Could it be Addison's disease?

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During his Fetch dvm360 Conference session Is that a Zebra? Yup, it’s Addison’s Disease, Christopher G. Byers, DVM, DACVECC, DACVIM (SAIM), CVJ, told a story about a 1-year-old, male intact, Chinese Crested dog named Rumble who was brought to a clinic presenting anorexia and adipsia.¹ The patient had been experiencing symptoms for 4 days, although his diet hadn’t changed. His owners had not reported the ingestion of any foreign body or toxin, and he showed no signs of polyuria/polydipsia, and he had not left home.

A physical examination (PE) performed during an urgent care visit 2 days prior concluded stuporous mentation. A complete blood count (CBC)/serum biochemical profile (CHEM) was performed at the urgent care, and he was treated with IVF. After 2 days of continuing symptoms, Rumble was brought to the clinic, where the results of a second PE showed he was quiet, alert, and responsive (QAR), lethargic, had weak synchronous femoral pulses, lost muscle weight (sarcopenia), and had mild hypothermia.

CBC/CHEM, urinalysis (UA), and radiography results showed a normal lymphocyte count despite being sick, a normal K+ with slightly low Na+, as well as hypoglycemia, which set off red flags. An Adrenocorticotropic hormone (ACTH) stimulation test was performed and showed no cortisol present, with or without cosyntropin stimulation. Rumble was finally diagnosed with hypoadrenocorticism (Addison’s disease).

Byers explained that no matter what, when evaluating a sick dog, Addison’s disease should be considered. Dogs of any age or sex can get the disease, although it’s most common in female dogs that are young to middle-aged. Over-represented dog breeds include standard poodles, West Highland, White terriers, Great Danes, bearded collies, German shorthair pointers, and Nova Scotia Duck Tolling retrievers. There is also believed to be a genetic basis for the condition in Portuguese Water dogs and Wheaten terriers, though further research is required. Alterations to a dog’s normal routine can precipitate disease-related crisis.

Adrenal physiology

Addison’s disease is caused by a problem in the adrenal cortex. Byers likened the adrenal gland to a peanut M&M, with the peanut representing the medulla and the chocolate exterior representing the cortex. The problem, Byers said, is in the chocolate. The adrenal cortex can be divided into 3 layers:

• Zona glomerulosa: The outermost layer; handles production and secretion of mineralocorticoid (aldosterone).
• Zona fasciculata: The middle layer; responsible for production and secretion of glucocorticoid (cortisol).
• Zona reticularis: The innermost layer; responsible for production and secretion of androgen.

Pathophysiology

Addison’s disease is classified as either primary or secondary, depending on a number of factors. The terms primary and secondary are used sparingly in discussions of the disease, however, according to Byers.

• Primary Addison’s: Primary Addison’s is either referred to as typical—indicating classic electrolyte changes—or Eunatremic eukalemic Addison’s (EEA), if there are no electrolyte derangements. This classification of the disease is the result of immune-mediated destruction of more than 90% of the adrenal cortex and glucocorticoid and/or mineralocorticoid deficiency.
• Secondary Addison’s: Formerly “atypical” Addison’s, secondary Addison’s is now more commonly referred to as EEA. It is the result of ACTH deficiency, specifically the lack of ACTH release from the pituitary gland, which then results in cortisol deficiency. The difference is especially notable because ACTH does not have a strong effect on the zona glomerulosa, which only limits glucocorticoids, sparing mineralocorticoid secretion and function.

Identifying mineralocorticoid deficiency is relatively easy. Indicators to look for include hyperkalemia and hyponatremia. Glucocorticoid deficiency indicators tend to be more subtle. Signs include the lack of a “stress leukogram,” hypoglycemia, hypoalbuminemia, and hypocholesterolemia.

“Never ignore low cholesterol,” Byers said in his presentation. “There are only 3 major differentials: liver disfunction, protein-losing enteropathy (PLE), and Addison’s disease. So, just by documenting hypocholesterolemia, your differential lists [got a lot smaller].”

Clinical presentation

Addison’s disease is often referred to as the Great Pretender, as there is no pathognomonic presentation for patients living with the disease. Patients could present acutely across various stages of hypovolemic shock, and other patients could have waxing and waning, vague gastrointestinal (GI) signs. These signs may include vomiting, diarrhea, anorexia/hyporexia, melena, among others. For patients in shock, signs may vary depending on the stage they are in (compensatory, early decompensatory, or late decompensatory).

Diagnosis

Initial testing

First, a physical examination should be conducted. Similar to the clinical presentations, results will be variable. “For the waxing and waning GI sign patients: dehydration, they’re not going to feel well, they’re going to have lost weight—especially muscle mass,” Byers said. In contrast, there will be patients that are, “actively trying to die in front of you.” They may show symptoms like bradycardia, hypovolemic shock, weak pulses, hypothermia, melena, or collapse.

A thorough diagnostic investigation is encouraged to establish a database of potential clues for Addison’s. Initial screening tests may include CBC, CHEM, venous blood gas (VBG), UA, fecal ova/parasites, electrocardiography, thoracic radiography (CXR), and abdominal sonography (AUS). Byers also recommends the use of basal cortisol levels in screening tests for Addison’s due to its high negative predictive value.

Definitive testing

“If you want to confirm Addison’s disease, you’ve got to do the ACTH stimulation test,” Byers said. “While the normal patient will experience an increase in their cortisol via stimulation with cosyntropin, the Addisonian patient will experience a flatline, just like we documented for Rumble.”

ACTH stimulation tests are considered the gold standard for diagnosing Addison’s. The test is conducted in 3 steps:

• Collect a baseline cortisol sample
• Administer synthetic ACTH (cosyntropin), 5 ug/kg IV
• Collect a post-cosyntropin cortisol sample after 1 hour

Cortisol levels <2 ug/dl (<55 nmol/L) before and after ACTH stimulation are consistent with Addison’s disease.

Treatment

There are 4 main points for the treatment of Addison’s disease: fluid therapy, correction of electrolyte abnormalities, all dogs need glucocorticoid replacement (typical/primary and EEA/secondary), and some dogs need mineralocorticoid replacement (typical/primary). In general, the interventions required for patients are largely dependent on their individual presentation. Stabilization is necessary for patients presented in shock—or Addisonian crisis. Available stabilization therapies include intravenous fluids, calcium gluconate, and regular insulin and dextrose supplementation to address a variety of individual issues.

Byers offered brief tips regarding the administration of fluid therapy:

• If a patient is hypotensive (from hypovolemic shock), they require a fluid bolus or a fluid challenge for the restoration of intravascular volume.
• If a patient is no longer in hypovolemic shock, their fluid therapy needs should be reassessed by calculating their hydration status and their daily physiologic requirements.
• He does not recommend twice maintenance, calling it dangerous, as it may not address hypovolemia, or it may be too much. He also advises that “maintenance is a type of fluid, not a rate of fluid.”

For the treatment of hyperkalemia, Byers recommends the use of calcium gluconate only to buy more time for fluid therapy. Dextrose, insulin, sodium bicarbonate, and terbutaline may also be for hyperkalemia. Glucocorticoid supplementation is key for all Addisonian patients. Initially, supraphysiologic supplementation with dexamethasone (0.05 to 0.07 mg/kg IV q24 hr) is recommended. Once the patient is cardiovascularly stable, and willing to eat and drink, they should be transitioned to prednisone at supraphysiologic doses (0.3 to 0.45 mg/kg PO q24 hr) lifelong. Doses should be adjusted based on clinical signs and any side effects.

Mineralocorticoid replacement is required for patients with primary Addison’s. Patients can be prescribed oral deoxycorticosterone pivalate (2.2 mg/kg) or fludrocortisone (0.01 mg/kg PO q12 hr) administered via injection every 25-30 days.

Takeaways

Regardless of electrolytes, Addison’s disease needs to be on the list of differentials anytime a sick dog is presented. Practitioners need to keep an eye out for red flags that may signal the presence of Addison’s, which could start by identifying an at-risk breed the second they walk through the clinic door. The ACTH stimulation test is the gold standard for Addison testing. If it’s recognized and treated, dogs who survive the initial crisis period have “an excellent prognosis, if managed properly,” said Byers.

Reference

Byers C. Is That a Zebra? Yup, It’s Addison’s Disease. Presented at: Fetch dvm360 Conference; August 23-25; Kansas City, MO.