Cushing’s disease is one of the highest-yield endocrine topics on the NAVLE, and it rewards students who know the details. The NAVLE loves to test the difference between pituitary-dependent hyperadrenocorticism (PDH) and adrenal-dependent hyperadrenocorticism (ADH), the interpretation of the low-dose dexamethasone suppression test, and how you manage each form. Get comfortable with those distinctions and you’ll handle whatever signalment they throw at you.
What Is Hyperadrenocorticism?
Hyperadrenocorticism means chronic excess of cortisol. In dogs, it’s almost always either PDH (overactive pituitary producing too much ACTH, which drives both adrenal glands to produce excess cortisol) or ADH (a unilateral adrenal tumor secreting cortisol autonomously). A small percentage is iatrogenic — caused by exogenous glucocorticoid administration.
PDH accounts for roughly 85% of naturally occurring Cushing’s. ADH accounts for about 15%. On the exam, if they give you a middle-aged to older dog with a pot belly, panting, PU/PD, and alopecia, your first thought should be PDH in a small-to-medium breed.
Classic Signalment and Clinical Signs
The typical PDH patient is a middle-aged to older dog (mean age around 9–11 years), often a Poodle, Dachshund, Beagle, Boxer, or Boston Terrier. ADH has no strong breed predisposition, tends to affect larger breeds more often, and the average age is slightly older.
Clinical signs of cortisol excess follow a predictable pattern. PU/PD is usually the owner’s chief complaint. Polyphagia is common. The classic physical exam findings are a pendulous abdomen, truncal alopecia (bilateral symmetric), skin thinning, comedones, calcinosis cutis, hepatomegaly, and muscle wasting. Panting is prominent — cortisol causes direct respiratory center stimulation. Neurologic signs (circling, behavioral changes, seizures) can occur with a large pituitary tumor (macroadenoma) causing mass effects.
Cortisol Excess: What It Does to the Body
Knowing the mechanism behind each clinical sign makes the diagnosis and monitoring questions much easier. Cortisol’s effects are far-reaching:
Routine Lab Changes You Will See
The CBC, chemistry, and urinalysis in Cushing’s are highly characteristic. A stress leukogram (mature neutrophilia, lymphopenia, eosinopenia, monocytosis) is classic. ALP is almost universally elevated in dogs — cortisol induces a liver-specific isoenzyme. ALT may be mildly elevated. Hypercholesterolemia and hypertriglyceridemia are common. The urine specific gravity is usually < 1.020 from the ADH-antagonism effect. UTI is present in about 40–50% of Cushing’s cases and is frequently subclinical, so always culture the urine even if the sediment looks clean.
Diagnostic Tests for Hyperadrenocorticism
There are three main tests used to diagnose Cushing’s and one screening tool. The NAVLE will ask you to choose the right test for the right scenario, and it will ask you to interpret results. Know the numbers cold.
| Test | Purpose | Protocol | Positive Result | Sensitivity / Notes |
|---|---|---|---|---|
| Urine Cortisol:Creatinine Ratio (UCCR) | Screening only | First morning urine collected at home (avoid in-clinic stress) | > 10 × 10&sup6; (lab-dependent) | ~99% sensitivity; very low specificity. A normal result rules OUT HAC. |
| Low-Dose Dexamethasone Suppression Test (LDDST) | Confirms HAC; can suggest PDH if escape pattern at 4h | Dexamethasone 0.01 mg/kg IV; cortisol at 0, 4, and 8 hours | 8-hour cortisol > 1.0 μg/dL | ~95% sensitivity; best first test for naturally occurring HAC |
| High-Dose Dexamethasone Suppression Test (HDDST) | Differentiates PDH from ADH only (NOT a screening test) | Dexamethasone 0.1 mg/kg IV; cortisol at 0, 4, and 8 hours | PDH: ≥50% suppression from baseline. ADH: no suppression. | ~75% sensitivity for PDH differentiation. 25% of PDH cases fail to suppress. |
| ACTH Stimulation Test | Confirms HAC; best for iatrogenic HAC; required for trilostane monitoring | Cosyntropin 5 μg/kg IV or 250 μg/dog IM; cortisol at 0 and 1 hour | Post-ACTH cortisol > 17–22 μg/dL | ~80–85% sensitivity; blunted response in iatrogenic HAC confirms HPA suppression |
| Endogenous ACTH | Differentiates PDH from ADH | Single plasma sample; chilled EDTA tube, immediate centrifuge and freeze | PDH: normal/elevated. ADH: suppressed/low. Iatrogenic: suppressed. | Highly specific but pre-analytical errors are common; strict handling required. |
PDH vs. Adrenal-Dependent HAC: Side by Side
Once you’ve confirmed Cushing’s, you need to figure out where it’s coming from. This drives treatment completely — PDH gets medical management, ADH usually gets surgery.
| Feature | PDH (Pituitary-Dependent) | ADH (Adrenal-Dependent) |
|---|---|---|
| Frequency | ~85% of cases | ~15% of cases |
| Cause | Pituitary micro- or macroadenoma secreting excess ACTH | Unilateral adrenocortical adenoma or carcinoma |
| Adrenal glands on ultrasound | Bilateral adrenal enlargement or normal size | Unilateral mass; contralateral gland atrophied |
| Endogenous ACTH | Normal to elevated | Suppressed (low or undetectable) |
| HDDST response | ≥50% suppression from baseline in ~75% of PDH cases | No suppression (autonomous cortisol production) |
| Breed predisposition | Poodle, Dachshund, Beagle, Boston Terrier, Boxer; small-medium breeds overrepresented | Large breeds more common; no specific breed predisposition |
| Treatment of choice | Trilostane or mitotane (medical) | Surgical adrenalectomy |
| Neurological signs | Possible with pituitary macroadenoma (>1 cm): circling, behavioral change, blindness | Not expected unless metastatic disease |
Imaging: What Abdominal Ultrasound Tells You
Abdominal ultrasound is the most clinically accessible way to distinguish PDH from ADH. Normal canine adrenal gland thickness is ≤ 7.4 mm. In PDH, both glands are bilaterally hyperplastic and may measure > 7.5 mm. In ADH, you’ll find one gland with a distinct mass and the contralateral gland atrophied — thin and difficult to visualize — because autonomous cortisol from the tumor suppresses ACTH and causes the normal adrenal to atrophy.
A mass > 2 cm with irregular borders raises concern for adrenocortical carcinoma and increases the risk of local invasion and vascular involvement. CT is the gold standard before surgery to evaluate for caval invasion and metastasis.
Medical Treatment: Trilostane vs. Mitotane
Both drugs are used for PDH and inoperable ADH, but they work completely differently. The NAVLE will ask you to distinguish them and interpret monitoring results.
Trilostane (Vetoryl) is the preferred drug in most practices. It blocks 3β-hydroxysteroid dehydrogenase, the enzyme required for cortisol synthesis. It does NOT destroy adrenal tissue — effects are reversible. Starting dose: 2–5 mg/kg PO SID with food (food increases absorption significantly). Monitor with an ACTH stimulation test at 10 days, 4 weeks, and 12 weeks after starting or any dose change, then every 3–6 months. The ACTH stim on trilostane must be performed 4–6 hours after the morning pill.
Target post-ACTH cortisol on trilostane: 2–5 μg/dL. Values < 1 μg/dL with clinical signs of hypocortisolism (weakness, vomiting, anorexia) require immediate attention — trilostane can cause acute adrenal necrosis in rare cases.
Mitotane (Lysodren, o,p’-DDD) is an adrenocorticolytic drug that selectively destroys the zona fasciculata and zona reticularis. It CAN cause permanent adrenal insufficiency. The loading phase uses 40–50 mg/kg/day PO divided BID with food until the dog shows clinical signs of cortisol reduction (reduced water consumption, reduced appetite, vomiting). Concurrent prednisolone at 0.2 mg/kg/day is given during induction to prevent Addisonian crisis. An ACTH stim confirms successful induction (post-ACTH cortisol ≤ 5 μg/dL).
| Feature | Trilostane (Vetoryl) | Mitotane (Lysodren) |
|---|---|---|
| Mechanism | Enzyme inhibitor: blocks 3β-HSD → reduces cortisol synthesis | Adrenocorticolytic: destroys zona fasciculata and reticularis |
| Starting dose | 2–5 mg/kg PO SID with food | 40–50 mg/kg/day PO divided BID with food (induction) |
| Monitoring test | ACTH stim at 10d, 4wk, 12wk, then q3–6 months; sample 4–6h post-pill | Clinical signs during loading; ACTH stim to confirm induction |
| Target post-ACTH cortisol | 2–5 μg/dL | ≤ 5 μg/dL at end of induction |
| Main risk | Acute adrenal necrosis (rare); clinical hypocortisolism if post-ACTH < 1 μg/dL | Iatrogenic hypoadrenocorticism; requires glucocorticoid co-administration during induction |
| Reversibility | Reversible (enzyme inhibition) | May be permanent (cell destruction) |
Iatrogenic Hyperadrenocorticism
Iatrogenic HAC is caused by prolonged exogenous glucocorticoid administration — and the source is not always obvious. Topical otic preparations (Mometamax, Panalog), ophthalmic drops, and intra-articular injections can cause systemic steroid exposure sufficient to suppress the HPA axis. The dog looks clinically Cushingoid, but the cortisol axis is actually suppressed rather than overactive.
The ACTH stimulation test shows blunted responses at both baseline and post-ACTH time points (low cortisol throughout), because the pituitary and adrenal cortex have both been suppressed by chronic exogenous steroid. The LDDST may also show suppression but is not the preferred test here.
Treatment: gradually taper the offending drug. Abrupt discontinuation risks an Addisonian crisis because the HPA axis needs time to recover. Monitor for weakness, vomiting, and lethargy during withdrawal.