Addison disease (hypoadrenocorticism) results from a lack of glucocorticoids, mineralocorticoids, or both. Isolated aldosterone insufficiency appears to be very rare, whereas isolated glucocorticoid insufficiency is likely underdiagnosed because of the lack of electrolyte abnormalities. The clinical signs of hypoadrenocorticism are often vague, can wax and wane over time, are rarely pathognomonic, and can be present for days, weeks, or months before diagnosis. Diagnosis depends on an accurate history, physical examination, and screening laboratory tests (CBC, chemistry panel, urinalysis). Confirmation requires adrenal function testing using the ACTH stimulation test. Treatment is highly successful but often lifelong.
Addison disease, or hypoadrenocorticism, results from mineralocorticoid and glucocorticoid deficiency. It occurs most commonly in dogs. The onset is usually in young to middle-aged adults, but a wide age range has been reported. Females are affected more commonly.
Addison disease can affect any breed of dog. Mixed-breed dogs are diagnosed most commonly; however, numerous breeds are overrepresented, including Nova Scotia Duck Tolling Retriever, Great Dane, Standard Poodle, West Highland White Terrier, Bearded Collie, and Portuguese Water Dog. Addison disease has been uncommonly reported in other domestic mammals, including cats and horses.
Most cases of canine Addison disease are due to primary adrenocortical failure, the cause of which is unknown but is suspected to be immune mediated. Other causes of adrenocortical failure include cytotoxic drugs (mitotane), adrenocortical enzyme inhibitors (trilostane), infiltration of the adrenal glands by metastatic neoplasia or granulomatous disease, and adrenal gland hemorrhage.
Some animals develop isolated glucocorticoid deficiency—termed "atypical Addison disease"—that can progress to mineralocorticoid deficiency.
Although rare, secondary Addison disease, resulting from deficient ACTH secretion from the pituitary gland, can occur and is clinically indistinguishable from isolated glucocorticoid deficiency resulting from primary adrenocortical failure. A low concentration of endogenous ACTH with a known diagnosis of Addison disease suggests a diagnosis of secondary Addison disease.
Clinical Findings of Addison Disease in Animals
Because so many body systems are affected by adrenocortical hormones, clinical signs of deficiency are variable and can be vague. Usually, GI signs predominate, including loss of appetite, weight loss, vomiting, and diarrhea. Lethargy is common, and polyuria/polydipsia is also reported. These signs can wax and wane, and they are typically brought on or exacerbated by stress.
Although the clinical signs of Addison disease in dogs can be mild initially, some dogs develop a life-threatening condition characterized by hypovolemia and hypotension (addisonian crisis). Affected animals can also have severe hyperkalemia resulting in bradyarrhythmias, hypoglycemia, and azotemia, as well as severe vomiting and diarrhea, which can be hemorrhagic.
Diagnosis of Addison Disease in Animals
History and clinical signs
Clinicopathological findings
ACTH stimulation test
The clinical signs associated with Addison disease are typically vague, nonspecific, and variable between patients; hence, clinicians must maintain an index of suspicion in patients with a history of such signs.
Mineralocorticoid and glucocorticoid deficiency result in a constellation of characteristic abnormalities that are evident on routine laboratory evaluation.
Glucocorticoid deficiency results in the absence of a stress leukogram on CBC, characterized by an inappropriate lack of lymphopenia or even a lymphocytosis with or without eosinophilia.
Mild, normocytic, normochromic, nonregenerative anemia is typically evident, because of the role of glucocorticoids in erythropoiesis. However, the erythrogram can also be altered by volume depletion (hemoconcentration) or GI blood loss.
Mineralocorticoid deficiency results in hyperkalemia, hyponatremia, and metabolic acidosis.
Sodium:potassium (Na:K) ratios < 27 suggest Addison disease but are not pathognomonic.
Azotemia can result from a combination of fluid loss due to polyuria, vomiting, and diarrhea, as well as from hypotension. Azotemia typically corrects rapidly with fluids, and progression to renal failure is not common; however, concurrent low urine specific gravity due to renal sodium and water losses can make an addisonian crisis mimic primary renal disease.
Hypoglycemia can result from glucocorticoid deficiency and can be severe.
Other common clinicopathological findings in Addison disease include hypoalbuminemia, hypocholesterolemia, and mild to moderate ionized hypercalcemia.
Definitive diagnosis of hypoadrenocorticism requires an ACTH stimulation test in which cortisol concentration is measured before and after the administration of exogenous ACTH. Protocols vary; however, the ACTH stimulation test technique most commonly used is to measure baseline serum cortisol concentration, administer synthetic ACTH (cosyntropin, at 5 mcg/kg, IV, once), and measure serum cortisol concentration again 1 hour later.
Dogs with Addison disease show minimal to no increase in cortisol concentration in response to ACTH (described as a “flatline” result). For a diagnosis of Addison disease, the post-ACTH cortisol concentration must be less than the laboratory reference interval (< 2 mcg/dL).
Alternatively, a baseline cortisol concentration > 2 mcg/dL effectively rules out hypoadrenocorticism. However, measurement of baseline cortisol concentration is not sufficient to diagnose the disease and, if it is < 2 mcg/dL, must be followed up with ACTH stimulation testing.
Note that an ACTH stimulation test that is diagnostic for Addison disease only confirms glucocorticoid deficiency. Practically, a diagnosis of mineralocorticoid deficiency is assumed in patients with Addison disease that have concurrent electrolyte abnormalities, specifically a low Na:K ratio.
Treatment of Addison Disease in Animals
IV fluid therapy
Correction of hypoglycemia
Antiemetic, antinausea, and nutritional supportive care
Glucocorticoid and mineralocorticoid replacement
Specific treatment of hypoadrenocorticism in dogs depends on the condition of the dog and the abnormalities present.
Emergency Treatment
Dogs in an addisonian crisis should be treated on an emergent basis.
The mainstay of treatment is IV fluid therapy to correct shock and dehydration. A replacement crystalloid fluid is appropriate in most cases; occasionally, alternative fluid types are needed because rapid correction of severe hyponatremia can result in neurological complications from myelinolysis.
Blood pressure and electrolyte concentrations should be monitored closely.
If hypoglycemia is present, IV dextrose supplementation is indicated.
In dogs with arrhythmias from severe hyperkalemia, emergency treatment with 10% calcium gluconate (1 mL/kg, IV, over 10 minutes) can be administered to protect the heart from the effects of hyperkalemia. Dextrose, with or without regular insulin (taking care to avoid hypoglycemia), can be administered to promote intracellular translocation of potassium. Alternatively, sodium bicarbonate or beta-adrenergic receptor agonists (eg, terbutaline) can be used.
Antiemetic, antinausea, and nutritional supportive care should be implemented when indicated.
Replacement IV glucocorticoids should be administered promptly. Multiple glucocorticoids are available in IV form; however, dexamethasone sodium phosphate (0.1 mg/kg, IV, every 12 hours, tapering when appropriate) is a reasonable first-line treatment because it acts rapidly and can be administered before sample collection for an ACTH stimulation test (if needed) without interfering with the test.
If a low Na:K ratio supports mineralocorticoid deficiency, desoxycorticosterone pivalate (DOCP; 2.2 mg/kg, IM, every 25 days, depending on patient response) should be administered as well. A lower starting dosage (1.1–1.5 mg/kg, IM) can be considered (1).
Alternatively, hydrocortisone (0.5–0.625 mg/kg/hour, IV), a steroid with mineralocorticoid and glucocorticoid activity, has been described in the initial management of canine addisonian crisis.
Nonemergency Treatment
For dogs with hypoadrenocorticism that are in stable condition, hormone replacement therapy can be implemented on an outpatient basis either with a combination of DOCP (mineralocorticoid replacement) and prednisone (glucocorticoid replacement), or with fludrocortisone (0.02 mg/kg, PO, every 24 hours or divided every 12 hours and adjusted as needed). Fludrocortisone is a mineralocorticoid that also has some glucocorticoid activity.
Some dogs receiving fludrocortisone can require additional glucocorticoid supplementation in the form of prednisone. Prednisone (0.5–1 mg/kg, PO, every 24 hours) is tapered over the first few days of treatment to the lowest dose needed to control clinical signs of glucocorticoid deficiency. After tapering, the minimum effective dosage is typically 0.05–0.1 mg/kg, PO, every 24 hours, but it may vary.
Signs of overtreatment of Addison disease are consistent with iatrogenic hyperadrenocorticism (polyuria/polydipsia, panting, polyphagia, increased susceptibility to infection, etc). In times of illness or stress, a maintenance dose of prednisone must be increased to prevent signs of glucocorticoid deficiency.
Treatment is monitored via observation of clinical signs (glucocorticoid deficiency versus excess) and electrolyte concentrations. For dogs with atypical Addison disease, electrolytes should be monitored periodically as well, because mineralocorticoid deficiency can develop. With appropriate treatment and monitoring, the longterm prognosis for dogs with Addison disease is good.
Key Points
Addison disease is often referred to as "the great imitator" because clinical signs are often vague and rarely pathognomonic. Therefore, the diagnosis should be considered for patients with the appropriate signalment and clinical signs.
Measurement of resting cortisol concentration can rule out the diagnosis in patients that are not acutely ill; however, an ACTH stimulation test should initially be performed in acutely ill patients or when the resting cortisol concentration is < 2 mcg/dL.
Treatment is generally highly successful, is often needed throughout the life of the patient, and results in an excellent longterm prognosis.
For More Information
Bugbee A, Rucinsky R, Cazabon S, et al. 2023 AAHA selected endocrinopathies of dogs and cats guidelines. J Am Anim Hosp Assoc. 2023;59(3):113-135. doi:10.5326/JAAHA-MS-7368
Lathan P, Thompson AL. Management of hypoadrenocorticism (Addison's disease) in dogs. Vet Med (Auckl). 2018;9:1-10. doi:10.2147/VMRR.S125617
Scott-Moncrieff JC. Hypoadrenocorticism. In Feldman EC, Nelson RW, Reusch C, Scott-Moncrieff, JCR. Canine & Feline Endocrinology. 4th ed. Elsevier Saunders; 2015:485-520.
Also see pet health content regarding Addison disease in dogs and cats.
References
Sieber-Ruckstuhl NS, Reusch CE, Hofer-Inteeworn N, et al. Evaluation of a low-dose desoxycorticosterone pivalate treatment protocol for long-term management of dogs with primary hypoadrenocorticism. J Vet Intern Med. 2019;33(3):1266-1271. doi:10.1111/jvim.15475
