Hyperadrenocorticism

Hyperadrenocorticism (HAC), commonly known as Cushing's syndrome, is a multisystemic endocrine disorder characterized by chronic excessive circulating glucocorticoids, primarily cortisol, produced by the adrenal cortex. In veterinary medicine, the condition is most frequently diagnosed in dogs, with a rare occurrence in cats. The disease can be classified into three main types: pituitary-dependent hyperadrenocorticism (PDH), which accounts for approximately 80-85% of canine cases and results from a functional adenoma or hyperplasia of the corticotroph cells in the pars distalis or pars intermedia of the pituitary gland, leading to excessive secretion of adrenocorticotropic hormone (ACTH); adrenal-dependent hyperadrenocorticism (ADH), which accounts for 15-20% of cases and is caused by a functional unilateral or bilateral adrenocortical tumor (adenoma or carcinoma) that autonomously secretes cortisol independent of ACTH regulation; and iatrogenic hyperadrenocorticism, which results from chronic exogenous administration of glucocorticoids. The clinical syndrome arises from the catabolic, immunosuppressive, and metabolic effects of cortisol excess, affecting nearly every organ system, including the skin, musculoskeletal system, cardiovascular system, urinary tract, and endocrine axes. The disease is progressive and, if left untreated, can lead to severe complications such as diabetes mellitus, pulmonary thromboembolism, and congestive heart failure. Early diagnosis and appropriate management are essential to improve quality of life and survival.

The etiology of hyperadrenocorticism varies depending on the type. Pituitary-dependent hyperadrenocorticism (PDH) is caused by a functional corticotroph adenoma (microadenoma <1 cm or macroadenoma >1 cm) or, less commonly, hyperplasia of the pars distalis or pars intermedia of the pituitary gland. These lesions autonomously secrete excessive ACTH, which stimulates the adrenal cortex to produce cortisol. The exact cause of pituitary adenoma formation is unknown, but genetic mutations (e.g., in the glucocorticoid receptor or proopiomelanocortin gene) and dysregulation of hypothalamic corticotropin-releasing hormone (CRH) have been implicated. Adrenal-dependent hyperadrenocorticism (ADH) arises from a functional adrenocortical adenoma or carcinoma, which secretes cortisol autonomously, leading to suppression of ACTH secretion via negative feedback. The etiology of adrenal tumors is also largely unknown, but chronic stimulation by ACTH or growth factors may play a role. Iatrogenic hyperadrenocorticism is caused by excessive or prolonged administration of exogenous glucocorticoids (e.g., prednisone, dexamethasone, methylprednisolone) for therapeutic purposes, which suppresses the hypothalamic-pituitary-adrenal (HPA) axis and leads to clinical signs of cortisol excess. In cats, the disease is almost exclusively iatrogenic or due to adrenal tumors, with PDH being rare. No infectious, toxic, or environmental agents have been directly implicated in the spontaneous forms.

Hyperadrenocorticism is primarily a disease of middle-aged to older dogs, with a median age at diagnosis of 10-12 years. There is no strong sex predilection, although some studies suggest a slight female predisposition for ADH. Certain breeds are overrepresented, including Poodles, Dachshunds, Beagles, Boxers, Boston Terriers, and Yorkshire Terriers, indicating a possible genetic component. PDH is more common in small-breed dogs, while ADH is more frequently diagnosed in larger breeds, particularly those weighing over 20 kg. The incidence in dogs is estimated at 1-2 cases per 1,000 dog-years. In cats, hyperadrenocorticism is rare, with a median age of 10-11 years, and no breed or sex predilection is reported. The condition is often associated with concurrent diabetes mellitus in cats. Geographic variation is not significant, but the disease is more commonly diagnosed in regions with advanced veterinary care. No seasonal pattern has been observed.

The pathophysiology of hyperadrenocorticism involves chronic exposure to excessive cortisol, which exerts profound effects on multiple organ systems. Cortisol promotes gluconeogenesis and insulin resistance, leading to hyperglycemia and, in some cases, overt diabetes mellitus. It has catabolic effects on protein and fat metabolism, causing muscle wasting, weakness, and redistribution of fat (e.g., abdominal fat deposition). Cortisol inhibits collagen synthesis and impairs wound healing, leading to thin, fragile skin and poor hair growth. It also suppresses the immune system by inhibiting lymphocyte proliferation, antibody production, and phagocytic activity, increasing susceptibility to infections. In the cardiovascular system, cortisol causes hypertension by enhancing vascular reactivity to catecholamines and promoting sodium and water retention. It also increases the risk of thromboembolism by altering coagulation factors and platelet function. In the urinary system, cortisol promotes polyuria by interfering with antidiuretic hormone (ADH) action in the renal collecting ducts, leading to dilute urine. It also increases glomerular filtration rate and can cause proteinuria. In the skeletal system, cortisol inhibits osteoblast function and stimulates osteoclast activity, leading to osteoporosis and pathological fractures. In the endocrine system, cortisol suppresses the HPA axis, leading to atrophy of the contralateral adrenal gland in ADH. In PDH, the pituitary tumor secretes ACTH, which stimulates bilateral adrenal hyperplasia. The clinical signs are a direct consequence of these pathophysiological changes.

Predisposing factors for hyperadrenocorticism include age (middle-aged to older animals), breed (certain breeds are genetically predisposed, such as Poodles, Dachshunds, and Boxers), and possibly sex (some studies suggest a higher risk in females for ADH). Iatrogenic HAC is predisposed by chronic glucocorticoid therapy, especially with long-acting injectable or oral formulations. Concurrent diseases such as diabetes mellitus may be a risk factor for developing HAC, particularly in cats. Obesity and metabolic syndrome may also increase the risk. Environmental factors are not well-defined, but stress and chronic inflammation may contribute to the development of pituitary tumors. Genetic mutations in tumor suppressor genes or oncogenes are suspected but not fully characterized.

Clinical signs of hyperadrenocorticism are insidious and progressive. The most common presenting signs are polyuria, polydipsia, polyphagia, and abdominal distension (pot-bellied appearance). Dermatological signs include bilateral symmetrical alopecia, thin fragile skin, comedones, hyperpigmentation, and calcinosis cutis. Musculoskeletal signs include muscle weakness, muscle atrophy, and exercise intolerance. Respiratory signs may include panting and dyspnea due to pulmonary thromboembolism or compression by an enlarged adrenal gland. Cardiovascular signs include hypertension, which may lead to retinal detachment or stroke. Urinary signs include urinary tract infections, proteinuria, and urolithiasis. Reproductive signs include anestrus in females and testicular atrophy in males. Neurological signs may occur if a pituitary macroadenoma is present, including stupor, circling, and behavioral changes. In cats, the most common signs are polyuria, polydipsia, polyphagia, weight loss, and fragile skin. The severity of signs varies with the duration and magnitude of cortisol excess.

Differential diagnoses for hyperadrenocorticism include: 1) Diabetes mellitus: presents with polyuria, polydipsia, polyphagia, and weight loss; hyperglycemia and glucosuria are present, but cortisol levels are normal. 2) Chronic renal failure: causes polyuria, polydipsia, and poor hair coat; azotemia and isosthenuria are present, but cortisol levels are normal. 3) Hypothyroidism: causes alopecia, weight gain, and lethargy; low T4 and high TSH are present, but cortisol levels are normal. 4) Acromegaly: causes polyuria, polydipsia, and weight gain; elevated growth hormone and IGF-1 are present. 5) Sex hormone imbalances (e.g., Sertoli cell tumor): cause alopecia and gynecomastia; sex hormone assays are abnormal. 6) Psychogenic polydipsia: causes polyuria and polydipsia; urine osmolality is low, but cortisol levels are normal. 7) Hepatic disease (e.g., portosystemic shunt): causes polyuria, polydipsia, and poor coat; liver enzymes and bile acids are abnormal. 8) Hypercalcemia: causes polyuria and polydipsia; ionized calcium is elevated. 9) Chronic urinary tract infection: may cause polyuria and polydipsia; urinalysis and culture are positive. 10) Drug-induced (e.g., phenobarbital) may cause polyuria and polydipsia; history of drug administration is key.

The diagnostic algorithm for hyperadrenocorticism begins with a thorough history and physical examination, focusing on the classic clinical signs. Initial screening tests include a complete blood count (CBC), serum biochemistry profile, and urinalysis. Common abnormalities include stress leukogram (neutrophilia, lymphopenia, eosinopenia), elevated alkaline phosphatase (ALP), mild hyperglycemia, and low urine specific gravity (<1.015). If these findings are suggestive, confirmatory testing is performed. The first-line screening test is the urine cortisol-to-creatinine ratio (UCCR) on a single morning urine sample; a normal UCCR (<13 in dogs, <30 in cats) effectively rules out HAC. If UCCR is elevated, the next step is the ACTH stimulation test or the low-dose dexamethasone suppression test (LDDST). The ACTH stimulation test is preferred for diagnosing PDH and is also used to monitor treatment. The LDDST is more sensitive for PDH and can help differentiate PDH from ADH. If LDDST is performed, a 4-hour post-dexamethasone cortisol concentration >1.5 μg/dL suggests PDH, while suppression to <1.5 μg/dL at 4 or 8 hours indicates PDH. If the LDDST does not suppress, an abdominal ultrasound is performed to assess adrenal gland size and symmetry. Bilateral symmetrical enlargement suggests PDH, while unilateral enlargement with contralateral atrophy suggests ADH. If ultrasound is inconclusive, an endogenous ACTH concentration can be measured: low ACTH (<10 pg/mL) indicates ADH, while high ACTH (>40 pg/mL) indicates PDH. Advanced imaging (CT or MRI) is indicated for suspected pituitary macroadenoma or for surgical planning.

Laboratory findings in hyperadrenocorticism include: Hematology: stress leukogram (neutrophilia, lymphopenia, eosinopenia), mild erythrocytosis, and thrombocytosis. Serum biochemistry: elevated alkaline phosphatase (ALP) in 85-90% of dogs, elevated alanine aminotransferase (ALT) in 50%, mild hyperglycemia (fasting glucose >100 mg/dL), hypercholesterolemia, and mild increases in bile acids. Electrolytes: usually normal, but mild hypokalemia may occur. Urinalysis: urine specific gravity typically <1.015 (isosthenuria), proteinuria (UPC >0.5), and evidence of urinary tract infection (pyuria, bacteriuria). Blood gas analysis: may show mild metabolic alkalosis. Specific biomarkers: cortisol levels are elevated, but a single cortisol measurement is not diagnostic. ACTH stimulation test: post-ACTH cortisol >20 μg/dL in dogs (normal <18 μg/dL) is consistent with HAC. LDDST: cortisol >1.5 μg/dL at 4 or 8 hours after dexamethasone administration is abnormal. Endogenous ACTH: low (<10 pg/mL) in ADH, high (>40 pg/mL) in PDH. In cats, similar tests are used, but the ACTH stimulation test is less sensitive; the LDDST is preferred.

Imaging findings in hyperadrenocorticism: Abdominal radiography may reveal hepatomegaly, adrenal mineralization (in ADH), and dystrophic mineralization of the skin or bronchi. Thoracic radiography may show pulmonary thromboembolism or metastatic lesions in cases of adrenal carcinoma. Abdominal ultrasonography is the most valuable imaging modality: in PDH, both adrenal glands are bilaterally enlarged (width >7.5 mm in dogs) and symmetrical; in ADH, one adrenal gland is enlarged (often >2 cm) with a mass effect, while the contralateral gland is atrophied (width <5 mm). Ultrasonography can also detect adrenal masses, invasion into the caudal vena cava, and hepatic changes (diffuse hyperechogenicity). Computed tomography (CT) and magnetic resonance imaging (MRI) are used to evaluate the pituitary gland for macroadenomas (height >1 cm) and to assess adrenal gland morphology in detail. CT is also useful for surgical planning and to detect metastasis. Echocardiography may be indicated if cardiac disease is suspected due to hypertension.

Cytology and histopathology are important for confirming the type of adrenal tumor and for evaluating pituitary lesions. Fine-needle aspiration (FNA) of an adrenal mass can be performed under ultrasound guidance, but it is not routinely recommended due to the risk of hemorrhage and the difficulty in distinguishing adenoma from carcinoma. Cytology of adrenal masses may show clusters of cortical cells with variable atypia. Histopathology of adrenal tumors after surgical excision is the gold standard for diagnosis: adenomas are well-circumscribed, encapsulated, and composed of well-differentiated cells; carcinomas show capsular invasion, vascular invasion, and cellular atypia. Pituitary tumors are rarely biopsied antemortem; histopathology is typically performed postmortem. In iatrogenic HAC, the adrenal glands are atrophied due to negative feedback suppression. Histopathology of the skin may show epidermal atrophy, follicular atrophy, and calcinosis cutis.

Treatment of hyperadrenocorticism depends on the underlying cause. For PDH, medical management is the mainstay. The drug of choice is trilostane (Vetoryl), a competitive inhibitor of 3β-hydroxysteroid dehydrogenase, which blocks cortisol synthesis. The initial dose is 2-5 mg/kg PO q24h, with food. The dose is adjusted based on clinical response and ACTH stimulation test results (target post-ACTH cortisol 2-5 μg/dL). Alternatively, mitotane (Lysodren) is used, which causes adrenocortical necrosis. The induction dose is 50 mg/kg/day PO for 5-7 days, followed by a maintenance dose of 50 mg/kg/week. Mitotane is more toxic and requires careful monitoring. For ADH, surgical adrenalectomy is the treatment of choice if the tumor is resectable and non-metastatic. Preoperative stabilization with trilostane or mitotane is recommended to reduce surgical risk. In cases of inoperable adrenal tumors, medical management with trilostane or mitotane can be used to control clinical signs. Iatrogenic HAC is treated by gradually tapering the exogenous glucocorticoid dose to allow recovery of the HPA axis. Supportive care includes treatment of hypertension (e.g., amlodipine 0.1-0.2 mg/kg PO q24h), management of urinary tract infections, and dietary modifications (low-fat, high-fiber diet to manage hyperlipidemia and obesity). In cats, treatment is more challenging; trilostane is used at a dose of 2-3 mg/kg PO q24h, but response is variable. Surgical adrenalectomy is often recommended for cats with adrenal tumors.

The prognosis for hyperadrenocorticism is generally good with appropriate treatment, but it depends on the type and presence of complications. For PDH treated with trilostane, the median survival time is approximately 2-3 years, with many dogs living longer if monitored properly. For ADH, the prognosis is more guarded: adrenal adenomas have a good prognosis after surgical resection, with a median survival of 3-4 years, while adrenal carcinomas have a poor prognosis due to high metastatic potential, with a median survival of 6-12 months. Iatrogenic HAC has an excellent prognosis if the glucocorticoid is tapered successfully. Negative prognostic indicators include the presence of a pituitary macroadenoma (neurological signs), pulmonary thromboembolism, concurrent diabetes mellitus, and poor response to treatment. Regular monitoring and dose adjustments are essential to prevent complications such as hypoadrenocorticism (Addisonian crisis) from overtreatment.

Follow-up for hyperadrenocorticism is critical. After initiating trilostane therapy, re-evaluation is recommended at 2-3 weeks, then every 3-6 months. At each recheck, a physical examination, ACTH stimulation test (performed 4-6 hours after trilostane administration), serum biochemistry (electrolytes, renal parameters), and urinalysis should be performed. The goal is to maintain post-ACTH cortisol between 2-5 μg/dL. If clinical signs are not controlled, the dose is increased by 10-20% and rechecked in 2 weeks. If signs of hypoadrenocorticism (lethargy, vomiting, diarrhea, collapse) occur, trilostane is discontinued and supportive care is given. For mitotane therapy, monitoring is more intensive: during induction, weekly ACTH stimulation tests are performed until cortisol is <5 μg/dL, then maintenance is initiated. For surgical adrenalectomy, rechecks are recommended at 1, 3, 6, and 12 months postoperatively, including imaging to detect recurrence or metastasis. Long-term management includes monitoring blood pressure, urine protein-to-creatinine ratio, and blood glucose levels.

Pearls: 1) The UCCR is an excellent screening test; a normal result rules out HAC, but an elevated result requires confirmation. 2) The ACTH stimulation test is the preferred test for monitoring trilostane therapy, but it is less sensitive than LDDST for diagnosing HAC. 3) In dogs with PDH, the LDDST often shows suppression at 4 hours but escape at 8 hours; this is diagnostic. 4) Abdominal ultrasound is essential to differentiate PDH from ADH; bilateral enlargement suggests PDH, while unilateral enlargement with contralateral atrophy suggests ADH. 5) Always rule out iatrogenic HAC by taking a thorough drug history. Pitfalls: 1) Do not rely on a single cortisol measurement for diagnosis; it is not diagnostic. 2) Avoid using the ACTH stimulation test as the sole screening test because it has a lower sensitivity (60-80%) compared to LDDST (90-95%). 3) Do not start treatment without confirming the diagnosis, as trilostane can cause hypoadrenocorticism. 4) In cats, the ACTH stimulation test is unreliable; use the LDDST or UCCR. 5) Be cautious with trilostane in animals with renal or hepatic disease; dose adjustments may be needed.

Trilostane (Vetoryl): Dogs: initial dose 2-5 mg/kg PO q24h with food. Adjust dose based on ACTH stimulation test (target post-ACTH cortisol 2-5 μg/dL). Maximum dose 20 mg/kg/day. Cats: 2-3 mg/kg PO q24h. Mitotane (Lysodren): Dogs: induction 50 mg/kg/day PO for 5-7 days, then maintenance 50 mg/kg/week. Monitor with ACTH stimulation tests. For hypertension: Amlodipine 0.1-0.2 mg/kg PO q24h. For proteinuria: Enalapril 0.5 mg/kg PO q12h or Benazepril 0.25-0.5 mg/kg PO q24h. For urinary tract infections: appropriate antibiotics based on culture and sensitivity. For diabetes mellitus: insulin therapy as needed. For hypoadrenocorticism (overtreatment): Discontinue trilostane, administer prednisone 0.2-0.5 mg/kg PO q12h, and IV fluids with dextrose if in crisis. Contraindications: Trilostane is contraindicated in animals with primary hepatic disease or renal insufficiency; use with caution in pregnant animals. Mitotane is contraindicated in animals with severe hepatic disease. Drug interactions: Trilostane may interact with potassium-sparing diuretics and ACE inhibitors; mitotane may increase the metabolism of warfarin.

Key studies and consensus guidelines: The ACVIM consensus statement on the diagnosis and treatment of hyperadrenocorticism in dogs and cats (2018) provides evidence-based recommendations. A landmark study by Galac et al. (2010) compared trilostane and mitotane for PDH, showing similar efficacy but fewer side effects with trilostane. Another study by Barker et al. (2005) reported that trilostane is effective in controlling clinical signs in 80-90% of dogs. For ADH, a study by Kyles et al. (2003) showed that surgical adrenalectomy is associated with a median survival of 3 years for adenomas and 6 months for carcinomas. The use of UCCR as a screening test was validated by Feldman et al. (1996). The LDDST is considered the most sensitive test for PDH, with a sensitivity of 90-95% (Feldman, 1983). Recent studies have investigated the use of low-dose trilostane (1 mg/kg) to reduce side effects, but standard dosing remains recommended. In cats, a study by Boag et al. (2004) showed that trilostane is effective in controlling clinical signs in some cats, but response is variable. Overall, the evidence supports trilostane as the first-line medical treatment for PDH in dogs, with careful monitoring to avoid hypoadrenocorticism.