Hyperadrenal Disorders

Question 1

What disorder is caused by excess cortisol?

Answer 1

Cushing’s syndrome (think C for cortisol, C for Cushing’s)

Question 2

What are clinical features of Cushing’s? (there’s a few!)

Answer 2

• Too much cortisol
• Put on weight
• Moon face and buffalo hump
• Proximal myopathy (weakness of the big muscles so struggle to squat and stand up from a chair
• Hypertension and hypokalaemia
• Red striae, thin skin, bruising, poor healing (due to turning off of protein synthesis and turning on of fat synthesis)
• Osteoporosis and diabetes

Question 3

What are the causes of Cushing’s?

Answer 3

• Taking too many steroids, includes anabolic steroid abuse as well as taking medicinal steroid for too long
• Pituitary dependent Cushing’s disease
• Ectopic ACTH production from lung cancer (tumour secretes ant. pituitary hormone)
• Adrenal adenoma secreting cortisol

Question 4

What are investigations you can do to find the cause of Cushing’s syndrome?

Answer 4

Need to find out how much cortisol the patient is making

• 24h urine collection for urinary free cortisol
• Blood diurnal cortisol levels (different times of day)
• Low dose dexamethasone (really potent cortisol imitator) suppression test

Question 5

How does the dexamethasone test work and what should be observed in normal and Cushing’s cases?

Answer 5

Dexamethasone is a really potent cortisol imitator
Given 0.5mg every 6 hours for 48 hours
- Normal people will suppress cortisol to zero
- Any cause of Cushing’s will fail to suppress

Question 6

What is meant by cortisol being ‘diurnal’?

Answer 6

Diurnal means its high in the morning and low at night
Usually highest at 9am and lowest at midnight, if asleep. With Cushing’s, their cortisol is always high, regardless time of day.

Question 7

How is Cushing’s diagnosed?

Answer 7

Urine test - very high total cortisol production compared with normal person

Diurnal blood test - cortisol levels are constant or thereabouts throughout the whole day

Low dose Dexa. test - failure to suppress cortisol release to zero

Question 8

What are two examples of drugs that can pharmacologically manipulate steroid levels?

Answer 8

Enzyme inhibitors

Receptor-blocking drugs

Question 9

What is the disorder when there is excess cortisol and when there is excess aldosterone?

Answer 9

Excess cortisol - Cushing’s syndrome

Excess aldosterone - Conn’s syndrome

Question 10

What type of drug is Cushing’s syndrome treated with and two examples?

Answer 10

Inhibitor of steroid biosynthesis

• metyrapone
• ketoconazole

Question 11

What type of drug is Conn’s syndrome treated with and two examples?

Answer 11

MR antagonist

• spironolactone
• epleronone

Question 12

What are the 3 arms of resulting steroid hormones synthesised from cholesterol?

Answer 12

1) Aldosterone (z. glomerulosa)
2) Cortisol (z. fasciculata)
3) Sex steroids (testosterone, oestrogen) (z. reticularis)

Question 13

How does metyrapone have its effect?

Answer 13

Inhibits 11beta-hydroxylase

• blocks final step in synthesis of cortisol
• ACTH secretion increased
• Plasma deoxycortisol increased

Question 14

What are the uses of metyrapone?

Answer 14

• Control of Cushing’s syndrome prior to surgery
  a) adjust dose according to cortisol aiming for mean serum cortisol of 150-300 nmol/L
  b) improves patient’s symptoms and promotes better post-op recovery (better wound healing, less infection etc)
• Control of Cushing’s symptoms after radiotherapy (usually slow to take effect)

Question 15

What are the unwanted effects of metyrapone?

Answer 15

Results in accumulation of deoxycorticosterone in z. glomerulosa

• This has mineralocorticoid-like activity (aldosterone-like)
• Leads to salt retention and hypertension

Increased sex steroid synthesis so increased adrenal androgen production - Hirsutism (excessive body hair) and acne in women

Question 16

How does ketoconzaole work?

Answer 16

Blocks multiple steps in the adrenal steroid synthesis pathway
- Blocks production of all 3 types of steroid

Question 17

What are the uses of ketoconazole?

Answer 17

Similar to metyrapone

• Treatment and control of symptoms prior to surgery
• Orally active

Question 18

What are the unwanted effects of ketoconazole?

Answer 18

• Liver damage - possibly fatal

Must monitor liver function weekly, clinically and biochemically

Question 19

What are the treatment options for Cushing’s?

Answer 19

Depends on cause

• Pituitary surgery
• Bilateral adrenalectomy
• Unilateral adrenalectomy for adrenal mass

As well as medical treatment with metyrapone or ketoconazole

Question 20

What is Conn’s syndrome?

Answer 20

• Usually a benign adrenal cortical tumour (zona glomerulosa)
• Produces excess aldosterone
• Results in hypertension and hypokalaemia

Question 21

How is Conn’s syndrome diagnosed?

Answer 21

Primary hyperaldosteronism

- Renin-angiotensin system should be suppressed i.e. aldosterone is high even with low renin = Conn’s syndrome

Question 22

What is the use of spironolactone?

Answer 22

Treatment of primary aldosteronism (Conn’s syndrome)

Question 23

How does spironolactone have its actions?

Answer 23

Converted to several active metabolites including canrenone
- Canrenone is a competitive antagonist of the mineralocorticoid receptor (MR)
- Blocks Na+ reabsorption and K+ excretion in kidney tubules
(potassium-sparing diuretic)

Question 24

What are the unwanted effects of spironolactone?

Answer 24

• Mnenstrual irregularities (activates progesterone receptor)
• Gynaecomastia (enlargement of breasts) (deactivates androgen receptor)

Question 25

What are the similarities and differences of epleronone compared with spironolactone?

Answer 25

• Also a mineralocorticoid receptor (MR) antagonist
• Similar affinity to the MR
• Less binding to androgen and progesterone receptors so better tolerated and preferred by patients
  (newer and more expensive than spironolactone)

Question 26

What are phaechromocytomas?

Answer 26

Tumours of the adrenal MEDULLA which secrete catecholamines (adrenaline and noradrenaline)

• very rapidly active
• very dangerous in excess

Question 27

How do phaechromocytomas release adrenaline/noradrenaline that make them dangerous?

Answer 27

Phaeo grows and grows and then suddenly release a lot of adrenaline in one go
- releases pulses of adrenaline very suddenly in large amounts, massive sudden sympathetic activation

Question 28

What are the clinical features of a phaeochromocytoma?

Answer 28

• Episodic severe hypertension (can be after abdominal palpation pressing on phaeo which causes it to release a bunch of adrenaline)
• Hypertension in young people (rare in young people so phaeo may always be possible)
• More common in certain inherited conditions, linked to certain genetic conditions

Question 29

What are the more severe clinical features of a phaeo?

Answer 29

• Sever hypertension can cause myocardial infarction or stroke
• High adrenaline can cause ventricular fibrillation and death

Thus this is a medical emergency but it’s very easy to treat IF you think of it

Question 30

How are phaeos managed?

Answer 30

Alpha-blocking drugs are the first therapeutic step

• Patients may need iv fluid as alpha blockade commences
• Beta blockade added to prevent tachycardia, MI overnight

Question 31

What are the 3 “10%” key facts about phaechromocytomas?

Answer 31

10% are extra-adrenal (outside adrenal gland, inside the sympathetic chain)
10% malignant
10% bilateral

Also extremely rare