6 - Hyperadrenal disorders

Question 1

What is the cause of Cushing’s syndrome?

Answer 1

too much cortisol

Question 2

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

Answer 2

Decrease protein synthesis
Increase fat synthesis

(fat deposition everywhere - moon face and buffalo hump)

Question 3

Why does someone with Cushing’s syndrome often get bruising?

Answer 3

normally, the tissues under the skin are full of proteins and proteins are needed to heal
if you are unable to make proteins, you start to leak and get bruising

Question 4

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

Answer 4

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 5

Describe the clinical features of Cushing’s syndrome.

Answer 5

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

Question 6

Why does Cushing’s syndrome cause hypertension and hypokalaemia?

Answer 6

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

Cortisol acts as a diuretic, increasing water diuresis, glomerular filtration rate, and renal plasma flow from the kidneys, as well as increasing sodium retention and potassium excretion. It also increases sodium and water absorption and potassium excretion in the intestines.

Question 7

What is Cushing’s disease?

Answer 7

caused by a pituitary tumour

Question 8

State four causes of Cushing’s syndrome

Answer 8

Pituitary adenoma (Cushing’s disease)
Ectopic ACTH
Adrenal adenoma

Oral glucocorticoid drugs - taking too many steroids

Question 9

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

Answer 9

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

Question 10

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 10

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 11

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

Answer 11

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 12

State some surgical treatments for Cushing’s syndrome.

Answer 12

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

(NOTE: start off with medical treatment and operation can be carried out once the patent is safe)

Question 13

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

Answer 13

Metyrapone

Ketoconazole

Question 14

Which enzyme is inhibited by metyrapone?

Answer 14

11β-hydroxylase

Question 15

What effect does metyrapone have on the steroid synthesis pathway? What pathways does it block?

Answer 15

It prevents the conversion of:
• 11-deoxycorticosterone -> corticosterone
• 11-deoxycortisol -> cortisol
This means that no corticosterone or cortisol is produced
This slows down the cortisol, pathway synthesis

Question 16

State two uses of metyrapone.

Answer 16

• 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 17

State two negative aspects of metyrapone.

Answer 17

• causes accumulation of 11-deoxycorticosterone (no negative feedback effects on the ACTH axis)
  11-deoxycorticosterone has mineralocorticoid effects so causes SALT RETENTION and HYPERTENSION
• increase in the production of sex steroids
  This leads to increased adrenal androgens, which has effects such as hirsuitism.

Question 18

State some unwanted effects of metyrapone.

Answer 18

Nausea, vomiting, dizziness
Hypertension
Hirsuitism
Sedation, hypoadrenalism

Question 19

What is ketoconazole and why is it no longer used?

Answer 19

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

Question 20

What are the effects of ketoconazole on steroid production?

Answer 20

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 21

State some unwanted actions of ketoconazole.

Answer 21

Nausea, vomiting, abdominal pain
Alopecia
Gynaecomasia, 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 22

What is Conn’s syndrome?

Answer 22

Benign adenocorticol tumour
Aldosterone secreting adenoma of the adrenal gland (zona glomerulosa)

(too much aldosterone)

Question 23

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

Answer 23

Hypertension
Hypokalaemia
(high bp with low potassium)

Question 24

What is primary hyperaldosteronism?

Answer 24

Hyperaldosteronism caused by an adrenal adenoma

Question 25

What can you test to exclude secondary hyperaldosteronism?

Answer 25

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 26

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

Answer 26

Medical management (spironolactone)
Surgery to remove the tumour

Question 27

What is spironolactone and how does it work?

Answer 27

Spironolactone is an aldosterone receptor antagonist

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

Question 28

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

Answer 28

Canrenone

Question 29

State some unwanted effects of spironolactone.

Spironolactone is very non-specific so it has several side effects

Answer 29

It is a progesterone receptor agonist —–> menstrual irregularities
Also a androgen receptor antagonist —–> gynaecomastia
GI tract irritation
Contra-indications:
• Renal and hepatic disease

Question 30

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

Answer 30

Eplerenone

Question 31

What is phaeochromocytoma?

Answer 31

Tumour of the adrenal medulla that is producing excessive amounts of catecholamines - RAPID EFFECT

Question 32

What are the features of phaeochromocytoma?

Answer 32

Episodic severe hypertension (in the young)

They will get sudden bursts of panic attacks, anxiety, palpitations and a rapid rise in blood pressure.

Question 33

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

Answer 33

(since anaesthetic could precipitate a hypertensive crisis)

• give an alpha-blocker (to prevent vasoconstriction caused by adrenaline binding to alpha-receptors)
• alpha-blockers cause a drop in blood pressure so they are usually given with some fluid.
• then 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.