Cushing syndrome and Cushing disease: Pathology review

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Cushing syndrome and Cushing disease: Pathology review



Cushing syndrome and Cushing disease: Pathology review

USMLE® Step 1 questions

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A 58-year-old man comes to the emergency department because of fatigue and a cough that is productive of blood-tinged sputum. His symptoms began four months ago. Past medical history is notable for emphysema and hypertension. He has a 40-pack-year smoking history. Physical examination reveals 4/5 strength in the bilateral upper and lower extremities. Ecchymoses and striae are noted on the abdomen. Laboratory testing reveals a fasting blood glucose of 147 mg/dL. Chest X-ray shows a mass in the perihilar region of the left lung. A 24-hour urine sample reveals an elevated cortisol level. A high-dose dexamethasone test is subsequently ordered as part of the patient’s work-up. Which of the following ACTH levels would be expected before and after the high-dose dexamethasone is administered?  


On the Endocrinology ward, two people came in with similar symptoms.

One of them is 45 year old Samantha, who complains of gaining a lot of weight lately.

Smantha also suffers from severe asthma for which she’s taking oral glucocorticoids.

She also had many viral and bacterial infections lately.

On clinical examination, there’s truncal obesity, a large hump behind her neck, and striae on her abdomen.

Her arterial pressure was elevated and she also had hyperglycemia.

The other person is 38 year old Dan who is also obese, and has an abnormally round face.

He has arterial hypertension and hyperglycemia.

Unlike Samantha, Dan is not taking any medications. A 24 hour urine free cortisol was done in both individuals and levels were high.

Further investigations were done, including ACTH levels.

Now, both individuals suffer from an endocrine disorder that involves high levels of cortisol. This is generally called Cushing syndrome.

Now, if Cushing syndrome results from a pituitary adenoma making excess ACTH, it’s called Cushing disease.

Normally, the hypothalamus secretes corticotropin-releasing hormone, known as CRH, which stimulates the pituitary gland to secrete adrenocorticotropic hormone, known as ACTH. ACTH travels to the adrenal glands where it targets cells in the adrenal cortex.

The adrenal cortex is the outer part of the adrenal gland and is subdivided into three layers- the zona glomerulosa, the zona fasciculata, and the zona reticularis.

Zona fasciculata is the middle zone and also the widest zone, and ACTH specifically stimulates cells in this zone to secrete cortisol.

This is a class of steroids, or lipid-soluble hormones, called glucocorticoids.

Glucocorticoids are not soluble in water, so most cortisol in the blood is bound to a special carrier protein and only about 5% is unbound or free.

In fact, only this small fraction of free cortisol is biologically active, and its levels are carefully controlled.


  1. "Robbins Basic Pathology" Elsevier (2017)
  2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
  3. "A Physiologic Approach to Diagnosis of the Cushing Syndrome" Annals of Internal Medicine (2003)
  4. "Cushing’s Syndrome: All Variants, Detection, and Treatment" Endocrinology and Metabolism Clinics of North America (2011)
  5. "Evaluation and treatment of Cushing’s syndrome" The American Journal of Medicine (2005)

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