Hypoadrenocorticism

Hypoadrenocorticism, commonly known as Addison's disease, is an endocrine disorder characterized by deficient production of glucocorticoids and/or mineralocorticoids from the adrenal cortex. In dogs, primary hypoadrenocorticism (spontaneous, immune-mediated destruction of the adrenal cortex) accounts for the vast majority of cases, leading to deficiencies in both cortisol and aldosterone. Secondary hypoadrenocorticism results from impaired pituitary adrenocorticotropic hormone (ACTH) secretion, causing glucocorticoid deficiency with preserved mineralocorticoid function. Atypical hypoadrenocorticism refers to glucocorticoid deficiency alone, often with normal electrolyte concentrations. The disease can manifest as a peracute, acute, or chronic condition, with clinical signs ranging from vague lethargy to life-threatening addisonian crisis (hypovolemic shock, bradycardia, hyperkalemia, and hyponatremia).

Primary hypoadrenocorticism is most commonly immune-mediated, with lymphocytic infiltration and destruction of the adrenal cortex. Other causes include granulomatous disease (histoplasmosis, blastomycosis), neoplastic infiltration (lymphoma, metastatic carcinoma), infarction, hemorrhage, amyloidosis, and iatrogenic causes such as mitotane (o,p'-DDD) or trilostane overdose in the treatment of hyperadrenocorticism. Secondary hypoadrenocorticism arises from pituitary destruction (neoplasia, inflammation, trauma) or iatrogenic suppression of the hypothalamic-pituitary-adrenal axis due to chronic exogenous glucocorticoid administration. In rare cases, congenital adrenal hypoplasia or enzyme deficiencies (e.g., 21-hydroxylase deficiency) may be identified.

Hypoadrenocorticism is most commonly diagnosed in dogs, with a reported prevalence of 0.06% to 0.28% in the general canine population. It is rare in cats, with fewer than 40 cases reported. Young to middle-aged female dogs are overrepresented, with a median age of 4 years (range 2 months to 12 years). Breeds with a genetic predisposition include the Standard Poodle, Portuguese Water Dog, Bearded Collie, West Highland White Terrier, Great Dane, and Leonberger. In Standard Poodles and Portuguese Water Dogs, an autosomal recessive mode of inheritance has been suggested. No clear geographic or seasonal pattern has been established, though some studies suggest a higher incidence in temperate climates.

In primary hypoadrenocorticism, immune-mediated destruction of the adrenal cortex leads to progressive loss of glucocorticoid (cortisol) and mineralocorticoid (aldosterone) production. Cortisol deficiency results in decreased gluconeogenesis, reduced stress response, and impaired vascular tone, contributing to hypotension and hypoglycemia. Aldosterone deficiency causes decreased renal sodium reabsorption and potassium excretion, leading to hyponatremia, hyperkalemia, and hypovolemia. The loss of sodium and water leads to decreased extracellular fluid volume, reduced cardiac output, and prerenal azotemia. Hyperkalemia can cause bradycardia and cardiac arrhythmias. In secondary hypoadrenocorticism, cortisol deficiency occurs without aldosterone deficiency, so electrolyte disturbances are typically absent. The lack of negative feedback on the pituitary results in elevated ACTH levels in primary disease, whereas ACTH levels are low in secondary disease.

Intrinsic risk factors include genetic susceptibility (breed predisposition), immune-mediated diseases (e.g., hypothyroidism, diabetes mellitus), and age (young to middle-aged). Extrinsic factors include chronic glucocorticoid therapy (iatrogenic secondary hypoadrenocorticism), administration of mitotane or trilostane for hyperadrenocorticism, and concurrent infections or stress that may precipitate an addisonian crisis. Stressful events such as surgery, trauma, or intercurrent illness can unmask latent hypoadrenocorticism.

Clinical signs vary depending on the chronicity and degree of hormone deficiency. In chronic hypoadrenocorticism, signs are often vague and intermittent, including lethargy, weakness, anorexia, vomiting, diarrhea, weight loss, and polyuria/polydipsia. Physical examination may reveal poor body condition, dehydration, weak pulse, and slow capillary refill time. In acute addisonian crisis, patients present with severe depression, collapse, hypothermia, bradycardia, weak femoral pulses, and signs of hypovolemic shock. Gastrointestinal signs such as hematemesis or melena may occur. In secondary hypoadrenocorticism, hyperkalemia and hyponatremia are absent, and signs are primarily related to glucocorticoid deficiency (lethargy, weakness, anorexia).

Differential diagnoses include: (1) Acute gastroenteritis (viral, bacterial, parasitic) – typically no electrolyte abnormalities, but may have prerenal azotemia; (2) Renal failure (acute or chronic) – hyperkalemia and hyponatremia may occur, but cortisol/ACTH stimulation test is normal; (3) Severe hepatic disease – may cause hypoglycemia and gastrointestinal signs, but electrolyte changes are unusual; (4) Pancreatitis – vomiting, abdominal pain, but no characteristic electrolyte pattern; (5) Septic shock – hypotension, but often fever and leukocytosis; (6) Cardiac disease (e.g., bradyarrhythmias) – may cause weakness, but no electrolyte disturbances; (7) Toxin exposure (e.g., ethylene glycol, lily toxicity in cats) – may cause acute kidney injury and electrolyte imbalances; (8) Hypothyroidism – lethargy and weight gain, but no electrolyte abnormalities; (9) Gastrointestinal obstruction – vomiting and dehydration, but no hyperkalemia unless severe; (10) Drug-induced hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors) – history of drug administration.

The diagnostic approach begins with a thorough history and physical examination. If hypoadrenocorticism is suspected, baseline laboratory tests (CBC, serum biochemistry, urinalysis) are performed. Classic findings include hyponatremia, hyperkalemia, and a sodium-to-potassium ratio < 27:1 (normal > 27:1). However, normal electrolytes do not rule out the disease, especially in atypical cases. The gold standard for diagnosis is the ACTH stimulation test: baseline cortisol is measured, then 5 mcg/kg (dogs) or 125 mcg (cats) of synthetic ACTH (cosyntropin) is administered intravenously, and a post-ACTH cortisol is measured 30-60 minutes later. A post-ACTH cortisol concentration < 2 mcg/dL (55 nmol/L) confirms hypoadrenocorticism. If baseline cortisol is > 2 mcg/dL, the disease is unlikely. Additional tests include measurement of endogenous ACTH concentration to differentiate primary (high ACTH) from secondary (low ACTH) disease. In atypical cases, aldosterone levels and electrolyte monitoring may be helpful. Imaging (abdominal ultrasound) may reveal small adrenal glands in primary disease, but is not diagnostic.

Hematology: Normocytic, normochromic anemia may be present due to chronic disease or gastrointestinal bleeding. Eosinophilia and lymphocytosis are classic but not consistent findings. Serum biochemistry: Hyponatremia (Na < 140 mEq/L), hyperkalemia (K > 5.5 mEq/L), Na:K ratio < 27:1, azotemia (BUN and creatinine elevated due to prerenal causes), hypoglycemia (in some cases), hypercalcemia (in up to 30% of dogs), and metabolic acidosis. Urinalysis: Typically isosthenuria (USG 1.008-1.012) due to medullary washout, but may be concentrated if dehydration is severe. Blood gas analysis: Metabolic acidosis may be present. Specific biomarkers: Baseline cortisol < 2 mcg/dL is highly suggestive; post-ACTH cortisol < 2 mcg/dL is diagnostic. Endogenous ACTH concentration: Elevated in primary disease (> 500 pg/mL), low or normal in secondary disease. Aldosterone concentration: Low in primary disease.

Radiography: Thoracic radiographs may show microcardia (due to hypovolemia), and abdominal radiographs may reveal small liver and spleen. Ultrasonography: Abdominal ultrasound may show bilaterally small adrenal glands (< 5 mm in diameter) in primary hypoadrenocorticism, but normal-sized adrenals do not rule out the disease. In secondary hypoadrenocorticism, adrenal glands may be normal or small. Computed tomography (CT) and magnetic resonance imaging (MRI) are rarely needed but may be used to evaluate the pituitary or adrenal glands in suspected secondary disease or adrenal neoplasia. Echocardiography is not routinely performed but may be indicated if cardiac arrhythmias are severe.

Cytology: Fine-needle aspiration of the adrenal glands is not routinely recommended due to risk of hemorrhage and low diagnostic yield. Histopathology: In primary immune-mediated hypoadrenocorticism, the adrenal cortex shows lymphocytic infiltration, atrophy, and fibrosis. In granulomatous disease, granulomas with fungal organisms may be seen. In secondary disease, the adrenal cortex is atrophied but not inflamed. Histopathology is rarely performed antemortem, as diagnosis is typically made based on endocrine testing.

Emergency stabilization of addisonian crisis: (1) Intravenous fluid therapy with 0.9% sodium chloride (NaCl) at a rate of 60-90 mL/kg/hour for the first hour, then adjusted based on hydration status and urine output. (2) Correct hyperkalemia if life-threatening (ECG changes or K > 7.0 mEq/L): administer 10% calcium gluconate at 0.5-1.0 mL/kg IV over 10-20 minutes, regular insulin at 0.1 U/kg IV with dextrose (2 g per unit of insulin), and sodium bicarbonate (1-2 mEq/kg IV) if severe acidosis. (3) Administer glucocorticoids: dexamethasone sodium phosphate at 0.1-0.2 mg/kg IV, or prednisolone sodium succinate at 2-4 mg/kg IV. (4) Once stabilized, initiate maintenance therapy: mineralocorticoid replacement with desoxycorticosterone pivalate (DOCP) at 2.2 mg/kg IM or SC every 25 days, or fludrocortisone acetate at 0.01-0.02 mg/kg/day PO. Glucocorticoid replacement: prednisone at 0.1-0.2 mg/kg/day PO, tapering to the lowest effective dose. In secondary hypoadrenocorticism, only glucocorticoid replacement is needed. Dietary management: Provide a balanced diet, avoid high-potassium foods, and ensure adequate sodium intake. Monitor for signs of over-replacement (polyuria, polydipsia, hypertension) or under-replacement (lethargy, vomiting).

With appropriate treatment, the prognosis for hypoadrenocorticism is excellent. Most dogs live a normal lifespan with good quality of life. The median survival time in dogs is > 4 years. Negative prognostic indicators include severe hyperkalemia at presentation, concurrent diseases, and delayed diagnosis. In cats, the prognosis is also good with treatment, but the disease is rare. Long-term complications may include iatrogenic hyperadrenocorticism due to over-replacement, urinary tract infections, and hypothyroidism (in dogs with concurrent immune-mediated diseases).

Initial follow-up: Recheck electrolytes (sodium, potassium) and clinical signs 1-2 weeks after starting mineralocorticoid therapy, then every 2-4 weeks until stable. Once stable, recheck electrolytes every 3-6 months. For DOCP, adjust dose based on electrolyte concentrations at the end of the dosing interval. For fludrocortisone, monitor electrolytes every 1-2 weeks initially, then every 3-6 months. Monitor for signs of glucocorticoid over- or under-replacement. In dogs with secondary hypoadrenocorticism, monitor for development of other endocrine deficiencies (e.g., hypothyroidism). Periodic ACTH stimulation tests are not necessary for monitoring, but may be used to assess cortisol levels if needed.

Pearls: (1) Always consider hypoadrenocorticism in any dog with vague gastrointestinal signs and weakness, especially if there is a history of stress or steroid use. (2) The Na:K ratio is a useful screening tool, but a normal ratio does not rule out the disease. (3) Baseline cortisol < 2 mcg/dL is highly suggestive; if > 2 mcg/dL, the disease is unlikely. (4) In addisonian crisis, administer 0.9% NaCl aggressively, as it helps correct both hyponatremia and hyperkalemia. (5) DOCP is the preferred mineralocorticoid in dogs due to its long duration of action. Pitfalls: (1) Do not delay treatment while waiting for ACTH stimulation test results; if the patient is unstable, treat empirically with dexamethasone (which does not interfere with cortisol assays). (2) Avoid using prednisone in the emergency setting, as it may interfere with cortisol measurements. (3) Do not use potassium-containing fluids (e.g., Lactated Ringer's) in hyperkalemic patients. (4) Be cautious with insulin and bicarbonate therapy in hyperkalemia, as they can cause hypoglycemia and metabolic alkalosis. (5) In cats, fludrocortisone is often preferred over DOCP due to ease of administration.

Emergency: Dexamethasone sodium phosphate: 0.1-0.2 mg/kg IV bolus, then 0.05-0.1 mg/kg IV q6-8h until stable. Prednisolone sodium succinate: 2-4 mg/kg IV, then 1-2 mg/kg IV q6-8h. Maintenance: Desoxycorticosterone pivalate (DOCP): 2.2 mg/kg IM or SC every 25 days (range 1.5-2.5 mg/kg). Fludrocortisone acetate: 0.01-0.02 mg/kg/day PO, divided q12h (typical starting dose 0.02 mg/kg/day). Prednisone: 0.1-0.2 mg/kg/day PO, tapering to 0.05-0.1 mg/kg every other day. For hyperkalemia: Calcium gluconate 10%: 0.5-1.0 mL/kg IV over 10-20 minutes with ECG monitoring. Regular insulin: 0.1 U/kg IV, followed by dextrose 2 g per unit of insulin (e.g., 2 mL/kg of 50% dextrose diluted). Sodium bicarbonate: 1-2 mEq/kg IV over 15-30 minutes if pH < 7.1. Contraindications: Avoid potassium-sparing diuretics and ACE inhibitors in patients with hypoadrenocorticism. Drug interactions: Glucocorticoids may antagonize the effects of insulin and oral hypoglycemics.

Key studies include: (1) A retrospective study by Peterson et al. (1996) evaluating 225 dogs with hypoadrenocorticism, which found that the most common clinical signs were lethargy, vomiting, and anorexia, and that the Na:K ratio was < 27:1 in 90% of cases. (2) A study by Kintzer and Peterson (1997) on DOCP therapy in dogs, which demonstrated that DOCP at 2.2 mg/kg every 25 days effectively controlled clinical signs and electrolytes in most dogs. (3) A consensus statement by the ACVIM (2016) on the diagnosis and treatment of hypoadrenocorticism in dogs and cats, which recommends the ACTH stimulation test as the gold standard and provides guidelines for mineralocorticoid and glucocorticoid replacement. (4) A study by Lathan et al. (2008) on atypical hypoadrenocorticism, which found that some dogs with glucocorticoid deficiency alone may later develop mineralocorticoid deficiency. (5) A study by Thompson et al. (2007) on breed predispositions, confirming the high risk in Standard Poodles and Portuguese Water Dogs. These studies support the current diagnostic and therapeutic approaches.