Cushing's syndrome

Question 1

What is Cushing’s syndrome?

Answer 1

This is the clinical manifestation of pathological hypercortisolism from any cause.

Question 2

What is the most common cause of Cushing’s syndrome?

Answer 2

Cushing’s disease is the most common cause of Cushing’s syndrome and is responsible for 70-80% of cases.

Question 3

Aetiology of Cushing’s syndrome

Answer 3

Exogenous corticosteroid exposure
Cushing’s disease
Adrenal adenomas

Question 4

Pathophysiology of Cushing’s syndrome

Answer 4

• This result from excess tissue exposure to cortisol.
• The degree of symptoms is dependent on the degree of cortisol excess.
• As hypercortisolism increases, physical features worsen with striae, supraventricular fat pads and proximal muscle weakness developing.

Question 5

Classification of Cushing’s syndrome

Answer 5

ACTH-dependent
ACTH-independent
Exogenous

Question 6

What causes ACTH-dependent Cushing’s syndrome?

Answer 6

Caused by conditions that have high ACTH levels, this stimulates adrenal cortisol overproduction.
Caused by:
ACTH-secreting pituitary adenomas.
Ectopic ACTH-dependent disease (bronchogenic or neuroendocrine origin and it is also extremely rare)

Question 7

What causes ACTH-independent Cushing’s syndrome?

Answer 7

Excessive cortisol secretion by the adrenal glands despite suppressed ACTH levels. 
Caused by: 
Adrenal adenomas.
Bilateral adrenal hyperplasia 
Adrenal carcinoma (rare)

Question 8

Signs and symptoms of Cushing’s syndrome

Answer 8

Facial plethora 
Supraclavicular fullness 
Violaceous striae 
Absence of pregnancy 
Menstrual irregularities 
Easy bruisability 
Facial rounding 
Hirsutism
Female sex 
HTN 
Glucose intolerance or DM 
Weight gain and central obesity 
Acne 
Weakness 
Dorsocervical fat pads 
Unexplained nephrolithiasis

Question 9

Risk factors for Cushing’s syndrome

Answer 9

Exogenous corticosteroid use 
Pituitary adenoma 
Adrenal adenoma 
Adrenal carcinoma 
Neuroendocrine tumours 
Thoracic or bronchogenic carcinoma

Question 10

Investigations for Cushing’s syndrome

Answer 10

Urine pregnancy test (negative) 
Serum glucose (elevated) 
Late-night salivary cortisol (elevated) 
1mg overnight dexamethasone suppression test 
24-hour urinary free cortisol 
48-hour 2mg  dexamethasone suppression test 
Consider: 
Morning plasma ACTH 
Pituitary MRI 
Adrenal CT 
Inferior petrosal sinus sampling 
CT of chest, abdomen and pelvis 
MRI chest 
PET scan 
Octreotide scanning

Question 11

How does the 1mg overnight dexamethasone suppression test (ODST) work?

Answer 11

• A positive test is defined as morning cortisol >50 nanomol/L (>1.5 mcg/dl).
• Patient given 1mg of dexamethasone at 11 pm and a plasma cortisol level is obtained the following morning at 8 am.
• Positive results confirmed with late-night salivary cortisol or 24 hours urinary free cortisol.
• Initial diagnostic test in incidentally discovered adrenal nodules without clinical features of Cushing syndrome.
• This should be a first-line test in any patient with suspected Cushing syndrome except those taking medications affecting dexamethasone metabolism.

Question 12

Which drugs affect dexamethasone metabolism?

Answer 12

Phenytoin
Carbamazepine
Rifampicin
Cimetidine

Question 13

How does the 24-hour urinary free cortisol work?

Answer 13

• A positive test is defined as cortisol of >50 mcg/24 hours.
• Sensitivity may be lower than late-night salivary cortisol or 1mg ODST.
• At least 2 24-hour urinary free cortisol samples should be collected.
• CI in renal failure

Question 14

Differentials of Cushing’s syndrome

Answer 14

Obesity

Metabolic syndrome

Question 15

What is dexamethasone?

Answer 15

• This is an exogenous steroid that causes suppression of the pituitary gland through negative feedback.
• It is used to test for the integrity of the HPA axis.
• Dexamethasone binds to glucocorticoid receptors in the pituitary gland and thereby inhibits ACTH secretion by the pituitary gland.

Question 16

How does dexamethasone help to diagnose Cushing’s syndrome?

Answer 16

• In Cushing’s disease, there’s no reduction in cortisol output after low dose dexamethasone but inhibition of cortisol output following high-dose dexamethasone.
• In adrenal tumour or ectopic ACTH: There is no reduction in steroid production after low or high dose dexamethasone.

Question 17

When should ectopic ACTH secretion be considered?

Answer 17

In patients with high-resting cortisol and ACTH levels, but with the ACTH levels being not suppressed with low or high dose dexamethasone.

Question 18

Management of Cushing’s syndrome

Answer 18

Treatment should not be undertaken until the diagnosis is firmly established AND the source of hypercortisolism is recognised.

Question 19

Treatment of Cushing’s disease

Answer 19

• The ultimate goal is the removal of the causative pituitary adenoma and normalises cortisol levels while preserving pituitary function.
• Somatostatin (pasireotide), steroidogenesis inhibitors or mifepristone is occasionally used for mild hypercortisolism.
• First-line therapy is transsphenoidal resection of the causative pituitary adenoma.
• Many patients supported with corticosteroids following surgery.

Question 20

Treatment of ectopic ACTH syndrome

Answer 20

-Surgical resection or ablation of the tumour with medical therapy (mifepristone, pasireotide) and chemotherapy or radiotherapy for the primary tumour.
-2nd line:
Bilateral adrenalectomy and permanent of corticosteroid replacement.

Question 21

Complications of Cushing’s syndrome

Answer 21

CVD 
HTN 
DM 
Osteoporosis 
Nephrolithiasis 
Nelson's syndrome after bilateral adrenalectomy