cushing's syndrome Flashcards
definition of Cushing’s syndrome
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)
aetiology of Cushing’s syndrome
ACTH dependent 80%
ACTH independant
ACTH-independent micro- or macronodular adrenal hyperplasia
oral steroids
ACTH dependant Cushing’s syndrome
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
ACTH independant Cushing’s syndrome
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
ACTH independent micronodular adrenal hyperplasia
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.
ACTH independant macronodular adreanl hyperplasia
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.
mx of nodular adrenal hyperplasia
Surgical bilateral adrenalectomy is used in patients with micronodular adrenal hyperplasia and most patients with macronodular adrenal hyperplasia.
epidemiology of Cushing’s syndrome
Incidence reported as 2–4/1000000 per year, but may be more.
Endogenous Cushing’s syndrome is more common in females.
20-40yrs
sx of cushing’s syndrome
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
signs of cushing’s syndrome
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
Ix for cushing’s syndrome
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
Ix to determine the cause of Cushing’s syndrome
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
Mx of iatrogenic cushings
discontinue admin
lower steroid dose
steroid sparing alternative
medical treatment of cushings
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.
surgical Mx of cushings
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
radiotherapy for Cushings
not cured and have persistant hypercortisolaemia after trans-sphenoidal resection
stereotactic radiotherapy = less irradiation to surrounding areas
done for adrenal carcinoma
Mx for refractory cushings
bilateral adrenalectomy possibly
complications from Cushings
diabetes
osteoporosis
HTN
pre-disposition to infections
complications from surgery for cushings
CSF leakage
meningitis
sphenoid sinusitis
hypopit
complications from radiotherapy for cushings
hypopit
radionecrosis
small increased risk of intracranial tumours and stroke
complications of bilateral adrenalectomy
development of Nelson’s syndrome (locally agressive pit tumour = skin pigmentation from excessive ACTH) - responds to pit irradiation
prognosis of cushing’s syndrome
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).
physiology of the adrenal cortex
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
special features of ectopic ACTH production
pigmentation - high ACTH
hypokalaemic metabolic alkalosis (V high cortisol = mineralocorticoid activity)
weight loss
hyperglycaemia
classical features of cushing’s are often absent
overnight dexamethasone suppression test
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)
midnight cortisol
admit
often inaccurate
normal circadian rhytmm (lowest at midnight) is lost - hogh cortisol at midnight (blood has to be taken from a cannula)
