4th April 2024

Cushing’s Syndrome

Pathophysiology

Cushing’s syndrome is caused by an excess of glucocorticoid within the body. The most common cause is exogenous administration in patients on long term steroid tablets but less commonly, the syndrome can be due to excess ACTH or cortisol release from tumours.

Cushing’s disease is the most common non-iatrogenic cause of Cushing’s syndrome. It is caused by an ACTH secreting pituitary tumour which leads to bilateral adrenal hyperplasia. Certain cancers, including small cell lung cancers and carcinoid tumours can also secrete ACTH. In rare cases, cortisol is secreted directly from adrenal adenomas.

Clinical manifestations

Cushing’s syndrome affects multiple body systems shown in the image below.

Image Source: Wikimedia Commons (2015). Cushing’s Syndrome, Licensed under a creative commons licence. Available for free at: https://en.wikipedia.org/wiki/Cushing%27s_syndrome (Accessed: 6 February 2024).

Diagnosis

Numerous other conditions can present similarly to Cushing’s syndrome and it is important to exclude differentials such as metabolic syndrome; alcohol excess, pregnancy and physiological stress, before making a diagnosis. Medication history is important as chronic steroid use makes a diagnosis of Cushing’s syndrome more likely. Blood glucose should be monitored as Cushing’s syndrome can lead to glucose intolerance and diabetes.

Initial investigations include measurement of cortisol levels. This has diurnal variation with a morning peak and nadir at midnight. Measurements are checked at night when levels are lowest and the sample can be from saliva or a blood test.

Dexamethasone suppression tests are performed to confirm the diagnosis. This involves giving the patient 1mg of dexamethasone at 11pm and then testing their cortisol level at 8am the following morning. In a person without Cushing’s syndrome, the dexamethasone should inhibit further cortisol release due to the negative feedback loop on the hypothalamus-pituitary-adrenal axis, but this feedback loop is suppressed in Cushing’s syndrome. A positive result is indicated by a morning cortisol of >50 nanomols/L (it is worth noting that in some causes of Cushing’s syndrome, such as Cushing’s disease, a drop in cortisol is seen in response to high doses of dexamethasone).  Following confirmation of Cushing’s syndrome, checking ACTH levels can differentiate between ACTH-dependent and ACTH-independent causes. High ACTH levels indicate ACTH dependent causes of Cushing’s syndrome. This includes pituitary tumour (Cushing’s disease) and ectopic ACTH producing tumours. In ACTH independent causes (adrenal adenoma/bilateral adrenal hyperplasia), ACTH levels will be low.

If exogenous steroids are excluded as a cause but initial investigations still suggest Cushing’s syndrome then imaging including CT TAP and pituitary MRI are required to try and find the source of a possible ACTH or cortisol secreting tumour.

Management

In most cases where exogenous steroids are the cause there should be a discussion regarding risk-benefit of continuing them. If discontinuing steroids, they should be tapered gradually as abrupt cessation can precipitate adrenal insufficiency.

In cases where tumours are the cause of the syndrome surgical removal is the mainstay of treatment. Pituitary adenomas are usually removed through transsphenoidal surgery. If there is mild disease or if the patient is not fit for surgery or, if surgery has failed, then medical options include somatostatin analogues such as pasireotide.

References

• Cushing’s syndrome. BMJ Best Practice. Last reviewed 24 Jan 2022
• Adrenal cortex and Cushing’s syndrome. Oxford handbook of clinical medicine 9ᵗʰ edition
• Image taken from Wikipedia: Cushing’s Syndrome. Last edited 13ᵗʰ June 2022. Available at: https://en.wikipedia.org/wiki/Cushing%27s_syndrome