Canine Adrenal Gland Disease: Hyperadrenocorticism and Hypoadrenocorticism

This article provides veterinarians and veterinary students with a side-by-side comparison of hyperadrenocorticism (Cushing's syndrome) and hypoadrenocorticism (Addison's disease) in dogs. The focus is on pathophysiology, diagnostic testing including ACTH stimulation and low-dose dexamethasone suppression (LDDS), and treatment protocols. The content is based on approved sources and is intended to support clinical decision-making, not replace individual patient assessment.

At a Glance: Cushing's versus Addison's Disease

Pathophysiology of Adrenal Gland Disease

The adrenal glands produce cortisol (glucocorticoid) and aldosterone (mineralocorticoid) in response to ACTH from the pituitary and angiotensin II/potassium levels, respectively. In hyperadrenocorticism, excessive cortisol is produced either from a pituitary tumor (pituitary-dependent hyperadrenocorticism, PDH) or an adrenal tumor (adrenal-dependent hyperadrenocorticism, ADH). In hypoadrenocorticism, destruction of the adrenal cortex leads to deficient production of glucocorticoids, mineralocorticoids, or both. The Merck Veterinary Manual provides an overview of these disorders in dogs.

Cortisol Excess in Hyperadrenocorticism

In PDH, a functional pituitary adenoma secretes excess ACTH, causing bilateral adrenal hyperplasia and increased cortisol production. In ADH, a functional adrenocortical tumor autonomously secretes cortisol, suppressing ACTH and causing atrophy of the contralateral adrenal gland. The distinction between PDH and ADH is important for treatment selection and prognosis.

Cortisol and Aldosterone Deficiency in Hypoadrenocorticism

Primary hypoadrenocorticism results from immune-mediated destruction of the adrenal cortex, leading to deficiency of both glucocorticoids and mineralocorticoids. Secondary hypoadrenocorticism results from deficient ACTH secretion, causing glucocorticoid deficiency alone. The article "Canine hypoadrenocorticism: pathogenesis, diagnosis, and treatment" in Topics in Companion Animal Medicine (2014) reviews these mechanisms.

Clinical Presentation and Signalment

Hyperadrenocorticism

Dogs with hyperadrenocorticism typically present with polyuria, polydipsia, polyphagia, a pot-bellied appearance, bilateral symmetrical alopecia, muscle weakness, and panting. Common breeds include Poodles, Dachshunds, Boxers, and Boston Terriers. The condition is most common in middle-aged to older dogs.

Hypoadrenocorticism

Dogs with hypoadrenocorticism often present with vague signs such as lethargy, vomiting, diarrhea, weight loss, and intermittent collapse. Some dogs present in an Addisonian crisis with hypovolemic shock, bradycardia, and severe electrolyte disturbances. Breeds at increased risk include Standard Poodles, Portuguese Water Dogs, Bearded Collies, and West Highland White Terriers. The condition is more common in young to middle-aged dogs.

Diagnostic Approach

Initial Database

A complete blood count, serum biochemistry profile, and urinalysis are essential initial tests. In hyperadrenocorticism, common findings include stress leukogram (neutrophilia, lymphopenia, eosinopenia), elevated alkaline phosphatase (ALP), and isosthenuria. In hypoadrenocorticism, classic findings include hyponatremia, hyperkalemia, and a sodium-to-potassium ratio below 27. Azotemia and mild hypercalcemia may also be present.

Screening Tests

Urine Cortisol:Creatinine Ratio (UCCR)

The UCCR is a sensitive screening test for hyperadrenocorticism. A normal result makes hyperadrenocorticism unlikely. However, false positives occur with stress or non-adrenal illness. The test requires a free-catch urine sample collected at home to minimize stress.

ACTH Stimulation Test

The ACTH stimulation test is the gold standard for diagnosing hypoadrenocorticism and is also used to diagnose hyperadrenocorticism. For hyperadrenocorticism, the test has moderate sensitivity (approximately 80-85%) but is less sensitive than the LDDS test. For hypoadrenocorticism, a blunted or absent cortisol response to ACTH is diagnostic. The Merck Veterinary Manual describes the protocol and interpretation.

Low-Dose Dexamethasone Suppression Test (LDDS)

The LDDS test is the most sensitive test for diagnosing hyperadrenocorticism (sensitivity >90%). It also helps differentiate PDH from ADH. The test involves measuring baseline cortisol, then administering a low dose of dexamethasone and measuring cortisol at 4 and 8 hours. In PDH, cortisol is suppressed at 4 hours but may escape suppression at 8 hours. In ADH, cortisol is not suppressed at any time point.

Confirmatory and Differentiation Tests

High-Dose Dexamethasone Suppression Test (HDDS)

The HDDS test is used to differentiate PDH from ADH when the LDDS result is ambiguous. In PDH, cortisol is suppressed by high-dose dexamethasone. In ADH, cortisol is not suppressed.

Endogenous ACTH Measurement

Measurement of endogenous ACTH concentration is the most reliable method to differentiate PDH from ADH. In PDH, ACTH is normal to elevated. In ADH, ACTH is suppressed. The sample requires special handling (collected in a chilled EDTA tube, centrifuged, and frozen promptly).

Abdominal Ultrasound

Ultrasound evaluation of the adrenal glands is useful for identifying adrenal tumors and assessing adrenal size. The article "Ultrasound evaluation of adrenal gland size in clinically healthy dogs and in dogs with hyperadrenocorticism" in The Veterinary Record (2021) provides reference values. In PDH, both adrenal glands are typically enlarged and symmetrical. In ADH, one adrenal gland is enlarged (tumor) and the contralateral gland is small or normal. The article "Ultrasonographic Characteristics of Both Adrenal Glands in 15 Dogs with Functional Adrenocortical Tumors" in the Journal of the American Animal Hospital Association (1999) describes typical findings.

Treatment Protocols

Hyperadrenocorticism

Medical Management for PDH

Trilostane is the most commonly used medication for PDH. It inhibits cortisol synthesis. The starting dose is based on body weight, and the response is monitored with ACTH stimulation tests 4-6 hours after dosing. The goal is to achieve a post-ACTH cortisol concentration within a target range. Mitotane is an alternative but has a narrower therapeutic index and more side effects.

Surgical Management for ADH

Unilateral adrenalectomy is the treatment of choice for functional adrenocortical tumors. The article "Risk factors influencing death prior to discharge in 302 dogs undergoing unilateral adrenalectomy for treatment of primary adrenal gland tumours" in Veterinary and Comparative Oncology (2023) identifies risk factors for perioperative mortality. Dogs with invasive tumors that do not undergo adrenalectomy have variable outcomes, as described in "Outcome in dogs with invasive adrenal gland tumors that did not pursue adrenalectomy" in the Journal of the American Veterinary Medical Association (2024).

Hypoadrenocorticism

Acute Management (Addisonian Crisis)

An Addisonian crisis requires immediate intravenous fluid resuscitation with 0.9% sodium chloride to correct hypovolemia and hyponatremia. Hyperkalemia is managed with fluids and, if severe, with insulin and dextrose or calcium gluconate. Glucocorticoid replacement (dexamethasone sodium phosphate) is given intravenously. Mineralocorticoid replacement is initiated once the patient is stable.

Chronic Management

Long-term management involves mineralocorticoid replacement with desoxycorticosterone pivalate (DOCP) given intramuscularly every 25-30 days or fludrocortisone acetate given orally twice daily. Glucocorticoid replacement with prednisone is given at a low dose. Monitoring includes serum electrolyte measurements and clinical assessment.

Monitoring and Follow-Up

Hyperadrenocorticism

Dogs on trilostane require ACTH stimulation tests 10-14 days after starting therapy or after a dose change. The goal is to achieve a post-ACTH cortisol concentration within the target range. Clinical signs such as polyuria, polydipsia, and appetite should improve within 2-4 weeks. Adverse effects include vomiting, diarrhea, lethargy, and weakness, which may indicate hypocortisolism.

Hypoadrenocorticism

Dogs on DOCP require serum electrolyte measurements 10-14 days after the first dose and then every 25-30 days before the next injection. The dose is adjusted to maintain normal sodium and potassium concentrations. Dogs on fludrocortisone require electrolyte monitoring every 2-4 weeks initially, then every 3-6 months. Clinical signs such as lethargy, vomiting, or diarrhea may indicate inadequate mineralocorticoid or glucocorticoid replacement.

Common Failure Patterns

Hyperadrenocorticism

• Poor response to trilostane: May be due to inadequate dose, poor owner compliance, or incorrect diagnosis. Repeat ACTH stimulation test and adjust dose.
• Recurrence of clinical signs: May indicate progression of disease or development of resistance to therapy. Re-evaluate with ACTH stimulation test and consider dose adjustment.
• Adverse effects: Vomiting, diarrhea, lethargy, and weakness may indicate hypocortisolism. Withhold trilostane and administer prednisone if signs are severe.

Hypoadrenocorticism

• Inadequate electrolyte control: May be due to incorrect dose of mineralocorticoid or concurrent illness. Adjust dose based on electrolyte measurements.
• Addisonian crisis during stress: May occur if glucocorticoid dose is not increased during illness or surgery. Advise owners to increase prednisone dose during stressful events.
• Poor owner compliance: Lifelong therapy requires commitment. Provide clear instructions and regular follow-up.

Limitations and Safety Context

Diagnostic Limitations

• ACTH stimulation test has moderate sensitivity for hyperadrenocorticism, false negatives occur.
• LDDS test is sensitive but requires multiple blood samples and is affected by non-adrenal illness.
• Endogenous ACTH measurement requires careful sample handling.
• Ultrasound is operator-dependent and may not detect small adrenal tumors.

Treatment Limitations

• Trilostane and mitotane require careful monitoring and dose adjustment.
• Adrenalectomy carries perioperative risk, especially for invasive tumors.
• Lifelong therapy is required for hypoadrenocorticism, owner compliance is essential.

Safety Context

• Glucocorticoid withdrawal can cause life-threatening hypocortisolism.
• Mineralocorticoid overdose can cause hypertension and hypokalemia.
• Trilostane overdose can cause hypocortisolism and electrolyte disturbances.

Professional Escalation Criteria

Urgent Escalation

• Suspected Addisonian crisis: collapse, bradycardia, hypovolemic shock, severe electrolyte abnormalities.
• Suspected hypocortisolism in a dog on trilostane: vomiting, diarrhea, lethargy, weakness, collapse.
• Suspected adrenal tumor rupture: acute abdominal pain, collapse, hemoperitoneum.

Routine Escalation

• Poor response to initial therapy: refer to a veterinary internal medicine specialist.
• Difficulty differentiating PDH from ADH: refer for advanced imaging or endogenous ACTH measurement.
• Invasive adrenal tumor: refer for surgical evaluation or radiation therapy.

Practical Decision Framework for Differentiating and Managing Canine Adrenal Disease in Clinical Practice

Veterinarians frequently encounter diagnostic ambiguity when distinguishing hyperadrenocorticism from hypoadrenocorticism, particularly in dogs presenting with vague clinical signs. The existing diagnostic algorithms often assume clear-cut presentations, but real-world cases frequently involve overlapping clinical features, concurrent non-adrenal illness, or equivocal test results. This section provides a structured decision framework that integrates clinical assessment, sequential testing strategies, and practical management adjustments based on the available evidence from the Merck Veterinary Manual and peer-reviewed literature.

Stepwise Clinical Decision Algorithm

The following algorithm prioritizes patient stability and diagnostic efficiency while minimizing unnecessary testing and treatment delays.

Step 1: Triage for Addisonian Crisis

Any dog presenting with collapse, bradycardia, hypovolemic shock, or severe electrolyte abnormalities requires immediate stabilization before diagnostic testing. The Merck Veterinary Manual emphasizes that an Addisonian crisis is a life-threatening emergency requiring intravenous fluid resuscitation with 0.9% sodium chloride and glucocorticoid administration. In this setting, collect blood for a baseline cortisol and ACTH stimulation test before administering exogenous glucocorticoids if the patient is stable enough to tolerate the 60-minute test. If the patient is unstable, administer dexamethasone sodium phosphate and perform the ACTH stimulation test once the patient is stabilized, understanding that dexamethasone does not cross-react with most cortisol assays.

Step 2: Assess Clinical Probability

Assign a pre-test probability based on signalment, history, and physical examination findings. For hyperadrenocorticism, high-probability features include polyuria, polydipsia, polyphagia, pot-bellied appearance, bilateral symmetrical alopecia, and muscle weakness in a middle-aged to older dog of a predisposed breed. For hypoadrenocorticism, high-probability features include waxing and waning lethargy, vomiting, diarrhea, weight loss, and intermittent collapse in a young to middle-aged dog of a predisposed breed. Dogs with intermediate or low probability require additional screening before proceeding to confirmatory testing.

Step 3: Initial Laboratory Screening

Perform a complete blood count, serum biochemistry profile, and urinalysis on all dogs with suspected adrenal disease. In hyperadrenocorticism, common findings include a stress leukogram (neutrophilia, lymphopenia, eosinopenia), elevated alkaline phosphatase, and isosthenuria. In hypoadrenocorticism, classic findings include hyponatremia, hyperkalemia, and a sodium-to-potassium ratio below 27. However, the article "Canine hypoadrenocorticism: pathogenesis, diagnosis, and treatment" in Topics in Companion Animal Medicine (2014) notes that electrolyte abnormalities are absent in approximately 10-30% of dogs with hypoadrenocorticism, particularly in secondary hypoadrenocorticism where mineralocorticoid production is preserved.

Step 4: Select the Appropriate Confirmatory Test

For dogs with high clinical probability of hyperadrenocorticism and supportive initial laboratory findings, proceed directly to the low-dose dexamethasone suppression test (LDDS) or ACTH stimulation test. The LDDS test has higher sensitivity (>90%) for hyperadrenocorticism compared to the ACTH stimulation test (approximately 80-85%), as described in the Merck Veterinary Manual. For dogs with high clinical probability of hypoadrenocorticism, perform the ACTH stimulation test, which is the gold standard for diagnosis.

For dogs with intermediate or low probability, consider the urine cortisol:creatinine ratio (UCCR) as a screening test for hyperadrenocorticism. A normal UCCR makes hyperadrenocorticism unlikely, but false positives occur with stress or non-adrenal illness. The sample should be collected at home to minimize stress. If the UCCR is elevated, proceed to LDDS or ACTH stimulation test.

Step 5: Interpret Test Results in Clinical Context

Interpret all test results in the context of the patient's clinical presentation and concurrent illnesses. Non-adrenal illness can cause false-positive results for both hyperadrenocorticism and hypoadrenocorticism. The article "Laboratory Diagnosis of Thyroid and Adrenal Disease" in The Veterinary Clinics of North America. Small Animal Practice (2023) emphasizes that no single test is perfect and that clinical correlation is essential.

Record System for Monitoring Treatment Response

A standardized record system improves treatment monitoring and reduces the risk of adverse events. The following template can be adapted for clinical use.

Hyperadrenocorticism Treatment Monitoring Record

Record water intake by measuring the volume of water consumed over 24 hours and dividing by body weight. Normal water intake in dogs is less than 60 mL/kg/day. Dogs with hyperadrenocorticism typically consume 100-200 mL/kg/day or more. Improvement in water intake is one of the earliest indicators of treatment response.

Hypoadrenocorticism Treatment Monitoring Record

For dogs on DOCP, measure serum electrolytes 10-14 days after the first dose and then every 25-30 days before the next injection. Adjust the DOCP dose to maintain sodium and potassium within the reference range. For dogs on fludrocortisone, monitor electrolytes every 2-4 weeks initially, then every 3-6 months once stable.

Troubleshooting Common Diagnostic and Treatment Challenges

Challenge 1: Equivocal ACTH Stimulation Test Results

The ACTH stimulation test has moderate sensitivity for hyperadrenocorticism, meaning that some dogs with the disease will have normal post-ACTH cortisol concentrations. If clinical suspicion remains high despite a normal ACTH stimulation test, perform the LDDS test, which has higher sensitivity. Conversely, the ACTH stimulation test has high sensitivity for hypoadrenocorticism, so a normal post-ACTH cortisol concentration effectively rules out the disease.

Challenge 2: Differentiating PDH from ADH

The LDDS test can help differentiate PDH from ADH. In PDH, cortisol is suppressed at 4 hours after dexamethasone administration but may escape suppression at 8 hours. In ADH, cortisol is not suppressed at any time point. However, approximately 20-30% of dogs with PDH show no suppression, making the LDDS test imperfect for differentiation. In these cases, measure endogenous ACTH concentration. In PDH, ACTH is normal to elevated. In ADH, ACTH is suppressed. The sample requires special handling: collect in a chilled EDTA tube, centrifuge immediately, and freeze the plasma promptly.

Challenge 3: Managing Trilostane Overdose

Trilostane overdose can cause iatrogenic hypoadrenocorticism, which is a medical emergency. Clinical signs include vomiting, diarrhea, lethargy, weakness, and collapse. If these signs occur, withhold trilostane and administer prednisone at a stress dose (0.5-1.0 mg/kg orally twice daily) until clinical signs resolve. Perform an ACTH stimulation test to assess adrenal function. Once the dog is stable, restart trilostane at a lower dose and recheck post-ACTH cortisol in 10-14 days.

Challenge 4: Managing Addisonian Crisis in Dogs with Concurrent Illness

Dogs with hypoadrenocorticism may present with concurrent illnesses such as pancreatitis, inflammatory bowel disease, or urinary tract infection. These conditions can complicate diagnosis and treatment. In the acute setting, prioritize fluid resuscitation and glucocorticoid replacement. Once the dog is stable, address the concurrent illness. Increase the glucocorticoid dose during periods of stress, such as illness or surgery, to prevent an Addisonian crisis.

Challenge 5: Monitoring Dogs with Invasive Adrenal Tumors

The article "Outcome in dogs with invasive adrenal gland tumors that did not pursue adrenalectomy" in the Journal of the American Veterinary Medical Association (2024) describes variable outcomes for dogs with invasive adrenal tumors that do not undergo surgery. These dogs may be managed medically with trilostane or mitotane to control cortisol excess. Monitor for signs of tumor progression, such as abdominal pain, vomiting, or hemoperitoneum. Serial ultrasound examinations can assess tumor size and invasiveness. Refer to a veterinary oncologist or surgeon for advanced treatment options.

Common Failure Patterns and Corrective Actions

Failure Pattern 1: Poor Response to Trilostane

If a dog with hyperadrenocorticism does not show clinical improvement within 2-4 weeks of starting trilostane, consider the following possibilities:

• Inadequate dose: Perform an ACTH stimulation test 4-6 hours after trilostane administration. If the post-ACTH cortisol is above the target range, increase the dose by 25-50%.
• Poor owner compliance: Verify that the owner is administering the medication as prescribed. Trilostane should be given with food to enhance absorption.
• Incorrect diagnosis: Re-evaluate the diagnostic test results. Consider performing an LDDS test or endogenous ACTH measurement to confirm the diagnosis.
• Concurrent non-adrenal illness: Illness can cause false-positive test results for hyperadrenocorticism. Treat any concurrent illness and reassess.

Failure Pattern 2: Recurrence of Clinical Signs in Dogs on Trilostane

If a dog that was previously well-controlled on trilostane develops recurrence of clinical signs, consider the following:

• Progression of disease: The pituitary or adrenal tumor may have grown, requiring a higher dose of trilostane. Perform an ACTH stimulation test and adjust the dose accordingly.
• Development of resistance: Some dogs develop resistance to trilostane over time. Consider switching to mitotane or adding ketoconazole as an adjunct therapy.
• Concurrent illness: Illness can cause stress and increase cortisol production. Treat any concurrent illness and consider temporarily increasing the trilostane dose.

Failure Pattern 3: Inadequate Electrolyte Control in Dogs with Hypoadrenocorticism

If a dog with hypoadrenocorticism has persistent electrolyte abnormalities despite mineralocorticoid replacement, consider the following:

• Incorrect dose: Adjust the DOCP or fludrocortisone dose based on serum electrolyte measurements. Increase the dose if sodium is low or potassium is high.
• Concurrent illness: Illness can cause electrolyte disturbances. Treat any concurrent illness and monitor electrolytes closely.
• Poor owner compliance: Verify that the owner is administering the medication as prescribed. DOCP injections should be given every 25-30 days. Fludrocortisone should be given twice daily.
• Secondary hypoadrenocorticism: Dogs with secondary hypoadrenocorticism do not require mineralocorticoid replacement because aldosterone production is preserved. If a dog with secondary hypoadrenocorticism is receiving mineralocorticoid replacement, it may develop hypertension or hypokalemia.

Failure Pattern 4: Addisonian Crisis During Stress

If a dog with hypoadrenocorticism develops an Addisonian crisis during a stressful event such as illness or surgery, consider the following:

• Inadequate glucocorticoid dose: Increase the prednisone dose to a stress dose (0.5-1.0 mg/kg orally twice daily) during periods of stress. For surgery, administer dexamethasone sodium phosphate intravenously at induction.
• Inadequate mineralocorticoid dose: Ensure that the mineralocorticoid dose is adequate. Consider increasing the dose temporarily during periods of stress.
• Concurrent illness: Treat any concurrent illness that may have precipitated the crisis.

Welfare and Safety Context

Adrenal gland disease in dogs has significant welfare implications. Hyperadrenocorticism causes chronic discomfort from polyuria, polydipsia, polyphagia, and muscle weakness. Hypoadrenocorticism causes episodic illness that can progress to life-threatening crises. The World Organisation for Animal Health (WOAH) emphasizes the importance of timely diagnosis and appropriate treatment to maintain animal welfare.

Treatment of adrenal disease requires careful monitoring to avoid adverse effects. Trilostane overdose can cause iatrogenic hypoadrenocorticism, which is a medical emergency. Mineralocorticoid overdose can cause hypertension and hypokalemia. Glucocorticoid withdrawal can cause life-threatening hypocortisolism. The article "Risk factors influencing death prior to discharge in 302 dogs undergoing unilateral adrenalectomy for treatment of primary adrenal gland tumours" in Veterinary and Comparative Oncology (2023) identifies risk factors for perioperative mortality, including tumor size, invasiveness, and concurrent disease.

Professional Escalation Criteria

Refer to a veterinary internal medicine specialist in the following situations:

• Difficulty differentiating PDH from ADH despite LDDS and endogenous ACTH measurement
• Poor response to initial therapy for hyperadrenocorticism or hypoadrenocorticism
• Suspected atypical hypoadrenocorticism (normal electrolytes)
• Concurrent non-adrenal illness that complicates diagnosis or treatment
• Need for advanced imaging such as computed tomography or magnetic resonance imaging

Refer to a veterinary surgeon in the following situations:

• Adrenal tumor that is amenable to surgical removal
• Invasive adrenal tumor that requires advanced surgical techniques
• Adrenal tumor causing clinical signs such as abdominal pain or hemoperitoneum

Refer to a veterinary oncologist in the following situations:

• Malignant adrenal tumor with metastasis
• Adrenal tumor that is not amenable to surgical removal
• Need for radiation therapy or chemotherapy

Limitations of the Decision Framework

This decision framework is based on the available evidence from the Merck Veterinary Manual and peer-reviewed literature. However, individual patient variation, concurrent illnesses, and owner compliance can affect outcomes. The framework should be adapted to the specific clinical context and updated as new evidence becomes available. The article "Ultrasound evaluation of adrenal gland size in clinically healthy dogs and in dogs with hyperadrenocorticism" in The Veterinary Record (2021) provides reference values for adrenal gland size, but these values may vary by breed and body size. The article "Morphometric and histopathological findings in the adrenal glands of dogs with chronic diseases" in the Brazilian Journal of Veterinary Pathology (2017) describes adrenal gland changes in dogs with chronic diseases, which may complicate interpretation of ultrasound findings.

Summary of Practical Recommendations

• Use a stepwise clinical decision algorithm that prioritizes patient stability and diagnostic efficiency.
• Maintain standardized treatment monitoring records to track response and detect adverse effects early.
• Troubleshoot common diagnostic and treatment challenges using evidence-based corrective actions.
• Recognize common failure patterns and implement appropriate corrective actions.
• Escalate to specialists when diagnostic or treatment challenges exceed the scope of general practice.
• Consider welfare implications and safety context when making treatment decisions.

Practical Decision Framework for Differentiating and Managing Canine Adrenal Disease in Clinical Practice

Veterinarians frequently encounter diagnostic ambiguity when distinguishing hyperadrenocorticism from hypoadrenocorticism, particularly in dogs presenting with vague clinical signs. The existing diagnostic algorithms often assume clear-cut presentations, but real-world cases frequently involve overlapping clinical features, concurrent non-adrenal illness, or equivocal test results. This section provides a structured decision framework that integrates clinical assessment, sequential testing strategies, and practical management adjustments based on the available evidence from the Merck Veterinary Manual and peer-reviewed literature.

Stepwise Clinical Decision Algorithm

The following algorithm prioritizes patient stability and diagnostic efficiency while minimizing unnecessary testing and treatment delays.

Step 1: Triage for Addisonian Crisis

Any dog presenting with collapse, bradycardia, hypovolemic shock, or severe electrolyte abnormalities requires immediate stabilization before diagnostic testing. The Merck Veterinary Manual emphasizes that an Addisonian crisis is a life-threatening emergency requiring intravenous fluid resuscitation with 0.9% sodium chloride and glucocorticoid administration. In this setting, collect blood for a baseline cortisol and ACTH stimulation test before administering exogenous glucocorticoids if the patient is stable enough to tolerate the 60-minute test. If the patient is unstable, administer dexamethasone sodium phosphate and perform the ACTH stimulation test once the patient is stabilized, understanding that dexamethasone does not cross-react with most cortisol assays.

Step 2: Assess Clinical Probability

Assign a pre-test probability based on signalment, history, and physical examination findings. For hyperadrenocorticism, high-probability features include polyuria, polydipsia, polyphagia, pot-bellied appearance, bilateral symmetrical alopecia, and muscle weakness in a middle-aged to older dog of a predisposed breed. For hypoadrenocorticism, high-probability features include waxing and waning lethargy, vomiting, diarrhea, weight loss, and intermittent collapse in a young to middle-aged dog of a predisposed breed. Dogs with intermediate or low probability require additional screening before proceeding to confirmatory testing.

Step 3: Initial Laboratory Screening

Perform a complete blood count, serum biochemistry profile, and urinalysis on all dogs with suspected adrenal disease. In hyperadrenocorticism, common findings include a stress leukogram (neutrophilia, lymphopenia, eosinopenia), elevated alkaline phosphatase, and isosthenuria. In hypoadrenocorticism, classic findings include hyponatremia, hyperkalemia, and a sodium-to-potassium ratio below 27. However, the article "Canine hypoadrenocorticism: pathogenesis, diagnosis, and treatment" in Topics in Companion Animal Medicine (2014) notes that electrolyte abnormalities are absent in approximately 10-30% of dogs with hypoadrenocorticism, particularly in secondary hypoadrenocorticism where mineralocorticoid production is preserved.

Step 4: Select the Appropriate Confirmatory Test

For dogs with high clinical probability of hyperadrenocorticism and supportive initial laboratory findings, proceed directly to the low-dose dexamethasone suppression test (LDDS) or ACTH stimulation test. The LDDS test has higher sensitivity (>90%) for hyperadrenocorticism compared to the ACTH stimulation test (approximately 80-85%), as described in the Merck Veterinary Manual. For dogs with high clinical probability of hypoadrenocorticism, perform the ACTH stimulation test, which is the gold standard for diagnosis.

For dogs with intermediate or low probability, consider the urine cortisol:creatinine ratio (UCCR) as a screening test for hyperadrenocorticism. A normal UCCR makes hyperadrenocorticism unlikely, but false positives occur with stress or non-adrenal illness. The sample should be collected at home to minimize stress. If the UCCR is elevated, proceed to LDDS or ACTH stimulation test.

Step 5: Interpret Test Results in Clinical Context

Interpret all test results in the context of the patient's clinical presentation and concurrent illnesses. Non-adrenal illness can cause false-positive results for both hyperadrenocorticism and hypoadrenocorticism. The article "Laboratory Diagnosis of Thyroid and Adrenal Disease" in The Veterinary Clinics of North America. Small Animal Practice (2023) emphasizes that no single test is perfect and that clinical correlation is essential.

Record System for Monitoring Treatment Response

A standardized record system improves treatment monitoring and reduces the risk of adverse events. The following template can be adapted for clinical use.

Hyperadrenocorticism Treatment Monitoring Record

Record water intake by measuring the volume of water consumed over 24 hours and dividing by body weight. Normal water intake in dogs is less than 60 mL/kg/day. Dogs with hyperadrenocorticism typically consume 100-200 mL/kg/day or more. Improvement in water intake is one of the earliest indicators of treatment response.

Hypoadrenocorticism Treatment Monitoring Record

For dogs on DOCP, measure serum electrolytes 10-14 days after the first dose and then every 25-30 days before the next injection. Adjust the DOCP dose to maintain sodium and potassium within the reference range. For dogs on fludrocortisone, monitor electrolytes every 2-4 weeks initially, then every 3-6 months once stable.

Troubleshooting Common Diagnostic and Treatment Challenges

Challenge 1: Equivocal ACTH Stimulation Test Results

The ACTH stimulation test has moderate sensitivity for hyperadrenocorticism, meaning that some dogs with the disease will have normal post-ACTH cortisol concentrations. If clinical suspicion remains high despite a normal ACTH stimulation test, perform the LDDS test, which has higher sensitivity. Conversely, the ACTH stimulation test has high sensitivity for hypoadrenocorticism, so a normal post-ACTH cortisol concentration effectively rules out the disease.

Challenge 2: Differentiating PDH from ADH

The LDDS test can help differentiate PDH from ADH. In PDH, cortisol is suppressed at 4 hours after dexamethasone administration but may escape suppression at 8 hours. In ADH, cortisol is not suppressed at any time point. However, approximately 20-30% of dogs with PDH show no suppression, making the LDDS test imperfect for differentiation. In these cases, measure endogenous ACTH concentration. In PDH, ACTH is normal to elevated. In ADH, ACTH is suppressed. The sample requires special handling: collect in a chilled EDTA tube, centrifuge immediately, and freeze the plasma promptly.

Challenge 3: Managing Trilostane Overdose

Trilostane overdose can cause iatrogenic hypoadrenocorticism, which is a medical emergency. Clinical signs include vomiting, diarrhea, lethargy, weakness, and collapse. If these signs occur, withhold trilostane and administer prednisone at a stress dose (0.5-1.0 mg/kg orally twice daily) until clinical signs resolve. Perform an ACTH stimulation test to assess adrenal function. Once the dog is stable, restart trilostane at a lower dose and recheck post-ACTH cortisol in 10-14 days.

Challenge 4: Managing Addisonian Crisis in Dogs with Concurrent Illness

Dogs with hypoadrenocorticism may present with concurrent illnesses such as pancreatitis, inflammatory bowel disease, or urinary tract infection. These conditions can complicate diagnosis and treatment. In the acute setting, prioritize fluid resuscitation and glucocorticoid replacement. Once the dog is stable, address the concurrent illness. Increase the glucocorticoid dose during periods of stress, such as illness or surgery, to prevent an Addisonian crisis.

Challenge 5: Monitoring Dogs with Invasive Adrenal Tumors

The article "Outcome in dogs with invasive adrenal gland tumors that did not pursue adrenalectomy" in the Journal of the American Veterinary Medical Association (2024) describes variable outcomes for dogs with invasive adrenal tumors that do not undergo surgery. These dogs may be managed medically with trilostane or mitotane to control cortisol excess. Monitor for signs of tumor progression, such as abdominal pain, vomiting, or hemoperitoneum. Serial ultrasound examinations can assess tumor size and invasiveness. Refer to a veterinary oncologist or surgeon for advanced treatment options.

Common Failure Patterns and Corrective Actions

Failure Pattern 1: Poor Response to Trilostane

If a dog with hyperadrenocorticism does not show clinical improvement within 2-4 weeks of starting trilostane, consider the following possibilities:

• Inadequate dose: Perform an ACTH stimulation test 4-6 hours after trilostane administration. If the post-ACTH cortisol is above the target range, increase the dose by 25-50%.
• Poor owner compliance: Verify that the owner is administering the medication as prescribed. Trilostane should be given with food to enhance absorption.
• Incorrect diagnosis: Re-evaluate the diagnostic test results. Consider performing an LDDS test or endogenous ACTH measurement to confirm the diagnosis.
• Concurrent non-adrenal illness: Illness can cause false-positive test results for hyperadrenocorticism. Treat any concurrent illness and reassess.

Failure Pattern 2: Recurrence of Clinical Signs in Dogs on Trilostane

If a dog that was previously well-controlled on trilostane develops recurrence of clinical signs, consider the following:

• Progression of disease: The pituitary or adrenal tumor may have grown, requiring a higher dose of trilostane. Perform an ACTH stimulation test and adjust the dose accordingly.
• Development of resistance: Some dogs develop resistance to trilostane over time. Consider switching to mitotane or adding ketoconazole as an adjunct therapy.
• Concurrent illness: Illness can cause stress and increase cortisol production. Treat any concurrent illness and consider temporarily increasing the trilostane dose.

Failure Pattern 3: Inadequate Electrolyte Control in Dogs with Hypoadrenocorticism

If a dog with hypoadrenocorticism has persistent electrolyte abnormalities despite mineralocorticoid replacement, consider the following:

• Incorrect dose: Adjust the DOCP or fludrocortisone dose based on serum electrolyte measurements. Increase the dose if sodium is low or potassium is high.
• Concurrent illness: Illness can cause electrolyte disturbances. Treat any concurrent illness and monitor electrolytes closely.
• Poor owner compliance: Verify that the owner is administering the medication as prescribed. DOCP injections should be given every 25-30 days. Fludrocortisone should be given twice daily.
• Secondary hypoadrenocorticism: Dogs with secondary hypoadrenocorticism do not require mineralocorticoid replacement because aldosterone production is preserved. If a dog with secondary hypoadrenocorticism is receiving mineralocorticoid replacement, it may develop hypertension or hypokalemia.

Failure Pattern 4: Addisonian Crisis During Stress

If a dog with hypoadrenocorticism develops an Addisonian crisis during a stressful event such as illness or surgery, consider the following:

• Inadequate glucocorticoid dose: Increase the prednisone dose to a stress dose (0.5-1.0 mg/kg orally twice daily) during periods of stress. For surgery, administer dexamethasone sodium phosphate intravenously at induction.
• Inadequate mineralocorticoid dose: Ensure that the mineralocorticoid dose is adequate. Consider increasing the dose temporarily during periods of stress.
• Concurrent illness: Treat any concurrent illness that may have precipitated the crisis.

Welfare and Safety Context

Adrenal gland disease in dogs has significant welfare implications. Hyperadrenocorticism causes chronic discomfort from polyuria, polydipsia, polyphagia, and muscle weakness. Hypoadrenocorticism causes episodic illness that can progress to life-threatening crises. The World Organisation for Animal Health (WOAH) emphasizes the importance of timely diagnosis and appropriate treatment to maintain animal welfare.

Treatment of adrenal disease requires careful monitoring to avoid adverse effects. Trilostane overdose can cause iatrogenic hypoadrenocorticism, which is a medical emergency. Mineralocorticoid overdose can cause hypertension and hypokalemia. Glucocorticoid withdrawal can cause life-threatening hypocortisolism. The article "Risk factors influencing death prior to discharge in 302 dogs undergoing unilateral adrenalectomy for treatment of primary adrenal gland tumours" in Veterinary and Comparative Oncology (2023) identifies risk factors for perioperative mortality, including tumor size, invasiveness, and concurrent disease.

Professional Escalation Criteria

Refer to a veterinary internal medicine specialist in the following situations:

• Difficulty differentiating PDH from ADH despite LDDS and endogenous ACTH measurement
• Poor response to initial therapy for hyperadrenocorticism or hypoadrenocorticism
• Suspected atypical hypoadrenocorticism (normal electrolytes)
• Concurrent non-adrenal illness that complicates diagnosis or treatment
• Need for advanced imaging such as computed tomography or magnetic resonance imaging

Refer to a veterinary surgeon in the following situations:

• Adrenal tumor that is amenable to surgical removal
• Invasive adrenal tumor that requires advanced surgical techniques
• Adrenal tumor causing clinical signs such as abdominal pain or hemoperitoneum

Refer to a veterinary oncologist in the following situations:

• Malignant adrenal tumor with metastasis
• Adrenal tumor that is not amenable to surgical removal
• Need for radiation therapy or chemotherapy

Limitations of the Decision Framework

This decision framework is based on the available evidence from the Merck Veterinary Manual and peer-reviewed literature. However, individual patient variation, concurrent illnesses, and owner compliance can affect outcomes. The framework should be adapted to the specific clinical context and updated as new evidence becomes available. The article "Ultrasound evaluation of adrenal gland size in clinically healthy dogs and in dogs with hyperadrenocorticism" in The Veterinary Record (2021) provides reference values for adrenal gland size, but these values may vary by breed and body size. The article "Morphometric and histopathological findings in the adrenal glands of dogs with chronic diseases" in the Brazilian Journal of Veterinary Pathology (2017) describes adrenal gland changes in dogs with chronic diseases, which may complicate interpretation of ultrasound findings.

Summary of Practical Recommendations

• Use a stepwise clinical decision algorithm that prioritizes patient stability and diagnostic efficiency.
• Maintain standardized treatment monitoring records to track response and detect adverse effects early.
• Troubleshoot common diagnostic and treatment challenges using evidence-based corrective actions.
• Recognize common failure patterns and implement appropriate corrective actions.
• Escalate to specialists when diagnostic or treatment challenges exceed the scope of general practice.
• Consider welfare implications and safety context when making treatment decisions.

Frequently Asked Questions

What is the difference between Cushing's disease and Cushing's syndrome in dogs?

Cushing's disease refers specifically to pituitary-dependent hyperadrenocorticism (PDH), caused by a pituitary tumor. Cushing's syndrome is a broader term that includes both PDH and adrenal-dependent hyperadrenocorticism (ADH), caused by an adrenal tumor. Both conditions result in excessive cortisol production.

How is the ACTH stimulation test performed in dogs?

The ACTH stimulation test involves collecting a baseline blood sample for cortisol measurement, then administering synthetic ACTH (cosyntropin) intravenously or intramuscularly. A second blood sample is collected 60 minutes later for cortisol measurement. In hyperadrenocorticism, the post-ACTH cortisol is elevated. In hypoadrenocorticism, the post-ACTH cortisol is blunted or absent.

What is the low-dose dexamethasone suppression test and when is it used?

The LDDS test is used to diagnose hyperadrenocorticism and to differentiate PDH from ADH. It involves collecting a baseline cortisol sample, then administering a low dose of dexamethasone intravenously. Cortisol is measured at 4 and 8 hours after injection. In normal dogs, cortisol is suppressed at both time points. In PDH, cortisol is suppressed at 4 hours but may escape suppression at 8 hours. In ADH, cortisol is not suppressed at any time point.

Can a dog have both Cushing's and Addison's disease?

It is extremely rare for a dog to have both conditions simultaneously. However, dogs treated for hyperadrenocorticism can develop iatrogenic hypoadrenocorticism if the dose of trilostane or mitotane is too high. This is a medical emergency that requires immediate withdrawal of the medication and administration of glucocorticoids.

What is the prognosis for a dog with an adrenal tumor?

The prognosis depends on the type and invasiveness of the tumor. Benign adenomas have a good prognosis after surgical removal. Malignant carcinomas have a guarded prognosis, especially if they are invasive or have metastasized. The article "Outcome in dogs with invasive adrenal gland tumors that did not pursue adrenalectomy" in the Journal of the American Veterinary Medical Association (2024) provides information on outcomes for dogs that do not undergo surgery.

How is hypoadrenocorticism managed long-term in dogs?

Long-term management involves mineralocorticoid replacement with desoxycorticosterone pivalate (DOCP) given intramuscularly every 25-30 days or fludrocortisone acetate given orally twice daily. Glucocorticoid replacement with prednisone is given at a low dose. Monitoring includes serum electrolyte measurements and clinical assessment. Owners should be advised to increase the prednisone dose during stressful events such as illness or surgery.

What are the side effects of trilostane in dogs?

Common side effects of trilostane include vomiting, diarrhea, lethargy, and weakness. These signs may indicate hypocortisolism and require dose adjustment or temporary withdrawal of the medication. Serious side effects include electrolyte disturbances and azotemia. Regular monitoring with ACTH stimulation tests is essential to avoid overtreatment.

When should I refer a dog with adrenal disease to a specialist?

Referral to a veterinary internal medicine specialist is recommended for cases that are difficult to diagnose, cases that do not respond to initial therapy, cases requiring advanced imaging or endogenous ACTH measurement, and cases with invasive adrenal tumors. Referral to a veterinary surgeon is recommended for adrenalectomy.

Related Veterinary Guides

• Dog
• Canine Hyperadrenocorticism Cushings Diagnostic Management
• How To Skin A Dog
• Dog Kidney Disease Diet
• Arthritis In Dogs Symptoms And Diagnosis

References and Further Reading

• www.merckvetmanual.com
• www.acvim.org
• Merck Veterinary Manual. Merck Veterinary Manual.
• Animal Health and Welfare. World Organisation for Animal Health.
• Ultrasound evaluation of adrenal gland size in clinically healthy dogs and in dogs with hyperadrenocorticism.. The Veterinary record, 2021.
• Canine hypoadrenocorticism: pathogenesis, diagnosis, and treatment.. Topics in companion animal medicine, 2014.
• Laboratory Diagnosis of Thyroid and Adrenal Disease.. The Veterinary clinics of North America. Small animal practice, 2023.
• Outcome in dogs with invasive adrenal gland tumors that did not pursue adrenalectomy.. Journal of the American Veterinary Medical Association, 2024.
• Adrenal Disease in Small Mammals.. The veterinary clinics of North America. Exotic animal practice, 2025.
• Risk factors influencing death prior to discharge in 302 dogs undergoing unilateral adrenalectomy for treatment of primary adrenal gland tumours.. Veterinary and comparative oncology, 2023.
• Bridging the gap-Rethinking the role of the adrenal gland in chronic kidney disease from the feline perspective.. Domestic Animal Endocrinology, 2025.
• Morphometric and histopathological findings in the adrenal glands of dogs with chronic diseases. Brazilian Journal of Veterinary Pathology, 2017.
• Ultrasonographic evaluation of the adrenal glands in dogs.. Journal of the American Veterinary Medical Association, 1995.
• Immunocytochemical study of tissue parasitism of dog adrenal glands in experimental chagas' disease. Parasite, 1994.
• Ultrasonographic Characteristics of Both Adrenal Glands in 15 Dogs with Functional Adrenocortical Tumors. Journal of the American Animal Hospital Association, 1999.

This article is educational and is not a substitute for veterinary diagnosis or treatment. Contact a veterinarian for advice about an individual animal.