Hyperadrenal disorders

Question 1

What are the clinical features of cortisol?

Answer 1

Too much cortisol
Centripetal obesity
Moon face and buffalo hump
Proximal myopathy
Hypertension and hypokalaemia (cortisol causes the retention of Na and loss of potassium)
Red striae, thin skin and bruising (cortisol turns off protein synthesis and turns on fat synthesis)
Osteoporosis, diabetes

Question 2

List the causes of Cushing’s

Answer 2

Taking too many steroids (glucocorticoids)
Pituitary dependent Cushing’s disease (tumour)
Ectopic ACTH from lung cancer
Adrenal adenoma secreting cortisol

Question 3

How would you investigate for Cushing’s syndrome?

Answer 3

1) 24 hour urine collection for urinary free cortisol
2) Blood diurnal cortisol levels (measuring daily cortisol levels - highest at 9am lowest at midnight. If it is high all the time then you have Cushing’s) See lecture for graph
3) Low dose of dexamethasone suppresion test

Question 4

How is a low dose of dexamethasone used to investigate for Cushing’s?

Answer 4

0.5mg 6 hourly for 48 hours. Dexamethasone = artificial steroid. In a normal person cortisol levels will be supressed to zero. Any cause of Cushing’s will fail to suppress

Question 5

What is the diagnosis of Cushing’s?

Answer 5

Basal (9am) cortisol level of 800nM

End of a LDDST: 680nM

Question 6

Pharmacological manipulation of steroids

Answer 6

Enzyme inhibitors - inhibit the enzymes of steroid (cortisol) synthesis.
Receptor blocking drugs

Question 7

How can you stop the adrenal cortex from producing too much cortisol? How do you treat Cushing’s?

Answer 7

Use inhibitors of steroid synthesis:

Metyrapone and ketoconazole

Question 8

Describe metrypone

Answer 8

See diagram = notes

Inhibits 11b-hyrdoxylase, s

Question 9

What are the clinical uses metrypone and ketoconazole?

Answer 9

Control of Cushing’s prior to surgery - adjust dose (oral) according to cortisol (aim for mean serum cortisol 150-300 nmol/L)

Control of Cushing’s symptoms after radiotherapy (radiotherapy is slow to work) Metrypone only

see notes

Question 10

What are the negative aspects of metrypone?

Answer 10

1) You get an accumulation of 11-deoxycorticosterone which has mineralcorticoid activity causing salt retention (retention of Na) and potassium excretion = hypertension
Therefore metrypone is good for short term not long term.
2) Because you blocked two limbs of the cholesterol biochemical pathway, all the precursors are funnelled into sex steroid synthesis. This affects females - hirsutism

Question 11

Describe ketoconazole

Answer 11

See diagram = notes. NOT really used
Main use as antifungal - withdrawn 2013 hepatotoxicity
At higher concentrations it inhibits steroidogenesis - off label use in Cushing’s syndrome
Blocks multiple steps

Question 12

What are the negative aspects of ketaconazole?

Answer 12

Liver damage - could be fatal. People are monitored with regular liver function tests

Question 13

How can you treat Cushing’s?

Answer 13

Drugs (metrypone and ketoconazole) are temporary short term solutions
Treatment is dependent on cause
Pituitary surgery (transsphenoidal hypophysectomy)
Bilateral adrenalectomy (hormone replacement)
Unilateral adrenalectomy for adrenal mass

Question 14

Describes Conn’s syndrome

Answer 14

Benign adrenal cortical tumour (zona glomerulosa)

Aldosterone in excess = Hypertension and hypokalaemia. Aldosterone is a mineralcorticoid

Question 15

How do you diagnose Conn’s syndrome?

Answer 15

If it is primary hyperaldosteronism the renin-angiotensin system should be suppressed. Renin is suppressed to zero.
High aldosterone, low renin = Conn’s syndrome
Low potassium should also trigger you to think Conn’s syndrome

Question 16

How do you treat Conn’s syndrome?

Answer 16

Use a mineralcorticoid receptor antagonist

spironolactone and epleronone

Question 17

Describe the uses and mechanism of action of spironolactone

Answer 17

Used to treat primary hyperaldosteronism (Conn’s disease)
Converted to canrenone (active) - competitive antagonist to the mineralcorticoid receptor. The effects are basically the opposite of a mineralcorticoid = blocks Na+ absorption and K+ excretion in the kidney tubules. Potassium sparing diuretic

Question 18

What are the unwanted actions of spironolactone?

Answer 18

Menstrual irregularities (+ progesterone receptor)
Gynaecomastia in men (- androgen receptor)

+ = stimulates, - = blocks

Question 19

Describe epleronone

Answer 19

Also a mineralcorticoid receptor antagonist - similar affinity to spironolactone however it is better tolerated because it binds less to progesterone and androgen receptors.

Question 20

Describe a type of pathology that causes the secretion of catecholamines

Answer 20

Phaeochromocytomas - tumours of the adrenal medulla which secrete catecholamines (A and NA). Releases pulse of A in large amounts all of sudden.

Question 21

What are the clinical features of phaeo?

Answer 21

Hypertension in young people
Episodic severe hypertension (after abdominal palpation) - can cause myocardial infarction or stroke
More common in certain inherited condition
High adrenaline = ventricular fibrillation + death

Question 22

How do you manage phaechromocytomas?

Answer 22

see notes