Adrenal Disorders Flashcards
What is a steroid?
A hormone derived from cholesterol
What three types of steroids are made in the adrenal cortex?
Mineralcorticoids (aldosterone)
Glucocorticoids (cortisol)
Sex steroids (androgens, oestrogens)
What is the effect of angiotensin II on the adrenals?
Production of aldosterone from cholesterol:
Side chain cleavage -> pregnenolone
3 hydroxysteroid dehydrogenase -> progesterone
21 hydroxylase -> 11-deoxycorticosterone
11 hydroxylase -> corticosterone
18 hydroxylase -> aldosterone
What is the role of aldosterone?
Controls blood pressure
Sodium retention
Lowers potassium
Where is aldosterone made?
Zona glomerulosa of adrenal cortex
What is the effect of ACTH on the adrenals?
Cortisol production from cholesterol:
Side chain cleavage -> pregnenolone
3 hydroxysteroid dehydrogenase -> progesterone
17 hydroxylase -> 17-alpha-hydroxyprogesterone
21 hydroxylase -> 11-deoxycortisol
11 hydroxylase -> cortisol
Where is cortisol produced?
Zona fasciculata of adrenal cortex
What is Addison’s disease?
Primary adrenal failure
What causes Addison’s Disease?
Autoimmune - immune system decides to destroy adrenal cortex
Tuberculosis of the adrenal glands (commonest worldwide cause)
Why do people with Addison’s Disease tan?
Pituitary starts secreting lots of ACTH and therefore MSH (melanocyte-stimulating hormone) - same precursor pro-opiomelanocortin
What are some features of Addison’s Disease?
Increased pigmentation
Low BP - no cortisol or aldosterone
Autoimmune vitiligo may coexist
Weight loss
What are the features of adrenal crisis?
Fever
Syncope (low BP)
Convulsions
Hypoglycaemia
Hyponatraemia
Severe vomiting and diarrhoea
What are the causes of adrenocortical failure?
Tuberculous Addison’s Disease
Autoimmune Addison’s Disease
Congenital adrenal hyperplasia (enzyme deficiency)
What are the consequences of adrenocortical failure?
Fall in BP
Loss of salt in urine
Increased plasma potassium
Fall in glucose due to glucocorticoid deficiency
High ACTH resulting in increased pigmentation
Eventual death due to severe hypotension
What are the tests for Addison’s?
9 am cortisol (low in Addison’s)
ACTH (high in Addison’s)
Short synACTHen test
What happens in the short synACTHen test?
Give 250 micrograms synachten IM
Measure cortisol response - do blood test before and after injection
What is the response of a typical Addison’s patient to the short synACTHen test?
Cortisol at 9am = 100 (270-900)
Administer injection of synacthen
Cortisol at 9.30 = 150 (>600)nM
*Typical values for no Addison’s in brackets
Why isn’t aldosterone given as a steroid replacement?
Half life is too short for once daily administration
What medication is given to replace aldosterone and what makes it suitable?
Fludrocortisone (50-100mcg daily)
Has an added fluorine - fluorine doesn’t exist in natural steroids - this slows metabolism giving it a longer half life - effects seen for 18 hrs
What happens when you give a high dose of hydrocortisone?
It acts on both aldosterone and cortisol receptors
Why isn’t hydrocortisone the most ideal steroid replacement treatment?
Short half-life - too short for once daily administration
Given three times daily - doesn’t mimic diurnal rhythm very well
Late cortisol peaks may be harmful
What are the benefits of taking prednisolone over hydrocortisone?
Contains an extra double bond - longer half life
More potent than cortisol - 2.3x binding affinity
3-4mg ONCE daily
What is the minimum dose of prednisolone in many developing countries and what may this cause?
5mg - too high?
Increased mortality due to excess steroid exposure
Prednisolone typically given in high doses for autoimmune conditions (e.g. asthma) but not adrenal failure so researchers still trying to pinpoint appropriate dosage
What is the commonest cause of congenital adrenal hyperplasia?
21-hydroxylase deficiency
What hormones are deficient in congenital adrenal hyperplasia?
Cortisol and aldosterone
What hormone do you have in excess in congenital adrenal hyperplasia and what does this cause?
Precursor in excess - 17-OH progesterone
Used to make testosterone - excess testosterone
How long can you survive with 21-hydroxylase deficiency?
Up to 24 hours after birth
What is the age of presentation with complete 21 hydoxylase deficiency?
Neonate with salt losing Addisonian crisis
In utero foetus gets steroids across placenta
Girls may have ambiguous genitalia due to excess testosterone (given saline)
Boys more likely to have crisis as they look normal
What happens in partial 21 hydroxylase deficiency?
Cortisol and aldosterone are deficient but enough for functioning
Excess testosterone
What signs of partial 21 hydroxylase deficiency arise later in life?
Hirsutism and virilsation in girls
Precocious puberty in boys - grow really quickly then stop prematurely
Male escutcheon - male appearance in someone who’s female
Where is 21 hydroxylase deficiency more common?
More common in populations with consanguineous marriages
Autosomal recessive condition
What happens when people are born with 11 hydroxylase deficiency?
No cortisol and aldosterone
Excess testosterone
However, excess pre-cursor 11 deoxycorticosterone behaves like aldosterone so causes hypertension and hypokalaemia
What are the problems caused by 11 hydroxylase deficiency?
Virilisation
Hypertension
Low potassium
How does 17 hydroxylase deficiency present?
Sex steroid deficiency - No testosterone
Don’t go through puberty - appearance of a child in adulthood
Slightly hypoglycaemic - glucocorticoid deficiency
Excess aldosterone - hypertension and hypokalaemia
How does excess cortisol affect protein synthesis?
Turns off protein synthesis
Increases fat storing and decreases protein synthesis
Is a low or high cortisol needed for wound healing?
Low cortisol
What effect does excess cortisol have on the immune system?
Dampens the immune system making people more susceptible to infection
What are the clinical features of Cushing’s Syndrome?
Excess cortisol:
Centripetal obesity
Moon face and buffalo hump
Proximal myopathy
Hypertension and hypokalaemia
Red striae, thin skin and bruising
Osteoporosis, diabetes
What are the causes of Cushing’s Syndrome?
Taking too many steroids
Pituitary dependent Cushing’s Disease
Ectopic ACTH from lung cancer
Adrenal adenoma secreting cortisol
What investigations are used to diagnose Cushing’s Syndrome?
24h urine collection for urinary free cortisol
Blood diurnal cortisol levels - midnight cortisol (high in Cushing’s)
Low dose dexamethasone suppression test
How does a low dose dexamethasone suppression test work?
Dexamethasone = artificial steroid
0.5mg every 6 hours for 48 hours
No Cushing’s - cortisol level would be suppressed to zero
Any cause of Cushing’s will fail to suppress
Aside for surgery, what other treatment options are there for Cushing’s?
Enzyme inhibitors
Receptor blocking drugs
What is the action of Metyrapone?
Inhibits steroid synthesis through inhibition of 11-beta-hydroxylase
Steroid synthesis arrested at 11-deoxycortisol stage
11-deoxycortisol has no negative feedback effect on hypothalamus and pituitary
Rapidly puts Cushing’s in remission
When is Metyrapone used?
Control of Cushing’s prior to surgery:
- adjust oral dose according to cortisol level (aim for 150-300 nmol/L mean serum cortisol)
- improves patient’s symptoms and promotes better post-op recovery
Control of Cushing’s symptoms after radiotherapy (slow to take effect)
What are the side effects of Metyrapone?
Hypertension due to accumulation of 11-deoxycorticosterone (aldosterone-like mineralcorticoid activity)
Hirsutism due to increased adrenal androgen production
What was the main use of Ketoconazole in the past?
Antifungal agent - withdrawn in 2013 due to hepatotoxcity risk
Inhibits steroidogenesis at higher concentrations (off-label use)
What is the mechanism of action of Ketoconazole?
Inhibits 17-alpha-hydroxylase
What is the benefit of using Ketoconazole over Metyrapone?
Ketoconazole actually reduces testosterone - doesn’t cause hirsutism
What is an unwanted action of Ketoconazole?
Can cause liver damage that is possibly fatal
Have to monitor liver function weekly - clinically and biochemically
What is the mechanism of action of Osilidrostat?
Mainly blocks 11-beta-hydroxylase and 17-alpha-hydroxylase
Was it the benefit of Osilidrostat over Metyrapone and Ketoconazole?
Less of nausea and vomiting side effects
What surgeries can be used for treatment of Cushing’s?
Depends on cause
Pituitary surgery - transsphenoidal hypophysectomy
Bilateral adrenalectomy
Unilateral adrenalectomy for adrenal mass
What are the features of Conn’s Syndrome?
Benign adrenal cortical tumour (Zona glomerulosa)
Excess aldosterone
Hypertension and hypokalaemia
How is Conn’s Syndrome diagnosed?
Primary hyperaldosteronism
Renin-angiotensin system should be suppressed
What is the mechanism of action of Spironolactone?
Converted to several active metabolites including canrenone - a competitive antagonist of the mineralcorticoid receptor
Blocks Na+ resorption and K+ excretion in kidney tubules
Describe the pharmacokinetics of Spironolactone?
Orally active
Highly protein bound, metabolised in liver
What are the unwanted side effects of spironolactone?
Menstrual irregularities
Gynaecomastia
What is epleronone and how do its effects compare to spironolactone?
Also a mineralcorticoid receptor (MR) antagonist
Similar affinity as spironolactone to MR
Better tolerated as less binding to androgen and progesterone receptors
What are phaeochromocytomas?
Tumours of the adrenal medulla that secrete catecholamines
What are the clinical features of a phaeochromocytoma?
Hypertension in young people
Episodic severe hypertension (e.g. after abdominal palpation)
More common in certain inherited conditions
Severe hypertension-> MI or stroke
High adrenaline -> ventricular fibrillation and death
How are pheos managed prior to surgery?
First therapeutic step is alpha blockade
IV fluid may be given with alpha blockers (drop in BP)
Beta blockers then given to prevent tachycardia
Why do patient with phaeochromocytomas require careful preparation prior to surgery?
Anaesthetic may precipitate a hypertensive crisis
List some extra facts about phaeochromocytomas
10% extra-adrenal (sympathetic chain)
10% malignant
10% bilateral
Extremely rare
