Hyperadrenal Disrders

Question 1

What are the clinical features of cushing’s syndrome/disease?

Answer 1

• Too much cortisol
• Centripetal obesity
• Moon face, buffalo hump
• Proximal myopathy
• Hypertension and hypokalaemia
• Red striae, thin skin and bruising
• Osteoporosis and diabetes

Question 2

What are the causes of Cushing’s?

Answer 2

• Taking too many steroids.
• Pituitary dependant Cushing’s disease.
• Ectopic ACTH (lung cancer).
• Adrenal adenoma

Question 3

What is the order of tests to determine the cause of Cushing’s syndrome?

Answer 3

1) Urinary free cortisol (24h)

2) Blood diurnal (varying levels depending upon time of day) cortisol analysis.
Normal = cortisol high in morning and low at night.
Cushing’s = cortisol high all the time.

3) Low-dose dexamethasone suppression test.
0.5mg 6-hourly for 48 hours.
Normal = dexamethasone supresses cortisol to zero due to feedback inhibition.
Cushing’s = ANY cause will fail to suppress.

Question 4

What are the treatment options for Cushing’s?

Answer 4

Drugs – enzyme inhibitors, receptor blocking drugs E.G. Metyrapone, Ketoconazole.

Surgery – pituitary surgery, bi-lateral adrenalectomy, unilateral adrenalectomy for adrenal mass

Question 5

What is metyrapone (mechanism of action, uses and side effects)?

Answer 5

Mechanism of action:

• Inhibits 11-beta-hydroxylase.
• Blocks production of cortisol but raises ACTH secretion (feedback systems).
• Steroid synthesis in the zona fasciculata (and reticularis) is arrested at 11-deoxycortisol stage : 11-deoxycortisol has NO feedback effect.

Uses of Metyrapone:
- Control of Cushing’s prior to surgery.
Dose adjusted to cortisol.
Improves patient’s symptoms and promotes post-op recovery.
- Control of Cushing’s after radiotherapy

Unwanted actions:

• Hypertension on long-term administration – 11- deoxycortisone accumulates in zona glomerulosa which has aldosterone-like activity leading to salt retention and hypertension.
• Hirsutism – increased androgen production

Question 6

What is ketoconazole ( mechanism of action, uses, unwanted actions?

Answer 6

Main use as an anti-fungal drug but not anymore.

At HIGH concentrations, inhibits steroidogenesis and so has an off-label use in Cushing’s syndrome.

Mechanism of action:
- Inhibits steroidogenesis.

Uses of Ketoconazole:

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

Unwanted actions:
- Liver damage

Question 7

What is Conn’s syndrome? How would you diagnose and treat Conn’s syndrome?

Answer 7

A benign adrenal cortical (zona glomerulosa) tumour.

Produces aldosterone in excess -> leads to hypertension and hypokalaemia – due to water retention, aldosterone enhances sodium reabsorption and potassium excretion in the kidneys.

Diagnosis:

• Primary hyperaldosteronism.
• The renin-angiotensin system should be supressed to exclude secondary hyperaldosteronism.

Treatment:

• Aldosterone receptor antagonists – Spironolactone.
• Surgery.

Question 8

What is spiranolactone (uses, mechanism of action, pharmacokinetics, unwanted actions)?

Answer 8

Mineralocorticoid receptor antagonist

Uses:
- Treatment of primary hyperaldosteronism (Conn’s syndrome).

Mechanism of action:
- Spironolactone is converted to several active metabolites including canrenone, a competitive antagonist of the MR -> blocks Na+ reabsorption and K+ excretion – potassium sparing diuretic.

Pharmacokinetics:

• Orally active.
• Highly protein bound and metabolised in the liver.

Unwanted actions:

• Menstrual irregularities – via progesterone receptor.
• Gynaecomastia – via androgen receptor

Question 9

What is the better treatment for Conn’s?

Answer 9

Epleronone

Also a MR antagonist (similar affinity to MR as spironolactone).

Less binding to androgen and progesterone receptors compared to spironolactone so better tolerated

Question 10

What are phaeochromocytomas?

Answer 10

tumours of adrenal MEDULLA which secrete catecholamines (A/NA)

Clinical features of a phaeo include:

• Hypertension in young people.
• Episodic SEVERE hypertension (after abdominal palpation – squeezes more adrenaline out).
• Different to Conn’s hypertension as this is episodic in the older population.
• Can cause MI or stroke.
• Can cause VF and death if not treated - classed as a MEDICAL EMERGENCY
• More common in certain inherited conditions
• 10% are extra-adrenal (down the sympathetic chain)
• 10% are malignant
• 10% are bilateral
• VERY RARE

Question 11

What is the treatment for phaeochromocytomas?

Answer 11

Patient requires surgery but needs careful preparation as anaesthetic can precipitate a hypertensive crisis.

Treatment:

• Alpha-blockade is the first step.
• Patients may need IV fluids during alpha-blockade as BP will drop.
• Beta-blockade is added to prevent tachycardia.