3.11 - Adrenal disorders 2/2 Flashcards
What kind of rhythm does cortisol have?
Diurnal - increase starts from 5am, peaks around 8:30-9am, then decreases again (usually lowest around midnight if asleep)
What is the difference between Cushing’s syndrome and Cushing’s disease?
- Cushing’s syndrome - excess cortisol in body
- Cushing’s disease - type of Cushing’s syndrome where there is a pituitary corticotroph tumour causing excess cortisol
What are the clinical features of Cushing’s syndrome?
- too much cortisol
- centripetal obesity
- moon face and buffalo hump
- proximal myopathy
- hypertension and hypokalaemia (11BHSD inhibited)
- red striae, thin skin, bruising
- osteoporosis, diabetes
How does 11-beta-hydroxysteroid dehydrogenase (11BHSD) protect the mineralocorticoid receptors from cortisol?
- cortisol can bind to either its own receptor (glucocorticoid receptors - GR), or the aldosterone receptors (MR)
- 11BHSD quickly deactivates cortisol into cortisone, protecting the MR and preventing cortisol from having mineralocorticoid effects
What happens to 11-beta-hydroxysteroid dehydrogenase in Cushing’s syndrome and how does this explain the hypertension/hypokalaemia observed?
- excess cortisol means that 11BHSD is overwhelmed and not able to deactivate all the cortisol once secreted
- cortisol has aldosterone-like effects in high concentrations
What are the causes of Cushing’s syndrome?
- taking too many steroids (glucocorticoids)
- pituitary dependent Cushing’s disease
- ectopic ACTH from lung cancer
- adrenal adenoma secreting cortisol
What investigations can be done to determine Cushing’s syndrome?
- 24h urine collection for urinary free cortisol
- blood diurnal cortisol levels (usually highest at 9am and lowest at 12am)
- low dose dexamethasone suppression test
How does the low dose dexamethasone suppression test work?
- dexamethasone = very potent artificial glucocorticoid (steroid)
- give 0.5mg every 6h for 48h
- healthy people will suppress cortisol to zero - pituitary will respond via -ve feedback thinking it is cortisol
- any cause of Cushing’s will fail to suppress cortisol
What types of drugs can be used to deal with high cortisol?
- enzyme inhibitors
- receptor blocking drugs
What specific drugs are used to treat Cushing’s syndrome? (3)
Inhibitors of steroid (cortisol) biosynthesis:
- metyrapone
- ketoconazole
- osilidrostat
What is the mechanism of action of metyrapone?
- inhibition of 11B-hydroxylase
- steroid synthesis in zona fasciculata (and reticularis) is arrested at 11-deoxycortisol stage
- 11-deoxycortisol has no negative feedback on hypothalamus/pituitary
What are the uses of metyrapone?
- control of Cushing’s prior to surgery and/or after radiotherapy (which is slow to take effect)
- 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 (better wound healing, less infection etc)
What are some unwanted actions of metyrapone?
- inhibition of 11-hydroxylase causes accumulation of 11-deoxycorticosterone in zona glomerulosa –> aldosterone-like effects –> hypertension and salt retention on long-term administration
- increased adrenal androgen production –> hirsutism (women)
What is the mechanism of action of ketoconazole?
- main use as an antifungal agent - withdrawn in 2013 due to risk of hepatotoxicity
- at higher concentrations, inhibits steroidogenesis = off-label use in Cushing’s syndrome
- mainly blocks 17-alpha hydroxylase, inhibiting cortisol production
What is ketoconazole used for?
- treatment and control of symptoms prior to surgery
- orally active
What is an unwanted side effect of ketoconazole?
Liver damage - possibly fatal (monitor liver function weekly - clinically and biochemically)
What is the mechanism of action for osilidrostat?
- similar to ketoconazole and blocks several enzymes in the steroid synthetic pathway
- mainly blocks 11b and 17a hydroxylase, inhibiting cortisol production
- newer agent - using in UK on named patient basis
What are other treatments of Cushing’s syndrome (other than drugs suppressing cortisol synthesis)? (3)
- pituitary surgery (trans-sphenoidal hypophysectomy)
- bilateral adrenalectomy
- unilateral adrenalectomy for adrenal mass
What is Conn’s syndrome?
- benign adrenal cortical tumour (zona glomerulosa)
- aldosterone in excess
- hypertension and hypokalaemia
Might also see metabolic alkalosis due to excess H+ secretion
What is a summary of the actions of aldosterone?
- increases renal sodium reabsorption
- increases renal potassium excretion
- increases blood pressure (sodium and water retention)
Also increases H+ secretion (so excess –> metabolic alkalosis)
How is Conn’s syndrome diagnosed?
- primary hyperaldosteronism
- renin-angiotensin system should be suppressed (exclude secondary hyperaldosteronism - normal physiological response)
How do we treat Conn’s syndrome?
Mineralocorticoid antagonists - spironolactone, eplerenone
What does spironolactone do?
- competitive antagonist of the MR
- blocks Na+ reabsorption and K+ excretion in the kidney tubules (potassium sparing diuretic)
What is an unwanted side effect of spironolactone?
Gynaecomastia (blocks androgen receptor - anti-androgen drug means reduced testosterone)
What does eplerenone do?
- also a MR antagonist
- similar affinity to the MR compared to spironolactone
- less binding to androgen receptors compared to spironolactone, so better tolerated (less gynaecomastia)
What are phaeochromocytomas?
Tumours of the adrenal medulla which secrete catecholamines (adrenaline and noradrenaline)
What are the clinical features of a phaeochromocytoma?
- hypertension in young people
- episodic severe hypertension (after abdominal palpitation)
- severe hypertension can cause MI/stroke
- high adrenaline can cause ventricular fibrillation and death = medical emergency
- more common in certain inherited conditions
What is the management of a phaeochromocytoma?
- eventually need surgery, but patient needs careful preparation as anaesthetic can precipitate a hypertensive crisis
- alpha blockade is first therapeutic step to block adrenaline effects for surgery (alpha receptors on arteries cause vasoconstriction)
- patients may need IV fluid as alpha blockade commences (blockage causes BP crash)
- beta blockade added to prevent tachycardia
Summary of three excess hormone pathologies.
- excess cortisol = Cushing’s syndrome
- excess aldosterone = Conn’s syndrome
- excess adrenaline = phaeochromocytoma
