Cushing's syndrome (E&M)

Question 1

Define Cushing’s syndrome.

Answer 1

Syndrome associated with chronic inappropriate elevations of free circulating cortisol (pathological hypercortisolism from any cause)

Question 2

How can we classify Cushing’s syndrome?

Answer 2

• ACTH dependent (80%)
  
  • pituitary adenoma (Cushing’s disease) –> excess ACTH
  • ectopic ACTH (small cell lung cancer, pulmonary carcinoid tumour)
• ACTH independent (20%)
  
  • adrenal adenoma (benign)
  • adrenal carcinoma
  • oral steroids - chief cause

Question 3

Which groups does Cushing’s syndrome happen most commonly in? (2)

Answer 3

• F>M
• 20-40 years old

Question 4

What are some risk factors for Cushing’s syndrome? (4)

Answer 4

• exogenous corticosteroid use (most common cause)
• pituitary adenoma (Cushing’s disease)
• adrenal adenoma
• adrenal carcinoma

Question 5

What else can mimic Cushing’s syndrome? (2)

Answer 5

• excess alcohol consumption (pseudo-Cushing’s)
• metabolic syndrome (central obesity with insulin resistance and hypertension)

Question 6

What are the clinical features of Cushing’s syndrome? (16)

Answer 6

• thin, easily bruisable skin with ecchymoses
• stretch marks (striae)
• proximal myopathy (muscle weakness)
• central obesity
• moon face
• facial plethora
• intracapsular fat pad - buffalo neck hump
• fatigue
• acne & hirsutism
• hyperpigmentation (if ACTH-dependent)
• lethargy & depression
• osteopenia & osteoporosis
• hypertension
• hyperglycaemia
• gonadal dysfunction & low libido
• increased susceptibility to infection

Question 7

What are the discriminatory features of Cushing’s syndrome? (6)

Answer 7

• bruising and thin skin
• purple striae >1cm wide
• myopathy (proximal)
• DM, HTN, osteoporosis at young age
• facial plethora
• supraclavicular fat pads

Question 8

What are the first-line, high sensitivity investigations for Cushing’s syndrome? (4)

Answer 8

• late-night salivary cortisol
• 1mg overnight low-dose dexamethasone suppression test
• 24h urinary free cortisol
• high-dose dexamethasone suppression test

Question 9

What is the first-line and most sensitive test for diagnosing Cushing’s syndrome?

Answer 9

Low-dose (1mg) overnight dexamethasone suppression test

• patient given 1mg dexamethasone at 11pm and plasma cortisol measured the following morning at 8am
• Cushing’s syndrome - failure to suppress morning cortisol spike (>50nmol/L)

Question 10

What does late night salivary cortisol or 24-hour free cortisol show in Cushing’s syndrome?

Answer 10

Elevated

Question 11

What test can we use to distinguish between adrenal Cushing’s syndrome, Cushing’s disease and ectopic ACTH production?

Answer 11

High-dose dexamethasone suppression test

Question 12

How does the high-dose dexamethasone suppression test work in Cushing’s syndrome?

Answer 12

High-dose dexamethasone inhibits excess ACTH production from pituitary, but autonomous cortisol production from adrenals is not inhibited

Question 13

What are the results of high-dose dexamethasone suppression test in different forms of Cushing’s syndrome?

Answer 13

• Cushing’s syndrome due to adrenal adenoma/carcinoma/steroids: ACTH suppressed, cortisol NOT suppressed
• Cushing’s disease (pituitary adenoma): ACTH AND cortisol suppressed
• ectopic ACTH: NEITHER ACTH nor cortisol suppressed

Question 14

What do we check for in bloods for Cushing’s syndrome? (4)

Answer 14

• hyperglycaemia
• hypokalaemia - ectopic ACTH production due to SCLC
• hypernatraemia
• metabolic alkalosis - increased H+ excretion and HCO3- reabsorption

Question 15

What might ABG show in Cushing’s syndrome?

Answer 15

Metabolic alkalosis - increased H+ excretion and HCO3- reabsorption

Question 16

What do tests show for ACTH-dependent Cushing’s syndrome?

Answer 16

• high plasma ACTH
• pituitary MRI if Cushing’s disease suspected
• CXR and bronchoscopy if SCLC suspected
• high-dose dexamethasone suppression test negative - both cortisol and ACTH suppressed

Question 17

How do we differentiate between pituitary and ectopic ACTH secretion in Cushing’s syndrome?

Answer 17

• petrosal sinus sampling of ACTH
• CRH stimulation - cortisol rises if pituitary, no change if ectopic/adrenal

Question 18

What do tests show for ACTH-independent Cushing’s syndrome (adrenal cause)?

Answer 18

• low plasma ACTH
• CT/MRI of adrenals
• high-dose dexamethasone suppression test = ACTH suppressed, cortisol not suppressed

Question 19

How can we differentiate between Cushing’s and pseudo-Cushing’s?

Answer 19

Insulin stress test

Question 20

How can we differentiate between primary and secondary aldosteronism?

Answer 20

Look at renin levels - if renin is high, then a secondary cause is more likely e.g. renal artery stenosis

Cushing’s syndrome = plasma renin would not be high

Question 21

What are some differential diagnoses for Cushing’s syndrome? (2)

Answer 21

• obesity
• metabolic syndrome
• (both lack: facial plethora, unexplained bruising, proximal myopathy, violaceous striae, supraclavicular fullness and osteoporotic fractures)

Question 22

How do we manage Cushing’s syndrome due to excess steroid use?

Answer 22

Discontinue steroids / use lower dose / use steroid-sparing agent

Question 23

What medical management is there for Cushing’s syndrome?

Answer 23

Steroidogenesis inhibitors: consider prior to surgery, only short-term use for severe hypercortisolism

• metyrapone (11b-hydroxylase inhibitor –> N&V, hypoadrenalism)
• ketoconazole (17a-hydroxylase inhibitor –> N&V, alopecia, liver damage)

(Dopamine agonist - cabergoline, glucocorticoid receptor antagonist - mifepristone, somatostatin analogue - pasireotide etc)

Question 24

How do we manage Cushing’s disease?

Answer 24

• transsphenoidal pituitary adenomectomy
• consider post-op corticosteroid replacement (hydrocortisone) and hormonal replacement (pituitary hormones)
• if unsuccessful, try medical therapies alone or pituitary radiotherapy or bilateral adrenalectomy (with hormone replacement)

Question 25

How do we manage Cushing’s syndrome due to adrenal adenoma/carcinoma?

Answer 25

Adrenalectomy (unilateral if possible)

Question 26

How do we manage ectopic ACTH Cushing’s syndrome?

Answer 26

• surgical resection with bridging medical therapy +/- chemo and radiotherapy
• second-line: bilateral adrenalectomy with replacement
• third-line: medical therapy only

Question 27

What are some complications of Cushing’s syndrome? (9)

Answer 27

• diabetes
• osteoporosis (excess bone exposure to glucocorticoids = decreased osteoblast activity, increased osteoclast activity)
• hypertension
• predisposed to infections
• adrenal insufficiency (secondary to adrenal suppression)
• CVD
• nephrolithiasis
• Nelson syndrome (after bilateral adrenalectomy - progression of pituitary adenoma –> intracranial mass effect and elevated ACTH)
• treatment-related central hypothyroidism/GH deficiency/adrenal insufficiency/hypopituitarism/hyponatraemia/hypogonadism/diabetes insipidus

Question 28

Describe the prognosis of Cushing’s syndrome.

Answer 28

• untreated disease has poor survival rate of 50% at 5 years
• patients may have decreased QoL after treatment