Adrenal Disorders Flashcards by Elizabeth Akeju

What is a steroid?

A hormone derived from cholesterol

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What three types of steroids are made in the adrenal cortex?

Mineralcorticoids (aldosterone)
Glucocorticoids (cortisol)
Sex steroids (androgens, oestrogens)

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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

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What is the role of aldosterone?

Controls blood pressure
Sodium retention
Lowers potassium

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Where is aldosterone made?

Zona glomerulosa of adrenal cortex

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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

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Where is cortisol produced?

Zona fasciculata of adrenal cortex

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What is Addison’s disease?

Primary adrenal failure

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What causes Addison’s Disease?

Autoimmune - immune system decides to destroy adrenal cortex
Tuberculosis of the adrenal glands (commonest worldwide cause)

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Why do people with Addison’s Disease tan?

Pituitary starts secreting lots of ACTH and therefore MSH (melanocyte-stimulating hormone) - same precursor pro-opiomelanocortin

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What are some features of Addison’s Disease?

Increased pigmentation
Low BP - no cortisol or aldosterone
Autoimmune vitiligo may coexist
Weight loss

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What are the features of adrenal crisis?

Fever
Syncope (low BP)
Convulsions
Hypoglycaemia
Hyponatraemia
Severe vomiting and diarrhoea

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What are the causes of adrenocortical failure?

Tuberculous Addison’s Disease
Autoimmune Addison’s Disease
Congenital adrenal hyperplasia (enzyme deficiency)

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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

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What are the tests for Addison’s?

9 am cortisol (low in Addison’s)
ACTH (high in Addison’s)
Short synACTHen test

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What happens in the short synACTHen test?

Give 250 micrograms synachten IM
Measure cortisol response - do blood test before and after injection

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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

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Why isn’t aldosterone given as a steroid replacement?

Half life is too short for once daily administration

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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

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What happens when you give a high dose of hydrocortisone?

It acts on both aldosterone and cortisol receptors

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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

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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

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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

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What is the commonest cause of congenital adrenal hyperplasia?

21-hydroxylase deficiency

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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