AssessmentsCushing syndrome and Cushing disease: Pathology review
USMLE® Step 1 style questions USMLE
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?
Content Reviewers:Yifan Xiao, MD
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.
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.
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.
In fact, only this small fraction of free cortisol is biologically active, and its levels are carefully controlled.
Excess free cortisol is filtered in kidneys and dumped into the urine.
Finally, cortisol receptors are present in the brain, where their full effect is still actually unclear but might influence things like mood and memory.
For all this to work properly, though, the levels of free cortisol have to stay within the normal range.
A very high yield fact is that the majority of cases of Cushing syndrome occur in individuals using exogenous cortisol, like prednisone, over a long period of time, often as a treatment for autoimmune and inflammatory conditions, like rheumatoid arthritis or poorly controlled asthma.
They have structures similar to endogenous cortisol and mimics its actions in various tissues.
In fact, exogenous cortisol can also cause negative feedback on the hypothalamus and the pituitary gland, leading to a decrease in CRH and ACTH, which in turn, shuts down cortisol production from the zona fasciculata.
Over time, this lack of stimulation can cause zona fasciculata of both adrenal glands to physically shrink or become atrophic.
If the cortisol level is low enough, it might trigger an adrenal crisis.
The exact reason for the development of this sort of benign tumor isn’t known, and the pituitary adenoma simply grows in size and secretes excess ACTH.
Apart from pituitary adenomas, there are ectopic sources of ACTH such as paraneoplastic syndromes.
Another common cause of endogenous Cushing syndrome is tumors of the adrenal glands that make excess cortisol, like adrenal adenomas, which are benign tumors, and adrenal carcinomas, which are malignant tumors.
Although this doesn’t have any effect on zona fasciculata of the involved adrenal gland, since the neoplastic cells are autonomous, meaning that they grow independently from ACTH.
The net result, though, is abnormally high levels of cortisol, and that causes Cushing syndrome. Regardless of the cause, the symptoms of Cushing syndrome are directly related to the effects of excess cortisol and other glucocorticoids on its various target tissues.
Since cortisol levels are elevated chronically, its effects will be exaggerated.
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- "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
- "A Physiologic Approach to Diagnosis of the Cushing Syndrome" Annals of Internal Medicine (2003)
- "Cushing’s Syndrome: All Variants, Detection, and Treatment" Endocrinology and Metabolism Clinics of North America (2011)
- "Evaluation and treatment of Cushing’s syndrome" The American Journal of Medicine (2005)