2.

Discus the physiological control of adrenal gland Discuss strategy that is used for the
Ix of adrenal dysfunction. Describe how would you Ix a pt suffering from Cushing’s
Synd, giving the rationale for your approach.

Discus the physiological control of adrenal gland

Hypothalamic-pituitary-adrenal axis

Renin-angiotensin-aldosterone system
Discuss strategy that is used for the Ix of adrenal dysfunction

1. screening
2. confirmatory
3. localization
4. long term management of the pt

Describe how would you Ix a pt suffering from Cushing’s Synd, giving the rationale
for your approach.

Def: any condition resulting from ↑ concentration of circulating glucocorticoid(cortisol)

level. Mineralocorticoid and androgen may be in excess.

Causes:
1. Physiological (Pseudo Cushing’s syndrome)
-severe stress, obesity, depression,alcoholism
2. Excess cortisol ( pituitary/ ACTH independent 25%)
-Adrenal tumour: adenoma 10%, carcinoma 15%
-Iatrogenic : steroid therapy
3.. Excess ACTH production (ACTH dependent) 75%
pituitary disease 60%(Cushing’s disease): adenoma 90%, hyperplasia 10%
hypothalamic disease (excess CRH production)
ectopic ACTH : malignancy (bronchus, thymus,pancreas, ovary) 15%
4. Excess CBG:
Ostrogen therapy: HRT, OCP
Pregnancy

Clinical features
Sudden weight gain
Central obesity
Hypertension
Facial plethora
Proximal muscle weakness
Glucose intolerance or DM
Acne
Decreased libido or impotence
Depression or psychosis
Osteopenia or osteoporosis
Easy bruising
Hyperlipidaemia
Menstrual disorders
Striae
Recurrent opportunistic or bacterial infections
Investigations

Screening
Aim : to establish that the pt actually has cushing syndrome. 3 characteristics:
High cortisol secretion rate
Loss of normal circadian rhythm
Loss of normal negative feedback by glucocorticoids on pituitary.

The test include:

1. Morning and evening serum cortisol
2. 24 hr urinary free cortisol
3. Dexamethasone suppression test:
1. Overnight dexamethasone suppresion test
2. Low dose dexamethasone suppresion test

*Insulin hypoglycaemic test is also used

-Cushing’s synd=no response
- Pseudocushing=+ response

1. Morning and evening cortisol

Measure at 0800h and 2300h but 1600h is chosen as it is more practical(no admission)
Plasma cortisol shows diurnal variation.
Highest in the morning and lowest in the evening(50% less than morning)
RR : random 68-469 nmol/L
0800h 214-497 nmol/L
midnight 32-331 nmol/L
Cushing’s disease, stress, anorexia, obesity, emotional disturbances, 2º to drugs(sedative,
antiepileptic)  Loss of diurnal variation  Elevated cortisols at both time

2. Measure free cortisol excreted in urine over 24hrs.

Normal UFC 357-851 nmol/L

free urine cortisol/24hrs

< 300 nmol/24hrs Normal
300-700 nmol/24hrs Severe depression, stress
>700 nmol/24hrs Diagnostic of Cushing’syndrome

Boric acid as preservative, if w/o need to be refrigerated and frozen immediately after
completion.
Good sensitivity : 95% for Cushing’s syndrome
False negative of 5% and false positive 1%(pseudo Cushing)

Problems:
↑ excretion can also occur in Pseudo cushing
Incomplete urine collection is v. common
3. Dexamethasone suppression test
Dexamethasone: synthetic glucocorticoid that is 30 times as potent as cortisol.
Bind to cortisol receptors in the pituitary and suppress the ACTH release, thus suppress
cortisol secretion by adrenals

Overnight suppression test :

1mg dexa given at night
Measure cortisol at 0900H cm : normal : <140nmol/L
Cushing’s syndrome > 280nmol/L.
Sensitivity 98% (false positive 1%)
Specificity not good.

Low dose dexa :

0.5mg QID X 2/7
24H urine cortisol is collected before and second day of dexa given
Blood for serum cortisol collected 6hrs after last dose.
Normal or pseudo-cushing:
UFC : suppress by at least 50% ( < 70nmol/24h.)
Plasma cortisol : suppress < 140nmol/L
Cushing’s syndrome : no supression of UFC and serum cortisol.

Confirmation Test
1) High dose dexa suppression test
2) Serum ACTH

3) Imaging technique
4) Inferior petrosal sinus sampling
5) CRH stimulation test

1 High dexa supression test

2mg QID x 2 days.
Sample for serum cortisol taken at baseline, 0900H of D1,D2,D3.
Result :
Pit dependent (cushing’s dis) : serum cortisol supp to below 50% of basal level on
D2, D3
adrenal tumour and ectopic ACTH : No supp is seen

Plasma ACTH
Essential in determining the specific cause.
Not generally available since difficult technically.
ACTH is a labile polypeptide hormone, should be collected in ice.
The plasma should be separated in a refrigerated centrifuge and stored frozen.
Result : normal ACTH < 50 ng/L
Adrenal tumor v. low almost undetecteable

Cushing’s dis in the upper limit of the reference

interval or up to 2x the upper limit of
normal.

Ectopic ACTH secretion v. high

3. CRH stimulation test

To differentiate between cushing’s dis & ectopic ACTH secretion.
Give 100ug CRH iv
Cushing’s dis
↑ ACTH by 50% of the baseline after 60 min & cortisol by 20%
Ectopic ACTH/ adrenal tumour – no response.
Condition Basal cortisol Dexamethasone CRH test Plasma
(nmol/L) suppression test ACTH
(ng/L)

Low dose High dose

Cushing’s dis ↑ (<100) Not suppress Suppression Response ↑

(<200)

Adrenal ↑ Not suppress Not suppress No response ↓

tumour (variable)

Ectopic ↑↑ Not suppress Not suppress No response ↑↑

ACTH (>1000) (>200)

Localisation
1. Imaging technique

Skull XR – widening of the pituitary fossa.

CT scan – i) Adrenal tumour
Ectopic ACTH ( thorax or abdomen)
 1) Pituitary MRI – majority are microadenoma
→ with/without contrast only revealed 50-60% of cases.

2. Petrosal sinus sampling

Now considered as a definitive test to identify pituitary cause of cushing’s syndrome.
Procedure is invasive & require skilled radiologist, therefore this test should not be
perfomed routinely to all patient suspected of having pituitary tumour.
Procedure:
A catheter inserted into both inferior petrosal sinuses via femoral vein. The sinus
drain from the anterior pituitary.
Venous sample are drawn from periphery and petrosal sinus simultananeously before
& 2,5 & 10 min after 100ug CRH administered iv.

Result:
Basal (w/o CRH) petrosal sinus to peripheral ratio of ACTH is > 2
After CRH stimulation the ratio raise >3
In ACTH dependent Cushing disease results show high ratio
In ectopic ACTH the result show low gradient

Conclussion

1. The dx of cushing’s syndrome can be difficult. Involves many tests. Diagnosis can’t be
made by a single test.

2. It is common to see pt who look cushingnoid but is much less common that cushing’s
syndrome is the cause.Clinical hx and examination – important to rule out autonomous
cortisol production/pseudocushing’s syndrome

3. Role of imaging technique in diagnosis