Hypoadrenocorticism: The great pretender

Hypoadrenocorticism, also known as Addison’s Disease, is an uncommon condition, with an estimated prevalence between 0.06% and 0.28%. Known as “the great pretender,” its vague, nonspecific clinical signs often mimic other illnesses, as do diagnostic findings. Early recognition, diagnosis, and treatment can prevent significant mortality secondary to hyperkalemia, hyponatremia, dehydration, and hypovolemic shock.^1-3

Pathophysiology and epidemiology

The adrenal gland comprises an inner medulla and an outer cortex. Three layers make up the cortex, and each is responsible for hormone production. The outermost layer, the zona glomerulosa, is responsible for mineralocorticoid (aldosterone) production, while glucocorticoids and androgens are produced by the zona fasiculata (middle layer) and reticularis (innermost layer).^1,2

Primary hypoadrenocorticism is most common and is most often caused by autoimmune destruction of the medullary layers. Thus, destruction of the zona glomerulosa results in mineralocorticoid deficiency, while cortisol (glucocorticoid) deficiency occurs secondary to destruction of the zona fasiculata and reticularis.⁴

Secondary hypoadrenocorticism is rare. It is caused by lack of secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland or lack of secretion of corticotropin-releasing hormone (CRH) from the hypothalamus. This, in turn, results in atrophy of the zona fasiculata and reticularis, and therefore lack of cortisol production; mineralocorticoid production from the zona glomerulosa is not affected. Secondary hypoadrenocorticism most commonly occurs secondary to neoplasia or intracranial trauma.^5,6

Most dogs with primary hypoadrenocorticism are deficient in both glucocorticoids and mineralocorticoids; however, glucocorticoid deficiency can occur without mineralocorticoid deficiency. The latter population lacks electrolyte abnormalities; this is referred to as ‘atypical.’^1,2,7These dogs can progress to develop mineralocorticoid deficiency, so sodium and potassium should still be monitored in these patients.⁴

Hypoadrenocorticism is thought to have a genetic basis in dogs, but mode of inheritance has not been established. Breeds with a known genetic predisposition include the Nova Scotia duck tolling retriever, standard poodle, bearded collie, and Portuguese water dog.^2,8-10 Other commonly affected breeds include great dane, West Highland white terrier, Saint Bernard, Wheaten terrier, leonberger, and rottweiler.^2,5,6 Young to middle-aged female dogs are predisposed.^2,4,5

Hypoadrenocorticism has also been reported in cats, but is rare.¹¹

Clinical presentation

Hypoadrenocorticism can present as an acute crisis or with waxing and waning clinical signs. The most common presentation is with a history of vague symptoms, such as lethargy, inappetence, weight loss, and/or waxing and waning gastrointestinal signs that have not fully responded to traditional supportive therapies. There may be a history of illness developing in association with a stressful event.

The array of clinical signs includes, but is not limited to, vomiting, diarrhea, inappetence, weight loss, lethargy, weakness, collapse, polyuria, polydipsia, shaking, abdominal pain, melena or hematochezia, and hematemesis. Patients in crisis can present with signs of hypovolemic shock, including bradycardia, tachycardia, collapse, hypothermia, weak pulses, and poor capillary refill time. Otherwise, physical examination findings are nonspecific and can include thin body habitus and dehydration.^2,4-6

Diagnostic approach

Diagnostic testing should begin with a minimum database, including complete blood count (CBC) and chemistry panel (including electrolytes). Pertinent CBC findings may include anemia (most often non-regenerative), lymphocytosis (or lack of the lymphopenia expected secondary to a normal stress response), eosinophilia, and neutrophilia. The most common biochemical abnormalities are hyperkalemia, hyponatremia, and hypochloremia. Other common findings include hypercalcemia, azotemia, hyperphosphatemia, hypoglycemia, hypocholesterolemia, and hypoalbuminemia. ^1-7 Abdominal ultrasound often reveals adrenal glands that are much smaller than normal or cannot be identified.^2,4 In patients with severe hyperkalemia, an EKG can reveal bradycardia, lack of P waves, wide QRS complexes, and tall T waves.^1,2,7

Because of the variety of vague presenting symptoms, veterinarians should be testing a large number of dogs for hypoadrenocorticism compared to the small number that are definitively diagnosed with the disease.^2,14 Several studies have documented that measurement of basal (resting) serum or plasma cortisol is a reliable screening test for dogs with a clinical history consistent with hypoadrenocorticism, with a 100% sensitivity for a cutoff of ≤2 µg/dL. This diagnosis is less likely if the cortisol is >2 µg/dL_.^2,12-14Because a basal cortisol of ≤2 µg/dL has a low specificity and a low positive predictive value, an ACTH stimulation test must be performed in these patients to obtain a definitive diagnosis.^12-14 Although cosyntropin doses of 5 µg/kg IV are most commonly employed, one study showed that doses of 1 µg/kg IV may be sufficient.^1,15

Treatment

Treatment of hypoadrenocorticism can be divided into management of the acute crisis and chronic management. Treatment of a hypoadrenocortical crisis is focused on restoration of tissue perfusion and correction of hypovolemia with IV fluid therapy, correction of electrolyte abnormalities, correction of hypoglycemia (if applicable), restoration of acid-base balance, and providing glucocorticoid support.^2,5 ECG should be monitored, and immediate treatment initiated for hyperkalemia if it is severe enough to cause ECG changes.

Intravenous regular insulin and dextrose should be utilized to shift potassium into cells along with glucose; blood glucose should be monitored for 6 hours concurrent with weaning of dextrose supplementation.^2,5 Calcium gluconate 10% is cardioprotective and can be administered to antagonize the cardiac effects of hyperkalemia.^2,5 A rapidly acting corticosteroid such as dexamethasone sodium phosphate should be administered to provide glucocorticoid support. A reasonable starting dose is 0.1-0.2mg/kg IV every 24 hours until an oral glucocorticoid, usually prednisone or prednisolone, can be tolerated. Mineralocorticoid supplementation should be delayed until the patient has recovered, and electrolytes are normal or nearly normal, and the patient’s perfusion has been restored.²

Chronic therapy for typical hypoadrenocorticism entails both mineralocorticoid and glucocorticoid supplementation; only glucocorticoid supplementation is required for an atypical Addisonian. Prednisone/prednisolone is used most with a starting dose of 0.2-0.25 mg/kg/day.^2,4,5 Once a diagnosis of hypoadrenocorticism has been established, the ACTH stimulation test is no longer useful; dose adjustments are made based on subjective information provided by the owner, making good client communication imperative for management.⁴

The glucocorticoid dose can be tapered to the minimum amount necessary, usually 0.1-0.2 mg/kg/day, to prevent symptoms of hypoadrenocorticism while avoiding side effects of corticosteroids.^2,4 For some large breed dogs, a dose of slightly less than 0.1 mg/kg/day may be required to accomplish these goals. During periods of stress, increased doses of glucocorticoids should be recommended; the author typically doubles the prednisone/prednisolone dose during the event and for 2-3 days before and after.^2,4

Either desoxycorticosterone pivalate (DOCP) or fludrocortisone acetate can be used for mineralocorticoid supplementation. The starting dose of fludrocortisone is 0.02 mg/kg/day orally, divided into 2 doses.^2,4 Electrolytes should be monitored weekly until stable within normal range, and the dose can be adjusted by 0.05-0.1 mg/kg/day as needed.² Fludrocortisone has glucocorticoid properties, therefore only about 50% of dogs treated with this medication will also require prednisone, though both should be started as initial management.^2,5 The prednisone dose can then be tapered to the minimum dose necessary to prevent symptoms while controlling side effects.²

DOCP is a long-acting mineralocorticoid supplement with no glucocorticoid activity. Traditionally, the starting dose has been 2.2 mg/kg subcutaneously or intramuscularly every 25-30 days (most commonly), but more recent studies have demonstrated that low-dose DOCP (1.1-1.5 mg/kg every 28-30 days) is safe and effective for most dogs.^{16, 17}

After initiation of treatment with DOCP, electrolyte levels should ideally be rechecked at weeks 2, 3, and 4 to determine the duration of action, dose, and dosing interval.^2,5 For both therapies, once an appropriate dose (and dosing interval for DOCP) has been established, electrolytes should be checked every 3-6 months indefinitely. ²

Prognosis

Prognosis for hypoadrenocorticism is excellent with prompt treatment of the initial crisis and early diagnosis.^2,4 Addisonian patients can have a normal quality of life and life expectancy, and most die of unrelated causes.²

References

1. Guzmán Ramos PJ, Bennaim M, Shiel RE, Mooney CT. Diagnosis of canine spontaneous hypoadrenocorticism. Canine Med Genet. 2022;9(1):6. Published 2022 May 3. doi:10.1186/s40575-022-00119-4
2. Van Lanen K, Sande A. Canine hypoadrenocorticism: pathogenesis, diagnosis, and treatment. Top Companion Anim Med. 2014;29(4):88-95. doi:10.1053/j.tcam.2014.10.001
3. Keich WLR, Smith C, New J. Canine hypoadrenocorticism (Addison´s disease). Compend Cont Educ Pract Vet. 1998;20(8):921-35.
4. Hess RS. Hypoadrenocorticism. In: Cote E, Ettinger SJ, Feldman EC, eds. Ettinger’s Textbook of Veterinary Internal Medicine. Ninth ed. Philadelphia: Elsevier; 2024: 2036-2045.
5. Scott-Moncrieff JC. Hypoadrenocorticism. In: Feldman EC, Nelson, RW, Reusch CE, Scott-Moncrieff JC, Behrend, EN, eds. Canine and Feline Endocrinology and Reproduction. 4th ed. St. Louis: Elsevier: 2015: 485-520.
6. Peterson ME, Kintzer PP. Hypoadrenocorticism. In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy. XIV ed. St. Louis: Elsevier; 2009: 231–235.
7. Peterson ME, Kintzer PP, Kass PH. Pretreatment clinical and laboratory findings in dogs with hypoadrenocorticism: 225 cases (1979-1993). J Am Vet Med Assoc. 1996;208(1):85-91.
8. Oberbauer AM, Benemann KS, Belanger JM, Wagner DR, Ward JH, Famula TR. Inheritance of hypoadrenocorticism in bearded collies. Am J Vet Res. 2002;63(5):643-647. doi:10.2460/ajvr.2002.63.643
9. Famula TR, Belanger JM, Oberbauer AM. Heritability and complex segregation analysis of hypoadrenocorticism in the standard poodle. J Small Anim Pract. 2003;44(1):8-12. doi:10.1111/j.1748-5827.2003.tb00096.x
10. Hughes AM, Nelson RW, Famula TR, Bannasch DL. Clinical features and heritability of hypoadrenocorticism in Nova Scotia Duck Tolling Retrievers: 25 cases (1994-2006). J Am Vet Med Assoc. 2007;231(3):407-412. doi:10.2460/javma.231.3.407
11. Glebocka MJ, Boag A. Hypoadrenocorticism in cats: a 40-year update. J Feline Med Surg. 2024;26(9):1098612X241248381. doi:10.1177/1098612X241248381
12. Lennon EM, Boyle TE, Hutchins RG, et al. Use of basal serum or plasma cortisol concentrations to rule out a diagnosis of hypoadrenocorticism in dogs: 123 cases (2000-2005). J Am Vet Med Assoc. 2007;231(3):413-416. doi:10.2460/javma.231.3.413
13. Bovens C, Tennant K, Reeve J, Murphy KF. Basal serum cortisol concentration as a screening test for hypoadrenocorticism in dogs. J Vet Intern Med. 2014;28(5):1541-1545. doi:10.1111/jvim.12415
14. Gold AJ, Langlois DK, Refsal KR. Evaluation of Basal Serum or Plasma Cortisol Concentrations for the Diagnosis of Hypoadrenocorticism in Dogs. J Vet Intern Med. 2016;30(6):1798-1805. doi:10.1111/jvim.14589
15. Botsford A, Behrend EN, Kemppainen RJ, Gaillard PR, Oprandy F, Lee HP. Low-dose ACTH stimulation testing in dogs suspected of hypoadrenocorticism. J Vet Intern Med. 2018;32(6):1886-1890. doi:10.1111/jvim.15256
16. Vincent AM, Okonkowski LK, Brudvig JM, et al. Low-dose desoxycorticosterone pivalate treatment of hypoadrenocorticism in dogs: A randomized controlled clinical trial. J Vet Intern Med. 2021;35(4):1720-1728. doi:10.1111/jvim.16195
17. 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