Atypical Addison's Disease

Atypical Addison's disease (AAD) is a variant of primary hypoadrenocorticism in dogs characterized by glucocorticoid deficiency in the absence of mineralocorticoid deficiency. Unlike classic Addison's disease, which involves destruction of the entire adrenal cortex leading to deficiencies of both cortisol and aldosterone, AAD results from selective destruction of the zona fasciculata and zona reticularis, sparing the zona glomerulosa. Consequently, affected dogs exhibit clinical signs attributable to cortisol deficiency (e.g., lethargy, anorexia, vomiting, diarrhea, weight loss) but maintain normal or near-normal serum electrolyte concentrations (sodium, potassium) and do not develop hyperkalemia or hyponatremia. The condition is also referred to as 'glucocorticoid-deficient hypoadrenocorticism' or 'cortisol-deficient Addison's disease'. It is important to distinguish AAD from secondary hypoadrenocorticism (due to pituitary ACTH deficiency), which also presents with isolated cortisol deficiency but is characterized by low endogenous ACTH concentrations, whereas AAD typically has elevated endogenous ACTH due to lack of negative feedback. AAD is a diagnosis of exclusion, requiring demonstration of a subnormal cortisol response to exogenous ACTH stimulation in a dog with compatible clinical signs and normal electrolytes. Early recognition is critical because affected dogs may progress to classic Addison's disease if the autoimmune destruction extends to the zona glomerulosa. The disease is most commonly reported in dogs, with rare cases in cats. AAD represents a diagnostic challenge because clinical signs are nonspecific and often mimic gastrointestinal, renal, or other endocrine disorders. The condition is managed with glucocorticoid replacement therapy, and prognosis is generally good with appropriate treatment.

The most common cause of AAD is immune-mediated destruction of the adrenal cortex, specifically targeting the cortisol-producing zones (zona fasciculata and zona reticularis) while sparing the aldosterone-producing zona glomerulosa. This selective destruction is thought to be mediated by autoreactive T lymphocytes and autoantibodies against steroidogenic enzymes, such as 21-hydroxylase, which are more highly expressed in the cortisol-producing zones. The exact trigger for this autoimmune response remains unknown, but genetic predisposition is suspected, with certain breeds (e.g., Standard Poodles, Bearded Collies, Portuguese Water Dogs, West Highland White Terriers) showing increased risk. Other less common etiologies include granulomatous diseases (e.g., histoplasmosis, blastomycosis), neoplastic infiltration (e.g., lymphoma, metastatic carcinoma), iatrogenic causes (e.g., bilateral adrenalectomy, mitotane or trilostane overdose), and vascular insults (e.g., adrenal infarction). In some cases, the cause is idiopathic. In cats, AAD is extremely rare but may occur secondary to immune-mediated destruction or neoplasia. Infectious causes are more common in endemic areas. Toxic causes, such as ketoconazole or mitotane, can selectively inhibit cortisol synthesis, but these typically cause more generalized adrenocortical dysfunction. Genetic mutations in genes encoding steroidogenic enzymes have been identified in rare familial forms of hypoadrenocorticism, but these usually result in classic disease. The autoimmune process may be triggered by environmental factors, such as viral infections or stress, but no specific trigger has been confirmed.

Atypical Addison's disease is a rare condition, with an estimated prevalence of less than 0.5% in the general canine population. It accounts for approximately 10-20% of all cases of primary hypoadrenocorticism in dogs. The disease is most commonly diagnosed in young to middle-aged dogs, with a median age of 4-6 years. There is a female predominance, with females affected approximately 1.5-2 times more often than males. Certain breeds are overrepresented, including Standard Poodles, Bearded Collies, Portuguese Water Dogs, West Highland White Terriers, Great Danes, and Leonbergers. These breeds may have a genetic predisposition, and a heritable component has been suggested in some breeds. AAD is rare in cats, with only isolated case reports. No geographic or seasonal predilection has been identified, although infectious causes may be more common in endemic regions. The condition is often underdiagnosed because clinical signs are vague and may be mistaken for gastrointestinal or renal disease. Early diagnosis is important to prevent progression to classic Addison's disease, which can be life-threatening. The incidence of AAD may be increasing as awareness and diagnostic testing improve.

In AAD, the autoimmune destruction of the adrenal cortex is limited to the zona fasciculata and zona reticularis, which are responsible for cortisol and androgens, respectively. The zona glomerulosa, which produces aldosterone, is spared. This selective destruction is likely due to differential expression of autoantigens, such as 21-hydroxylase, which is present in higher concentrations in the cortisol-producing zones. The immune-mediated attack leads to progressive loss of cortisol production, resulting in decreased negative feedback on the hypothalamus and pituitary, leading to increased secretion of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH). Elevated ACTH levels may cause hyperplasia of the remaining adrenal cortex, but cortisol production remains inadequate. The deficiency of cortisol leads to a variety of systemic effects: decreased gluconeogenesis, increased insulin sensitivity, reduced glycogen stores, and impaired response to stress. Cortisol also plays a role in maintaining vascular tone and cardiac contractility, and its deficiency can lead to hypotension and decreased cardiac output. Additionally, cortisol has anti-inflammatory properties, and its absence can result in an exaggerated inflammatory response. Unlike classic Addison's disease, aldosterone production is preserved, so electrolyte balance and extracellular fluid volume are maintained. However, some dogs with AAD may have subtle abnormalities in electrolyte concentrations that are within the reference range but may become more pronounced during stress or illness. The lack of mineralocorticoid deficiency means that hyperkalemia and hyponatremia are not present, which distinguishes AAD from classic Addison's disease. The clinical signs of AAD are primarily due to glucocorticoid deficiency and include lethargy, weakness, anorexia, vomiting, diarrhea, and weight loss. These signs are often intermittent and may be triggered by stress or intercurrent illness. If left untreated, AAD can progress to classic Addison's disease if the autoimmune process extends to the zona glomerulosa, leading to aldosterone deficiency and potentially life-threatening electrolyte disturbances.

Genetic predisposition is the most significant risk factor for AAD. Breeds such as Standard Poodles, Bearded Collies, Portuguese Water Dogs, West Highland White Terriers, and Great Danes have a higher incidence, suggesting an inherited component. A familial pattern has been observed in some breeds, and specific major histocompatibility complex (MHC) haplotypes have been associated with increased risk. Age is a predisposing factor, with young to middle-aged dogs (2-6 years) most commonly affected. Female dogs are at higher risk than males. Concurrent autoimmune diseases, such as hypothyroidism, diabetes mellitus, or immune-mediated hemolytic anemia, may increase the risk of developing AAD due to a shared autoimmune predisposition. Environmental factors, such as stress, infection, or trauma, may precipitate clinical signs in dogs with subclinical adrenal insufficiency. Iatrogenic causes, such as prior treatment with mitotane or trilostane for hyperadrenocorticism, can lead to selective cortisol deficiency if the zona glomerulosa is relatively spared. However, these drugs typically cause more generalized adrenocortical necrosis. In cats, AAD is extremely rare, and predisposing factors are poorly defined. Overall, the most important predisposing factor is breed-related genetic susceptibility.

Clinical signs of AAD are typically chronic and intermittent, reflecting the gradual loss of cortisol production. Common signs include lethargy, weakness, anorexia, vomiting, diarrhea, and weight loss. These signs may wax and wane and are often exacerbated by stress, such as boarding, surgery, or intercurrent illness. Some dogs may exhibit polyuria and polydipsia, although this is less common than in classic Addison's disease. Physical examination findings are often nonspecific and may include dehydration, poor body condition, and mild depression. In contrast to classic Addison's disease, dogs with AAD do not typically present with bradycardia, weak pulses, or signs of hypovolemic shock, because aldosterone production is preserved and electrolyte balance is maintained. However, in severe cases or during an addisonian crisis, hypotension and collapse can occur due to cortisol deficiency alone, although this is rare. Some dogs may have gastrointestinal signs that mimic inflammatory bowel disease or foreign body obstruction. Chronic weight loss and poor appetite may be the only signs in some cases. In cats, signs are similar but may include lethargy, anorexia, and weight loss. It is important to note that clinical signs of AAD are indistinguishable from many other diseases, and a high index of suspicion is required for diagnosis.

The differential diagnoses for AAD include: 1) Classic Addison's disease (hypoadrenocorticism with mineralocorticoid deficiency) - distinguished by the presence of hyperkalemia and hyponatremia, and a low aldosterone concentration. 2) Secondary hypoadrenocorticism (pituitary ACTH deficiency) - distinguished by low endogenous ACTH concentration, whereas AAD has elevated ACTH. 3) Gastrointestinal diseases such as inflammatory bowel disease, foreign body, or gastroenteritis - may cause similar clinical signs but are differentiated by lack of response to ACTH stimulation test and normal cortisol. 4) Renal disease (chronic kidney disease, pyelonephritis) - may cause polyuria, polydipsia, and weight loss, but renal parameters (creatinine, SDMA) are typically elevated, and cortisol response is normal. 5) Hepatic disease (portosystemic shunt, chronic hepatitis) - may cause vomiting, diarrhea, and weight loss, but liver enzymes and bile acids are abnormal, and cortisol response is normal. 6) Diabetes mellitus - may cause polyuria, polydipsia, and weight loss, but hyperglycemia and glucosuria are present, and cortisol response is normal. 7) Hypothyroidism - may cause lethargy and weight gain, but cortisol response is normal. 8) Neoplasia (lymphoma, other malignancies) - may cause weight loss and lethargy, but diagnostic imaging and biopsy are needed, and cortisol response is normal. 9) Toxin exposure (e.g., chocolate, grapes) - may cause gastrointestinal signs, but history and toxicology testing are helpful. 10) Parasitic infections (e.g., whipworms) - may cause diarrhea and weight loss, but fecal examination is positive, and cortisol response is normal. The ACTH stimulation test is the gold standard to differentiate AAD from these conditions.

The diagnostic algorithm for AAD begins with a thorough history and physical examination, with particular attention to signalment (young to middle-aged, female, predisposed breeds) and clinical signs (chronic intermittent gastrointestinal signs, lethargy, weight loss). Baseline laboratory tests, including complete blood count (CBC), serum biochemistry profile, and urinalysis, should be performed. In AAD, these may be normal or show mild abnormalities such as lymphocytosis, eosinophilia, or mild anemia. Electrolytes are typically normal, which is a key distinguishing feature from classic Addison's disease. If clinical suspicion remains high, the next step is to measure baseline serum cortisol concentration. A low baseline cortisol (<2 μg/dL) is suggestive but not diagnostic. The definitive diagnostic test is the ACTH stimulation test: administer 5 μg/kg of synthetic ACTH (cosyntropin) intravenously, and measure serum cortisol before and 30-60 minutes after injection. In AAD, the post-ACTH cortisol concentration is <2 μg/dL (or <5 μg/dL in some laboratories), indicating an inadequate adrenal response. If the ACTH stimulation test is consistent with hypoadrenocorticism, the next step is to differentiate AAD from secondary hypoadrenocorticism by measuring endogenous ACTH concentration. In AAD, endogenous ACTH is elevated (>500 pg/mL), whereas in secondary hypoadrenocorticism it is low or undetectable. Additionally, measurement of serum aldosterone concentration before and after ACTH stimulation can help confirm mineralocorticoid reserve: in AAD, aldosterone response is normal or exaggerated, whereas in classic Addison's disease it is blunted. Imaging (abdominal ultrasound) may be performed to assess adrenal gland size; in AAD, the adrenal glands may be small or normal, but this is not diagnostic. In some cases, a therapeutic trial with glucocorticoid replacement may be considered if the diagnosis is uncertain, but this should be done cautiously. The diagnostic algorithm should also include screening for concurrent autoimmune diseases, such as thyroid function testing.

In AAD, the CBC may show mild nonregenerative anemia, lymphocytosis, and eosinophilia, which are classic but not specific findings in glucocorticoid deficiency. The serum biochemistry profile is typically unremarkable, with normal sodium and potassium concentrations, which is the hallmark of AAD. However, some dogs may have mild hyponatremia or hyperkalemia that is within the reference range but may become more pronounced during stress. Blood urea nitrogen (BUN) and creatinine are usually normal, unless dehydration is present. Blood glucose may be normal or mildly decreased. Urinalysis is typically normal, with urine specific gravity appropriate for hydration status. Baseline serum cortisol concentration is usually low (<2 μg/dL), but this is not diagnostic. The ACTH stimulation test is the gold standard: post-ACTH cortisol <2 μg/dL (or <5 μg/dL in some labs) confirms hypoadrenocorticism. Endogenous ACTH concentration is elevated (>500 pg/mL) in AAD, distinguishing it from secondary hypoadrenocorticism. Serum aldosterone concentration, measured before and after ACTH stimulation, is normal or increased in AAD, confirming mineralocorticoid reserve. Other biomarkers, such as plasma renin activity, may be normal or elevated. In some cases, measurement of adrenal autoantibodies (e.g., anti-21-hydroxylase) may be available, but this is not widely used. Electrolyte ratios (Na:K) are typically normal (>27). Blood gas analysis may show mild metabolic acidosis or alkalosis, but this is not consistent. Overall, the key laboratory finding is a subnormal cortisol response to ACTH with normal electrolytes.

Imaging findings in AAD are often unremarkable. Abdominal radiography may show no abnormalities, although in some cases, the adrenal glands may be small or mineralized. Thoracic radiography is typically normal. Abdominal ultrasonography is the most useful imaging modality for evaluating the adrenal glands. In AAD, the adrenal glands may be small (hypoplastic) or normal in size. In some cases, they may be asymmetrical. The adrenal glands may be difficult to visualize if they are severely atrophied. Ultrasonography can also help rule out other causes of clinical signs, such as gastrointestinal or renal disease. Computed tomography (CT) or magnetic resonance imaging (MRI) is rarely needed but may be used to evaluate the adrenal glands in detail, especially if neoplasia is suspected. In cases of secondary hypoadrenocorticism, the pituitary gland may be abnormal on MRI, but this is not a feature of AAD. Imaging is not diagnostic for AAD but can support the diagnosis and rule out other conditions.

Cytology and histopathology are not typically used for the diagnosis of AAD, as the diagnosis is based on endocrine testing. However, if adrenal tissue is obtained via fine-needle aspiration or biopsy, it may show lymphocytic infiltration and destruction of the zona fasciculata and zona reticularis, with relative sparing of the zona glomerulosa. Histopathology may reveal atrophy of the cortisol-producing zones, with fibrosis and lymphocytic infiltration. Immunohistochemistry may demonstrate the presence of T lymphocytes and autoantibodies. In cases of infectious or neoplastic causes, the underlying etiology may be identified. However, adrenal biopsy is rarely performed due to the risk of complications and the availability of noninvasive diagnostic tests. In research settings, histopathology has been used to characterize the autoimmune process, but it is not part of the routine diagnostic workup.

The treatment of AAD involves lifelong glucocorticoid replacement therapy. The goal is to provide adequate cortisol to maintain normal physiological function and prevent clinical signs, while avoiding the adverse effects of glucocorticoid excess. The most commonly used glucocorticoid is prednisone or prednisolone, administered at a starting dose of 0.2-0.5 mg/kg/day orally, divided every 12 hours. The dose is then titrated to the lowest effective dose based on clinical response and resolution of signs. Some dogs may require higher doses during periods of stress, such as surgery, illness, or travel. In these situations, a 'stress dose' of glucocorticoids is recommended, typically 2-4 times the maintenance dose, or parenteral dexamethasone (0.1-0.2 mg/kg IV) or prednisolone sodium succinate (1-2 mg/kg IV) for severe stress. Hydrocortisone is another option, but it has mineralocorticoid activity and may be less desirable in AAD. Mineralocorticoid replacement is not necessary in AAD, as aldosterone production is preserved. However, some dogs may develop mineralocorticoid deficiency over time, so electrolytes should be monitored periodically. In the event of an addisonian crisis (which is rare in AAD but possible), aggressive fluid therapy with 0.9% sodium chloride, intravenous glucocorticoids (dexamethasone 0.1-0.2 mg/kg IV), and supportive care are indicated. Dietary management is not specific, but a high-quality diet is recommended. Owner education is crucial to ensure compliance and recognition of signs of stress. The prognosis is good with appropriate treatment, and most dogs live a normal lifespan.

The prognosis for AAD is generally excellent with appropriate glucocorticoid replacement therapy. Most dogs respond well to treatment and have a normal quality of life and lifespan. The clinical signs resolve within days to weeks of initiating therapy. However, the prognosis depends on early diagnosis and consistent treatment. If left untreated, AAD can progress to classic Addison's disease, which is more serious and can be life-threatening. The risk of progression is estimated to be 10-20% over time. Dogs that develop concurrent autoimmune diseases may have a more guarded prognosis. The prognosis is also influenced by the underlying cause; if AAD is secondary to neoplasia or infection, the prognosis is poorer. Overall, with proper management, the long-term prognosis is good, and most dogs require lifelong medication but can lead normal lives.

Follow-up for AAD involves regular monitoring of clinical signs and serum electrolyte concentrations. Initially, re-evaluation should occur 1-2 weeks after starting treatment to assess response and adjust the glucocorticoid dose. Thereafter, re-checks are recommended every 3-6 months. At each visit, a thorough physical examination, body weight, and serum biochemistry profile (including electrolytes) should be performed. The owner should be educated to monitor for signs of glucocorticoid excess (e.g., polyuria, polydipsia, panting, weight gain) or deficiency (e.g., lethargy, vomiting, diarrhea). If the dog experiences a stressful event, the owner should be instructed to increase the glucocorticoid dose temporarily. Periodic measurement of endogenous ACTH or cortisol may be performed to ensure adequate suppression, but this is not routinely necessary. If the dog develops electrolyte abnormalities, mineralocorticoid replacement may be needed. Long-term monitoring for the development of other autoimmune diseases is also recommended. The follow-up schedule should be individualized based on the dog's clinical status and owner compliance.

Pearls: 1) Atypical Addison's disease should be suspected in any young to middle-aged dog with chronic intermittent gastrointestinal signs, especially if there is a history of stress-related episodes. 2) Normal electrolytes do not rule out hypoadrenocorticism; always consider AAD. 3) The ACTH stimulation test is the gold standard for diagnosis; a post-ACTH cortisol <2 μg/dL confirms the diagnosis. 4) Endogenous ACTH measurement is essential to differentiate AAD from secondary hypoadrenocorticism. 5) Glucocorticoid replacement should be started at a low dose and titrated to the lowest effective dose. 6) Stress doses of glucocorticoids are critical during illness or surgery. Pitfalls: 1) Failing to perform an ACTH stimulation test in a dog with normal electrolytes but suggestive clinical signs can lead to misdiagnosis. 2) Using a high dose of glucocorticoids initially can cause iatrogenic Cushing's syndrome. 3) Not increasing the glucocorticoid dose during stress can precipitate an addisonian crisis. 4) Assuming that AAD will not progress to classic Addison's disease; electrolytes should be monitored periodically. 5) Overlooking concurrent autoimmune diseases, which are common in these dogs.

Based on Plumb's Veterinary Drug Handbook, the following protocols are recommended for AAD: 1) Prednisone or prednisolone: Initial dose 0.2-0.5 mg/kg/day PO divided q12h. Maintenance dose is typically 0.1-0.2 mg/kg/day PO divided q12h or given once daily. For stress, increase to 2-4 times the maintenance dose for 2-3 days. 2) Dexamethasone: For emergency use, 0.1-0.2 mg/kg IV once, then taper. 3) Hydrocortisone: 0.5-1 mg/kg/day PO divided q12h, but it has mineralocorticoid activity and may cause electrolyte imbalances. 4) For addisonian crisis: IV fluids (0.9% NaCl) at shock doses (90 ml/kg/hr for dogs, 60 ml/kg/hr for cats) initially, then maintenance. Dexamethasone 0.1-0.2 mg/kg IV once, then prednisone as above. 5) Mineralocorticoid replacement is not needed in AAD, but if the dog progresses to classic Addison's disease, desoxycorticosterone pivalate (DOCP) at 2.2 mg/kg SC every 25 days or fludrocortisone acetate at 0.01-0.02 mg/kg/day PO divided q12h may be used. 6) In cases of iatrogenic AAD due to mitotane or trilostane, discontinue the offending drug and provide glucocorticoid support. 7) For infectious causes, treat the underlying infection. 8) For neoplastic causes, consider surgery or chemotherapy. 9) Always adjust doses for hepatic or renal impairment; prednisone requires hepatic conversion to prednisolone, so prednisolone may be preferred in liver disease. 10) Monitor for drug interactions; glucocorticoids may interact with NSAIDs, phenobarbital, and insulin.

The literature on AAD is limited, but several key studies have contributed to our understanding. A landmark study by Peterson et al. (1996) described the clinical and laboratory features of dogs with glucocorticoid-deficient hypoadrenocorticism, highlighting the presence of normal electrolytes in a subset of dogs. A more recent study by Lathan et al. (2014) evaluated the prevalence of AAD in dogs with hypoadrenocorticism and found that approximately 10-20% of cases were atypical. The ACVIM consensus statement on hypoadrenocorticism (2016) provides guidelines for diagnosis and management, emphasizing the importance of ACTH stimulation testing and endogenous ACTH measurement. Studies have also investigated the genetic basis of the disease, with a heritable component identified in Standard Poodles and Bearded Collies. Research on autoantibodies, such as anti-21-hydroxylase, has shown promise for diagnosis and understanding the pathogenesis. A study by Boag et al. (2015) found that dogs with AAD have elevated endogenous ACTH concentrations, confirming the primary nature of the disease. Treatment protocols are largely based on expert opinion and extrapolation from classic Addison's disease, as no randomized controlled trials have been conducted specifically for AAD. However, the use of prednisone at low doses is well-established. Overall, the evidence supports the recognition of AAD as a distinct entity that requires a high index of suspicion for diagnosis and careful long-term management.