Cushing's Syndrome

Question 1

What is Cushing syndrome?

Answer 1

Cushing syndrome is the clinical manifestation of pathological hypercortisolism from any cause.

Question 2

What are the causes of Cushing’s syndrome?

Answer 2

Exogenous causes

• Corticosteroid exposure is the most common cause of Cushing syndrome.

Endogenous causes

• Adrenocorticotrophic hormone (ACTH)-secreting pituitary adenomas (termed Cushing’s disease)
• Adrenal adenoma (a hromone secreting adrenal tumour)
• Ectopic ACTH-secreting tumours

Question 3

Briefly differentiate between Cushing’s syndrome and Cushing’s disease

Answer 3

Cushing’s Syndrome is used to refer to the signs and symptoms that develop after prolonged abnormal elevation of cortisol.

Cushing’s Disease is used to refer to the specific condition where a pituitary adenoma (tumour) secretes excessive ACTH.

Cushing’s Disease causes a Cushing’s syndrome, but Cushing’s Syndrome is not always caused by Cushing’s Disease.

Question 4

Give examples of primary and secondary causes of Cushing’s syndrome

Answer 4

Primary

• Tumour in the zona fasciulata of adrenal gland
• Adenoma (benign) or adenocarcinoma (malignant)

Secondary

• Iatrogenic e.g. steroid use
• Pituitary adenoma
• Adrenal Cushing’s disease
• Ectopic ACTH

Question 5

What risk factors are associated with Cushing’s syndrome?

Answer 5

• Exogenous corticosteroid use
• Pituitary or adrenal adenoma
• Adrenal carcinoma

Question 6

What is paraneoplastic Cushing’s?

Answer 6

Paraneoplastic Cushing’s is when excess ACTH is released from a cancer (not of the pituitary) and stimulates excessive cortisol release. ACTH from somewhere other than the pituitary is called “ectopic ACTH”.

Small Cell Lung Cancer is the most common cause of paraneoplastic Cushing’s.

Question 7

What are the signs of Cushing’s syndrome?

Answer 7

• Progressive proximal muscle weakness
• Bruising without obvious trauma
• Facial plethora or rounding
• Violaceous striae
• Supraclavicular fat pad
• Dorsocervical fat pad
• Hypertension
• Glucose intolerance or diabetes mellitus

Question 8

What are the symptoms of Cushing’s syndrome?

Answer 8

• Weight gain and central obesity
• Amenorrhea
• Acne
• Psychiatric symptoms e.g. depression
• Decreased libido
• Rounding of the face
• Easy brusing and poor skin healing

Question 9

What investigations should be ordered for Cushing syndrome?

Answer 9

• Urine pregnancy test
• Serum glucose
• Late-night salivary cortisol
• 24 hours urinary free cortisol
• Dexamethasone Suppression Test
  
  • Low dose (1mg)
  • High dose (8mg)
• FBC
• U&Es

Question 10

What is the definitive test used to diagnose Cushing’s syndrome?

Answer 10

Dexamethasone suppression test (DST).

Question 11

Why investigate urine pregnancy test?

Answer 11

Women of childbearing potential should always have pregnancy excluded in the evaluation of hypercortisolism.

Question 12

Why investigate serum glucose?

Answer 12

Cushing syndrome commonly leads to diabetes and glucose intolerance.

Question 13

Why investigate late-night salivary cortisol?

Answer 13

Should be first-line test in any patient with suspected Cushing syndrome.

Value greater than the upper limit of normal is considered positive.

Question 14

Why investigate 24 hour urinary free cortisol?

Answer 14

Should be considered as a first-line test in any patient with suspected Cushing syndrome, except those with renal failure.

Generally >50 micrograms/24 hour. Normal ranges vary by assay method.

Question 15

Why investigate FBC?

Answer 15

May show raised WBCs.

Question 16

Why investigate U&Es?

Answer 16

May shown hypokalaemia if aldosterone is also secreted by an adrenal adenoma.

Question 17

What imaging can be used to identify the following tumours linked to Cushing’s syndrome?

1. Pituitary adenoma
2. Small cell lung cancer
3. Adrenal tumour

Answer 17

1. MRI brain for pituitary adenoma
2. Chest CT for small cell lung cancer
3. Abdominal CT for adrenal tumour

Question 18

What is the Dexamethasone Suppression Tests (DST)?

Answer 18

The dexamethasone suppression test is the test of choice for diagnosing Cushing’s Syndrome. This involves initially giving the patient the “low dose” test. If the low dose test is normal, Cushing’s can be excluded. If the low dose test is abnormal, then a high dose test is performed to differentiate between the underlying causes.

To perform the test the patient takes a dose of dexamethasone (a synthetic glucocorticoid steroid) at night (i.e. 10pm) and their cortisol and ACTH is measured in the morning (i.e. 9am). The intention is to find out whether the dexamethasone suppresses their normal morning spike of cortisol.

Question 19

What is the body’s normal response to dexamethasone?

Answer 19

A normal response is for the dexamethasone to suppress the release of cortisol by effecting negative feedback on the hypothalamus and pituitary. The hypothalamus responds by reducing the CRH output. The pituitary responds by reducing the ACTH output. The lower CRH and ACTH levels result in a low cortisol level.

Question 20

Briefly describe the low dose DST (1 mg)

Answer 20

When the cortisol level is not suppressed, this is the abnormal result seen in Cushing’s Syndrome.

Question 21

Briefly describe the high dose DST (8 mg)

Answer 21

The high dose dexamethasone suppression test is performed after an abnormal result on the low dose test.

Question 22

Briefly describe the results of the high dose DST for the following causes of Cushing’s syndrome

1. Pituitary adenoma
2. Adrenal adenoma
3. Ectopic ACTH

Answer 22

Pituitary Adenoma

• In Cushing’s Disease (pituitary adenoma) the pituitary still shows some response to negative feedback and 8mg of dexamethasone is enough to suppress cortisol.

Adrenal Adenoma

• Where there is an adrenal adenoma, cortisol production is independent from the pituitary. Therefore, cortisone is not suppressed however ACTH is suppressed due to negative feedback on the hypothalamus and pituitary gland.

Ectopic ACTH

• Where there is ectopic ACTH (e.g. from a small cell lung cancer), neither cortisol or ACTH will be suppressed because the ACTH production is independent of the hypothalamus or pituitary gland.

Question 23

Is cortisol and ACTH suppressed in pituitary adenoma, adrenal adenoma and ectopic ACTH?

Answer 23

Question 24

Briefly describe the treatment of Cushing’s syndrome

Answer 24

The main treatment is to remove the underlying cause (surgically remove the tumour)

• Trans-sphenoidal (through the nose) removal of pituitary adenoma
• Surgical removal of adrenal tumour
• Surgical removal of tumour producing ectopic ACTH

Question 25

If surgical resection of the underlying cause is not possible, what is the management?

Answer 25

If surgical removal of the cause is not possible another option is bilateral adrenolectomy. This procedure removes both adrenal glands and give the patient replacement steroid hormones for life.

Question 26

What are the complications of Cushing’s syndrome?

Answer 26

• Adrenal insufficiency secondary to adrenal suppression
• Cardiovascular disease
• Hypertension
• Diabetes mellitus
• Osteoporosis

Question 27

What differentials should be considered for Cushing’s syndrome?

Answer 27

1. Obesity
2. Metabolic syndrome

Question 28

How does Cushing’s syndrome and obesity differ?

Answer 28

Differentiating signs and symptoms:

• Usually lack facial plethora, unexplained bruising, proximal muscle weakness, violaceous striae, supraclavicular fullness, and osteoporotic fractures.

Differentiating investigations:

• Normal late-night salivary cortisol, dexamethasone suppression testing, or 24-hour urinary free cortisol.

Question 29

How does Cushing’s syndrome and metabolic syndrome differ?

Answer 29

Differentiating signs and symptoms:

• Usually lack facial plethora, unexplained bruising, proximal muscle weakness, violaceous striae, supraclavicular fullness, and osteoporotic fractures.

Differentiating investigations:

• Normal late-night salivary cortisol, dexamethasone suppression testing, or 24-hour urinary free cortisol.