Hyperadrenal Disorders

Question 1

List 12 clinical signs of Cushing’s syndrome

Answer 1

1. Thin Skin
2. Proximal Myopathy
3. Bruising
4. Poor wound healing
5. Red striae
6. Scapular fat pads (buffalo humps)
7. Centripetal obesity (lemon on a stick)
8. Diabetes
9. Hypertension
10. Osteoporosis
11. Moon face
12. Immunosuppression - hence reactivation of infection e.g. TB

Question 2

What is Cushing’s disease?

Answer 2

A form of Cushing’s syndrome caused exclusively by pituitary adenoma - hence ACTH oversecretion and thus stimulates excess cortisol production in the adrenals

Question 3

What is the difference between Cushing’s syndrome and Cushing’s disease?

Answer 3

Cushing’s syndrome is an umbrella term for a type of hyperadrenalism where you get the classic Cushing’s symptoms, whereas Cushing’s disease is specifically caused by pituitary adenoma

Question 4

The symptoms of ‘steroid’ use is similar to some of those clinical signs of Cushing’s syndrome, list 8 of them

Answer 4

1. Hypertension
2. Hypokalaemia
3. Diabetes
4. Osteoporosis
5. Immunosuppression and thus reactivation of infection
6. Easy bruising
7. Poor wound healing
8. Thin skin

Question 5

What is proximal myopathy and what’s actually happening?

Answer 5

• Gain fat
• Lose protein
• Therefore become weaker

Question 6

Give the 4 causes of Cushing’s syndrome and then specify which of these is the commonest cause and which is the most common endogenous cause

Answer 6

1. Steroid use - commonest
2. Pituitary dependent (Cushing’s disease) - most common endogenous cause
3. Ectopic ACTH from lung cancer
4. Adrenal adenoma secreting cortisol

Question 7

List 3 ways you can test for Cushing’s and what a positive result will yield

Answer 7

1. 24 urine free cortisol sample - if high then positive for Cushings
2. Midnight sleeping cortisol test - if cortisol is still high then positive for Cushing’s
3. LDDS - Low Dose Dexamethasone Suppression Test - you start with 800nM cortisol at 9 am and if by the end of the LDDS test cortisol is at 680nM, this is positive for Cushing’s

Question 8

Why can’t you just take a blood sample at any time of the day to test for Cushing’s?

Answer 8

Because there is a diurnal cortisol rhythm - so you can get false positives if you measure cortisol in the blood in the morning when it is very high

Question 9

What is the logic behind using a midnight sleeping cortisol test to test for Cushing’s?

Answer 9

• In Cushing’s there is loss of the normal diurnal cortisol rhythm - cortisol is released at a FIXED RATE throughout the day
• You can’t take it early in the morning because you could get false positives as everybody’s cortisol is high early in the morning
• So you take the blood sample at midnight when you would expect a low cortisol level in normal people but the cortisol will remain high in those with Cushing’s

Question 10

1) What is the logic behind the LDDS test (Low Dose Dexamethasone Suppression test) for Cushing’s?
2) How do you administer the Dexamethasone (dose and time range)?
3) What does a positive test for Cushing’s show in an LDDS test?

Answer 10

1)

• Dexamethasone is an analogue of cortisol
• So pituitary detects the cortisol and releases less ACTH - therefore there is a negative feedback inhibition (suppression) of cortisol production
• In Cushing’ s (of any cause) there is a resistance to this suppression and cortisol will remain high

2)

• Give 0.5mg of dexamethasone every 6 hours for 48 hours

3)

• You start with 800nM of cortisol at 9am
• If, by the end of the LDDS test, cortisol is >680nM, then this is positive for Cushing’s

Question 11

What is the treatment for Cushing’s caused by pituitary adenoma (Cushing’s disease)?

Answer 11

Transsphenoidal hypophysectomy (removing the pituitary tumour)

Question 12

What is the treatment for Cushing’s caused by adrenal tumour?

Answer 12

Bilateral adrenalectomy

Question 13

What is the treatment for Cushing’s caused by adrenal mass?

Answer 13

Unilateral adrenalectomy

Question 14

Name 2 drugs used to treat Cushing’s

Answer 14

1. Metyrapone
2. Ketoconazole

Question 15

1) How does metyrapone work to treat Cushing’s?
2) What changes will be seen in the blood (what chemicals will have changed concentrations ad why?)

Answer 15

1)

• Inhibits 11ß-hydroxylase
• Thereby preventing the conversion of 11-deoxycortisol into cortisol which is otherwise catalysed by this. So lowers [cortisol]

2)

• [11-deoxycortisol] increases as not broken down as much due to inhibition of 11ß-hydroxylase - increases in conc
• [Cortisol] lowers as less conversion of 11-deoxycortisol into cortisol due to inhibition of 11ß-hydroxylase
• [ACTH] increases because 11-deoxycortisol does not have negative feedback effect and [cortisol] which does have negative feedback is lowered
• [11-deoxycorticosterone] increases due to inhibition of 11ß-hydroxylase which otherwise converts 11-deoxycorticosterone into corticosterone
• [Corticosterone] decreases due to inhibition of 11ß-hydroxylase
• [Adrenal androgen] increases

Question 16

When is metyrapone used to treat Cushing’s?

Answer 16

• Controls Cushing’s prior to surgery in order to improve symptoms and promote better post-operative recovery
• Controls symptoms after radiotherapy (which is slow to take effect)

Question 17

What are the 2 main side effects of metyrapone and explain the mechanism for them?

Answer 17

1. HTN:

• 11ß-hydroxylase inhibition prevents conversion of 11-deoxycorticosterone into corticosterone so there is a build up of 11-deoxycorticosterone
• 11-deoxycorticosterone has mineralocorticoid effects, sometimes acting like aldosterone
• Therefore it causes K⁺ excretion, Na⁺ reabsorption and thus water retention - thereby increasing blood volume and thus causing HTN. This is a problem as you are already at risk of HTN with Cushing’s anyway

2. Hirsutism:
   * Increased [adrenal androgen] production

Question 18

How does ketoconazole work to treat Cushing’s?

Answer 18

• Blocks multiple steps in the adrenal steroidal pathways
• Mainly, it blocks a CYP450 group of enzymes which converts cholesterol (the beginnning molecule) into pregnenolone, which is a precursor molecule for the mineralocorticoid, glucocorticoid and adrenal androgen pathways, so affects all of these
• So it reduces cortisol production too

Question 19

When is ketoconazole used to treat Cushing’s?

Answer 19

• To improve symptoms and post-operative recovery before and after surgery respectively

Question 20

Give one unwanted effect of ketoconazole and how to manage it?

Answer 20

• Potentially fatal liver damage
• Monitor liver function weekly, clinically and biochemically

Question 21

What is another term for Conn’s syndrome?

Answer 21

Primary hyperaldosteronism

Question 22

What is the pathophysiology that occurs in Conn’s syndrome?

Answer 22

• Benign adrenal cortical tumour in the zona glomerulosa (where aldosterone is produced)
• Aldosterone produced in excess
• This causes renal sodium (and thus water) retention and potassium excretion
• So HTN and hypokalaemia due to Conn’s syndrome
• Also the RAAS will be suppressed due to high BP

Question 23

How do you diagnose Conn’s syndrome and explain why it can be diagnosed this way?

Answer 23

• High aldosterone - this is just primary hyperaldosteronism (Conn’s syndrome)
• Low renin - because high BP due to the hyperaldosteronism suppresses the renin production in the RAAS system

Question 24

List 3 treatments for Conn’s syndrome

Answer 24

1. Spironolactone
2. Epleronone
3. Surgery - image and remove adenoma

Question 25

How does spironolactone work to treat Conn’s?

Answer 25

• Its a potassium sparing diuretic
• Spironolactone is converted into many metabolites including canrenone
• Canrenone is a competitive antagonist of mineralocorticoid receptor (MR)
• So prevents the binding of XS aldosterone onto mineralocorticoid receptors and so prevents the excess retention of sodium (and thus water too) and excretion of potassium. So prevents HTN and hypokalaemia

Question 26

How is spironolactone administered?

Answer 26

• Orally - it is orally active

Question 27

Why does spironolactone have a low availability?

Answer 27

• Highly protein bound
• Highlt metabolised in the liver

Question 28

Give 2 unwanted side effects of spironolactone and why they occur

Answer 28

1. Menstrual irregularities (it is progesterone receptor agonist)
2. Painful gynaecomastia (it is an androgen receptor antagonist)

Question 29

1) How is epleronone useful in treating Conn’s syndrome?
2) Why is it the drug of choice, preferred over spironolactone?

Answer 29

1) Its an MR (mineralocorticoid receptor) antagonist

2)

• Similar affinity for MR compared to spironolactone
• YET less binding to androgen and progesterone receptors compared to spironolactone, so better tolerated (less side effects from painful gynaecomastia and menstrual irregularities respectively)

Question 30

What is the pathophysiology of Phaeochromocytomas?

Answer 30

• Tumours of the adrenal medulla that secrete catecholamines
• The tumour suddenly degranulates and secretes loads of catecholamines

Question 31

What are the clinical features and possible complications of Phaeochromocytoma and explain why they arise pathophysiologically?

Answer 31

• Episodic severe HTN due to sudden XS release of catecholamines (vasoconstriction etc) → can lead to MI, stroke, ventricular fibrillation and DEATH
• Increased CO
• Increased BMR
• Airway dilatation
• Mental effects: anxiety, panic

Question 32

In the management of Phaeochromocytoma…

1) What is the ultimate treatment and why must you be careful in preparation for this treatment?
2) What other treatments are involved (giving a specific drug name for one of them) ?

Answer 32

1)

• Surgery to remove the tumour in the adrenal medulla
• Anaesthesia can precipitate a hypertensive crisis

2)

• Alpha blockade is the first therapeutic step - blocking adrenoreceptors causes a fall in BP (phenoxybenzamine)
• IV fluids to prevent to drastic a fall in BP during treatment by alpha blockade by phenoxybenzamine
• Beta-blockade to prevent tachycardia