Addison’s Disease in Dogs: Testing and Treatment

Hemopet’s last post about Addison’s Disease in dogs (hypoadrenocorticism; HA) reviewed the disease and its genetics. This post will review traditional screening methods and newer diagnostics that are becoming available. Additionally, we will discuss whether dosages of the medications given to manage HA need to be adjusted. Please refer to the last post for any potential clarification you may need here.

Screening Addison’s Disease in Dogs

The only commercially available genetic test is for HA in Nova Scotia Duck Tolling Retrievers.

Routine Complete Blood Count and Serum Blood Chemistries

Pre-screening tool. Untreated HA will typically reveal the following: low blood sodium levels and high potassium levels (not enough aldosterone), low blood glucose (not enough cortisol), increased blood calcium, and high kidney function values due to dehydration but yet with diluted urine.

Serum Cortisol

A low serum cortisol result signals that further testing should be performed. The test has a high sensitivity (99%), but a low specificity (63-78%). So, it should only be used as a pre-screen. Note: While people may think that basal resting cortisol levels slightly below the reference range of 5 ug/dL could indicate Addison’s disease, a true Addison’s case has resting cortisol at or below 1 ug/dL.

For the more commonly seen Cushing’s disease, however, a high serum cortisol (hyperadrenocorticism) is present.

Urinary Cortisol-Creatinine Ratio (UCCR)

The UCCR test is practical, easy to perform and should be run to pre-screen for HA and Cushing’s disease. We use this test successfully not only to pre-screen for suspected canine Addison’s or Cushing’s disease but also for monitoring the response of our patients on therapy for HA or Cushing’s disease. It must be run on the patient’s first urine collected before any exercise in the morning [exercise increases cortisol output].

A small 2022 retrospective analysis argued that in light of serum cortisol’s low specificity, UCCR should be considered as an alternative or an additional pre-screening test for HA. The team out of Bologna, Italy looked at 19 healthy dogs, 18 dogs with diseases mimicking HA, and 10 dogs with a confirmed HA diagnosis. According to their results, a UCCR cut‐off value of <1.4 yielded 100% sensitivity and 97.3% specificity in diagnosing HA. Additionally, no overlap was detected between dogs with HA and the dogs with mimicking diseases.

Machine Learning Model

Researchers at University of California – Davis (UCD) created a machine learning model. Basically, they took retrospective data of dogs that had either a baseline cortisol or ACTH stimulation test, setup parameters, and created an algorithm to detect potential cases of the disease. They then tested it against suspected or actually confirmed cases. Their results were promising and over time may become more precise. As the team noted, this will probably not replace standard testing any time soon.

Serum Metabolomics

A newer serum diagnostic test appears to be on the market in Europe that measures metabolic abnormalities. The study for the test found that patients with Cushing’s Syndrome had elevated levels of lipoproteins and fatty acids, which is in accordance with an excessive amount of circulating cortisol. The study also stated that these same markers were decreased in HA – intimating that these results were below reference range.

The pooled results of untreated dogs with HA were primarily on the lower end of the reference ranges for fatty acids and lipoproteins with a couple of minor exceptions that exceeded the range.

The data becomes interesting once you compare the untreated dogs with HA to the treated dogs. Many of the treated dogs showed an increase of fatty acids and lipoproteins, which is to be expected with cortisol treatment. The study highlighted that some of the treated dogs might have been “overcompensated” with medication because their numbers started to creep above the reference range. In essence, their dosages might have been too high and needed to be adjusted.

In conclusion, this test might be promising for ongoing monitoring of cortisol treatment in dogs with HA, but not for pre-screening. Additional studies will need to occur.

ACTH Stimulation Test

The ACTH stimulation test is currently the gold standard for diagnosing HA in dogs. Dogs are injected with a synthetic form of ACTH. Remember, ACTH is released from the pituitary gland to signal the adrenal glands to produce cortisol. After an hour or so, blood is withdrawn and sent to a laboratory for testing. If cortisol levels did not increase or increase significantly compared to the pre-ACTH sample or a previous blood draw, confirmation of HA is considered to be positive.

Cortisol-to-ACTH Ratio

This test lowers the amount of ACTH administered during the stimulation test and divides the circulating cortisol level by the circulating ACTH level.

In a 2014 study that was comprised of 8 healthy dogs, 19 dogs with non-adrenal illness (NAI) and 15 dogs with HA, the baseline serum cortisol concentration was significantly lower, and ACTH concentration was significantly higher, in the HA group versus the other 2 groups. However, there was overlap among groups. The cortisol-to-ACTH ratio was significantly lower in the HA group versus the healthy and NAI groups, and there was no overlap between the HA group and the other 2 groups.

A larger 2015 research study included 23 dogs with newly diagnosed HA, 79 dogs with diseases mimicking HA, and 30 healthy dogs. This team did find some overlap, but concurred that the cortisol-to-ACTH ratio is a useful screening tool to diagnose primary HA.

Aldosterone Testing

Aldosterone tests are not readily available and may not be reliable. Periodically, a research study is published about testing ACTH-stimulated aldosterone during the ACTH test, measuring baseline aldosterone, or measuring the aldosterone-to-renin ratio. The latter is considered difficult to perform. However, aldosterone testing should be an area of research that is actively pursued to be more accurate and available.

Endogenous ACTH (eACTH) Measurement

This test is rarely performed. Veterinarians may use it to differentiate between primary and secondary hypoadrenocorticism, especially if sodium and potassium levels are normal.

Discussion of Diagnosing Addison’s Disease

HA is considered a rare disease and mimics more common diseases like gastrointestinal disorders. In general, veterinarians will exhaust the more common options and finally test HA as the last resort. We understand the reasoning behind this decision making.

Yet, an Addisonian Crisis is acute, fast and life-threatening compared to a chronic gastrointestinal disorder. Put in another way, there is more time for the patient to diagnose a gastrointestinal disorder than HA.

Yet…certain questions persist.

With so many known breeds considered at increased risk of the disease and if any dog can have HA, why is HA still considered rare?

A Swedish study reviewed 525,028 cases from 1995-2006 and 534 dogs were identified with HA. They brought up a good point, “Because the present study is based on data from many different veterinarians, irrespective of level of specialization, there is a risk that dogs with HA have been misdiagnosed as other more common disorders such as renal failure or gastrointestinal disease, alternatively HA could have been erroneously diagnosed.”

Why stop testing a dog after a gastrointestinal condition is identified in a breed at increased risk for HA? A dog could have both a gastrointestinal disease and HA. (By the way, a condition called “polyglandular autoimmunity” occurs in people and dogs whereby both Addison’s disease and autoimmune thyroiditis and/or type 1 diabetes mellitus, i.e. Schmidt’s syndrome, occurs. The Old English Sheepdog is an example of a susceptible breed and affected dogs can have gastrointestinal symptoms).

Of course, many veterinarians are quick to treat signs of gastrointestinal disorders with glucocorticoids. So if a dog actually has HA, but is misdiagnosed with a gastrointestinal disorder, the dog is receiving possibly some or all of the medication he needs for HA.

We looked over some more recent retrospective analyses. Gallego et al. reviewed hundreds of records of dogs presented to The Royal (Dick) School of Veterinary Studies (University of Edinburgh) between May 2013 and September 2017. They determined that only 1 of 282 dogs actually had HA upon referral for gastrointestinal disorders.

Hauck et al. reviewed cases from Germany and the Netherlands between November 2014 and December 2015. Out of 151 dogs, 6 dogs were diagnosed with HA. They calculated the prevalence at 4% compared to the estimated prevalence in the general canine population (between 0.06 and 0.28%).

If you want to take HA out of the equation for your symptomatic companion dog that is considered high risk due to breed, discuss the sodium, potassium and cortisol levels with your veterinarian and then decide to rule in or out HA with an ACTH stimulation test while concurrently exploring a possible gastrointestinal disorder. Basically, prioritize the test.

Treatment for Addison’s Disease

Cortisol is supplemented daily by glucocorticoids such as prednisone.

Aldosterone is supplemented by desoxycorticosterone pivalate (DOCP; Percorten®-V or Zycortal®). It is an injectable medication approved by the Food and Drug Administration for the treatment of HA in dogs. It is injected every 3–4 weeks, depending on the patient, and replaces the missing mineralocorticoid aldosterone.

Some dogs cannot tolerate DOCP, so fludrocortisone (Florinef®) is an alternative that can replace both the mineralocorticoid and glucocorticoid.

As previously mentioned, the serum metabolites study suggested that some dogs with HA might be overly supplemented with cortisol and that possibly a decrease in dosage may be necessary.

Additionally, two studies released around the same time were intriguing regarding the use of DOCP and fludrocortisone. In April 2021, Diaz et al. evaluated kidney function of dogs with primary HA that had received either DOCP or fludrocortisone for a minimum of 12 months by analyzing serum symmetric dimethylarginine and serum creatinine levels. Based on the data, they determined that the prevalence of chronic kidney disease could be higher in dogs receiving long-term mineralocorticoid replacement therapy than in the general dog population.

Two months later, a team at Michigan State University (MSU) led by Alysha Vincent, published their findings of treating dogs with a low-dose of DOCP. They mentioned that the cost of the manufacturer recommended dosage might exclude companion pet parents from seeking regular treatments whereas a lower dosage would reduce the cost barrier. They also noted manufacturer recommended dosages might be higher than what is necessary to control HA because lower dosages and longer dosing intervals have been used successfully for the management of HA.

The Vincent MSU study was the first prospective study to compare two DOCP dosing protocols in dogs with HA. The 37 dogs participating in the study included 19 test population dogs receiving 1.1 mg/kg DOCP, and 18 controls receiving 2.2 mg/kg DOCP. Every dog received a treatment every thirty days for 90 days. Dogs were evaluated approximately 10-14 days after treatment and again 30 days after a treatment. Each evaluation entailed a physical examination, hematocrit, total plasma protein concentration, serum biochemical profile, urinalysis, urine protein‐to‐creatinine ratio, baseline plasma renin activity (PRA) measurement, and blood pressure measurement.

Bear in mind that a June 2023 study also conducted at MSU by Langlois et al. stated that measuring urine electrolytes like the protein-to-creatinine ratio were not useful for assessing the adequacy of mineralocorticoid therapy in HA dogs that were treated with DOCP. Remember, the Vincent study measured serum as well.

The Vincent study stated, “No dog in either population required treatment, or developed clinical illness, because of electrolyte disturbances.”

They concluded, “1.1 mg/kg starting and maintenance dosages of DOCP for treatment of HA appeared to be safe and effective in our study population. Based on serum electrolyte concentrations and PRA, dosages of 2.2 mg/kg were unlikely to have been necessary for most dogs in the standard‐dose population.”

We encourage you to read their fascinating, comprehensive and revealing study.

Additional References

Baumstark, M E et al. “Evaluation of aldosterone concentrations in dogs with hypoadrenocorticism.” Journal of Veterinary Internal Medicine vol. 28,1 (2014): 154-9, doi:10.1111/jvim.12243, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4895548/.

Dodds, W. Jean. “Guest Editor’s Introduction to Endocrinology.” American Holistic Veterinary Medical Association Journal vol. 40, Fall 2015, 8-14.

Dodds, W. Jean. “Understanding Your Pet’s Blood, Tissue and Urine Laboratory Results.” Pet Health Resource, Tumblr, 19 Apr. 2015, https://drjeandoddspethealthresource.tumblr.com/post/116836320986/pet-laboratory-results.

Guzmán Ramos, Pedro J et al. “Diagnosis of canine spontaneous hypoadrenocorticism.” Canine Medicine and Genetics vol. 9,1 6. 3 May. 2022, doi:10.1186/s40575-022-00119-4, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9066729/.

Javadi S, Galac S, Boer P, Robben JH, Teske E, Kooistra HS. Aldosterone-to-renin and cortisol-to-adrenocorticotropic hormone ratios in healthy dogs and dogs with primary hypoadrenocorticism. J Vet Intern Med. 2006 May-Jun;20(3):556-6,. doi: 10.1892/0891-6640(2006)20[556:aachri]2.0.co;2, PMID: 16734089, https://pubmed.ncbi.nlm.nih.gov/16734089/.

Klein, Susan C, and Mark E Peterson. “Canine hypoadrenocorticism: part II.” The Canadian Veterinary Journal = La Revue Veterinaire Canadienne vol. 51,2 (2010): 179-84, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808283/.

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