6. Hyperadrenal disorders Flashcards
What is the cause of Cushing’s disease?
- Pituitary tumour making ACTH
- ACTH makes adrenal gland grow
- Too much cortisol
What happens to protein and fat in Cushing’s syndrome?
- Cortisol switches protein synthesis off and fat synthesis on
- Lose protein and gain fat
What are the clinical features of Cushing’s syndrome?
- Too much cortisol
- Centripetal obesity
- Moon face
- Buffalo hump (interscapular fat pad)
- Proximal myopathy
- Hypertension and hypokalaemia
- Red striae, thin skin and easy bruising
- Osteoporosis, diabetes
Why is bruising common in Cushing’s syndrome?
- Normally, lots of protein in tissues under skin, used to heal
- Protein synthesis turned off - start to leak and get bruises
Why is hypertension and hypokalaemia common in Cushing’s?
- Cortisol starts to bind to receptors in the kidney
- Retention of sodium
- Excretion of potassium
What are the causes of Cushing’s syndrome?
- Taking too many steroids orally (first question to ask patient)
- Pituitary dependent Cushing’s disease
- Ectopic ACTH from lung cancer
- Adrenal adenoma making cortisol
How can you determine the cause of Cushing’s syndrome?
• CUSHINGS - LOW DOSE dexamethasone suppression test (gold standard)
- give patient extra steroid
- normally ACTH and cortisol should go to zero
• 24 hour urine collection for urinary free cortisol
- patients often forget to sample urine, not ideal
• Blood diurnal cortisol levels
- normally high in the morning and low when sleeping
- loss of rhythm, high levels at night - suspicious
How is the low dose dexamethasone suppression test carried out and how do people with Cushing’s react?
- Blood test before
- Give dexamethasone for 48 hours
- Cushing’s - keep making cortisol, no reaction to dexamethasone
- Does not tell you the cause
Why would people with Cushing’s die more quickly in the past?
- Infection
- Can’t synthesise proteins and heal
- Immunosuppressed
- Sepsis
How can Cushing’s be treated?
Inhibitors of steroid biosynthesis, e.g.
• metyrapone
• ketoconazole
What is Conn’s and how can it be treated?
• Too much aldosterone
• MR (mineralocorticoid receptor) antagonist
- spironolactone
- epleronone
What type of hormones are produced in the adrenal medulla?
Catecholamines
What is phaeochromocytoma?
- Tumour of adrenal medulla
* Excess catecholamines
How do you block the effects of excess catecholamines?
• First give alpha blocker
- urgent issue is really high BP caused by catecholamines binding to alpha receptors in vasculature => vasoconstriction
• When BP decreases, give beta blocker
- catecholamines stimulate beta receptors to cause vasodilation
- BB prevents too much vasodilation
- alpha blocker given first as you could have unopposed alpha mediated vasoconstriction causing a hypertensive crisis and possible stroke
Where is aldosterone, cortisol and 17b-oestradiol produced?
- Aldosterone - zona glomerulosa
- Cortisol - zona fasciculata
- 17b-oestradiol - zona reticularis
How does metyrapone work?
- Medication that inhibits 11b-hydroxylase
- Slows down cortisol synthesis pathway
- Reduces production of cortisol and corticosterone
- Treatment for Cushing’s
- ACTH levels rise because of this - no negative feedback from 11-deoxycorticosterone
When is metyrapone used?
• Control prior to surgery
- improves symptoms
- promotes better post-op recovery
- done as patients are predisposed to infection, very thin skin, weak blood vessels
• Control of Cushing’s symptoms after radiotherapy
- given for control until beneficial effects of radiotherapy come about
What is the normal dose of oral metyrapone the same as?
- Dose according to cortisol production
* Aim for mean serum cholesterol of 150-300 nmol/L
What are the negative (biochemical) aspects of metyrapone?
• Accumulation of 11-deoxycorticosterone and 11-deoxycortisol
• 11-deoxycorticosterone has mineralocorticoid properties (works like aldosterone)
- sodium retention
- potassium excretion
- hypertension
• When the drug blocks 2 limbs of the pathway, all the precursors funnel towards sex steroid synthesis
- increase in adrenal androgens
- hirsuitism and acne
What are the negative side effects of metyrapone?
- Nausea, vomiting, dizziness
- Sedation
- Hypoadrenalism - leads to impaired performance of skilled tasks
- Hypertension on long-term administration
- Hirsuitism
What is ketoconazole used for?
- Mainly used as anti-fungal agent - withdrawn due to hepatotoxicity
- Inhibits cortisol production at higher concentrations - unlicensed use for operation preparation
- Short-term use
How does ketoconazole work?
- Inhibits Cytochrome P450 SCC enzymes (cholesterol => pregnenolone)
- Blocked production of glucocorticoids, mineralocorticoids and sex steroids
What are the negative side effects of ketoconazole?
- Nausea, vomiting, abdominal pain
- Alopecia
- Gynaecomastia, oligospermia, impotence, decreased libido
- Ventricular tachycardias
- Liver damage - patients monitored ever week as it can be fatal
How can Cushing’s syndrome be treated (invasively)?
- Pituitary surgery (transsphenoidal hypophysectomy)
- Bilateral adrenalectomy - remove both adrenal glands, provide hormone replacement
- Unilateral adrenalectomy for adrenal mass
(round of medical treatment until patient is safe for one of the above operations, depending on cause)
What is the cause of Conn’s syndrome and what are the features?
- Benign adrenocortical tumour
- Excess aldosterone - retain sodium, lose potassium
- Hypertension and hypokalaemia
What 2 (3) things should you look out for when diagnosing Conn’s syndrome?
1) Primary hyperaldosteronism
• Tumour just making aldosterone
• Patient has high BP and blood test shows low potassium
2) Renin-angiotensin system should be suppressed
• If aldosterone is high, measure renin - suppressed by very high BP
• High BP, low potassium, low renin => Conn’s syndrome
How can Conn’s syndrome be treated?
1) Mineralocorticoid receptor antagonists - spironolactone, epleronone
- prevents the produced aldosterone from working at the MR
2) Remove the tumour
Stay on (long-term) spironolactone if bilateral adrenal hyperplasia, as surgery will remove production of any cortisol or aldosterone
Why is spironolactone used before surgery?
- Bad to give general anaesthetic to someone with high BP
* Reduces BP for surgery preparation
Describe the mechanism of action of spironolactone
- Converted to several active metabolites including Canrenone (competitive antagonist of MR)
- Blocks sodium channels too
- Prevents Na+ reabsorption and K+ excretion in kidney tubules - potassium sparing diuretic
What is Eplerenone and how does it compare to Spironolactone?
- MR antagonist
- Newer
- As effective
- Fewer side effects
- More specific - interferes less with progesterone and androgen receptors
- More expensive
What happens in Phaeochromocytoma?
- Tumours of the adrenal medulla
- Produces more adrenaline
- Rapid effect
- With sudden releases of adrenaline from tumour => massive rise in blood pressure (can cause a sudden stroke)
- Sudden onset panic, anxiety, tachycardia and severe hypertension (can last about 10 minutes)
- Fatal if going into ventricular fibrillation
What can cause a sudden release in phaeochromocytoma?
- After abdominal palpation
* Trauma
How is a phaeochromocytoma patient prepared before surgery and why?
• Preparation as:
- anaesthetic can cause tumour to suddenly release adrenaline
- hypertensive crisis
• First give drug to block adrenaline receptor - alpha blocker
- IV fluid as blockade commences due to drop in BP
• Then give beta blocker
- prevents tachycardia
• Therefore, if adrenaline is released, receptors are blocked so there is no effect
Where are the majority of phaeochromocytomas found and how curable by operation are they?
- inside the adrenal - 90%
* curable by operation - 90%
How common is phaeochromocytoma?
Extremely rare
