Taking a closer look at atypical Addison's

The West Highland white terrier is one of the breeds genetically predisposed to Addison's disease (HOC). Photo courtesy Samantha Ashenhurst. Dogs with “classic” hypoadrenocorticism (HOC), aka Addison’s disease, manifest clinical signs reflecting deficiencies in both cortisol and aldosterone. These patients are relatively easily identified, often based on predictable electrolyte derangements. However, we are now increasingly recognizing a subset of dogs with hypoadrenocorticism, but normal electrolytes.1-3 Clinical signs in these patients reflect hypocortisolemia only, and are often subtler and more insidious. This condition is referred to as glucocorticoid deficient HOC (GDHOC) or “atypical” Addison’s/hypoadrenocorticism (AHOC). Adrenal gland physiology The adrenal gland consists of a capsule, an outer cortex, and an inner medulla. The cortex is subdivided into three sections, based primarily on physiologic function. These sections are the zona glomerulosa, the zona fasciculate, and the zona reticularis; they secrete mineralocorticoids (aldosterone), glucocorticoids (cortisol) and sex hormones (androgens and estrogens), respectively. The functions of the adrenal gland are complex, and various hormonal influences play an important role in releasing various steroid hormones. Adrenocorticotrophic hormone (ACTH) is needed for the synthesis of glucocorticoids, whilst angiotensin II is the primary trigger for the release of aldosterone. Hyperkalemia also triggers aldosterone release, while the natriuretic peptides suppress its release. There are two main mechanisms for spontaneous adrenal insufficiency, i.e. HOC. The most important is the primary type, in which a pathological process (most often, an immune-mediated attack) results in destruction of the adrenal cortex. Over 90 percent of the tissue must be lost before clinical signs are noted.4 In some patients, the attack may be initially directed against the zona fasciculata; the glomerulosa is spared and the ability to secrete aldosterone is preserved. However, a study of dogs with all forms of HOC indicated that many dogs with so-called AHOC and normal serum electrolytes had substantially subnormal or even undetectable aldosterone production.5 It is unclear how these dogs manage to maintain normal electrolyte levels; clearly, other mechanism must play a key role in this process. Secondary HOC is rare, but describes patients with pituitary dysfunction and compromised ACTH release.4 In this disorder, the adrenal glands are not directly injured and continue to make mineralocorticoids. Patients with AHOC may have primary or secondary HOC. They can be reliably categorized by measurement of endogenous ACTH concentrations; dogs with primary HOC have high levels and those with secondary HOC have subnormal concentrations.4 Clinical signs and findings AHOC can affect any age or breed of dog, but the classic signalment is a middle-aged female. Certain breeds (e.g. Portuguese water dog, West Highland white terrier, standard poodle) are genetically predisposed to HOC.4 Cortisol is a remarkably important hormone: it influences most body systems and has a profound effect on many metabolic processes. Glucocorticoid receptors are expressed by most tissues, and the full effects of cortisol are still incompletely understood. Under normal circumstances, secretion is increased at times of physical or psychological stress, in response to increased corticotropin releasing hormone from the hypothalamus and the subsequent release of ACTH from the pituitary. Adequate amounts of cortisol are needed for gluconeogenesis, smooth muscle function, gastrointestinal (GI) health, hepatic function (including albumin synthesis) and adequate food intake. The signs of hypocortisolemia are vague and nonspecific, which is why so many patients with AHOC are initially misdiagnosed. In addition, the manifestations often wax and wane, and owners may report periods of apparent improvement. The most prevalent complaints include hyporexia or complete anorexia, along with changes in stool consistency. Some patients will vomit or manifest abdominal discomfort. Lethargy and depression are also frequently noted. More severe signs are occasionally reported. Hypoglycemia may result in exercise-induced collapse or seizures; a reversible megaesophagus may cause regurgitation; gastrointestinal hemorrhage with melena and hematemesis may occur (Figure 1). Figure 1: Gastroscopic image of a 6-year-old terrier-mix evaluated for lethargy, hyporexia and diarrhea; serum electrolytes were within reference ranges. Fresh hemorrhage can be seen associated with a mucosal defect within the antrum of the stomach. An ACTH stimulation test confirmed hypoadrenocorticism. Image from author’s collection. The signs of hypocortisolemia are often exacerbated by stressful events, such as boarding, grooming, or surgery. Any patient with an episodic illness which appears to be triggered by stress should be evaluated carefully for AHOC. In addition, dramatic improvements are noted if glucocorticoids are administered, followed by a quick decline when therapy is discontinued. Laboratory evaluation The complete blood count is usually within normal limits. The “normal” CBC is, in fact, a useful clue, as dogs with AHOC are unable to mount a stress response with the expected white cell pattern (i.e. neutrophilia, lymphopenia, monocytosis, eosinopenia). Some patients may be mildly anemic, due to GI loss and depressed erythropoiesis.6,7 A relative eosinophilia (meaning more than 500 eosinophils/µl in a sick dog) is commonly noted and is a very useful flag for HOC. The serum biochemical profile often shows some changes, but they are generally mild. It is often helpful to look back to previous lab work for the patient, as “normal” parameters may still be substantially different. For example, the serum albumin and cholesterol may have dropped 30 percent, but still be within the published ranges. Hypoalbuminemia, hypocholesterolemia, and hypoglycemia are routinely noted in dogs with AHOC, and may cause concerns about hepatic function.3,8 GI hemorrhage is noted in significant proportion of dogs with AHOC and can be severe. This will increase the BUN concentration, as the blood becomes a high protein “meal.” Serum creatinine levels are unchanged, so the BUN:creatinine ratio is often more than 20. Serum electrolytes are within normal limits. The urine analysis is also unremarkable, with evidence of acceptable renal concentrating ability. Imaging studies Megaesophagus is a rare complication of hypocortisolemia, and may be noted on survey radiographic images or identified with a contrast study (Figure 2).9 A skilled ultrasonographer may note small adrenal glands or a change in echogenicity (Figure 3). In one study describing adrenal imaging in 30 dogs with confirmed HOC, a left adrenal gland thickness of <3.2 mm was found to be highly suggestive of the disease.10 Figure 2: Right lateral thoracic radiograph of a 4-year-old female spayed Rottweiler with regurgitation. The patient has been given liquid barium and barium-soaked kibble, both of which are seen within a moderately dilated esophagus. An ACTH stimulation test confirmed hypoadrenocorticism. Image courtesy Texas A&M Diagnostic Imaging Service. Figure 3: Transabdominal ultrasonographic image of the left adrenal gland of a 4-yr old labradoodle with atypical hypoadrenocorticism. The adrenal gland is smaller than expected for a dog of this size, and the caudal pole (highlighted by white arrowheads) is just 2.6 mm. Image courtesy Texas A&M Diagnostic Imaging Service. When to consider AHOC The possibility of AHOC should be considered for every nonspecific GI case, particularly if the initial bloodwork is relatively unexciting or suggests a protein-losing enteropathy (low albumin and cholesterol) or GI bleeding. I screen every “chronic enteropathy” case for AHOC before pursing endoscopy or other more invasive or expensive testing. It is also reasonable to add AHOC to the list of differential diagnoses for dogs with acute hemorrhagic diarrhea syndrome (AHDS; formerly hemorrhagic gastroenteritis) as GI bleeding is often associated with cortisol deficiency and can be substantial. AHOC is also worth considering in dogs with esophageal dysfunction, hypoglycemia, or evidence of hepatic compromise. Diagnosis Patients can be inexpensively screened for AHOC by measuring a resting (baseline) cortisol concentration. This can be added to a standard reference lab serum or plasma biochemical profile at little extra cost. As there is very little peer-reviewed and independently generated data regarding the accuracy of some of the currently available in-house assays for cortisol, it is prudent to submit samples for cortisol determination to a reference laboratory or use a dedicated endocrine platform. Dogs with HOC always have a resting cortisol concentration below 2.0 µg/dL, so the diagnosis can be confidently discounted if the resting cortisol is more than 2.0 µg/dL.11,12 Bear in mind, however, many synthetic glucocorticoids will cross react with standard “cortisol” assays, so the recent administration of a drug such as prednisone will push the baseline cortisol value above this threshold. Although the 2.0 µg/dL value is an extremely sensitive screening test for HOC, it lacks specificity, and well over 20 percent of dogs with nonadrenal disease will fall below this value. Therefore, a low resting cortisol measurement is not enough to diagnose HOC and confirmatory testing is needed. The gold standard test for the diagnosis of HOC is the ACTH stimulation test. A baseline serum sample is collected, and then the patient is injected with a dose of synthetic ACTH. Cosyntropin is recommended at may be given at 5 µg/kg IV or IM, or 1 µg/kg IV.13,14 One vial can be divided aseptically into small aliquots (e.g. 50 µg) and frozen at -20oC in plastic syringes for up to 6 months without appreciable loss of potency (Figure 4). The maximum dose is 250 µg, even in dogs weighing less than 50 kg. A second serum sample is collected 60 minutes later. Figure 4: Aliquots (0.2 ml; 50 µg) of reconstituted Cortrosyn are pulled up into plastic syringes and sealed with sterile cap prior to storage at -20oC for up to 6 months. A small amount of air is included in the syringe to allow for expansion of the liquid during freezing. Image from author’s collection. Patients with healthy adrenal glands will respond robustly, with a post-ACTH stim cortisol concentration more than 5 µg/dL (over 10 µg/dl is generally expected). Most dogs with AHOC have a “flat-line” response, with both pre-and post-cortisol concentrations less than 1.0 µg/dL, and most experts will confidently diagnose HOC if the post-ACTH cortisol is less than 2 µg/dL If a subnormal response is noted (i.e. a post-cortisol that is between 2 and 5 µg/dl), the possibility of iatrogenic HOC should be considered. If this is reliably excluded, it may be worthwhile to consult with a specialist.8 The patient history usually identifies dogs with this disorder, but occasionally topical medications are overlooked and can confuse the issue. We may also see a response like this in dogs with secondary HOC; prolonged ACTH deficiency results in atrophy of the zona fasciculata but some response may occur with exogenous ACTH. Dexamethasone does not cross react with the cortisol assay, so this can be administered without impacting the post-ACTH cortisol measurement (although it will depress the baseline value). Ideally, all short-acting steroids should be withheld for at least 24 hours before any adrenal function tests are performed. In order to differentiate between primary and secondary AHOC, a sample of EDTA plasma can be collected prior to administering cosyntropin for measurement of endogenous ACTH concentrations.4 This hormone is very labile, so careful sample handling (chilled plastic EDTA tubes; spun and the plasma harvested and frozen ASAP) or the use of special EDTA tubes with a preservative (aprotinin; available from most reference labs) is necessary. High endogenous ACTH concentrations indicate primary AHOC, whilst low levels support a diagnosis of secondary. Dogs with primary AHOC can also be diagnosed on the basis of the cortisol: ACTH ratio (CAR). This number is much lower in dogs with HOC than normal dogs.15,16 Measuring this ratio avoids the need to perform an ACTH stimulation test. Bear in mind, this ratio will be normal in that very rare dog with secondary HOC. Therapy Glucocorticoids should be provided as soon as all adrenal testing is completed. If the patient is unwilling to eat, parenteral steroids should be provided. Prednisolone sodium succinate (5 mg/kg IV) is a good choice. Dexamethasone (0.1 – 0.2 mg/kg) is also very acceptable, and is less expensive and more readily available. This dose is equivalent to 10-20 times normal physiologic levels of cortisol, so it is certainly adequate. Some older publications suggest much higher doses of dexamethasone for dogs with HOC, but there is no reason to administer these higher doses, and side effects are more likely. Dexamethasone is particularly tough on the GI tract and high doses may result in substantial ulceration and compromise. As soon as the patient is eating, oral glucocorticoids can be started. In general, it is assumed physiologic replacement doses of prednisone are around 0.1 mg/kg, once daily. This may be more than some giant breeds need. However, patients are under substantial stress at the time of diagnosis, so higher doses (up to 0.5 mg/kg twice daily) are warranted. The dose can then be slowly tapered down over the next two to three weeks to the target physiological dose. Higher doses should be given before, during, and after any perceived stress, such as boarding or surgery. It is really important to give steroids every single day. Additional therapies may be necessary at the time of diagnosis. Fluid support is rarely needed, but may improve well-being in severely compromised patients or those with hypoglycemia. GI protectants and antacids may be necessary, particularly if there is evidence of gastric ulceration. Monitoring It appears most dogs with AHOC are able to maintain normal electrolytes, and less than 20 percent will show signs of aldosterone deficiency, characterized by hyponatremia and hyperkalemia.8 The time taken for electrolyte disorders to manifest is variable, but is usually less than six months following the diagnosis of AHOC. Consequently, regular (quarterly) checks of serum electrolytes and renal parameters are indicated for the first year. If routine lab work shows patterns associated with cortisol excess, such as elevated alkaline phosphatase activity or hypercholesterolemia, the prednisone dose should be reduced. Similarly, excessively dilute urine may be a sign of over supplementation. There is no need to repeat an ACTH stim test in a dog with spontaneous AHOC, as the results will never change. Looking to the future… A team from UC Davis recently reported on the use of machine learning methods to support the diagnosis of HOC. Essentially, a computer was provided with the results of CBC and chemistry profiles for a cohort of dogs with HOC (both classic and atypical) and a cohort in which that disease was suspected, but discounted on the basis of ACTH stimulation testing.2 The machine then created complex algorithms to different the two populations and was then challenged with results from new cases. The model was over 96 percent sensitive and 97 percent specific, and easily outperformed a panel of internists. It is likely this system will be offered commercially in the near future, allowing us to easily screen dogs for HOC on the basis of routine bloodwork alone. Diagnostic pearls Atypical HOC is easily overlooked but most patients do provide us with key clues or hints that should prompt consideration of Addison’s disease. These include: A waxing and waning clinical history Episodes of illness are triggered by stressful events Lack of a stress leukogram: the totally “normal” white blood cell findings are inappropriate in a clinically unwell dog Eosinophil count more than500 µ/L Hypoalbuminemia, hypocholesterolemia, +/- hypoglycemia If atypical Addison’s is a possibility, always run a baseline cortisol. If this is less than 2 µg/dL and a plausible alternative diagnosis has not been established, follow up with an ACTH stimulation test. Audrey Cook, BVM&S, MRCVS, MSc Vet Ed, Dip ACVIM (SAIM), Dip ECVIM (CA), Dip ABVP (feline practice) is professor of Small Animal Internal Medicine at Texas A&M University. She is chief of the Internal Medicine Section, and currently divides her time between the Internal Medicine Service and the Interventional Radiology and Endoscopy Service. References 1. Borin-Crivellenti S, Garabed RB, Moreno-Torres KI, et al. Use of a combination of routine hematologic and biochemical test results in a logistic regression model as a diagnostic aid for the diagnosis of hypoadrenocorticism in dogs. Am J Vet Res. 2017;78:1171-1181. 2. Reagan KL, Reagan BA, Gilor C. Machine learning algorithm as a diagnostic tool for hypoadrenocorticism in dogs. Dom Anim Endo. 2020;72:106396. 3. Thompson AL, Scott-Moncrieff JC, Anderson JD. Comparison of classic hypoadrenocorticism with glucocorticoid-deficient hypoadrenocorticism in dogs: 46 cases (1985-2005). J Am Vet Med Assoc. 2007;230:1190-1194. 4. Kintzer PP, Peterson ME. Primary and secondary canine hypoadrenocorticism. Vet Clin NA Small Anim Pract. 1997;27(2):349-357. 5. Baumstark M, Sieber-Ruchstuhl NS, Muller C, et al. Evaluation of aldosterone concentrations in dogs with hypoadrenocorticism. J Vet Intern Med. 2013;28:154-159. 6. Kintzer PP, Peterson ME. Treatment and long-term follow-up of 205 dogs with hypoadrenocorticism. J Vet Intern Med.1997;11:43-49. 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;208:85-91. 8. Wakayama JA, Furrow E, Merkel LK, Armstrong PJ. A retrospective study of dogs with atypical hypoadrenocorticism: a diagnostic cutoff or continuum? J Small Anim Pract. 2017;58:365-371. 9. Bartges JW, Nielson DL. Reversible megaesophagus associated with atypical primary hypoadrenocorticism in a dog. J Am Vet Med Assoc. 1992;201:889-891. 10. Wenger M, Mueller C, Kook PH, Reusch CE. Ultrasonographic evaluation of adrenal glands in dogs with primary hypoadrenocorticism or mimicking diseases. Vet Rec. 2010;167(6):207-210. 11. Lennon EM, Boyle TE, Hutchins RG, Friedenthal A. 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;231:413-416. 12. 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. 13. Lathan P, Moore GE, Zambon S, Scott‐Moncrieff JC. Use of a low‐dose ACTH stimulation test for diagnosis of hypoadrenocorticism in dogs. J Vet Intern Med. 2008;22(4):1070-1073. 14. Botsford A, Behrend EN, Kemppainen RJ, et al Low‐dose ACTH stimulation testing in dogs suspected of hypoadrenocorticism. J Vet Intern Med. 2018;32(6):1886-1890. 15. Boretti FS, Meyer F, Burkhardt WA, Riond B, et al. Evaluation of the cortisol-to-ACTH ratio in dogs with hypoadrenocorticism, dogs with diseases mimicking hypoadrenocorticism and in healthy dogs. J Vet Intern Med. 2015;29(5):1335-1341. 16. Javadi S, Galac S. Boer P, et al. Aldosterone-to-renin and cortisol-to-adrenocorticotropic hormone ratios in healthy dogs and dogs with primary hypoadrenocorticism. J Vet Intern Med. 2006;20:556-561.

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Taking a closer look at atypical Addison's

How to spot the great pretender

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