous abdomen), a diffusely enlarged liver (hepatomegaly), muscle atrophy, dermatological abnormalities (thin skin, hair loss, blackheads, hyperpigmentation, calcinosis cutis).
- Routine bloodwork (CBC and biochemistry):
- Leukocytosis, a.k.a. increased white blood cells (WBCs), with a stress leukogram (increased mature neutrophils, decreased lymphocytes and eosinophils).
- May sometimes have erythrocytosis, a.k.a. high red blood cells (RBCs).
- Increased liver enzymes, particularly ALP and ALT.
- Hypercholesterolemia (i.e. high cholesterol). Lipemia (i.e. high lipid/fat levels in the bloodstream).
- May feature a mild hyperglycemia (i.e. high blood glucose, or blood sugar) or overt diabetes mellitus.
Urinalysis:
- Dilute urine (lower urine specific gravity/USG).
- Often proteinuria (a.k.a. protein in the urine).
- Often bacteriuria (or bacteria in the urine) due to a secondary urinary tract infection (UTI).
- Abdominal imaging (radiographs/x-rays and ultrasound):
- Enlarged liver (hepatomegaly).
- May see an adrenal mass on x-ray, which can be confirmed via ultrasound. A mass in only one adrenal gland indicates adrenal-dependent hyperadrenocorticism (ADH). Pituitary-dependent hyperadrenocorticism (PDH) is to be suspected if both the adrenal glands are either normal in size or both enlarged. Sometimes, the adrenal gland may feature mineralization. Imaging also helps rule out other disease processes that can cause clinical signs similar to Cushing’s disease.
- May see dystrophic mineralization (mineral deposits) throughout the body, including the stomach lining and kidneys.
- May see evidence of calcium deposit formation under the skin (calcinosis cutis).
- Blood pressure measurement: Roughly 60% of patients with Cushing’s disease will have systemic hypertension (or high blood pressure).
Learn how to interpret your pet’s bloodwork or urinalysis results with The Meowing Vet’s other articles:
Bloodwork Interpretation
Urinalysis Interpretation
Treatment and Prognosis
The treatment plan and prognostic outlook differ between cases of adrenal-dependent hyperadrenocorticism (ADH) vs. pituitary-dependent hyperadrenocorticism (PDH). Secondary consequences of Cushing’s Disease may or may not resolve with therapeutic management of the Cushing’s disease (though most at least partially improve). For instance, hypertension (high blood pressure) may resolve once the Cushing’s Disease is treated; other cases may require anti-hypertensive medications. Similarly, diabetes mellitus complicated by Cushing’s Disease may continue to require insulin therapy while other cases may resolve when the Cushing’s is treated. Most dermatological effects and other abnormalities in appearance resolve with Cushing’s treatment (hair grows back, skin infections resolve, potbellied appearance returns to normal), though already-formed calcinosis cutis may persist. Sadly for some dogs, side effects of certain medications may prevent successful continuation of treatment. Additionally, some drugs may be cost-prohibitive to some owners.
Pituitary-dependent hyperadrenocorticism (PDH)
Unfortunately, PDH cases cannot be cured and instead must be managed with lifelong medications. Due to the anatomy of where the pituitary gland lies off the brain and because of the vital importance of this “master gland”, it can be very difficult to be safely accessed and removed via surgery. (However, some vets with advanced training may consider transphenoidal surgery and/or radiation of the pituitary gland in some cases.)
Instead, PDH is primarily managed with one of three medications: mitotane (a.k.a. o,p’-DDD), trilostane (Vetoryl®), or L-deprenyl (or selegiline) . These drugs inhibit cortisol production. Mitotane is essentially a controlled poison that kills adrenal cortex cells. Though effective, it carries a higher risk of side effects (vomiting, diarrhea, decreased appetite, etc.). Trilostane works well in 89% of cases; though side effects can occur, this drug tends to be better tolerated than mitotane. L-deprenyl (selegiline), predominately used to help manage canine cognitive dysfunction (or canine dementia), is also used in PDH cases. However, it is not very effective in managing PDH, reducing cortisol levels in only 15-20% of patients. Despite the type of therapy drug used, frequent bloodwork rechecks (ACTH stimulation test and biochemistry) are required to ensure that the drug dose is appropriate for a given patient — i.e. actually reducing cortisol level to a normal measurement and reducing the clinical signs of Cushing’s Disease while not going overboard and causing iatrogenic hypoadrenocorticism (Addison’s Disease) in which the body is producing too little cortisol and can have dangerously low blood sugar and electrolyte abnormalities.
With mitotane therapy, 70% of dogs survive for 1 year, 50% survive for 2 years, yet only 20% remain alive after 4 years of therapy. Statistics involving trilostane therapy are very similar (although mitotane therapy may yield slightly better prognostic results). Due to the progressive and inoperable nature of this type of pituitary tumor, euthanasia is often considered in unmanageable cases of PDH in which the patient’s quality of life and overall health suffers.
Adrenal-dependent hyperadrenocortcism (ADH)
These cases will eventually require surgery to remove the causative adrenal tumor. Only surgical excision of the affected adrenal gland results in a cure. However, such cases must be managed with medical therapy first, either by one of three medications: mitotane, trilostane (Vetoryl®), or ketoconazole. Mitotane or trilostane therapy (as discussed above under ‘PDH’) are the most effective medication choices. However, ketoconazole (typically used as an anti-fungal medication) interestingly inhibits cortisol production and can help 80% of cases (though not always as wellas mitotane or trilostane can). Routine bloodwork rechecks (ACTH stimulation test and biochemistry) are also required in ADH cases undergoing medical management.
Once the Cushing’s disease is better under control with medical therapy, surgery may be attempted. To avoid an iatrogenic Addisonian crisis, the patient must be aggressively supplemented with synthetic glucocorticoids during surgery to replace the cortisol that would otherwise be produced in excess by the adrenal gland tumor that is being removed. The remaining adrenal gland will eventually compensate by producing a normal amount of cortisol, but not right away. [Unfortunately, side effects (such as thromboembolism, or blood clot, formation) often develop due to this necessary level of glucocorticoid replacement.]
As explained previously, 40% of ADH cases are caused by benign adenomas while 60% are due to malignant adenocarcinomas. 50% of cases of adenocarcinomas are sadly inoperable and will eventually be fatal. Euthanasia may be considered in such cases to prevent unnecessarily suffering. Surgery to remove an adrenal gland can be risky (regardless of tumor type), and immediate post-op survival is variable (though the post-op prognosis of cases caused by adenomas is better than malignant adenocarcinomas).
– Maranda Elswick, DVM
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If your dog is displaying signs consistent with Cushing’s Disease as discussed in this article (increased thirst and urination, increased appetite, hair loss, and the development of a potbelly), The Meowing Vet recommends that you talk to your personal veterinarian today about testing for canine hyperadrenocorticism and subsequent treatment.
