Endocrinology · Adrenal Disorders
The facts most likely to be tested
The initial screening tests for Cushing Syndrome are 24-hour urinary free cortisol, late-night salivary cortisol, or the low-dose dexamethasone suppression test.
Cushing Disease is defined specifically as ACTH-secreting pituitary adenoma, which is the most common cause of endogenous hypercortisolism.
An ACTH-independent etiology is confirmed by a low plasma ACTH level, typically indicating an adrenal adenoma or adrenal carcinoma.
The high-dose dexamethasone suppression test is used to differentiate Cushing Disease (suppression of cortisol) from ectopic ACTH production (no suppression).
Ectopic ACTH production, most commonly from small cell lung cancer, presents with hyperpigmentation, hypokalemia, and metabolic alkalosis due to extreme cortisol levels.
Clinical features of Cushing Syndrome include central obesity, moon facies, buffalo hump, purple abdominal striae, and proximal muscle weakness.
Bilateral inferior petrosal sinus sampling (BIPSS) is the gold standard diagnostic procedure to localize the source of ACTH when imaging is inconclusive.
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A 42-year-old woman presents with a 6-month history of weight gain, fatigue, and easy bruising. Physical examination reveals central obesity, thin skin with ecchymoses, and wide purple striae on the abdomen. Laboratory studies show an elevated 24-hour urinary free cortisol and a suppressed plasma ACTH level. An abdominal CT scan reveals a 3-cm mass on the left adrenal gland.
What is the most likely diagnosis?
ACTH-independent Cushing Syndrome (Adrenal Adenoma)
The low plasma ACTH indicates an ACTH-independent process, and the adrenal mass confirms an adrenal source of excess cortisol, which is a classic presentation of an adrenal adenoma.
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High yield triage
Etiology / Epidemiology
Most common cause is exogenous glucocorticoid use. Endogenous causes include Cushing Disease (pituitary adenoma).
Clinical Manifestations
Look for moon facies, buffalo hump, and purple striae. Proximal muscle weakness is a high-yield discriminator.
Diagnosis
24-hour urinary free cortisol or late-night salivary cortisol are initial screens. High-dose dexamethasone suppression test differentiates pituitary vs. ectopic.
Treatment
Transsphenoidal resection is first-line for pituitary adenoma. Adrenal insufficiency is a risk post-op.
Prognosis
Untreated, it carries high cardiovascular mortality. 5-year survival improves significantly with surgical cure.
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Epidemiology & Etiology
Exogenous steroid use is the most frequent cause in clinical practice. Endogenous cases are categorized as ACTH-dependent (pituitary adenoma, ectopic ACTH) or ACTH-independent (adrenal adenoma, carcinoma). Women are affected more frequently than men, typically in the 3rd to 4th decade of life.
Pertinent Anatomy
The hypothalamic-pituitary-adrenal (HPA) axis regulates cortisol. Pituitary adenomas arise from the anterior lobe, while adrenal tumors originate in the cortex, specifically the zona fasciculata.
Pathophysiology
Excessive cortisol leads to protein catabolism, causing muscle wasting and skin thinning. Hypercortisolism induces insulin resistance, leading to secondary diabetes and central obesity. Mineralocorticoid effects from high cortisol levels cause hypertension and hypokalemia.
Clinical Manifestations
Purple striae (>1cm) are the most specific physical exam finding. Patients present with moon facies, buffalo hump, and proximal muscle weakness. Psychiatric disturbances and pathologic fractures are critical red flags requiring immediate workup.
Diagnosis
Initial screening requires 24-hour urinary free cortisol, late-night salivary cortisol, or 1mg overnight dexamethasone suppression test. If abnormal, measure plasma ACTH to distinguish ACTH-dependent (<5 pg/mL is independent) from ACTH-independent. The high-dose dexamethasone suppression test confirms Cushing Disease if cortisol suppresses >50%.
Treatment
Surgical resection is the definitive treatment for all localized tumors. Transsphenoidal resection is the gold standard for pituitary sources. Ketoconazole is used for medical management in patients who are poor surgical candidates. Monitor for adrenal crisis post-operatively, requiring glucocorticoid replacement.
Prognosis
Untreated Cushing syndrome leads to increased cardiovascular mortality due to hypertension and metabolic syndrome. Patients require lifelong monitoring for recurrence and bone density screening for osteoporosis.
Differential Diagnosis
Pseudo-Cushing: alcohol use disorder or severe depression
Metabolic Syndrome: lacks the specific skin/muscle findings
Polycystic Ovary Syndrome: hyperandrogenism without cortisol excess
Adrenal Carcinoma: rapid onset with virilization
Ectopic ACTH: often presents with severe hypokalemia and weight loss