P. J. Guzmán Ramos LV, MSc, DVMS, PhD, Dip. ECVIM-CA
A/Prof in Small Animal Medicine
School of Veterinary Medicine
Murdoch University
Canine hypoadrenocorticism is an uncommon endocrinopathy with reported prevalence that ranges from 0.06 per cent to 0.08 per cent1. Primary hypoadrenocorticism (Addison’s disease) is referred to as ‘typical’ when describing glucocorticoid and mineralocorticoid deficiency with hyponatraemia and/or hyperkalaemia. ‘Atypical’ hypoadrenocorticism loosely describes the presence of glucocorticoid deficiency in the absence of the electrolyte changes expected with hypoaldosteronism and can be primary (affecting cortisol production by the adrenal glands) or secondary (affecting ACTH production by the pituitary gland).2 The European Society of Veterinary Endocrinology (ESVE) established project (Agreeing Language In Veterinary Endocrinology (ALIVE)) has suggested that ‘atypical’ disease is better referred to as eunatraemic, eukalaemic hypoadrenocorticism (EEHA; Figure 1).
Historical, clinical and clinicopathological features may immediately raise suspicion for the presence of typical primary hypoadrenocorticism (e.g. hypovolaemic shock in a young, previously well, purebred dog with characteristic electrolyte changes). However, in dogs with less severe illness, including most with EEHA, these features are often non-specific and characterized by a waxing and waning presentation. Dogs with EEHA are often older, and the disease may occur in any breed. Most commonly reported clinical signs are gastrointestinal, including anorexia, regurgitation, vomiting, diarrhoea and weight loss (Figure 2).2 The prominence of gastrointestinal signs is not unexpected because of the physiological role of glucocorticoids in maintenance of gastrointestinal integrity. Dogs with glucocorticoid deficiency alone often remain undiagnosed for longer periods because signs are indistinguishable from primary gastrointestinal disease, and more specific clinical and clinicopathological consequences of mineralocorticoid deficiency are absent.2In view of this, hypoadrenocorticism should be considered a differential in dogs with chronic intermittent gastrointestinal signs. The prevalence of EEHA in dogs with chronic gastrointestinal signs was originally described to be 4 per cent (6/151), greater than the prevalence in the general population.3 However, more recent studies have identified lower prevalences of 0.3 per cent (1/282)4 and 0.9 per cent (1/112)5. The lower suggested prevalence opens discussion about the need for testing for hypoadrenocorticism in all dogs with chronic gastrointestinal signs; although hypoadrenocorticism is unlikely to be present in these dogs, identification of the disease can prevent further unnecessary testing and identify a disease that is readily treatable.
Given the intermittent and poorly specific nature of the clinical signs an index of suspicion is required from veterinarians to test and diagnose EEHA. Main clinicopathological abnormalities that can raise the suspicion for EEHA include the lack of stress leukogram in a dog that is systemically unwell; however, many dogs with primary gastrointestinal disease are not severely ill, and the absence of a stress leukogram is not particularly notable. Lymphocytosis or eosinophilia is reported in only 10 to 20 per cent of cases of hypoadrenocorticism; therefore, most cases would be missed if relying on the presence of these widely recognised albeit uncommon features. Furthermore, eosinophilia is common in dogs with primary gastrointestinal diseases including parasitism and eosinophilic chronic enteropathies. On serum biochemistry, the presence of hypocholesterolaemia (75 per cent in EEHA cases), hypercalcaemia (up to 30 per cent of cases), hypoglycaemia (up to 30 per cent of cases) and/or hypoalbuminaemia (up to 75 per cent in EEHA cases) should also raise the suspicion for EEHA and prompt further testing (Figure 3).2 In particular, hypoadrenocorticism is a major differential for severe hypocholesterolaemia, along with chronic gastrointestinal disease, liver failure and lymphoproliferative disease.
Abdominal imaging via ultrasound is usually part of the investigation of dogs with chronic/intermittent gastrointestinal signs and can provide further insight as to whether adrenocortical function testing is required. One study evaluated the adrenal gland size of 30 dogs with hypoadrenocorticism, 14 healthy dogs and 10 dogs with diseases mimicking hypoadrenocorticism. The study suggested that identifying a left adrenal gland thickness less than 3.2 mm was highly suggestive of hypoadrenocorticism.6 However, caution must be taken due to the small size of this study and the lack of consideration of effects of body size.6-8 Furthermore, a more recent study suggested that higher adrenal gland cut-off values of 3.9 and 4.2 mm be used for the left and right adrenal glands, respectively, in dogs with EEHA.9 However, adrenal glands of greater thickness can be seen in 10-20 per cent of dogs with EEHA.
The gold standard diagnostic test to confirm or exclude hypoadrenocorticism is the ACTH stimulation test. In the absence of recent corticosteroid administration, this test has near perfect sensitivity and specificity. This test has some limitations such as the high cost and intermittent unavailability of synthetic ACTH (Figure 4).
Resting cortisol concentrations <55nmol/L have been described to have a sensitivity of 99.4-100 per cent but regrettably its poor specificity (63.3-78.2 per cent) prevents its use to confirm the diagnosis.10-12 Given its high sensitivity, it can be used as a screening test to rule out hypoadrenocorticism. If EEHA is confirmed, measurement of aldosterone concentrations pre- and post-ACTH could be considered. Aldosterone secretion is reduced or absent in some dogs with reference interval electrolyte concentrations, and presumably these dogs are at higher risk of developing an Addisonian crisis unless appropriately treated. In addition, endogenous ACTH concentrations should be assessed to differentiate between primary and secondary disease. If the latter is confirmed, advanced imaging could be considered to determine the underlying causes., and other pituitary deficiencies could be considered, such as central hypothyroidism.
Upon confirmation of the diagnosis and in the absence of mineralocorticoid deficiency, treatment with physiological dose of corticosteroids should be implemented lifelong.
Summary:
Ideally, and if possible, adrenocortical function testing should be recommended in all dogs with chronic intermittent gastrointestinal signs, but even more if the above clinicopathological and/or abdominal imaging features are identified such as the lack of stress leukogram in a very ill dog, lymphocytosis, eosinophilia, hypercalcaemia, hypocholesterolaemia, hypoglycaemia or hypoalbuminaemia or small adrenal gland size. The test is unlikely to be positive in many cases, especially in the absence of these features, but identifying hypoadrenocorticism would dramatically alter the course of diagnosis and treatment. Failure to exclude EEHA could lead to more invasive diagnostic tests such as endoscopy and intestinal biopsies that could precipitate deterioration and also have a high economic cost. In addition, misdiagnosing EEHA as a chronic enteropathy could lead to inappropriate therapeutic interventions such as the unnecessary use of antimicrobials, excessive dosages of corticosteroids, or administration of other immunosuppressive drugs that can be potentially associated with adverse effects.
References:
1 Hanson, J.M., Tengvall, K., Bonnett, B.N. and Hedhammar, A. (2016), “Naturally Occurring Adrenocortical Insufficiency – An Epidemiological Study Based on a Swedish-Insured Dog Population of 525,028 Dogs”, Journal of Veterinary Internal Medicine, John Wiley & Sons, Ltd, Vol. 30 No. 1, pp. 76–84, doi: 10.1111/JVIM.13815.
2 Guzmán Ramos, P.J., Bennaim, M., Shiel, R.E. and Mooney, C.T. (2022), “Diagnosis of canine spontaneous hypoadrenocorticism”, Canine Medicine and Genetics, Springer Science and Business Media LLC, Vol. 9 No. 1, pp. 1–13, doi: 10.1186/S40575-022-00119-4/TABLES/3.
3 Hauck, C., Schmitz, S.S., Burgener, I.A., Wehner, A., Neiger, R., Kohn, B., Rieker, T., et al. (2020), “Prevalence and characterization of hypoadrenocorticism in dogs with signs of chronic gastrointestinal disease: A multicenter study”, Journal of Veterinary Internal Medicine, John Wiley & Sons, Ltd, Vol. 34 No. 4, pp. 1399–1405, doi: 10.1111/JVIM.15752.
4 Gallego, A.F., Gow, A.G. and Boag, A.M. (2022), “Evaluation of resting cortisol concentration testing in dogs with chronic gastrointestinal signs”, Journal of Veterinary Internal Medicine, John Wiley & Sons, Ltd, Vol. 36 No. 2, pp. 525–531, doi: 10.1111/JVIM.16365.
5 Tardo, A.M., Del Baldo, F., Leal, R.O., Galiazzo, G., Pietra, M., Gaspardo, A. and Fracassi, F. (2024), “Prevalence of eunatremic, eukalemic hypoadrenocorticism in dogs with signs of chronic gastrointestinal disease and risk of misdiagnosis after previous glucocorticoid administration”, Journal of Veterinary Internal Medicine, John Wiley & Sons, Ltd, Vol. 38 No. 1, pp. 93–101, doi: 10.1111/JVIM.16921.
6 Wenger, M., Mueller, C., Kook, P.H. and Reusch, C.E. (2010), “Ultrasonographic evaluation of adrenal glands in dogs with primary hypoadrenocorticism or mimicking diseases”, The Veterinary Record, Vet Rec, Vol. 167 No. 6, pp. 207–210, doi: 10.1136/VR.C4235.
7 Büttelmann, G., Harder, L.K., Nolte, I. and Wefstaedt, P. (2023), “Impact of body weight and sex in selected dog breeds on the canine adrenal gland dimensions measured by computed tomographic imaging”, BMC Veterinary Research, BioMed Central Ltd, Vol. 19 No. 1, pp. 1–11, doi: 10.1186/S12917-023-03641-0/TABLES/5.
8 Soulsby, S.N., Holland, M., Hudson, J.A. and Behrend, E.N. (2015), “ULTRASONOGRAPHIC EVALUATION OF ADRENAL GLAND SIZE COMPARED TO BODY WEIGHT IN NORMAL DOGS”, Veterinary Radiology & Ultrasound, John Wiley & Sons, Ltd, Vol. 56 No. 3, pp. 317–326, doi: 10.1111/VRU.12236.
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10 Bovens, C., Tennant, K., Reeve, J. and Murphy, K.F. (2014), “Basal Serum Cortisol Concentration as a Screening Test for Hypoadrenocorticism in Dogs”, Journal of Veterinary Internal Medicine, John Wiley & Sons, Ltd, Vol. 28 No. 5, pp. 1541–1545, doi: 10.1111/JVIM.12415.
11 Gold, A.J., Langlois, D.K. and Refsal, K.R. (2016), “Evaluation of Basal Serum or Plasma Cortisol Concentrations for the Diagnosis of Hypoadrenocorticism in Dogs”, Journal of Veterinary Internal Medicine, John Wiley & Sons, Ltd, Vol. 30 No. 6, pp. 1798–1805, doi: 10.1111/JVIM.14589.
12 Lennon, E.M., Boyle, T.E., Hutchins, R.G., Friedenthal, A., Correa, M.T., Bissett, S.A., Moses, L.S., et al. (2007), “Use of basal serum or plasma cortisol concentrations to rule out a diagnosis of hypoadrenocorticism in dogs: 123 cases (2000–2005)”, Journal of the American Veterinary Medical Association, American Veterinary Medical Association, Vol. 231 No. 3, pp. 413–416, doi: 10.2460/JAVMA.231.3.413.