Hyperadrenalism

Question 1

Describe the adrenal steroid synthesis pathway.

Answer 1

.

Question 2

Describe the effects of excess cortisol on protein and fat synthesis.

Answer 2

Decrease protein synthesis

Increase fat synthesis

Question 3

Explain why people with Cushing’s disease get stretch marks.

Answer 3

They are putting on a lot of fat quickly, which stretches the skin.
Because protein synthesis is switched off, you can’t make the protein required for skin growth so the skin tears.

Question 4

Describe the clinical features of Cushing’s syndrome.

Answer 4

Moon face 
Interscapular fat pad (buffalo hump) 
Proximal myopathy 
Easy bruising 
Striae 
Thin skin 
Osteoporosis 
Diabetes 
Centripetal adiposity (lemon on sticks) 
Hypertension and hypokalaemia

Question 5

Why does Cushing’s syndrome cause hypertension and hypokalaemia?

Answer 5

At high concentrations, cortisol can have mineralocorticoid effects –> increased sodium absorption and potassium excretion

Question 6

State four causes of Cushing’s syndrome.

Answer 6

Pituitary adenoma
Ectopic ACTH
Oral glucocorticoid drugs
Adrenal adenoma

Question 7

What are the three main tests used to diagnose Cushing’s syndrome?

Answer 7

24-hour urine free cortisol
Blood diurnal cortisol levels (or midnight serum cortisol)
Low dose dexamethasone suppression test

Question 8

Describe the results you’d expect from a normal subject and a patient with Cushing’s syndrome in the 24-hour urine free cortisol and blood diurnal cortisol tests.

Answer 8

You would expect lower cortisol at night in a normal subject and high cortisol in the morning.
In someone with Cushing’s syndrome they would have high cortisol all the time.

NOTE: a problem with this test is that the cortisol levels are affected by stress.

Question 9

Explain the scientific basis of the low dose dexamethasone suppression test.

Answer 9

Dexamethasone is a glucocorticoid so by giving this extra glucocorticoid, it should suppress ACTH and reduce cortisol production.
So in a normal subject undertaking the dexamethasone suppression test, you would expect zero cortisol.
In a Cushing’s patient, cortisol will remain high despite the presence of dexamethasone.

Question 10

State some surgical treatments for Cushing’s syndrome.

Answer 10

Treatment is dependent on cause
Transsphenoidal Hypophysectomy (for Cushing’s disease)
Bilateral adrenalectomy
Unilateral adrenalectomy for adrenal mass

Question 11

State two drugs that are used to treat Cushing’s syndrome before surgery.

Answer 11

Metyrapone (inhibits 11-Beta-hydroxylase)

Ketoconazole

Question 12

What effect does metyrapone have on the steroid synthesis pathway?

Answer 12

It prevents the conversion of:
11-deoxycorticosterone –> corticosterone
11-deoxycortisol –> cortisol
This means that no corticosterone or cortisol is produced

Question 13

State two uses of metyrapone.

Answer 13

Preparation of a Cushing’s patient for surgery (improves their healing abilities and makes them better surgical candidates)
Treatment of Cushing’s syndrome symptoms following radiotherapy (radiotherapy has a delayed effect)

Question 14

State two negative aspects of metyrapone.

Answer 14

Metyrapone causes the accumulation of 11-deoxycorticosterone (because it doesn’t have any negative feedback effects on the ACTH axis)
11-deoxycorticosterone has mineralocorticoid effects so causes SALT RETENTION and HYPERTENSION.
Metyrapone inhibits two limbs of the steroid synthesis pathway so it funnels the precursors towards the sex steroid synthesis pathway.
This leads to increased adrenal androgens, which has effects such as hirsutism.

Question 15

State some unwanted side-effects of metyrapone.

Answer 15

Nausea, vomiting, dizziness
Hypertension
Hirsutism
Sedation, hypoadrenalism

Question 16

What is ketoconazole and why is it no longer used?

Answer 16

Ketoconazole is an anti-fungal, which has an effect on the steroid synthesis pathway.
It is no longer used because of its hepatotoxicity.

Question 17

What are the effects of ketoconazole on steroid production?

Answer 17

Ketoconazole inhibits cytochrome P450 short chain cleavage enzyme.
This enzyme converts cholesterol –> pregnenolone
This means that it inhibits the production of glucocorticoids, mineralocorticoids and sex steroids.

Question 18

State some unwanted actions of ketoconazole.

Answer 18

Nausea, vomiting, abdominal pain
Alopecia
Gynaecomastia, oligospermia, impotence, decreased libido Ventricular tachycardias
LIVER DAMAGE (could be fatal)
These unwanted effects are due to loss of sex steroids, glucocorticoids and mineralocorticoids

Question 19

What is Conn’s syndrome?

Answer 19

Aldosterone secreting adenoma of the adrenal gland (zona glomerulosa)

Question 20

What are the two main features of Conn’s syndrome?

Answer 20

Hypertension

Hypokalaemia

Question 21

What is primary hyperaldosteronism?

Answer 21

Hyperaldosteronism caused by an adrenal adenoma.

Question 22

What can you test to exclude secondary hyperaldosteronism?

Answer 22

Check for suppression of the renin-angiotensin system
Measure aldosterone and if that’s high, measure the renin and that should be low because it would be suppressed by the high blood pressure.

Question 23

What is the usual treatment plan for someone with Conn’s syndrome?

Answer 23

Medical management (spironolactone, Epleronone) 
Surgery to remove the tumour

Question 24

What is spironolactone and how does it work?

Answer 24

Spironolactone is an aldosterone receptor antagonist

It reduces the effects of aldosterone, so it decreases sodium reabsorption and decreases potassium excretion.

Question 25

What is the active metabolite of spironolactone that acts as a mineralocorticoid receptor antagonist?

Answer 25

Canrenone

Question 26

What treatment would you give for someone with bilateral adrenal hyperplasia?

Answer 26

Long-term spironolactone
You don’t want to remove both adrenals because then they wouldn’t produce any cortisol or aldosterone, so you give them long-term spironolactone to reduce the effects of excess aldosterone.

Question 27

Describe the pharmacokinetics of spironolactone.

Answer 27

Orally active
Given daily in single or divided doses
Highly protein-bound and metabolised in the liver

Question 28

State some unwanted effects of spironolactone.

Answer 28

Spironolactone is very non-specific, with several side effects
Progesterone receptor agonist –> menstrual irregularities
Androgen receptor antagonist –> gynaecomastia
GI tract irritation

Contra-indications:
Renal and hepatic disease

Question 29

Name another mineralocorticoid receptor antagonist that has fewer side effects than spironolactone.

Answer 29

Eplerenone

Question 30

What is a phaeochromocytoma and its features?

Answer 30

Tumour of the adrenal medulla that is producing excessive amounts of catecholamines (chromo = chromaffin cells)
Episodic severe hypertension (in the young)
They will get sudden bursts of panic attacks, anxiety, palpitations and a rapid rise in blood pressure.
NOTE: VERY SHORT LIVED EPISODES BUT VERY SEVERE.

Question 31

State some fatal consequences of phaeochromocytoma.

Answer 31

Myocardial infarction and stroke
It can also cause sudden cardiac death through ventricular fibrillation
It is a MEDICAL EMERGENCY

Question 32

Describe the steps that must be taken when preparing a phaeochromocytoma patient for surgery.

Answer 32

Anaesthetic could precipitate a hypertensive crisis.
You give the patient an alpha-blocker to prevent the vasoconstriction caused by adrenaline binding to alpha-receptors.
Alpha-blockers cause a drop in blood pressure so they are usually given with a bit of fluid.
Then you give beta-blockers to prevent tachycardia.
Once all the receptors are blocked, it means that a massive release in adrenaline will not be able to have its effects.

Question 33

What percentage of phaeochromocytoma is intra-adrenal?

Answer 33

90% (Even this version is an extremely rare condition however)
10% extra adrenal
10% bilateral
10% malignant

Question 34

What genetic condition increases risk of phaeochromocytoma?

Answer 34

Neurofibromatosis (tumours in nervous system)

Question 35

What is a high dose Dexamethasone suppression test used for?

Answer 35

To diagnose Cushing’s DISEASE

Ectopic ACTH will not be suppressed at all.