Cushing's disease and syndrome

Question 1

What is cushing’s syndrome?

Answer 1

Cushing’s disease is an endocrine disorder with increased cortisol levels in the blood.

Question 2

What are the 3 zones of the adrenal cortex and what do they produce?

Answer 2

Zona glomerulosa - mineralocorticoids eg aldosterone
Z. Fasciculata - corticosteroids eg cortisol
Z. Reticularis - androgens eg testosterone

Question 3

What is 95% of cortisol bound to in the blood?

Answer 3

Cortisol binding globulin

Question 4

How is the free cortisol in blood kept within the normal range?

Answer 4

Excess cortisol is filtered in the kidneys and excreted in urine. High cortisol levels inhibit CRH and ACTH directly, and because CRH normally causes ACTH, there is also indirect inhibition of ACTH.

Question 5

Where is cortisol-releasing hormone released?

Answer 5

Paraventricular nucleus of the hypothalamus

Question 6

Where is ACTH released?

Answer 6

Anterior pituitary gland

Question 7

When are levels of free cortisol highest and lowest?

Answer 7

High on waking, low in evening.

Question 8

Give 3 effects of cortisol.

Answer 8

1. Increases blood glucose
2. Causes peripheral vasoconstriction
3. Dampens immune response
   (4. Affects brain function - memory and mood.
4. Inhibits GnRH)

Question 9

How does cortisol raise blood glucose?

Answer 9

It increases gluconeogenesis, proteolysis and lipolysis

Question 10

How does cortisol cause peripheral vasoconstriction?

Answer 10

It increases the sensitivity of peripheral blood vessels to catecholamines such as adrenaline/noradrenaline which narrow the lumen.

Question 11

How does cortisol dampen the immune response?

Answer 11

Decreases production and release of inflammatory mediators such as prostaglandins and interleukins and inhibits T lymphocyte activity.

Question 12

Give 3 symptoms of Cushing’s syndrome.

Answer 12

Weight gain - glucose –> insulin –> activates lipoprotein lipase in adipocytes, causing increased storage of fat.
Proximal weakness (tissue breakdown)
Gonadal dysfunction - erectile dysfunction, irregular periods (decreased GnRH)
Depression, lethargy, irritability

Question 13

Give 3 signs of Cushing’s syndrome

Answer 13

Central obesity
Purple abdominal striae (weak skin - breaks when stretched)
Skin and muscle atrophy
Bruises
Osteoporosis

Question 14

Why does Cushing’s cause hypertension?

Answer 14

1. Excess cortisol increases peripheral blood vessels sensitivity to catecholamines so amplifies vasoconstriction
2. Cortisol mimics mineralocorticoid structure, binds to MC receptors and triggers the mineralocorticoid effect (ie aldosterone) causing fluid retention.

Question 15

Give 3 complications of Cushing’s syndrome

Answer 15

Increased infections due to decreased immune response
Hyperglycaemia -> Hypertension, DM, CVS risk
Osteoporosis

Question 16

What is the most common cause of Cushing’s syndrome?

Answer 16

Exogenous steroid medication, eg for asthma, RA, IBD.

Question 17

What is Cushing’s disease?

Answer 17

A common endogenous cause of Cushing’s syndrome in which a benign pituitary adenoma causes excess ACTH secretion, causing excess cortisol production.

Question 18

Give 2 endogenous causes of Cushing’s syndrome other than pituitary adenoma.

Answer 18

Ectopic ACTH production - eg small cell lung cancer

Adrenal gland adenoma/carcinoma

Question 19

Will ACTH be high or low in Cushing’s disease caused by adrenal tumours?

Answer 19

Low in response to excess cortisol produced by the adrenals.

Question 20

How can you confirm the diagnosis of Cushing’s?

Answer 20

24 hour urinary free cortisol test

Overnight dexamethasone suppression test

Question 21

What is the overnight dexamethasone suppression test and what does a positive result indicate?

Answer 21

Overnight dexamethasone suppression test. Dexamethasone is a steroid which should suppress ACTH and lower serum cortisol. 1mg PO at midnight, serum cortisol at 8am. If cortisol does not decrease, it is likely Cushing’s. [OHCM]

Question 22

What investigation would you do if the overnight dexamethosone suppression test showed no change in cortisol?

Answer 22

This is an abnormal result. Do 48h DST - failure to suppress cortisol in Cushing’s.

Question 23

What investigation would you do if the 1st and 2nd-line tests were +ve for Cushing’s?

Answer 23

Determine lesion using localisation tests - plasma ACTH. If low, likely adrenal tumour
If high, could be either pituitary of ectopic cause. Use CRH test - cortisol rises with pituitary production but not with ectopic.

Question 24

Give 3 diseases in your differential diagnosis for a patient with weight gain.

Answer 24

Cushing's 
Hypothyroidism
Oedema
Steroids
Polycystic ovarian syndrome (PCOS)

Question 25

Describe the management of iatrogenic Cushing’s syndrome.

Answer 25

Iatrogenic - stop medications. Stop steroids gradually in order to avoid adrenal crisis.

Question 26

Why can steroids not be stopped immediately?

Answer 26

Like natural cortisol, steroids can inhibit CRH and ACTH production in the zona fasciculata. Prolonged steroids cause so much inhibition that the ZF atrophies and stops producing endogenous cortisol. Therefore stopping steroids immediately can cause adrenal crisis.

Question 27

How is Cushing’s disease treated?

Answer 27

Selective removal of pituitary adenoma.

Question 28

How is Cushing’s syndrome caused by adrenal tumour treated?

Answer 28

Adenoma can be cured by adrenalectomy but carcinoma requires additional radiotherapy and adrenolytic drugs.

Question 29

How is Cushing’s syndrome caused by ectopic ACTH treated?

Answer 29

Surgery if localised tumour located

Decrease cortisol with metyrapone.