Primary hypoadrenocorticism (HA) is an uncommon disease in dogs and rare in cats.
Adrenal gland physiology
First, we’ll go over some basic adrenal gland physiology.
The adrenal cortex is primarily responsible for secreting several important hormones including cortisol and aldosterone. Cortisol has several functions including carbohydrate, lipid and protein metabolism, immune system modulation and proper catecholamine function. The amount of cortisol being released is determined by a negative feedback system:
The hypothalamus produces corticotropin releasing hormone (CRH) which stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH).
ACTH stimulates the zona fasiculata and reticularis of the adrenal cortex to produce and release cortisol.
Increased serum cortisol inhibits the release of CRH and ACTH.
Aldosterone is also released from the cortex; however its release is stimulated by hypovolaemia which is recognised by the kidney. In times of hypovolaemia.
Angiotensin II is released via a hormonal cascade and stimulates the zona glomerulosa to release aldosterone.
Aldosterone stimulates cells in the renal collecting duct to resorb sodium (leading to secondary water retention and restoration of the effective circulating volume) and excrete potassium.
Causes of HA
Primary HA is caused by adrenal gland dysfunction. Although much more rare, secondary HA can also occur; this is caused by hypothalamic or pituitary dysfunction. Most cases of primary HA involve concurrent cortisol and aldosterone deficiency although atypical HA can also occur where only cortisol is deficient.
The typical signalment for HA is young-to-middle aged dogs with females more likely to be affected. Average age of onset is 4 years old.
The most commonly affected breeds include Portuguese water dogs, Great Danes, Westies, Standard Poodle, Wheaton Terrier and Rottweilers.
In cats there is no known sex or breed predisposition.
The exact cause of primary HA is unknown but is believed to be immune-mediated destruction of the adrenal cortex. Less common causes of primary HA include trauma, infiltrative disease or iatrogenic destruction due to mitotane or trilostane therapy for hyperadrenocorticism. In one study evaluating 156 dogs on chronic trilostane treatment for hyperadrenocorticism, the relative risk of developing HA was 15% at 2 years and 26% by 4 years.
The clinical presentation of typical HA can be vague and non-specific. We will focus on the emergent Addisonian crisis:
Common clinical signs of a crisis include lethargy or collapse, hypothermia, hypovolaemic shock and bradycardia. Much of these signs occur secondary to the electrolyte changes induced by this disease (mainly hyperkalaemia and hyponatraemia).
On blood work, common findings include hyponatraemia, hyperkalaemia, azotaemia with a concurrent inappropriately low urine specific gravity (typically < 1.030) and possible lack of a stress leucogram.
Most of these patients (> 90% in some studies) will also have a low sodium/potassium ratio, typically less than 28. Other differentials of this include any disease which leads to severe dehydration including renal failure, severe gastrointestinal disease, and body cavity effusions among others.
Other less common blood work findings include hypoglycaemia and hypercalcaemia. Cortisol promotes gluconeogenesis and glucogenolysis and calciuresis leading to these respective electrolyte derangements.
In cases of severe hyperkalaemia, patients can experience significant bradycardia and/or dysrhythmias. Common ECG changes noted include:
Diminished/absent P waves
Tented T waves
Wide/bizarre QRS complexes
There are several ways to evaluate if a dog may have HA:
1. A screening test evaluating the resting cortisol can be performed initially with values less than 1 mcg/dl having excellent sensitivity (100%) and good specificity (98%) for HA in dogs.
Values < 2 mcg/dl were also 100% sensitive but only 78% specific for HA.
Dogs with values > 2 mcg/dl are very unlikely to have HA
2. A confirmatory ACTH stimulation test should be performed in all cases of suspected HA. This test is considered the gold standard.
The drug used in this test (cortisyn) is very expensive and recent studies have shown that the low dose ACTH (5 mcg/kg) stimulation test is as effective as the standard dose (using a 250 mcg vial in a dog or 125 mcg vial in a cat).
3. In cases where primary vs. secondary HA needs to be differentiated or to diagnose atypical HA, endogenous ACTH levels can be measured.
Animals with atypical HA (cortisol deficiency without concurrent aldosterone deficiency), should have normal electrolyte values and an elevated endogenous ACTH level.
4. Evaluation of a dog’s cortisol/ACTH ratio: in one study, all dogs with HA had ratios < 0.17 vs. healthy dogs who had values > 0.79 (reference range 1-1.26).
5. Urine sodium levels: in a recent study dogs with HA had significantly higher urine sodium levels when compared to dogs with non-adrenal illness
While there are several tests that may increase suspicion for HA, the ACTH stimulation is the gold standard confirmatory test.
It is important to note that most exogenous glucocorticoids can interfere with adrenal function tests; therefore tests should be delayed if the patient has recently received steroids. Of all types of glucocorticoids dexamethasone has the least effect on testing. In a true Addisonian crisis, fluid resuscitation is the most important first step so delaying steroid administration until after the ACTH stimulation test likely does not have a significant impact on survival.
Intravenous fluids are the mainstay of therapy in a crisis. Despite their potassium content, a balanced electrolyte solution is recommended over 0.9% sodium chloride solution. This is because the latter could increase the patient’s blood sodium levels too quickly which can cause neurological complications. Once the effective circulating volume is restored, kidney function and GFR will increase leading to kaliuresis; this negates the risk of using fluids with low potassium levels in a hyperkalaemic patient.
Patients who have life-threatening hyperkalaemia require rapid intervention.
In animals that are experiencing significant cardiotoxic effects, calcium gluconate can be administered. This will not lower potassium levels and its cardioprotectant effects last approximately 15-20 minutes so more definitive treatments need to be instituted following calcium administration.
Treatments to lower plasma potassium levels include fluid resuscitation as well as administration of substances which shift potassium from the extracellular compartment into the intracellular compartment:
The most commonly used is 50% glucose solution and regular (neutral, soluble) insulin (0.1 u/kg with concurrent glucose supplementation to avoid hypoglycaemia)
Sodium bicarbonate is used less commonly as this drug carries significant risks due to several possible side effects and should only be considered a last resort.
Following adrenal function testing, patients with typical HA can be started on mineralocorticoid and glucocorticoid supplementation:
Mineralocorticoids can be given daily in tablet form or as an injection given approximately every 25-30 days.
Glucocorticoids are typically administered intravenously to begin with and then per os. They are usually weaned off over time.
The timeline for clinical recovery is different for every patient although it can be anywhere from hours following supplementation to 3-5 days.
Animals with atypical HA (singular glucocorticoid deficiency) only require glucocorticoid supplementation.
Cats typically take longer to respond than dogs.
The prognosis for this disease is quite good, especially in those who survive the initial crisis. However they do require lifelong monitoring and treatment. This is typically long-term mineralocorticoid administration with intermittent glucocorticoid administration at times of physiological stress or illness.