Hyperadrenal disorders

Question 1

What are the clinical features of Cushing’s syndrome?

Answer 1

Too much cortisol- switches protein synthesis off and fat synthesis on.
Centripetal obesity
Moon face
Interscapular fat pad 
Proximal myopathy
Hypertension
Hypokalaemia
Red striae, thin skin and easy bruising
Osteoporosis, diabetes

Question 2

What are the causes of Cushing’s?

Answer 2

Taking too many steroids
Pituitary dependent (Cushing’s disease)
Ectopic ACTH from lung cancer
Adrenal adenoma secreting cortisol

Question 3

What investigations may be carried out to determine the cause of Cushing’s syndrome?

Answer 3

24 hour urine collection for urinary free cortisol.
Blood diurnal cortisol levels- usually highest at 9am and lowest at midnight, if asleep- suspicious if high.
Low dose dexamethasone suppression test.

Question 4

What is a low dose dexamethasone suppression test used for?

Answer 4

0.5mg 6-hourly for 48 hours.
Dexamethasone is an artificial steroid.
If normal, will suppress cortisol to zero.
Any cause of Cushing’s will fail to suppress.

Question 5

How can steroids be pharmacologically manipulated?

Answer 5

Enzyme inhibitors- inhibit enzymes of steroid synthesis.

Receptor blocking drugs.

Question 6

What is the treatment of Cushing’s syndrome?

Answer 6

Depends on cause.
Pituitary surgery (transsphenoidal hypophysectomy).
Bilateral adrenalectomy.
Unilateral adrenalectomy for adrenal mass.

Question 7

What is Conn’s?

Answer 7

Too much aldosterone.

Question 8

Where are catecholamines produced?

Answer 8

Adrenal medulla.

Question 9

What is phaeochromocytoma?

Answer 9

Tumour of the adrenal medulla that leads to production of excess catecholamines.

Question 10

How are the effects of excess catecholamines (e.g. in phaeochromocytoma) blocked?

Answer 10

Alpha blocker to reduce blood pressure caused by catecholamines binding to alpha receptors on vasculature and causing vasoconstriction.
Then beta blocker.

Question 11

What are the actions of metyrapone?

Answer 11

Inhibition of 11 beta hydroxylase.
Steroid synthesis in the zona fasciculata (and reticularis) is arrested at the 11-deoxycortisol stage.
11-deoxycortisol has no negative feedback effect on the hypothalamus and pituitary gland so it accumulates. ACTH levels rise.

Question 12

What is metyrapone used for?

Answer 12

Control of Cushing’s syndrome prior to surgery. Adjust oral dose according to cortisol (aim for mean serum cortisol 150-300nmol/L). Improves patient’s symptoms and promotes better postoperative recovery (better wound healing, less infection, etc.).

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

Question 13

What are the unwanted actions of metyrapone?

Answer 13

Hypertension on long-term administration.

Hirsutism.

Question 14

What are the actions of ketoconazole?

Answer 14

Main use as an anti-fungal agent- withdrawn due to risk of hepatotoxicity.
At higher concentrations, inhibits steroidogenesis- off-label use in Cushing’s syndrome.
Blocks production of glucocorticoids, mineralocorticoids, and sex steroids.

Question 15

What is ketoconazole used for?

Answer 15

Treatment and control of symptoms of Cushing’s syndrome prior to surgery- orally active.

Question 16

What are the unwanted actions of ketoconazole?

Answer 16

Liver damage- possibly fatal. Monitor liver function weekly, clinically and biochemically.

Question 17

What are two medical treatment options for Cushing’s syndrome?

Answer 17

Metyrapone

Ketoconazole

Question 18

What are the clinical features of Conn’s syndrome?

Answer 18

Benign adrenocortical tumour (zona glomerulosa- makes aldosterone).
Aldosterone is in excess.
Retain sodium and lose potassium.
Hypertension and hypokalaemia.

Question 19

How is primary hyperaldosteronism (Conn’s) diagnosed?

Answer 19

Hypertension and blood test showing low potassium.

Question 20

How is secondary hyperaldosteronism excluded as a diagnosis?

Answer 20

Renin-angiotensin system should be suppressed. High aldosterone and low renin (suppressed by hypertension).

Question 21

What is the treatment for Conn’s syndrome?

Answer 21

Aldosterone receptor antagonist: spironolactone.
Surgery: image and remove adenoma.
If bilateral adrenal hyperplasia, can stay on spironolactone.

Question 22

What are the uses and mechanism of action of spironolactone?

Answer 22

Primary hyperaldosteronism (Conn's syndrome).
Converted to several active metabolites, including canrenone, a competitive antagonist of the mineralocorticoid receptor (MR).
Blocks sodium resorption and potassium excretion un the kidney tubules (potassium sparing diuretic).

Question 23

Discuss the pharmacokinetics of spironolactone.

Answer 23

Orally active.

Highly protein bound and metabolised in the liver.

Question 24

What are the unwanted actions of spironolactone?

Answer 24

Menstrual irregularities (agonist at progesterone receptor).
Gynaecomastia (antagonist at androgen receptor).

Question 25

What is epleronone’s significance?

Answer 25

It is a mineralocorticoid receptor antagonist with similar affinity to the MR compared to spironolactone, but with less binding to androgen and progesterone receptors- better tolerated.

Question 26

What are the clinical features of phaeochromocytoma?

Answer 26

Hypertension in young people.
Episodic severe hypertension (after abdominal palpation).
More common in certain inherited conditions.
Severe hypertension can cause myocardial infarction or stroke.
High adrenaline can cause ventricular fibrillation and death- medical emergency.

Question 27

How is phaeochromocytoma managed?

Answer 27

Eventually need surgery, but patient needs careful preparation as anaesthetic can precipitate hypertensive crisis.
Alpha blockade is first therapeutic step.
Beta blockade added to prevent tachycardia.