Cushing's Syndrome

DEFINITION
Hyperadrenalism.
D E A B M I M


EPIDEMIOLOGY
Age:
Most common in 25-45 year olds.
Gender:
Females (5:1).
Ectopic Cushing's is more common in males.

D E A B M I M

AETIOLOGY

Four possible sources of excess:


Tumour

1. Pituitary tumour producing ACTH
-
"Cushing's disease"
- >50% of endogenous cases.

- these are usually small and do not produce a mass effect, and have basophilic or chromophobe cells.
- in many cases there is corticotroph cell hyperplasia without discrete adenoma.
- in some excess CRF release may also be possible.

2. Adrenal tumour producing cortisol
- "ACTH- independent or adrenal Cushing's"
-
15-30% of endogenous cases.
- adenomas = carcinomas in adults; more carcinomas in children.
- rest of gland undergoes atrophy

3. Ectopic ACTH production

- e.g. small cell lung carcinoma, carcinoids, medullary carcinoma of thyroid, islets of pancreas.
- often a downhill course.
- rarely there may be auto-antibodies to ACTH receptors like in Grave's Disease.
 
Iatrogenic
4. Exogenous corticosteroids
- in clinical practice this is most common.

 
Pseudo-Cushing's
With stress, illness, alcoholism or depression.
CRF is elevated, but not overnight.


D E A B M I M

BIOLOGICAL BEHAVIOUR

Pathophysiology
CRH released from the hypothalamus stimulates ACTH secretion from the anterior pituitary gland.
This in turn results in cortisol production from the adrenal gland. 

The system is modulated by negative feedback inhibition by cortisol of both CRH and ACT secretion. 
 
Cushing's disease:
-       Excess ACTH is secreted from a pituitary corticotroph adenoma. 
-       Cortisol levels are high
-       CRH levels are low due to negative feedback by cortisol on the hypothalamus
 
Cortisol producing adrenal tumour:
-       Cortisol levels are high
-       CRH and ACTH levels are low due to negative feedback of cortisol on the hypothalamus and pituitary
 
Ectopic ACTH production:
-       ACTH and cortisol levels are high
-       CRH is low due to negative feedback on the hypothalamus. 
-       Pituitary production of ACTH is also suppressed.
 
Pseudo-Cushing's syndrome:
-       Central output increases CRH production resulting in high ACTH and hypercortisolism.

Pathology
Pituitary
Granular cytoplasm changed to homogenous, lightly basophilic due to intermediate keratin-filament build-up.
Adrenals
Either atropy, show diffuse hyperplasia, nodular hyperplasia (same but in nodules), or tumour depending on type.
Adenomas are like zona fasculata cells, while carcinomas are larger, unencapsulated and anaplastic, frequently greater than 200-300g.
- both have adjacent atrophic cortex.
D E A B M I M

MANIFESTATIONS


Symptoms
CVS
-       Hypertension
 
Endocrine
-   impaired glucose tolerance/diabetes mellitus
-  weight gain
-  hirsuitism, menstrual abnormalities

Mental
-  mood swings
-  even psychosis

Skin
-       Thin skin, easy bruising
-       Striae
-       Acne, hirsutism (due to increased adrenal androgens)
-       Round face
 
Musculoskeletal
-       Fractures (due to osteoporosis)
-       Weakness getting out of chairs (proximal myopathy, esp of type II myofibers)
 
Psychological
-       Easily irritated, depression
-       Hypomania
-       Psychosis
-       Lethargy
 
Genitourinary
-       Amenorrhoea
-       Infertility
-       Decreased libido (all due to increased adrenal androgens)
 
Immunes
- Increased infection risk.

Signs
General observation
-       Truncal obesity with thin limbs
-       Cervical fat pad
 
Vitals
-       Hypertension
 
Hand/Arms
-       Thin skin & striae and bruising
-       Proximal muscle wasting
 
Face
-       Moon-shaped facies
-       Increased colour of face/plethora
-       Acne, greasy skin, hirsutism
 
Chest
-       Axillary striae
 
Abdomen
-       Striae
 
Neuro
-    Proximal myopathy
D E A B M I M


INVESTIGATIONS

Urine analysis
Elevated urinary free cortisol (good screening test, 24 hrs)
--> most sensitive and specific initial test

Plasma cortisol
High plasma cortisol levels without usual 24hr variations.

Plasma ACTH
Elevated in Cushing's disease (ACTH producing pituitary adenoma) and with ectopic ACTH production.
Low with an adrenal cortisol producing tumour.

Dexamethasone suppression test

Measure urinary secretion of 17-hydroxycorticosteroids as marker of endogenous cortisol production and hence ACTH suppression.
3 patterns:
i) pituitary problem: ACTH elevated, only suppressed with very high levels of dex.
ii) ectopic problem: ACTH elevated, completely insensitive to dex.
iii) adrenal tumour: ACTH low anyway, completely insensitive to dex.


image

Insulin stress test

Insulin-induced hypoglycaemia usually results in a rise of plasma cortisol of at least 220nmol/L.
In Cushing's syndrome the stress response to hypoglycaemia is suppressed


FBC
Polycythaemia

Electrolytes
Hypokalaemia and hypernatremia may be present due to the mild mineralocorticoid action of cortisol

Blood glucose
Elevated due to anti-insulin effect of cortisol
 
Imaging
Adrenal CT
Pituitary CT/MRI
D E A B M I M


MANAGEMENT

Medical
Block steroid synthesis
Ketoconazole (600-1200 mg daily) cytochrome P-450 inhibitors

Preop
Need stress steroids, usually 100mg IV hydrocortisone then 100mg further every 6h.
--> gradually transitioned to oral steroids (tapered when ACTH-stimulation test normalizes and other gland no longer suppressed).

Operative
If adrenal adenoma, lap adrenalectomy
If adrenal carcinoma, usually require an open approach; en bloc resection using a subcostal or midline incision.

Occasionally, patients with Pituitary Cushing's may be referred for bilateral adrenalectomy for control.




D E A B M I M


REFERENCES