QuestionSBA
QuestionChoice
This is an appropriate test for this patient as hypercortisolism can cause hyperglycaemia which may need treatment. However this test would not help to establish the **cause** of these symptoms
33369
b
Fasting blood glucose levels
QuestionChoice
This patient has many symptoms pointing towards hypercortisolism. The first step in investigation here would be to confirm this clinical suspicion. An overnight 1mg dexamethasone suppression test is a suitable first line investigation in patients with suspected Cushing's syndrome. 1mg of dexamethasone is given at midnight and cortisol levels are checked at 8 am. An 8 am cortisol result of <50 nmol/L is normal (as the axis should be suppressed) and >50 nmol/L is abnormal. This requires further investigation (to confirm the result and classify into ACTH dependent vs ACTH independent)
33368
a
1mg overnight dexamethasone suppression test
QuestionChoice
An adrenal CT may be appropriate further into this patients work up, if it is confirmed that she has ACTH-independent hypercortisolism - a solitary secretory adrenal adenoma is the most common cause
33372
e
Computer tomography (CT) of the adrenal glands
QuestionChoice
Before checking the ACTH level, it first needs to be established if the patient has hypercortisolism
33371
d
Adrenocorticotrophic hormone (ACTH) level
QuestionChoice
A pituitary MRI may be appropriate further into this patient's work up, if it is confirmed that she has ACTH-dependant hypercortisolism (suggestive of pituitary adenoma/**"Cushing's disease"** or an ectopic source of cortisol)
33370
c
Pituitary magnetic resonance imaging (MRI)
Concept
Chapter
# Summary

Cushing's syndrome is an endocrine disorder characterised by excess glucocorticoids, which can have ACTH-dependent or independent origins. Clinically, patients may present with symptoms such as proximal myopathy, obesity, hypertension, and various dermatological changes. Diagnosis is made through investigations such as a 24-hour urinary free cortisol test and low-dose dexamethasone suppression test, alongside imaging for localisation. Management includes medical therapy to reduce cortisol levels, surgery, radiotherapy, and the need for post-operative steroid replacement in successful cases.

# Definition

Cushing's syndrome is an endocrine disorder characterised by excess glucocorticoids, often resulting in distinctive clinical symptoms and signs. It is important to distinguish Cushing's syndrome from **Cushing's disease,** which specifically refers to glucocorticoid excess caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumour.

# Epidemiology

Cushing's syndrome is a relatively rare condition, estimated to affect 2 to 3 per million people each year. It is more common in adults, particularly women, with a peak incidence between 25-40 years.

# Aetiology

The causes of Cushing's syndrome can be divided into ACTH-dependent and ACTH-independent:

- **ACTH-dependent disease:** This is caused by excessive production of ACTH, most often due to a pituitary tumour (Cushing's disease) or ectopic ACTH-producing tumours (e.g. lung carcinoids, thymic carcinoids, and others).
- **ACTH-independent:** This arises from primary adrenal diseases, such as adrenal adenomas or adrenal carcinomas, which produce excess cortisol independently of ACTH stimulation. Exogenous steroids can also cause ACTH-independent Cushing's.

# Signs and Symptoms

Clinical features of Cushing's syndrome may include:

- Proximal myopathy
- Striae and easy bruising
- Osteoporosis and fractures
- Glucose intolerance or diabetes mellitus
- Obesity, particularly truncal or "centripetal" obesity
- Hypertension
- Hypokalaemia
- Facial changes, such as moon face and acne
- Hirsutism in women
- Fat redistribution leading to interscapular and supraclavicular fat pads
- Thin extremities due to muscle wasting
- Thin, fragile skin
- Erectile dysfunction in men
- Psychological issues, such as depression or cognitive dysfunction
- Osteopenia or osteoporosis

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# Differential Diagnosis

Key differentials include conditions that may cause similar clinical features, such as:

- Metabolic syndrome
- Polycystic ovary syndrome
- Adrenal insufficiency
- Alcohol excess
- Depression. 

Distinguishing these conditions often relies on biochemical and imaging investigations.

# Investigations

To confirm the diagnosis and identify the cause:

Biochemical evidence of cortisol excess:

- 24-hour urinary free cortisol test
- Low-dose Dexamethasone suppression test:
  - Not suppressed by low dose - Cushing’s syndrome (e.g. exogenous steroid use)
  - Not suppressed by low dose but suppressed by high dose - Cushing’s disease (pituitary source)
  - Not suppressed by low dose or by high dose dexamethasone – ectopic ACTH (not under axis control, likely ACTH-producing tumour)

Localisation of the source:

- Plasma ACTH levels to distinguish between ACTH-dependent and independent causes
- High-dose dexamethasone suppression test for suspected Cushing's disease
- Inferior petrosal sinus sampling for suspected pituitary cause
- MRI of the pituitary and/or CT of chest and abdomen for tumour localisation


# Management

Management of Cushing's syndrome varies according to the underlying cause and may involve a combination of medical, surgical, and radiotherapy options:

- **Medical Management:** Initial therapy often involves medications to decrease cortisol levels. These include Metyrapone, an inhibitor of cortisol synthesis; Ketoconazole, an adrenolytic agent; Mifepristone, a glucocorticoid receptor antagonist; and Pasireotide, a somatostatin analog.

- **Surgical Management:** Resection of the pituitary tumour is the treatment of choice for Cushing's disease, often after initial control of hypercortisolaemia with medical therapy to improve surgical outcomes.
  - NB: Old treatment for Cushing's disease used to be bilateral adrenalectomy, which has risk of developing into Nelson syndrome - enlarging of an adrenocorticotropic hormone-producing tumour in the pituitary gland.

- **Radiotherapy:** May be considered for cases where hypercortisolaemia persists post-surgery, or in cases where surgery is not possible or declined.

Successful treatment of Cushing's disease leads to cortisol deficiency and subsequently, steroid replacement post-operatively is essential. Patients need to carry a steroid card and ideally wear a medic alert bracelet in case of acute illness or emergency situations.

Patients unfit for surgery or with unresectable lesions are managed with medical therapy alone.

# References

[BNF - Cushing's syndrome](https://bnf.nice.org.uk/treatment-summaries/cushings-syndrome/#:~:text=Cushing's%20syndrome%20results%20from%20chronic,%2C%20ectopic%20ACTH%2Dsecreting%20tumours.)
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A typical appearnce of hirsutism in a woman with a cushingoid face.
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Abdominal striae  and central adiposity seen in a  gentleman with cushings.
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A 30-year-old woman attends to see her GP with concerns about her fertility. For the past two years, she has noted increasingly irregular menses. This is in addition to 15 kilograms of weight gain with notable purple striae across her abdomen.

On examination, the patient is noted to have hyperpigmentation in her palmar folds, multiple unexplained bruises across her arms and facial plethora.

What is the most appropriate first line test to investigate the cause of these symptoms?
a