Hyperadrenal disorders

Question 1

List the clinical features of Cushing’s syndrome

Answer 1

• Too much cortisol
• Impaired glucose tolerance (due to chronic elevation of blood glucose)
• Centripetal obesity
• Moon face and buffalo hump
• Proximal myopathy
• Hypertension and hypokalaemia
• Red striae, thin skin and bruising
• Osteoporosis, diabetes

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 get striae

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

Why does Cushing’s syndrome cause hypertension and hypokalaemia?

Answer 4

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

Question 5

State four causes of Cushing’s syndrome

Answer 5

• Too much oral glucocorticoid drugs
• Pituitary dependent Cushing’s disease (i.e. pituitary adenoma)
• Ectopic ACTH from lung cancer
• Adrenal adenoma secreting cortisol

Question 6

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

Answer 6

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

Question 7

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 7

NORMAL: lower cortisol at night and higher cortisol in the morning

Cushing’s syndrome: they would have high cortisol all the time

Question 8

Explain the use of a low dose dexamethasone

Answer 8

Dosage = 0.5mg every 6 hrs for 48hrs
Dexamethasone is an artificial steroid so by giving this extra steroid, it should suppress ACTH and reduce cortisol production.

Normals will suppress cortisol to zero.
Any cause of Cushing’s will fail to suppress

Question 9

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

Answer 9

Metyrapone

Ketoconazole

Question 10

Which enzyme is inhibited by metyrapone, and what effect does metyrapone have on the steroid synthesis pathway?

Answer 10

11-Beta-hydroxylase

It prevents the conversion of 11-deoxycorticosterone => corticosterone (in the z. glomerulosa)
and 11-deoxycortisol => cortisol (in the z. fasciculata)

Question 11

What are the three biochemical effects of metyrapone?

Answer 11

• Cortisol synthesis blocked
• ACTH secretion increased
• Plasma deoxycortisol increased

Question 12

When might metyrapone be used and why?

Answer 12

Control of Cushing’s syndrome prior to surgery:

• Adjust oral dose according to cortisol (aim for mean serum cortisol 150-300 nmol/L)
• Improves patient’s symptoms and promotes better post-op recovery

Control of Cushing’s symptoms after radiotherapy (which is usually slow to take effect)

Question 13

What are the two unwanted effects of metyrapone and why do they occur?

Answer 13

1. Hypertension on long-term administration:
   - deoxycorticosterone accumulates in z. glomerulosa; its aldosterone-like activity leads to salt retention => hypertension.
2. Hirsutism:
   - Increased adrenal androgen production in women (precursors are funnelled towards the sex steroid synthesis pathway)

Question 14

What is the main use of ketoconazole and why is it no longer used for this purpose?

Answer 14

Antifungal agent

Withdrawn in 2013 due to risk of hepatotoxicity

Question 15

What are the effects of ketoconazole on steroid production?

Answer 15

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

Question 16

When might ketoconazole be used and what is its unwanted effect?

Answer 16

Uses similar to metyrapone (orally active)

Unwanted effect = Liver damage (possibly fatal); monitor liver function weekly, clinically and biochemically

Question 17

What are the surgical methods of treatment for Cushing’s?

Answer 17

Depending on the cause, you can have:

• Pituitary surgery (trans-sphenoidal hypophysectomy)
• Bilateral adrenalectomy
• Unilateral adrenalectomy for adrenal mass

Question 18

What is Conn’s syndrome?

Answer 18

Aldosterone secreting adenoma of the adrenal gland (zona glomerulosa)

Question 19

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

Answer 19

Hypertension

Hypokalaemia

Question 20

What is primary hyperaldosteronism?

Answer 20

Hyperaldosteronism caused by an adrenal adenoma

Question 21

What can you test to exclude secondary hyperaldosteronism?

Answer 21

Check for suppression of the renin-angiotensin system;
In primary hyperaldosteronism aldosterone is high but renin should be low (it would be suppressed by the high blood pressure)

Question 22

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

Answer 22

• Medical management using spironolactone

- Surgery to remove the tumour

Question 23

How does spironolactone work?

Answer 23

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

Question 24

What are the two unwanted effects of spironolactone?

Answer 24

1. Menstrual irregularities (+progesterone receptor)

2. Gynaecomastia (-androgen receptor)

Question 25

Name one other mineralocorticoid receptor (MR) antagonist? Why is it preferred?

Answer 25

Epleronone

Similar binding affinity to MRs but less so to androgen and progesterone receptors

Question 26

What is a phaeochromocytoma?

Answer 26

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

Question 27

What are the clinical features of phaeochromocytoma?

Answer 27

• Episodic severe hypertension (in the young)

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

Question 28

State some fatal consequences of a phaeochromocytoma

Answer 28

• Severe hypertension can cause myocardial infarction or stroke
• High adrenaline can cause ventricular fibrillation + death

Question 29

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

Answer 29

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 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 30

State some key facts relating to phaeochromocytomas

Answer 30

• 10 % extra-adrenal (sympathetic chain)/90% intra-adrenal
• 10 % malignant
• 10 % bilateral
• Extremely rare