Atypical canine Hypoadreno-corticism

Published 21/06/2023

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Addison’s disease may not be the first diagnosis that comes to mind when a dog with gastrointestinal signs presents, but this possibility should not be dismissed, as Romy Heilmann describes.

Key points

Dogs with typical hypoadrenocorticism usually present with an obvious clinical picture and clinicopathologic findings, and may offer a straightforward diagnosis.

Atypical hypoadrenocorticism is often associated with nonspecific, waxing and waning chronic gastrointestinal signs, which may be triggered or exacerbated by stress and often respond to symptomatic treatment.

Evaluation of dogs with atypical hypoadrenocorticism requires a "detective approach” to the patient in order to arrive at the correct diagnosis.

Both forms of hypoadrenocorticism are generally associated with a very good long-term prognosis.

Introduction

Hypoadrenocorticism in its typical form (Addison’s disease) is often a straightforward diagnosis when the classic signs and clinicopathological changes are obvious and tie in nicely with the patient’s history and signalment – so it may seem odd that a gastroenterologist should need to consider this condition when doing an examination. However, the clinical picture of affected dogs – particularly those with spontaneous atypical hypoadrenocorticism – may be nonspecific. These can include chronic gastrointestinal signs that wax and wane and which can be triggered or exacerbated by stressful events, and often respond to fluid therapy and symptomatic treatment. Thus, hypoadrenocorticism – particularly its atypical form – can mimic primary gastrointestinal diseases and should not be omitted from the differential diagnosis list in dogs presenting with vague and nonspecific gastrointestinal signs.

Some background details

Terminology

Hypoadrenocorticism, or Addison’s disease, develops when the adrenal cortex is unable to produce and release sufficient amounts of endogenous glucocorticoids and – particularly in typical cases – also mineralocorticoids (Figure 1) 1. As opposed to the typical presentation of hypoadrenocorticism, with characteristic clinical and clinicopathological features caused by the concurrent glucocorticoid and mineralocorticoid deficiency, cases of atypical hypoadrenocorticism in dogs are more challenging to diagnose, as this form of adrenal insufficiency is not only less common but also produces a more subtle, non-specific clinical picture 1,2. A transition from atypical to typical hypoadrenocorticism is possible, for which atypical cases should be monitored over time 2. In dogs with the typical presentation, where clinical decompensation with dehydration and hypovolemic shock (Addisonian crisis) can occur, the progression from a sole glucocorticoid deficiency can merely be assumed based on the retrospective impression of a slow onset of the disease and associated clinical signs. However, this progression is difficult to prove in typical cases of hypoadrenocorticism. Breed predispositions are reported in Standard Poodles, Portuguese Water dogs, Nova Scotia Duck-tolling Retrievers, Soft-Coated Wheaten Terriers, and Bearded Collies, but dogs of any breed and age can be affected by either form of this condition 2,3,4,5. Compared to typical cases, dogs with atypical hypoadrenocorticism tend to be older.

Figure 1. Current classification of spontaneous hypoadrenocorticism in dogs.

Etiology

Hypoadrenocorticism can be caused by any condition that decreases hormone production and release from the adrenal cortex. Most commonly it is caused by an immune-mediated process that reduces the functional mass of the hormone-producing adrenal cortex, particularly the middle-to-inner glucocorticoid-producing portion (zona fasciculata) 5,6,7. Other, less common or rare causes of primary hypoadrenocorticism include granulomatous conditions (e.g., fungal disease), vascular causes (e.g., hemorrhage, ischemia), amyloid deposits (particularly in breeds predisposed to develop amyloidosis), necrosis, or metastatic neoplasia 8,9,10. Secondary (central) hypoadrenocorticism can evolve from conditions affecting production and release of hypothalamic corticotropin-releasing hormone (CRH) and/or pituitary adrenocorticotropic hormone (ACTH), including inflammation, infections, trauma, and neoplasia 1,11.

Pathophysiology

In the typical form of hypoadrenocorticism, uncompensated glucocorticoid and mineralocorticoid deficiency result in the characteristic plasma electrolyte shifts (hyperkalemia, hyponatremia) 1. In contrast, in the atypical form, there is either only glucocorticoid deficiency or combined corticosteroid (glucocorticoid and mineralocorticoid) deficiency without electrolyte shifts, due to aldosterone-independent compensatory mechanisms (e.g., renal compensation) 1,2.

Detecting hypoadrenocorticism – the great pretender

Clinical signs

Given the various effects of endogenously released glucocorticoids on the body (Figure 2), including cardiac and gastrointestinal functions 12,13, dogs with atypical hypoadrenocorticism usually present with vague, waxing and waning nonspecific signs such as reduced activity (e.g., during agility performance), lethargy, weakness, inappetence, weight loss or lean body condition (Figure 3), vomiting (with or without hematemesis) or regurgitation, diarrhea (which may be hemorrhagic), abdominal pain, and incontinence 1,2,13,14.

Figure 2. Effects of endogenous glucocorticoids (cortisone) on different body tissues. With glucocorticoid deficiency (hypoadrenocorticism), these effects cannot be mounted whenever there is increased stress (indicated by red arrows), leading to an insufficient stress response (gray arrows).
© Romy Heilmann/redrawn by Sandrine Fontègne

Figure 3. Clinical appearance of a 9½-year-old male Boxer dog with atypical hypoadrenocorticism. The dog presented for further diagnostic evaluation of long-term gastrointestinal signs, with a history of chronic vomiting, hematemesis, intermittent hyporexia, diarrhea, and weight loss (14% over 3 months). Physical examination was unremarkable except for a low body condition score (BCS, 2.5/9).
© Ms Wendler, Bischofswerda, SN, Germany

Laboratory diagnostics

The minimal database should comprise a complete blood count, serum biochemistry and urinalysis (with evaluation of the urine sediment and, if indicated, bacterial culture with antimicrobial susceptibility testing and a urine protein-to-creatine ratio). These may often reveal subtle and non-specific changes in dogs with atypical hypoadrenocorticism. However, a mild non-regenerative anemia is a common finding, as cortisol increases erythropoiesis and decreases erythrocyte turnover, but the absence of an expected stress leukogram (or even opposite trends in individual cell counts, often referred to as “reverse stress leukogram”) may be a subtle indicator, and can be missed if not specifically evaluated (Box 1). Given the opposing effects of glucocorticoids on neutrophil and lymphocyte counts, a neutrophil-to-lymphocyte ratio of ≤ 2.3 should raise a suspicion of hypoadrenocorticism 15.

Box 1. Relevant hematologic findings in a 6-year-old female dog with hypoadrenocorticism. Notice the presence of a “reverse stress leukogram” with mild lymphocytosis, eosinophilia, and a decreased neutrophil-to-lymphocyte ratio (N/L-R) of 1.31. Any N/L-R of ≤ 2.3 should raise a suspicion of hypoadrenocorticism.

Parameter	Result	Unit	Reference interval
Erythrogram
Hematocrit	33.8	%	37.3-61.7
MCV	61.2	fL	61.6-73.5
MCH	22.3	pg	21.2-25.9
Leukogram
Neutrophil count	7.53*	x 10⁹/L	2.95-11.64
Lymphocyte count	5.75*	x 10⁹/L	1.05-5.10
Monocyte count	0.67	x 10⁹/L	0.16-1.12
Eosinophil count	1.25	x 10⁹/L	0.06-1.23
Basophil count	0.07	x 10⁹/L	0.00-0.10
Thrombocytes
Platelet count	368	K/µl	148-484
MPV	9.7	fL	8.7-13.2

*N/L-R = 1.31

Hypoglycemia (or a low-normal blood glucose concentration), hypoalbuminemia, hypocholesterolemia, increased liver enzyme activities (with a hepatocellular pattern of enzyme increase – i.e., serum ALT increased more than ALP increase), and mild to moderate prerenal azotemia may be detected 1. However, distinction from renal azotemia can be challenging, as dogs with hypoadrenocorticism often have reduced urine-concentrating ability (urine specific gravity < 1.030). At best, some or all of these clinicopathologic findings might raise the suspicion of hypoadrenocorticism, or at least should be a reason not to abandon the possibility of the condition being the underlying cause of the clinical presentation prior to evaluating other differential diagnoses (e.g., protein-losing enteropathy, chronic hepatopathy) with a more invasive diagnostic approach and involving general anesthesia. This is important, because stress associated with invasive procedures could potentially place the dog in a life-threatening situation of decompensated hypoadrenocorticism if the condition remains unrecognized. Hyperkalemia and hyponatremia, which are often expressed as a decreased sodium-to-potassium ratio (Na/K < 27), are characteristic findings in the typical form of hypoadrenocorticism, but are absent in the atypical form (Box 2) 4. Digital health tools, particularly algorithms incorporating the results of several routine findings, may help to improve the detection of atypical hypoadrenocorticism cases in the future 16.

Box 2. Serum biochemistry panel with electrolytes from the Boxer dog in Figure 3. Except for mild hypoalbuminemia and low-normal serum cholesterol and glucose concentrations, this dog’s serum biochemistry was unremarkable, and a protein-losing enteropathy was suspected.

Parameter	Result	Unit	Reference interval
Glucose	97	mg/dL	57-126
Cholesterol	167	mg/dL	139-398
SDMA	11	µg/dL	0-14
Creatinine	1.1	mg/dL	0.5-1.5
BUN	21	mg/dL	9-29
Phosphate	1.1	mmol/L	0.9-1.7
Calcium	2.3	mmol/L	2.1-2.9
ALT	72	U/L	25-122
ALP	37	U/L	14-147
Total protein	5.9	g/dL	5.4-7.6
Albumin	2.3	g/dL	2.8-4.3
Bilirubin	0.2	mg/dL	0-0.4
Sodium	145	mmol/L	142-153
Potassium	4.2	mmol/L	3.9-5.8

Endocrine testing

Measurement of the serum baseline cortisol concentration is a useful screening test (Box 3). Using a cut-off baseline of 2 µg/dL (55 nmol/L) excludes a diagnosis (100% sensitivity, 63-78% specificity) of hypoadrenocorticism (Box 4) 17,18. If the baseline is < 2 µg/dL an ACTH stimulation test should be performed to either diagnose or exclude hypoadrenocorticism 1,17,18. With this test, serum cortisol < 2 µg/dL is diagnostic, whilst levels > 6 µg/dL are exclusive. Low-dose ACTH-stimulation testing (using 1 µg/kg of cosyntropin IV instead of the standard dose of 5 µg/kg) is effective in diagnosing hypoadrenocorticism in dogs 19. Measurement of endogenous ACTH (eACTH) concentration can be used to confirm and further classify hypoadrenocorticism as either primary or secondary in nature (Box 5) 1,15. Primary hypoadrenocorticism (i.e., adrenal origin) is associated with a normal or high eACTH concentration, whilst secondary hypoadrenocorticism (i.e., central origin involving the hypothalamus and/or pituitary gland) is associated with an undetectable or low eACTH concentration.

Box 3. The thyroid and gastrointestinal panel from the Boxer dog with atypical hypoadrenocorticism in Figure 3. Low total and free thyroxine concentration, hypercobalaminemia (without prior supplementation), and hypocortisolemia (below the cut-off concentration of 55 nmol/L used for the screening for hypoadrenocorticism) are detected. These results should be followed with an ACTH stimulation test.

Parameter	Result	Unit	Reference interval
Thyroid panel
Total T₄	0.8	µg/dL	1.0-4.0
Free T₄	< 0.3	ng/dL	0.6-3.7
Gastrointestinal panel
Spec cPL	142	µg/dL	0-200
cTLI	37	µg/dL	8.5-35
Cobalamin	1 355	pmol/L	173-599
Folate	25.9	nmol/L	21.1-54
Cortisol (baseline)	6.5	nmol/L	25-125

Box 4. Diagnostic algorithm for endocrine testing in dogs with suspected hypoadrenocorticism. The flow chart shows the suggested diagnostic screening for hypoadrenocorticism (left-hand panels) if the clinical suspicion for this condition is moderate or low. Correct interpretation of the confirmatory diagnostic test (right-hand panels), which is performed if the clinical suspicion for the disease is moderate to high, requires any prior treatment that could interfere with the results (*e.g.*, glucocorticoids (including topical) treatment, azole antifungal drugs) within 4 weeks of the test to be excluded. Most dogs with hypoadrenocorticism will have a baseline and post-ACTH serum cortisol concentration below 2 µg/dL (55 nmol/L). ACTH-stimulated serum cortisol concentrations > 2 µg/dL (> 55 nmol/L) but < 6 µg/dL (< 165 nmol/L) are equivocal and reflect some adrenal reserve capacity, and potential causes for adrenal suppression should be explored.

Box 5. Diagnostic algorithm for further evaluation of the adrenal hormone status in dogs with atypical hypoadrenocorticism. If the ACTH stimulation test confirms a diagnosis of hypoadrenocorticism, particularly if the ACTH-stimulated serum cortisol concentration is < 2 µg/dL, endogenous ACTH (eACTH) concentration can be measured to differentiate primary (adrenal) from secondary (central) hypoadrenocorticism. The absence of any electrolyte changes, plus pre- and post-ACTH stimulated serum aldosterone measurement, can distinguish atypical hypoadrenocorticism cases with glucocorticoid deficiency only from those dogs with concurrent (compensated) mineralocorticoid insufficiency or deficiency. Mineralocorticoid deficiency is presumed and usually not confirmed by serum aldosterone measurement in dogs with typical hypoadrenocorticism (confirmed hyperkalemia and/or hyponatremia).

The urine cortisol-to-creatinine ratio (UCCR) has recently received attention for the diagnosis of canine hypoadrenocorticism, and a low UCCR (≤ 2 measured by radioimmunoassay or ≤ 10 by chemiluminescent immunoassay) was highly sensitive and specific to distinguish affected dogs from those with a disease mimicking hypoadrenocorticism 20.

Mineralocorticoid deficiency without hyperkalemia and/or hyponatremia, presumed to be primarily compensated via renal mechanisms, can be detected by measuring serum aldosterone pre- and post-ACTH stimulation (Box 6). This test can help differentiate atypical hypoadrenocorticism cases with glucocorticoid deficiency only from dogs with combined corticosteroid deficiency but without electrolyte changes 21. Thyroid profiles in dogs with hypoadrenocorticism may reveal increased serum TSH levels and, in some cases, decreased thyroxine levels (Box 3); these do not reflect true hypothyroidism and levels will normalize within weeks (up to 4 months) after starting treatment of hypoadrenocorticism 22.

Box 6. Pre- and post-ACTH stimulated serum cortisol and aldosterone levels from the Boxer dog in Figure 3. Neither serum cortisol nor aldosterone concentration increased after ACTH stimulation, confirming both glucocorticoid and (compensated) mineralocorticoid deficiency in this dog.

Parameter	Result	Unit	Reference interval
ACTH stimulation test (serum cortisol)
Cortisol (baseline)	< 2.8	nmol/L	25-125
Cortisol (post-ACTH)	< 2.8	nmol/L	> 165
ACTH stimulation test (serum aldosterone)
Aldosterone (baseline)	< 20	pmol/L	0-393
Aldosterone (post-ACTH)	< 20	pmol/L	82-859

Diagnostic imaging

Thoracic and abdominal radiographs are usually unrewarding in dogs with hypoadrenocorticism, unless evaluating for the presence of hypoadrenocorticism-associated megaesophagus, but may be considered to rule out some differential diagnoses. Abdominal ultrasonography, including a thorough evaluation of both adrenal glands, is often also unremarkable but may suggest hypoadrenocorticism if the adrenal gland diameter is small (Figure 4). Ultrasound is also recommended in suspected cases to diagnose or rule out adrenal neoplasia, infarction, or hemorrhage 1.

Figure 4. A sonographic image of the left adrenal gland in a dog with hypoadrenocorticism; note the decreased adrenal size (dorsoventral diameter 2.6 mm). Generally, a maximum dorsoventral dimension (adrenal gland thickness) of < 2.8 mm for the left adrenal gland suggests hypoadrenocorticism, but the dog’s body weight must also be considered.
© Texas A&M University

Treating atypical hypoadrenocorticism

Treatment initiation

Dogs with atypical hypoadrenocorticism are typically clinically stable and can be treated on an outpatient basis. However, evidence of dehydration during the physical examination warrants at least a short period of in-patient care with fluid replacement therapy (using a balanced electrolyte solution) and additional symptomatic treatment (e.g., antiemetic and gastroprotective drugs) as indicated. Hypoglycemia should be corrected by IV glucose administration (dextrose solution), and blood glucose should be monitored.

Prednisolone (or prednisone) is the drug of choice to replace endogenous glucocorticoid deficiency 1,2,3. Fast-acting glucocorticoids (i.e., dexamethasone, hydrocortisone) are more commonly used for acute glucocorticoid replacement therapy in patients with an Addisonian crisis. Prednisone or prednisolone is initially administered at a low anti-inflammatory dose (0.3-0.5 mg/kg PO q12-24h) for a few days 1,2. This short induction phase is followed by gradually reducing the dose to the lowest possible (“physiological”) level that still effectively treats the endogenous glucocorticoid deficiency without causing overt side effects, and continuing it as maintenance therapy. Finding the optimal dose for an individual dog will require some time (and patience from the owner), but is usually between 0.05-0.2 mg/kg PO q24h depending on the size and age of the dog (Box 7). Depending on the character and temperament of the dog, a short-term increase in the prednisone/prednisolone maintenance dose may be considered during periods of anticipated stress 1,2.

Box 7. Recommended adjustments in the glucocorticoid dose based on clinical signs and suspicion of underdosing or over-supplementation.

• Noticeable glucocorticoid side effects
→ dose reduction (by approx. 10-25%)

• Recurrence of clinical signs (lethargy, anorexia, diarrhea)
→ dose increase (by approx. 50%)

• Anticipated significant stress (e.g., agility trial, holiday fireworks, elective surgery)
→ consider briefly increasing the dose (by approx. 100-200%) in individual dogs

Mineralocorticoid replacement therapy is indicated in typical hypoadrenocorticism cases (i.e., dogs presenting with electrolyte changes reflecting concurrent mineralocorticoid deficiency) but should be carefully considered in dogs diagnosed with atypical hypoadrenocorticism depending on the endogenous mineralocorticoid status. If serum aldosterone concentrations are low or undetectable, the serum electrolytes should be closely monitored. Alternatively, low-dose mineralocorticoid supplementation (desoxycorticosterone pivalate at an initial dose of 1.5 mg/kg SC q25-28d) 23 may be considered. While this, at least in theory, can relieve the mechanisms compensating for (measured) mineralocorticoid deficiency, long-term mineralocorticoid replacement therapy also requires careful monitoring of the patient (serum electrolytes, systemic blood pressure) and may carry the risk of potential adverse effects 24. Dogs diagnosed with atypical hypoadrenocorticism having a normal baseline and/or ACTH-stimulated serum aldosterone concentrations require only glucocorticoid substitution, but serum electrolytes should be monitored regularly in these dogs.

Treatment monitoring

Glucocorticoid side effects (e.g., polydipsia/polyuria, polyphagia, weight gain, lean muscle loss, panting, skin and coat changes, behavioral changes) may still occur with very low prednisone/prednisolone doses, and require a dose reduction by approximately 10-15% (Box 7). Whether hydrocortisone may be a good alternative choice for glucocorticoid supplementation in some dogs requires further investigation. Lethargy, weakness, hyporexia or anorexia, vomiting, and diarrhea can indicate suboptimal glucocorticoid substitution in dogs with hypoadrenocorticism and will require a dose increase of approximately 50% 1,2,3.

Dogs with atypical hypoadrenocorticism receiving mineralocorticoid substitution should initially be rechecked every 2-4 weeks (usually 10-14 days and again 25-28 days after starting supplementation with desoxycorticosterone pivalate) 23. If serum electrolyte (sodium and potassium) concentrations are within the target ranges, systemic blood pressure is normal, and the dose of desoxycorticosterone has not been recently adjusted, treatment monitoring is recommended to be continued every 1-3 months (depending on whether the owner can administer the mineralocorticoid injections at home) and in well-controlled dogs, every 3-6 months (unless monthly injection of desoxycorticosterone has to be performed at the veterinary clinic). Detection of hypokalemia, hypernatremia, or systemic hypertension (systolic blood pressure > 140 mmHg) requires the dose of desoxycorticosterone pivalate to be reduced by approximately 10-20%, or at least temporarily discontinued 23. Careful evaluation of any potential side effects of treatment is warranted in dogs with hypoadrenocorticism. Polyuria and polydipsia, which are typically interpreted as a side effect of predniso(lo)ne (over)supplementation, can also reflect mineralocorticoid (i.e., desoxycorticosterone) overdose 1,23.

Dogs diagnosed with atypical hypoadrenocorticism having a normal baseline and/or ACTH-stimulated serum aldosterone concentrations require only glucocorticoid substitution, but serum electrolytes should be monitored regularly in these dogs.

Romy M. Heilmann

Prognosis for hypoadrenocorticism cases

With adequate glucocorticoid and, if indicated or elected, mineralocorticoid supplementation and follow-up evaluation of the patient at regular intervals, atypical hypoadrenocorticism usually carries a very good long-term prognosis (Figure 5) 1,2,25. Monitoring for the progression to typical hypoadrenocorticism (i.e., development of hyperkalemia and/or hyponatremia) is an important aspect in the long-term management of dogs with atypical hypoadrenocorticism receiving glucocorticoid monotherapy 2,21. The author recommends serum electrolyte rechecks in these cases every 3-6 months, but guidelines about the frequency of monitoring or the initiation of mineralocorticoid supplementation in dogs with aldosterone deficiency without any electrolyte changes are currently lacking.

Figure 5. The Boxer dog with atypical hypoadrenocorticism in Figure 3 after 6 months of glucocorticoid replacement therapy. Serum electrolyte levels remained stable, and the dog had returned to normal activity and body condition (BCS 5-6/9). Vomiting and hematemesis ceased shortly after initiation of treatment.
© Ms Wendler, Bischofswerda, SN, Germany

Conclusion

Owners will often retrospectively recognize the slow onset of hypoadrenocorticism and its related subtle clinical changes when their pet shows a rapid improvement and better quality of life in response to treatment. The disease requires life-long therapy and management, and this is often perceived as increasing the pet-human bond, but some owners fear the development of an Addisonian crisis and are reluctant to leave the dog unsupervised. However, most owners are very comfortable managing a dog that has any form of spontaneous hypoadrenocorticism at home and know or soon learn what to observe for quality-of-life changes that require further veterinary care.

References

Kalenyak K, Heilmann RM. Canine hypoadrenocorticism – an update on pathogenesis, diagnosis and treatment. Tierarztl Prax. Ausg. K. Kleintiere Heimtiere 2018;46(3):163-175.
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.
Schofield I, Woolhead V, Johnson A, et al. Hypoadrenocorticism in dogs under UK primary veterinary care: frequency, clinical approaches and risk factors. J. Small Anim. Pract. 2021;62(5):343-350.
Gershony LC, Belanger JM, Hytönen MK, et al. Genetic characterization of Addison’s disease in Bearded Collies. BMC Genomics 2020;21(1):833.
Treeful AE, Rendahl AK, Friedenberg SG. DLA class II haplotypes show sex-specific associations with primary hypoadrenocorticism in Standard Poodle dogs. Immunogenetics 2019;71(5-6):373-382.
Boag AM, Short A, Kennedy LJ, et al. Polymorphisms in the CTLA4 promotor sequence are associated with canine hypoadrenocorticism. Canine Med. Genet. 2020;7:2.
Boag AM, Christie MR, McLaughlin KA, et al. Autoantibodies against cytochrome P450 side-chain cleavage enzyme in dogs (Canis lupus familiaris) affected with hypoadrenocorticism (Addison’s disease). PLoS One 2015;10(11):e0143458.
Labelle P, DeCock HEV. Metastatic tumors to the adrenal glands in domestic animals. Vet. Pathol. 2005;42:52-58.
Buckley ME, Chapman PS, Walsh A. Glucocorticoid-deficient hypoadrenocorticism secondary to intravascular lymphoma in the adrenal glands of a dog. Aust. Vet. J. 2017;95(3):64-67.
Lee N, Choi J, Yoon J. Presumptive nontraumatic adrenal hemorrhage preceding hypoadrenocorticism in a dog. J. Vet. Intern. Med. 2022;DOI: 10.1111/jvim.16531.
Polledo L, Oliveira M, Adamany J, et al. Hypophysitis, panhypopituitarism, and hypothalamitis in a Scottish Terrier dog. J. Vet. Intern. Med. 2017;31(5):1527-1532.
Gunasekaran T, Sanders RA. Ventricular systolic dysfunction in dogs diagnosed with hypoadrenocorticism. J. Vet. Cardiol. 2022;41:231-235.
Hauck C, Schmitz SS, Burgener IA, et al. Prevalence and characterization of hypoadrenocorticism in dogs with signs of chronic gastrointestinal disease: a multicenter study. J. Vet. Intern. Med. 2020;34(4):1399-1405.
Gallego AF, Gow AG, Boag AM. Evaluation of resting cortisol concentration testing in dogs with chronic gastrointestinal signs. J. Vet. Intern. Med. 2022;36(2):525-531.
Zeugswetter FK, Schwendenwein I. Diagnostic efficacy of the leukogram and the chemiluminometric ACTH measurement to diagnose canine hypoadrenocorticism. Tierarztl. Prax. Ausg. K. Kleintiere Heimtiere 2014;42(2):223-230.
Reagan KL, Reagan BA, Gilor C. Machine learning algorithm as a diagnostic tool for hypoadrenocorticism in dogs. Domest. Anim. Endocrinol. 2020;72:106396.
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.
Bovens C, Tennant K, Reeve J, et al. Basal serum cortisol concentration as a screening test for hypoadrenocorticism in dogs. J. Vet. Intern. Med. 2014;28(5):1541-1545.
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.
Moya MV, Refsal KR, Langlois DK. Investigation of the urine cortisol to creatinine ratio for the diagnosis of hypoadrenocorticism in dogs. J. Am. Vet. Med. Assoc. 2022;260(9):1041-1047.
Baumstark ME, Sieber-Ruckstuhl NS, Müller C, et al. Evaluation of aldosterone concentrations in dogs with hypoadrenocorticism. J. Vet. Intern. Med. 2014;28(1):154-159.
Reusch CE, Fracassi F, Sieber-Ruckstuhl NS, et al. Altered serum thyrotropin concentrations in dogs with primary hypoadrenocorticism before and during treatment. J. Vet. Intern. Med. 2017;31(6):1643-1648.
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.
Casado Diaz JI, Sieber-Ruckstuhl NS, Boretti FS, et al. Evaluation of symmetric dimethylarginine and creatinine in dogs with primary hypoadrenocorticism receiving long-term mineralocorticoid replacement therapy. Vet. Rec. 2022;190(1):e242.
Hupfeld J, Dölle M, Volk H, et al. Effect of long-term management of hypoadrenocorticism on the quality of life of affected dogs and their owners. Vet. Rec. 2022;8:e1977.

Romy M. Heilmann

Professor Heilmann is an ACVIM- and ECVIM-boarded certified small animal internist, with a special interest in gastroenterology, hepatology, clinical immunology, and interventional radiology and endoscopy Read more