cushing's syndrome

Question 1

definition of Cushing’s syndrome

Answer 1

Syndrome associated with chronic inappropriate elevation of free circulating cortisol.

loss of the normal feedback mechanisms of the hypothalamo-pituitary-adrenal axis and loss of the circadian rhythm of cortsiol secretion (normally highest on waking)

Question 2

aetiology of Cushing’s syndrome

Answer 2

ACTH dependent 80%

ACTH independant

ACTH-independent micro- or macronodular adrenal hyperplasia

oral steroids

Question 3

ACTH dependant Cushing’s syndrome

Answer 3

excess ACTH secreted from a pituitary tumour - cushing’s disease - 80% = bilateral adrenal hyperplasia - A low dose dexamethasone test leads to no change in plasma cortisol, but 8mg may be enough to more than halve morning cortisol (as occurs in normals).

ACTH secreted from an ectopic source, e.g. small-cell lung carcinomas, pulmonary carcinoid tumours (20%) - Dexamethasone even in high doses (8mg) fails to suppress cortisol production.

rare - ectopic CRF production - some medullary thyroid and prostate ca

Question 4

ACTH independant Cushing’s syndrome

Answer 4

Excess cortisol secreted from a benign adrenal adenoma (60%).

Excess cortisol secreted from an adrenal carcinoma (40%).

adrenal cancer/adenoma may cause abdo pain +- virilisation in females - tumours are autonomous so no amout of dexamethasone will suppress cortisol

adrenal nodular hyperplasia - as for adrenal adenoma - no dex suppression

iatrogenic - steroids

rare - carney complex, McCune-Albright syndrome

Question 5

ACTH independent micronodular adrenal hyperplasia

Answer 5

may be isolated or part of Carney’s complex - autosomal dominant syndrome, characterised by spotty skin, endocrine tumours, myxomas of the skin, heart, breast

genes: PRKAR1A,PDE11A, andMYH8.

Question 6

ACTH independant macronodular adreanl hyperplasia

Answer 6

ectopic expression of G protein coupled receptors or increased expression/activity of some eutopic receptors

McCune–Albright syndrome is a rare variant caused by activating mutations of thea-subunit of stimulatory G protein - cafe au lait spots, polyostotic fibrous dysplasia, precocious puberty and other endocrine disorders.

Question 7

mx of nodular adrenal hyperplasia

Answer 7

Surgical bilateral adrenalectomy is used in patients with micronodular adrenal hyperplasia and most patients with macronodular adrenal hyperplasia.

Question 8

epidemiology of Cushing’s syndrome

Answer 8

Incidence reported as 2–4/1000000 per year, but may be more.

Endogenous Cushing’s syndrome is more common in females.

20-40yrs

Question 9

sx of cushing’s syndrome

Answer 9

increased weight and fatigue

prox muscle weakness

myalgia

thin skin

easy bruising

poor wound healing

fractures - from osteoporosis

hirsutism

acne

frontal balding

oligo- or amenorrhoea

erectile dysfunction

recurrent achiles tendon rupture

occaisionally virilisation in female

depression

psychosis

irritability

lethargy

Question 10

signs of cushing’s syndrome

Answer 10

facial fullness

facial plethora

intrascapular fat pad

supraclavicular fat distribution

central obesity

skin and muscle atrophy

pink/purple striae on abdo, breast and thighs

infection prone

signs of cause eg abdo mass

kyphosis due to vertebral fracture

osteoporosis

hyperglycaemia

poorly healing wounds

hirsuitism

acne

frontal balding

HTN

ankle oedema - salt and water retention as a result of mineralocorticoid effect of excess cortisol

pigmentation in ACTH dependent cases

Question 11

Ix for cushing’s syndrome

Answer 11

blood

• hypokalaemia - particularly in ectopic cushings
• high glucose

random plasma glucose misleading - influenced by illness, time of the day and stress

urinary free cortisol - 2 or 3 24hr collections (normal <280nmol/24hr)

late night salivary cortisol

overnight dexamethasone suppression test

low dose dexamethasone suppression test

• 0.5mg dexamethasone orally every 6hr for 48hr
• serum cortisol fails to suppress below 50nmol/L after the 48hrs = dx

48h high-dose dexamethasone suppression test:

• (2mg/6h.) May distinguish pituitary (suppression) from others causes (no/part suppression)

midnight cortisol

imaging might show incidentalomas

Question 12

Ix to determine the cause of Cushing’s syndrome

Answer 12

ACTH independant - low ACTH, CT/MRI adrenals - if no mass do adrenal vein sampling

pit adenoma - high plasma ACTH, pit MRI, high dose dexamtheosone suppression (or inferior petrosal sinus sampling - central:peripheral ratio of venous ACTH >2:1 or >3:1 after CRH admin

ectopic acth - if suspect lung cancer: CXR, sputum cytology, bronchoscopy, CT scan. Radiolabelled octreotide scans to detect carcinoid tumours as they express somatostatin receptors. IV contrast CT of chest, abdo, pelvis +- MRI of neck, thorax, abdo - for small ACTH secreting carcinoid tumours

if ACTH high - corticotropin-releasing hormone (CRH) test: 100mcg ovine or human CRH IV. Measure cortisol at 120min. Cortisol rises with pituitary disease but not with ectopic ACTH production

Question 13

Mx of iatrogenic cushings

Answer 13

discontinue admin

lower steroid dose

steroid sparing alternative

Question 14

medical treatment of cushings

Answer 14

pre-op/unfit

metyrapone, ketoconazole and fluconzole - inhibit cortisol synthesis

treat osteoporosis

physio for muscle weakness

Ectopic ACTH - Intubation + mifepristone (competes with cortisol at receptors) + etomidate (blocks cortisol synthesis) may be needed, eg in severe ACTH-associated psychosis.

Question 15

surgical Mx of cushings

Answer 15

pit adenomas - trans-spehnoidal adenoma resection (hydrocortisone replaced until pit function recovers) - bilateral adrenalectomy if source unlocatable or recurrence

adrenal adenoma/carcinoma - removal of tumour, and adjuvent mitotane for carcinoma

adrenalectomy cures adenomas

ectopic ACTH - treatment directed at tumour

Question 16

radiotherapy for Cushings

Answer 16

not cured and have persistant hypercortisolaemia after trans-sphenoidal resection

stereotactic radiotherapy = less irradiation to surrounding areas

done for adrenal carcinoma

Question 17

Mx for refractory cushings

Answer 17

bilateral adrenalectomy possibly

Question 18

complications from Cushings

Answer 18

diabetes

osteoporosis

HTN

pre-disposition to infections

Question 19

complications from surgery for cushings

Answer 19

CSF leakage

meningitis

sphenoid sinusitis

hypopit

Question 20

complications from radiotherapy for cushings

Answer 20

hypopit

radionecrosis

small increased risk of intracranial tumours and stroke

Question 21

complications of bilateral adrenalectomy

Answer 21

development of Nelson’s syndrome (locally agressive pit tumour = skin pigmentation from excessive ACTH) - responds to pit irradiation

Question 22

prognosis of cushing’s syndrome

Answer 22

if untreated - 5yr survival 50%

high vascular mortality

depression after successful treatment for years

Treated, prognosis is good (but myopathy, obesity, menstrual irregularity, HTN, osteoporosis, subtle mood changes and DM often remain—so follow up carefully, and manage individually).

Question 23

physiology of the adrenal cortex

Answer 23

adrenal cortex produces steroids:

• glucocorticoids (cortisol) - affect carb, lipid and protein metabolism
• mineralocorticoids - control Na and K balance
• androgens - sex hormones that have weak effect until peripheral conversion to testosterone adn dihydrotestosterone

corticotrophin releasing factor (CRF) from the hypothalamus stimulates ACTH secretion drom the pituitary -> stimulates cortisol and androgen production from the adrenal cortex

cortisol is excreted as urinary free cortsiol and various 17-oxogenic steroids

Question 24

special features of ectopic ACTH production

Answer 24

pigmentation - high ACTH

hypokalaemic metabolic alkalosis (V high cortisol = mineralocorticoid activity)

weight loss

hyperglycaemia

classical features of cushing’s are often absent

Question 25

overnight dexamethasone suppression test

Answer 25

good outpt test

dexamethasone 1mg PO at midnight - serum cortisol at 8am

normally cortisol suppressed to <50nmol/L - no suppression in Cushing’s syndrome

false +ves (pseudo -Cushing’s) are seen in depression, obesity, alcohol excess, and inducers of liver enzymes (increased rate of dexamethasone metabolism)

Question 26

midnight cortisol

Answer 26

admit

often inaccurate

normal circadian rhytmm (lowest at midnight) is lost - hogh cortisol at midnight (blood has to be taken from a cannula)