Cushing's syndrome (hyperadrenocorticism)

Question 1

What is it

Answer 1

Clinical state prod by chronic glucocorticoid excess + loss norm feedback mechanism (hypothalamo-pituitary-adrenal axis) + loss circadian rhythm of cortisol secretion

• Cushing’s disease –> ACTH-Dependent pituitary adenoma (pituitary dependent hyperadrenalism)

Question 2

How common is it

Answer 2

• 10-15 per million

Question 3

Who is affected

Answer 3

Cushing’s syndrome due to adrenal/pituitary tumour = F>M (5:1)
- Peak age = 25-40 years

When older age = ectopic ACTH production due to lung cancer

Question 4

What are some risk factors

Answer 4

Incidence higher in those w/ diabetes, HTN, osteoporosis or obesity

Question 5

What causes Cushing’s

Answer 5

ACTH-DEPENDENT (Increase ACTH)

• CUSHING’S DISEASE - hyperplasia from pituitary adenoma –> excessive ACTH (X dexamethasone test)
• Ectopic ACTH-producing tumours = small cell lung cancer, carcinoid tumours
• Endocrine tumour = phaeochromocytoma, pancreatic neuroendocrine tumour

ACTH-INDEPENDENT (decrease ACTH - -ve feedback)

• Adrenal adenoma/carcinoma (unilat) - tumour autonomous so dexamethasone will not suppress
• Iatrogenic - pharm doses steroids (COMMON)
• Adrenal nodular hyperplasia
• rarely = McCune-Albright Syndrome

Question 6

What is the pathophysiology

Answer 6

• CRF (corticotropin releasing factor) from hypothalamus –> Stim ACTH secretion from pituitary –> stim cortisol + androgen production by adrenal cortex

Adrenal cortex produces steroids:

• Glucocorticosteroids e.g. cortisol - affect carb, lipid, protein meta
• Mineralcorticoids e.g. aldosterone - control Na + K balance
• Androgens - sex hormones - weak effect until peripherally converted –> (dihydro-)testosterone

Question 7

What are the symptoms of cushing’s

Answer 7

• Increased weight
• Mood change (depression, lethargy, irritability, psychosis)
• Proximal weakness
• Gonad dysfunction (irregular meses, hirsutism (++hair), erectile dysfunction
• Ance
• Reccurrent achilles tendon rupture

Question 8

What are the signs of cushing’s

Answer 8

• central / truncal obesity
• plethoric, moon face
• Buffalo neck hump + supraclavicular fat distribution
• Skin + muscle atrophy
• Bruises
• Abdo striae
• Osteoporosis
• Increased BP + glucose
• Impaired immune function - increased infection, difficulty wound healing

Question 9

What is a DDx

Answer 9

• Pseudo-cushings

Question 10

What investigations would you do

Answer 10

• Random plasma cortisol may MISLEAD – influenced by time of day, illness, stress etc
• Confirm Dx ( plasma cortisol), localize source using imaging + lab

1st line OVERNIGHT DEXAMETHASONE SUPPRESSION TEST
• Dexamethasone PO at midnight + serum cortisol at 8am
• If NORMAL person = will decrease ACTH + decrease cortisol secretion <50nmol/L (high dose of steroid causes –ve feedback)
• If CUSHINGS – no cortisol suppression
• 24hr urinary free cortisol (normal <280nmol/24h) = alternative

2nd LINE
• 48hr dexamethasone suppression test – give dexamethasone over long period time – suppression in cushings
• Midnight cortisol – Needs admission – normal circadian rhythm (cortisol lowest at midnight + highest early morning) lost in Cushing’s midnight blood shows cortisol

LOCALISATION TESTS
• Plasma ACTH – if ACTH undetectable adrenal tumour is likely –> CT adrenal glands
• If no mass ADRENAL VEIN SAMPLING or ADRENAL SCINTIGRAPHY (radiolabeled cholesterol derivative)
• If ACTH detectable – distinguish pituitary cause from ectopic ACTH production by:

• HIGH-DOSE DEXAMETHASONE SUPPRESSION TEST – high dose over 2 days – check after 48hrs – complete or partial = Cushing’s as pituitary retains some feedback control, ectopic cause not under feedback control
• Or CORTICOTROPIN RELEASING HORMONE TEST – human CRH IV measure after 120mins cortisol rises w/ pituitary disease but not w/ ectopic
• If test indicate that cortisol responds to manipulation Cushing’s disease = likely

Question 11

What is the treatment

Answer 11

• Iatrogenic - stop steroid/medication
• Cushing’s disease - selective removal of pituitary adenoma, bilateral adrenalectomy if source unlocatable or recurrence post-op
• Adrenal adenoma/carcinoma –> adrenalectomy ‘cures’ but need radiotherapy
• Ectopic ACTH production - surgery if tumour located - fluconazole to inhibit synthesis
• Pituitary radiation - used in persisting hypercortisolaemia after trans-sphenoidal surgery