16th September 2024

Cushing’s disease

Cushing’s disease is characterised by increased ACTH production, leading to excess cortisol and adrenal hyperplasia. It is a rare disease, and the majority of cases are caused by a pituitary adenoma, typically a microadenoma. To a lesser extent, the condition can arise from excess CRH production by the hypothalamus. Cushing’s disease is the second most common cause of Cushing syndrome, with the leading cause being the exogenous use of corticosteroids.

Clinical features

As mentioned, Cushing disease is typically caused by a microadenoma and thus the local mass effects on surrounding structures can occur, but it is rare.

Although much less common than GH-secreting tumours, macroadenomas that secrete can also present with mass effects on surrounding structures.

Investigations

High levels of cortisol can be identified in the saliva, blood, and urine. A 24-hour urinary free cortisol, a late-night salivary cortisol test and the low dose dexamethasone suppression test which should suppress cortisol so if it is high, it is in keeping with Cushing syndrome. After this is confirmed, further localisation tests need to be performed which include:

• Plasma ACTH and cortisol levels at 9am and midnight.
  • If ACTH is high the cause is ACTH dependent (exogenous steroid or adrenal tumour)
  • If ACTH is low the cause is ACTH independent (Cushing disease or ectopic ACTH secretion)
• High dose dexamethasone suppression test (if cortisol suppressed then it indicates Cushing disease/pituitary adenoma)
• CRH stimulation test (if cortisol rises then it indicates a pituitary source)
• Petrosal sinus sampling measures the difference in ACTH level found in the inferior petrosal sinus (where the pituitary gland drains) compared to the periphery

By using these tests, healthcare providers can accurately diagnose Cushing disease and determine its underlying cause.

Management

Transsphenoidal microadenomectomy is the first-line treatment choice, with radiotherapy being a second-line option for patients in whom surgery is contraindicated or was not successful. Medications are often used either prior to surgery or after to aid with suppression of cortisol suppression. Two agents licensed for this include metyrapone and ketoconazole. Post-operative vasopressin deficiency and SIADH can occur.

References

• Kairys N, Anastasopoulou C, Schwell A. Cushing Disease. [Updated 2023 Feb 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK448184/
• Nieman L. Establishing the cause of Cushing syndrome [Internet]. Lacroix A, Rubinow K, editors. UpToDate. 2023. Available from: https://www.uptodate.com/contents/establishing-the-cause-of-cushing-syndrome#H1760641735
• NICE Treatment summaries. Cushing’s syndrome [Internet]. NICE. 2024. Available from: https://bnf.nice.org.uk/treatment-summaries/cushings-syndrome/