Cushing syndrome

Def:Clinical states caused by prolonged inappropriate elevation of circulating

glucocorticoids.
Cushing disease:chronic glucocorticoid excess due to ↑ ACTH produced by pituitary
adenoma.
Causes
• Exogenous
– Iatrogenic-Glucocorticoid administered iv, im, orally, transdermally, by
inhalation
– Illegal herbal remedies
• Endogenous
– ACTH-dependent(85% of endogenous cause)
• Pituitary adenoma;F:M>1, peak age 30-50Y.
• Extrapituitary /ectopic ACTH syndrome*-usually small cell
carcinoma/carcinoid tumour
 * Specific features-pigmentation due to ↑↑ACTH, hypokalaemia?↑↑cortisol leads to
mineralocorticoid activities, weight loss,hyperglycemia.Other features of CS absent.

– ACTH-independent
• Adrenal adenoma
• Adrenal carcinoma
• Macronodular adrenal hyperplasia.
• Rare-carney complex and Mc Cune Albright syndrome.
• Psedo-cushing syndrome-chronic alcoholic & pts with depression may
has ↑ urinary excretion of steroids, absent diurnal variation and +ve
overnight dexamethasone test.All test return to normal on
discontinuation of alcohol/improvement of emotion.
History
1. Hx of steroid theraphy/herbal remedies
2. Central weight gain
3. Hirsutism-not common in cushing syndrome cause by exogenous steroid
4. Easy bruising
5. Acne
6. Weakness of muscle
7. Menstrual disturbance
8. Loss of libido
9. Depression, sleep disturbance
10.Back pain?-spinal osteoporosis
Examination
-All signs below
-Tell examiners that you would like to
 Test the urine for glucose
 Check visual field?......
  Examine Fundus-optic atrophy,papilloedema, signs of HTN (4 stages)/diabetic
retinopathy.

Symptoms Signs
Weight gain(central) Depression/psychosis Frontal balding (F)
Change of appearance Ache/hirsuties Moon face
Depression Thin skin Plethora
Psychosis Bruising “Buffalo Hump”(don’t use
Insomnia Hypertension in exam)
Amenorrhoea/oligomenorr Rib # Supraclavicular fat
hoea Osteoporosis distribution
Poor libido Pathological # Kyphosis
Thin skin/easy bruising Poor wound healing Centripetal obesity
Hair grow/acne Proximal muscle wasting Pimentation
Muscular weakness Proximal myopathy Striae(purple)-abdomen,
Growth arrest in children oedema shoulder & thigh.
Back pain Skin Infections
Polyuria/polydipsia Glycosuria
NB:old photograph might Bold type indicates signs of most value in
be useful discriminating CS from simple obesity& hirsute.
Symptoms of
hypopituitarism are rare.

Investigation

1.Confirm diagnosis(Biochemical studies)-raise cortisol

1st line
• Overnight Dexamethasone suppression test
- Outpts test,give dexamethasone 1mg PO midnight,
- Take serum cortisol level b4 and 8 am in the morning
- N pts-cortisol ↓ to <50nmol/L,ACTH ↓
- Cushing Syndrome-failure to suppress cortisol
- False –ve< 2%, false +ve :2% in normal population,
13% in obese and 23% in hospital inpts.
• Late night salivary cortisol
• 24-hour urine free cortisol
-N is <280nmol/24h.

2nd line
• 48H dexamethasone suppression test
-give 0.5mg dexamethasone/6hourly PO for 2 days
- measure cortisol level at 0 and 48H
-Cushing syndrome-failure of suppression.
• Midnight cortisol
 - Requires admission, N circadian –cortisol lowest at midnight, highest in the early
morning
- Cushing syndrome-this fluctuation is not detected.

2.ACTH-dependent or ACTH-independent?(plasma ACTH)-also help in localising lesion

 ACTH not detected-adrenal tumour likely.
 ACTH detected-distinguish pituitary from ectopic
o High dose dexamethasone suppressiom test
-2mg/6H PO for 2 days.
-measure plasma cortisol at 0 and 48 H
-Cushing syndrome(pituitary)-complete or partial suppression since pituitary retains
some feedback control.
-Ectopic-no changes in cortisol level.
o Corticotrophin releasing hormone (CRF)test
-100 microgram ovine/human CRH IV
-measure cortisol at 120 min
-Pituitary disease-cortisol ↑ and ectopic;cortisol ↓.

3.Localisation
• Imaging
 Pituitary-MRI(can use gadolinium enhancement)/CT
 Adrenal-PFA/USS/CT/MRI
 Ectopic source-CXR.If cortisol do not respond to manipulation (CT±MRI of
neck,thorax,abdomen)-----looking for small ACTH secreting carcinoid tumour.
• Inferior petrosal sinus sampling –done when no mass seen despite all the other
positive test.May help to confirm pituitary adenoma.
TREATMENT –depends on the cause

1. Iatrogenic-stop the steroid medications(if possible)/taper dose

2. Surgery

-pituitary- adenoma(transphenoidal microadenomectomy), may also hv pituitary

irradiation.

- adrenal- adenoma(adrenalectomy* is curative and carcinoma(resection-rarely sx

done);usually radiotherapy and adrenolytics drugs (mitotane) used following sx.

-ectopic source-surgical resection of tumour.

*follow up for ACTH and imaging for pituitary tumour.

Nelson Syndrome-rapidly undergoing pituitary adenoma post
adrenalectomy.Very ↑ACTH and hyperpigmentation. Happen up to 50% of pts
undergone this procedure.

3. Medical treatment
 a. Drugs that block adrenal steroidogenesis
i. Ketoconazole
Use presurgery to reduce cortisol secretion/awaiting radiation to
ii. Metyrapone become effective
iii. Mitotane

Prognosis
- Untreated increases mortality due to ↑ CVS risk.
- Treatment usually lead to resolution of physical and physiological disorders
- Osteoporosis, HTN, obesity,subtle mood changes , glucose intolerance and DM may
persist.This requires follow up.