Testing and Monitoring in Addison’s Disease

What is Addison's disease?

Addison's disease (also known as hypoadrenocorticism) is caused by decreased production of two hormones from the adrenal gland. These hormones are cortisol, a stress hormone, and aldosterone, a different type of hormone (mineralocorticoid) that controls the body's water balance through its effects on sodium and potassium.

What causes Addison's disease?

In humans, Addison's disease is usually caused by immune-mediated destruction of the adrenal glands (called primary hypoadrenocorticism). The immune system wrongly recognizes the gland tissue as "foreign" and destroys it as it would destroy a virus. This is also thought to be the main cause of Addison's disease in pets. 

Less common causes of damage to the adrenal glands include trauma, bleeding, or infection. Regardless of the cause of adrenal gland destruction, the levels of cortisol and aldosterone will decrease, resulting in illness.

Addison's disease may also result from decreased stimulation of the glands by the pituitary hormone ACTH (called secondary hypoadrenocorticism). Secondary Addison's disease is rare, and may be related to trauma, inflammation, or tumors near the pituitary gland. Decreased cortisol production is the main feature of this form of Addison's disease, while the production of aldosterone is less affected. Secondary Addison’s disease is also known as atypical Addison’s disease.

If a pet receives corticosteroid-containing medications such as prednisone over a prolonged period, the normal production of cortisol by the adrenal glands is reduced. If this medication is withdrawn rapidly, the adrenal glands will not be prepared to suddenly resume cortisol production. Therefore, a temporary condition similar to Addison's disease may result.

Finally, Addison's disease may occasionally occur following treatment for hyperadrenocorticism (Cushing's disease). This form of Addison's disease is termed iatrogenic (caused by medical intervention).

What tests are used to diagnose Addison's disease?

The signs of Addison's disease are often vague and may mimic other diseases. Therefore, it is important to perform initial screening tests that evaluate blood and urine samples to help rule out other disease conditions and to establish further evidence of Addison's disease. Given the slowly progressive nature of this disease, the number of changes or “clues” to Addison's disease that are found in this initial testing are variable.

What can these screening tests indicate?

Common screening tests are the complete blood count (CBC), serum biochemistry profile, and urinalysis.

Complete Blood Count (CBC)

A complete blood count (CBC) is a simple blood test that provides information about the different cell types in blood. These include the red blood cells, which carry oxygen to the tissues; white blood cells, which fight infection and respond to inflammation; and platelets, which help the blood to clot. Occasionally, a mild anemia (low red blood cell count) is noted with Addison's disease, as cortisol is required for optimal red blood cell production by the bone marrow.

Often, sick or otherwise stressed pets will have characteristic changes in their white blood cell populations. These changes can be brought about by the effects of cortisol (a stress hormone), and by the effects of an ongoing infection. When cortisol decreases in Addison's disease, these characteristic stress-induced changes may disappear.

Serum Biochemistry Profile

Serum (the liquid portion of blood) contains enzymes, proteins, lipids (fats), glucose (sugar), and metabolites. These serum components are derived from different organs such as the liver, kidneys, and pancreas, and measuring them can give an indication of the function of these organs.

Changes seen with Addison's disease are usually related to the lack of hormonal (cortisol and aldosterone) effects on organs, rather than actual organ damage. Cortisol is required for maintenance of proper serum glucose (blood sugar) concentrations, so cortisol deficiency may result in hypoglycemia  (low blood sugar).

Aldosterone regulates the body's fluid balance by affecting sodium and potassium. A lack of aldosterone may be reflected by changes in the amount of sodium and potassium in the serum, causing an abnormal sodium:potassium (Na:K) ratio, and by a decrease in total body fluid. This decreased body fluid makes it difficult for the kidneys to rid the body of waste products. An increase in kidney values, such as blood urea nitrogen and creatinine may be seen in the serum.

Urinalysis

The decrease in total body fluid related to Addison's disease cannot be measured directly but can be estimated by the concentration of urine that an animal produces. A special instrument called a refractometer is used to evaluate the concentration of the urine. The kidneys generally produce concentrated urine when water is less available.

The changes outlined above are not specific to Addison's disease; they may also be seen with dysfunction of other organs because cortisol and aldosterone have multiple effects on body organs. Therefore, if a pattern of changes is found that supports a diagnosis of Addison's disease, that diagnosis will need to be confirmed using an ACTH stimulation test.

How does the ACTH stimulation test work?

ACTH is a hormone naturally produced by the pituitary gland (located in the brain). The purpose of ACTH is to tell the adrenal glands when to produce cortisol and how much to produce.

The ACTH stimulation test mimics this natural stimulatory pathway and demonstrates the ability of the pet's adrenal glands to produce cortisol in response to an injection of synthetic ACTH.

This test requires two blood samples taken a specific length of time apart. In dogs, the first blood sample is taken before injecting synthetic ACTH (Cortrosyn™ or Synacthen®), and the second sample is taken one to two hours after the injection. In cats, this time frame may be shorter. Cortisol levels in the two samples are measured and compared to assess the response.

What do we expect to see if the patient has Addison's disease?

In a pet with Addison’s disease, the first test (taken before the ACTH injection) shows a low amount of cortisol. The second test (taken after the ACTH injection) shows little or no increase in the amount of. A lack of response to synthetic ACTH confirms the diagnosis of Addison's disease. Regardless of the underlying cause of Addison's disease, the results of the ACTH stimulation test are similar.

Why would my veterinarian ask to check a resting cortisol level before running an ACTH stimulation test?

Many illnesses can have signs like those caused by Addison’s disease, so your veterinarian may recommend checking your pet’s resting or baseline cortisol level. If resting cortisol is elevated, it can rule out Addison’s disease without the additional expense of synthetic ACTH. This test does not diagnose Addison’s disease.

How can the cause of Addison's disease be differentiated?

A thorough review of all medications that your pet has been receiving (both oral and topical formulations) is essential. If your pet has received medication containing corticosteroids that are suddenly stopped, they may have a temporary Addisonian condition that only requires treatment for a short time.

"Most cases of Addison's disease that are not related to the effects of medication are caused by immune-mediated destruction of the adrenal glands."

If your pet has been treated for hyperadrenocorticism (Cushing’s disease), the adrenal glands may become incapable of producing cortisol and aldosterone. This condition is permanent, and your pet will require treatment for their lifetime.

Most cases of Addison's disease that are not related to the effects of medication are caused by immune-mediated destruction of the adrenal glands. As the function of these glands decreases, the amount of cortisol in the blood also decreases. Decreased blood cortisol levels prompt the normal pituitary gland to secrete more stimulating hormone (ACTH) to increase cortisol production. Over time, this effort becomes futile, but an increased blood ACTH (endogenous ACTH) concentration can be measured. 

• Endogenous ACTH concentration is typically increased in pets with Addison's disease due to adrenal gland disease. 
• Endogenous ACTH concentration is typically decreased in pets with Addison's disease due to lack of production of ACTH by the pituitary gland.

Since both cortisol and aldosterone hormones are usually decreased with Addison's disease, do we need to measure aldosterone as well?

Studies have shown that measuring aldosterone concentrations does not reliably differentiate the different causes of Addison's disease. Therefore, it is rarely indicated.