Canine hypoadrenocorticism (Addison\u2019s disease) is an endocrine condition caused by a deficiency of glucocorticoids (primarily cortisol), often with a concurrent deficiency in mineralocorticoids (primarily aldosterone). Most resources on hypoadrenocorticism focus on acute management of the addisonian crisis or general principles of diagnosis and treatment. However, long-term management requires careful reassessment of each patient while considering comorbidities and patient variability. This article reviews key concepts in the pathoetiology, diagnosis, and treatment of canine hypoadrenocorticism. A case example is used to illustrate how long-term therapy and monitoring should be adjusted on a case-by-case basis.<\/p>\n
Take-Home Points<\/strong><\/p>\n <\/div><\/div><\/p>\n Hypoadrenocorticism (HOAC; Addison\u2019s disease) is an uncommon endocrine disease of dogs with a prevalence ranging from 0.06% to 0.28%.1-3<\/sup> However, among dogs with chronic gastrointestinal signs, the prevalence has been reported to reach 4%.4<\/sup> With vague clinical signs, nonspecific clinicopathologic changes, and a relatively low disease prevalence, canine HOAC is often referred to as \u201cthe great pretender.\u201d<\/span><\/p>\n The biggest challenge in the diagnosis of HOAC is recognizing when it should be a differential. Once HOAC is suspected, obtaining a definitive diagnosis is relatively straightforward. Although HOAC can be life-threatening, early identification and treatment can result in an overall excellent long-term prognosis.<\/span><\/p>\n Primary HOAC accounts for 95% of canine HOAC cases and is characterized by the loss of functional adrenocortical tissue. In health, the adrenal cortex consists of 3 functionally and morphologically distinct zones: the zona glomerulosa, zona fasciculata, and zona reticularis. Only the zona glomerulosa contains the enzyme aldosterone synthase, meaning it is the sole producer of mineralocorticoids (e.g., aldosterone). The zonae fasciculata and reticularis both synthesize glucocorticoids (e.g., cortisol) and androgens. When 85% to 90% of this functional adrenocortical tissue is destroyed, primary HOAC results.<\/span><\/p>\n Although large studies describing the underlying histopathologic abnormalities in dogs with HOAC are lacking, lymphoplasmacytic inflammation of the adrenal glands caused by an immune-mediated adrenalitis is suspected in most cases.5<\/sup> This immune-mediated etiology is further supported by the presence of autoantibodies in some dogs.6<\/sup> Although thought to be less common than immune-mediated destruction of the adrenal cortex, primary HOAC can also result from infiltrative disease (e.g., neoplasia, granulomatous diseases) or iatrogenically from the administration of drugs used to treat hyperadrenocorticism (e.g., trilostane, mitotane).7<\/sup><\/span><\/p>\n Most dogs with primary HOAC present with hyponatremia and hyperkalemia in conjunction with low cortisol, reflecting deficiencies of both mineralocorticoids and glucocorticoids. However, a small subset of dogs with HOAC present with normal electrolyte levels.8-11<\/sup> Some of these dogs go on to develop electrolyte derangements supportive of mineralocorticoid deficiency, while others maintain normal levels.10,12<\/sup> The latter are referred to as having eunatremic, eukalemic hypoadrenocorticism (EEH), a term that has recently replaced the term \u201catypical\u201d HOAC. Why some dogs with HOAC develop electrolyte changes while others do not is not fully understood. In some dogs with EEH, the zona glomerulosa appears to be spared in the immune-mediated cortical destruction,5<\/sup> while in others, renal compensation is thought to maintain normal electrolytes in the face of subnormal aldosterone concentrations.10<\/sup><\/span><\/p>\n Secondary and tertiary HOAC result from disease of the pituitary gland and hypothalamus, respectively, and are collectively known as central HOAC. The most common cause of secondary HOAC is the sudden cessation of long-term steroid therapy that has resulted in suppression of adrenocorticotropic hormone (ACTH) secretion by the pituitary gland. Spontaneous central HOAC is rare in dogs but can be caused by neoplasia or intracranial trauma.13<\/sup> Given that aldosterone secretion is primarily regulated by circulating potassium and angiotensin II concentrations rather than ACTH, dogs with central HOAC do not have concurrent mineralocorticoid deficiency.14<\/sup><\/span><\/p>\n The median age of diagnosis for dogs with HOAC is 4\u00a0years, although it has been reported in dogs aged 2\u00a0months to 14 years.14<\/sup> Female dogs have a higher risk of developing HOAC than male dogs, with 60% to 70% of HOAC patients being female.1,14<\/sup> Compared with dogs with concurrent mineralocorticoid deficiency, dogs with glucocorticoid deficiency alone (i.e., EEH) are generally older (median age, 6 to 7\u00a0years).8,11<\/sup><\/span><\/p>\n Although HOAC can occur in any breed of dog, a strong heritable component has been identified in standard poodles, Portuguese water dogs, Nova Scotia duck tolling retrievers, and bearded collies.15<\/sup> Great Danes, Rottweilers, West Highland white terriers, and wheaten terriers have been shown to have an increased risk of HOAC, but inheritance has not been proven.16<\/sup><\/span><\/p>\n The clinical presentation of HOAC is highly variable. Some dogs present for acute collapse while others present with a chronic history of intermittent nonspecific signs, such as vomiting, diarrhea, hyporexia, or lethargy. Dogs with HOAC can present with mild, waxing and waning episodes of illness that worsen during times of stress or in a life-threatening state known as an addisonian crisis. The clinical manifestations seen with HOAC are related to deficiencies in glucocorticoids and mineralocorticoids and have been summarized elsewhere.17<\/sup><\/span><\/p>\n HOAC can present in a variety of ways, sometimes with vague, intermittent clinical signs. Consequently, the biggest challenge in diagnosis is recognizing when HOAC should be a differential. <\/span>BOX 1<\/b><\/span> highlights scenarios in which evaluation for HOAC should be considered. The general approach to HOAC diagnosis is provided in <\/span>FIGURE 1<\/b><\/span>.<\/span><\/p>\n When the clinical suspicion of HOAC is not particularly high but it is important to consider HOAC as a possible diagnostic differential before proceeding to other diagnostic tests (e.g., dogs presenting with chronic gastrointestinal signs), a baseline cortisol test should be performed. A baseline cortisol concentration ><\/span>\u2009<\/span>2 \u00b5g\/dL rules out HOAC, with a reported sensitivity of 99.4% to 100%.18-20<\/sup> However, if the baseline cortisol is \u2264<\/span>\u2009<\/span>2 \u00b5g\/dL, an ACTH stimulation test must be performed to definitively rule HOAC in or out.<\/span><\/p>\n In a pooled sample of 190 dogs with HOAC across 3\u00a0studies,18-20<\/sup> all but 1 dog had a baseline cortisol \u2264<\/span>\u2009<\/span>2\u00a0\u00b5g\/dL. Consequently, if the suspicion of HOAC is high in a dog with a baseline cortisol of 2.1 to 3 \u00b5g\/dL, ACTH stimulation could be performed, provided other diagnostic differentials have been considered and the dog has no recent history of glucocorticoid administration.<\/span><\/p>\n Definitive diagnosis of HOAC necessitates demonstration of a diminished cortisol reserve using the ACTH stimulation test (<\/span>TABLE 1<\/b><\/span>). During an ACTH stimulation test, a supraphysiological dose of synthetic ACTH (e.g., cosyntropin) is administered, and the cortisol concentration is measured 1 hour later. A diagnosis of HOAC is defined by a post-ACTH cortisol concentration \u2264<\/span>\u2009<\/span>2 \u00b5g\/dL.16<\/sup> In most dogs with HOAC, both pre- and post-ACTH cortisol concentrations are <<\/span>\u2009<\/span>1 \u00b5g\/dL. As diagnosis is based on the post-ACTH cortisol concentration alone, some clinicians might choose to forgo measurement of pre-ACTH cortisol to reduce expenses.<\/span><\/p>\n Interpreting Equivocal Test Results<\/b><\/p>\n A post-ACTH cortisol concentration ><\/span>\u2009<\/span>2 \u00b5g\/dL but below the accepted cutoff for adequate adrenal reserve (8 \u00b5g\/dL) does not provide a definitive diagnosis of HOAC. Possible explanations for an inadequate response to an ACTH stimulation test include prior glucocorticoid administration; loss of potency of the administered ACTH product (most often due to poor or extended storage); errors in administration or sample collection; and previous treatment with mitotane, trilostane, or ketoconazole.16<\/sup> As HOAC is believed to result from immune-mediated destruction of the adrenal glands, it is possible that dogs early in the disease course may have borderline results, but this is poorly documented. In 1 study, 7 dogs with suspected EEH but equivocal post-ACTH cortisol concentrations were followed for a median of 2 years; ultimately none of them were diagnosed with HOAC.25<\/sup><\/span><\/p>\n If an equivocal ACTH stimulation result is obtained, it is recommended to (1) confirm the dog was not recently exposed to glucocorticoids, (2) ensure the test was appropriately conducted and the cosyntropin properly stored, and (3) consider other differentials. If the clinical suspicion of HOAC remains high, retesting in 1 to 4 weeks can be considered.<\/span><\/p>\n Testing Dogs on Glucocorticoids<\/b><\/p>\n When administration of glucocorticoids is clinically necessary prior to performing the ACTH stimulation test, dexamethasone should be used, as it does not cross-react with the cortisol assay.16<\/sup> However, it should be noted that dexamethasone, like all glucocorticoids, suppresses the hypothalamic-pituitary-adrenal (HPA) axis. In healthy beagles, a single dose of 0.1\u00a0mg\/kg IV dexamethasone decreased cortisol concentrations after ACTH stimulation for up to 3\u00a0days.26<\/sup> Although the response was suppressed, there was still adequate stimulation to exclude a diagnosis of HOAC. Thus, an ACTH stimulation test can be still performed after a single dose of dexamethasone. Longer durations of treatment with dexamethasone prior to testing are likely to result in a false-positive diagnosis of HOAC.<\/span><\/p>\n If a clinician wants to test for HOAC in a dog that is currently on or has recently received glucocorticoids, the glucocorticoids must be tapered off and followed by a 3-week minimum washout period. In a study of 12\u00a0dogs that received oral prednisone (0.55 mg\/kg PO q12h) for 35 days, HPA axis recovery was complete by 2 weeks; however, this study only included healthy male research dogs.27<\/sup> A recent study evaluated the length of time it took the HPA axis to recover (defined as an ACTH-stimulated cortisol concentration ><\/span>\u2009<\/span>6 \u00b5g\/dL) in 20 dogs receiving intermediate-acting steroids for the treatment of various conditions.28<\/sup> Most dogs (17\/20) exhibited HPA axis recovery by 16 to 18 days; however, recovery took over 8 weeks in 2 dogs.28<\/sup> The time to HPA axis recovery was not associated with patient body weight, median daily dose, cumulative dose, maximum dose, or duration of treatment.28<\/sup><\/span><\/p>\n Although the author recommends waiting a minimum of 3 weeks following glucocorticoid discontinuation to evaluate the HPA axis, it should be noted that false-positive results on the ACTH stimulation test are still possible in a small number of patients. In such scenarios, if the ACTH-stimulated cortisol concentration falls between 3 and 8 \u00b5g\/dL and the patient is clinically stable, it is recommended to retest at a later date, as a post-stimulation cortisol value within this range is more suggestive of recent glucocorticoid administration than true HOAC.15<\/sup><\/span><\/p>\n Cost of Testing<\/b><\/p>\n The cost of synthetic cosyntropin has led to investigations into more cost-effective dosing and storage strategies. In 1 study, a 1-\u00b5g\/kg dose of cosyntropin was equivalent to the standard dose of 5\u00a0\u00b5g\/kg for screening dogs with clinical signs of HOAC.23<\/sup> However, it should be noted that only 2 dogs in this study had HOAC. Furthermore, 1 dog had an equivocal ACTH-stimulated cortisol concentration of 3.4 \u00b5g\/dL when 1 \u00b5g\/dL of cosyntropin was used, whereas the ACTH-stimulated cortisol concentration using the standard 5-\u00b5g\/dL dose was 12.3 \u00b5g\/dL, allowing HOAC to be ruled out. Consequently, the author prefers to use the standard cosyntropin dose (5\u00a0\u00b5g\/kg) to avoid gray-zone cases that may cloud interpretation. To save on costs, reconstituted cosyntropin can be stored in plastic syringes (it will bind to glass) and frozen for up to 6 months without losing efficacy.29<\/sup> The author\u2019s institution freezes cosyntropin in 0.2-mL (50-\u00b5g) aliquots so that 1\u00a0aliquot is needed per 10 kg of body weight.<\/span><\/p>\n Mineralocorticoid deficiency is usually inferred from documenting the presence of hyponatremia, hyperkalemia, or both at initial diagnosis. However, it has been shown that sodium and potassium concentrations correlate poorly with aldosterone concentrations.10<\/sup> This lack of correlation and the knowledge that dogs with EEH can go on to develop electrolyte derangements make measuring aldosterone an attractive option.<\/span><\/p>\n Aldosterone secretory capacity can be evaluated by measuring aldosterone concentrations before and 1\u00a0hour after administration of synthetic ACTH.30<\/sup> By definition, it is expected that dogs with typical HOAC will have low baseline and ACTH-stimulated aldosterone concentrations, whereas those with isolated glucocorticoid deficiency (EEH, central HOAC) will have normal aldosterone concentrations.8<\/sup> However, this is not always the case. Some HOAC patients can have electrolyte derangements despite normal aldosterone concentrations, while others maintain electrolyte <\/span>balance despite low plasma aldosterone concentrations.10<\/sup><\/p>\n Whether mineralocorticoid supplementation in dogs with EEH is of benefit remains to be determined. Thus, in dogs with EEH it is reasonable to provide glucocorticoid supplementation alone and monitor electrolytes and clinical signs. However, some clinicians may elect to evaluate ACTH-stimulated aldosterone concentrations in EEH cases and institute mineralocorticoid supplementation when concentrations are low. This practice is unlikely to be harmful but, as yet, has no known benefit.<\/span><\/p>\n In states of aldosterone deficiency, the inability to retain sodium leads to hypovolemia and subsequent renin release. Thus, a low plasma aldosterone concentration in the face of a high plasma renin activity can allow differentiation of primary and secondary HOAC. In humans, renin is also used to evaluate mineralocorticoid dose and is more effective than monitoring electrolytes or blood pressure.31<\/sup> In dogs, plasma renin activity has been shown to be higher in dogs with primary HOAC than in healthy dogs or dogs with diseases mimicking HOAC.32<\/sup> In addition, the aldosterone-to-renin ratio has been shown to be a more sensitive measure of mineralocorticoid deficiency than aldosterone or renin alone, with no observed overlap between healthy dogs and dogs with HOAC.33<\/sup> Unfortunately, measurement of plasma renin activity is currently not commercially available.<\/span><\/p>\n Treatment of HOAC largely depends on patient presentation. Some dogs present in an acute, life-threatening addisonian crisis with severe electrolyte derangements and hypovolemia and require acute stabilization and intensive therapy. Others exhibit chronic, less severe clinical signs. Although many dogs need fluid therapy and supportive care in the acute setting, the mainstay of treatment for all dogs with HOAC is lifelong supplementation of glucocorticoids with or without mineralocorticoid replacement. Acute management of the addisonian crisis has been thoroughly covered elsewhere.15,17<\/sup> Long-term treatment options, including recommended doses and adjustments, are summarized in <\/span>TABLE 2<\/b><\/span>.<\/span><\/p>\n See the <\/span>CASE EXAMPLE<\/b><\/span> sidebar for the 6-year-long management of a female flandoodle with HOAC.<\/span><\/p>\n Diagnosis<\/strong> Initial Treatment<\/strong> Three months after her diagnosis, Hannah developed hyponatremia and hyperkalemia, consistent with typical HOAC. She was started on desoxycorticosterone pivalate (DOCP) at 1.1 mg\/kg SC q25d and did well with this regimen. Given the expense of DOCP and desire for less frequent injections, Hannah\u2019s DOCP protocol was slowly adjusted while monitoring her electrolytes until she was on 0.4 mg\/kg DOCP every 4 weeks.<\/p>\n Treatment for Addisonian Crisis\n
Pathoetiology<\/h2>\n
Signalment<\/h2>\n
Presentation<\/h2>\n
Diagnostic Overview<\/h2>\n
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<\/a><\/p>\nScreening for Hypoadrenocorticism<\/h3>\n
Definitive Diagnosis of Hypoadrenocorticism<\/h3>\n
<\/a><\/p>\nRole of Aldosterone Measurement<\/h3>\n
Potential Role of Renin Activity<\/h3>\n
Therapeutic Approach<\/h2>\n
<\/a><\/p>\n
\nHannah, a 4-year-old female spayed flandoodle, presented to the University of Tennessee College of Veterinary Medicine for evaluation of chronic intermittent hyporexia and vomiting. Initial blood analysis revealed lymphocytosis, hypoalbuminemia, hypocholesterolemia, hyperphosphatemia, hypercalcemia, and mild azotemia (TABLE A)<\/strong>. Sodium and potassium concentrations were normal and fell in the middle of the reference range. Given these findings, Hannah was suspected to have eunatremic, eukalemic hypoadrenocorticism (EEU).<\/p>\n<\/a><\/p>\n
\nA baseline cortisol test was performed, with a result of less than 0.1 \u00b5g\/dL. To confirm hypoadrenocorticism (HOAC), an adrenocorticotropic hormone (ACTH) stimulation test was performed and revealed a subnormal response (post-ACTH cortisol concentration <\u20090.1 \u00b5g\/dL). Although Hannah\u2019s electrolytes were within the normal reference range, her aldosterone concentration was not assessed. EEH was diagnosed.<\/p>\n
\nHannah was started on glucocorticoid replacement only: 0.5 mg\/kg\/day prednisone for the first week of treatment, followed by decrease to a maintenance dose of 0.2 mg\/kg\/day prednisolone with instructions to double the dose during times of anticipated stress or excitement. Hannah\u2019s clinical signs and blood abnormalities resolved on prednisone. Given the potential for EEH to progress to typical HOAC, her electrolytes were monitored.<\/p>\n
\n<\/strong>Hannah did well on this reduced dose of DOCP until she was sedated for routine abdominal imaging 3 years after her diagnosis of HOAC. Following this visit, Hannah developed acute vomiting and profuse hematochezia and presented to the emergency room in hypovolemic shock. She was found to have hyponatremia, hyperkalemia, hypoglycemia, azotemia, hyperphosphatemia, and a mild mixed hepatopathy (TABLE B)<\/strong>. Her DOCP dose was increased to 1.1 mg\/kg SC every 4\u00a0weeks, and she received an anti-inflammatory dose of prednisone (0.5 mg\/kg\/day) for 1 week before returning to her maintenance dose of 0.2 mg\/kg\/day.<\/p>\n