🧪Endocrinology🧪 - Adrenal Disorders Flashcards
What is a steroid (hormone)?
A hormone synthesised from cholesterol
How can a steroid be identified from its molecular structure?
If it contains the 4 benzene rings in the arrangement as seen in cholesterol
What is made in the adrenal cortex?
Corticosteroids:
Mineralocorticoids (aldosterone)
Glucocorticoids (Cortisol)
Sex steroids (Androgens, oestrogens)
What stimulates the production of angiotensin II?
Decrease in blood pressure
How does a decrease in blood pressure lead to increased levels of angiotensin II (A2)?
Decrease in blood pressure detected by juxtaglomerular cells, which secrete renin
Renin converts angiotensinogen in the liver to angiotensin I
ACE converts angiotensin I to angiotensin II (A2)
A2 promotes 21,11,18 hydroxylases, therefore promoting aldosterone synthesis
Aldosterone promotes sodium retention in the kidneys (by increasing reabsorption), therefore raising blood volume and pressure
What effect does ACTH have on the adrenals?
Promotes 17,21,11 hydroxylases, therefore increasing cortisol production
Compare the effect of A2 to ACTH on the adrenal cortex
ACTH increases activity of 17-hydroxylase, meaning cholesterol goes down the pathway of reactions to cortisol instead
What pattern of secretion does cortisol show?
Diurnal rhythm
What is Addison’s disease?
Primary adrenal failure
Main causes are either immune damage (atrophy) of the adrenals, or tuberculosis
Autoimmune destruction most common in UK
Tuberculosis most common worldwide
What are the biochemical markers for Addison’s?
Low steroid hormones (low cortisol, low aldosterone so low blood pressure)
High ACTH and MSH (no negative feedback from cortisol)
What are the symptoms of Addison’s?
Hyperpigmentation
Low blood pressure
Weakness
Weight loss
Gastrointestinal disturbances
What are the signs and symptoms of an adrenal crisis?
Fever
Syncope
Convulsions
Hypoglycaemia
Hyponatraemia
Sever vomiting/diarrhoea
What causes the increased pigmentation in Addison’s?
Increased MSH production
Why does MSH production increase in Addison’s?
Low cortisol means increased ACTH production
ACTH comes from precursor protein pro-opiomelanocortin (POMC)
POMC broken down to make ACTH, this process also creates MSH
MSH stimulates melanin production in melanocytes, causing hyperpigmentation
What are the causes of adrenocortical failure?
Destruction of adrenal glands (autoimmune/TB)
Dysfunction of enzymes in steroid synthesis pathway
Dysfunction of enzymes leads to congenital adrenal hyperplasia (CAH)
What are the consequences of adrenocortical failure?
Fall in blood pressure (postural hypotension)
Loss of salt in the urine (low sodium in plasma = hyponatraemia)
Increased plasma potassium (less potassium excreted in urine = hyperkalaemia)
Low glucose due to glucocorticoid deficiency
High ACTH causing increased pigmentation
Eventual death due to severe hypotension
What would prompt a test for Addison’s?
Clinical suspicion due to fatigue, classic biochemistry (low Na, high K)
What is the initial test for suspected Addison’s?
9am Cortisol
ACTH
What results after a 9am cortisol test would you expect to see in a patient suffering from Addison’s?
9am cortisol = low
ACTH = high
What test is carried out to confirm the diagnosis of Addison’s?
Short synACTHen test
Give 250μg of synACTHen intramuscularly
Measure cortisol response
What response would a typical Addison’s patient have to the short synACTHen test?
No/very little response to the synACTHen
E.G.:
9am cortisol = 100 (nm: 270-900)
9:30am cortisol = 150 (nm: >600)
Very little response, whereas a healthy person’s cortisol would rise to 600 or higher
What is the treatment for primary adrenocortical failure?
Patient needs replacement of cortisol and aldosterone
How is aldosterone replaced?
Fludrocortisone is given
Aldosterone has too short a half life for once daily injections
Fludrocortisone has an extra fluorine atom, this makes it non-biodegradable therefore dramatically increasing its half life
How is cortisol replaced?
Hydrocortisone (same molecule as cortisol) 3x daily
Prednisolone 1x daily
Why is prednisolone preferred to cortisol?
Longer half life, so can be given once daily
This means the multiple peaks and troughs of 3x daily doses can be avoided, instead giving a single smooth curve
2-3x higher affinity than hydrocortisone/cortisol, so smaller dose can be given
What is congenital adrenal hyperplasia?
Deficiency of an enzyme(s) in the steroid synthesis pathway of the adrenal cortex
Most common is 21-hydroxylase deficiency
Can be complete or partial
Which hormones would be affected by a 21-hydroxylase deficiency?
Cortisol and aldosterone
What will the consequences be of a 21-hydroxylase deficiency?
Babies will present within 1-3 weeks with a salt-losing crisis (presents as acutely unwell and dehydrated)
Low aldosterone and cortisol, high sex steroids (androgens/oestrogens)
Why will sex steroids be in excess with a 21-hydroxylase deficiency?
Cholesterol is unable to become cortisol or aldosterone, so can only follow the sex steroid synthesis pathway
How does partial 21-hydroxylase deficiency differ from complete 21-hydroxylase deficiency?
Some cortisol and aldosterone will be present
Sex steroids and testosterone still in excess, but not to the same extreme
Much more variety in age of presentation - main presentation may be later in life with hirsutism+virilisation in girls and precocious puberty in boys due to adrenal testosterone
What would result from a 11-hydroxylase deficiency?
Accumulation of 11-deoxycorticosterone, testosterone and sex steroids
What are the potential consequences of an accumulation of 11-deoxycorticosterone?
Behaves as a mineralocorticoid (i.e. like aldosterone)
In excess, can cause hypertension and hypokalaemia
Why does mineralocorticoid excess cause hypokalaemia, but not hypernatraemia?
Mineralocorticoids promote potassium excretion and sodium reabsorption
Sodium reabsorption means increased water retention, and so increased blood volume
Increased blood volume mitigates the increased sodium reabsorption, but compounds the increased potassium excretion
What are the problems caused by 11-hydroxylase deficiency?
Virilisation
Hypertension
Hypokalaemia
What will result from a 17-hydroxylase deficiency?
Low cortisol and sex steroids
Excess aldosterone and 11-deoxycorticosterone (mineralocorticoids)
Hypertension
What is Cushing’s syndrome?
Excess cortisol from an overactive adrenal cortex
What are the clinical features of Cushing’s syndrome?
Centripetal obesity
Moon face, buffalo hum
Proximal myopathy
Hypertension, hypokalaemia (cortisol acts as aldosterone at high enough concentrations)
Red striae, thin skin, bruising
Osteoporosis
Diabetes
How does Cushing’s cause diabetes?
Both directly and indirectly
Cortisol directly interferes with insulin signalling pathways
Indirectly by stimulating gluconeogenesis in the liver, raising blood glucose
Combination of raising blood glucose, and interfering with cellular glucose uptake
How can aldosterone receptors (mineralocorticoid receptors/MR) be protected from excess cortisol?
11β-hydroxysteroid dehydrogenase (11βHSD) catalyses reaction of cortisol to cortisone, which is inactive
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
What investigations can be taken to determine the cause of Cushing’s?
24h urine collection for urinary free cortisol
Blood diurnal cortisol levels (levels highest at 8/9am an lowest at midnight, if asleep)
Low dose dexamethasone suppression test
What is the low dose dexamethasone test?
0.5mg dexamethasone hourly for 48hrs
dexamethasone = artificial glucocorticoid
Healthy people will suppress cortisol to zero
All causes/forms of Cushing’s will fail to suppress cortisol
What are the 2 categories of pharmacological treatment for Cushing’s?
Enzyme inhibitors
Receptor blocking drugs
What are some inhibitors of steroid biosynthesis?
Metyrapone
Ketoconazole
Osilodrostat
What is the action of Metyrapone?
Inhibits 11β-hydroxylase
Steroid synthesis is arrested at the 11-deoxycortisol stage
11-deoxycortisol is less potent than cortisol and has no negative feedback effect on the pituitary and hypothalamus
What are the side/adverse effects of metyrapone?
Hypertension on long-term administration (build up of 11-deoxycorticosterone which has mineralocorticoid properties)
Hirsutism (increased sex steroid production)
What is the action of Ketoconazole?
Inhibits steroidogenesis at high concentrations
Inhibits cortisol production by inhibiting 17-hydroxylase
What are the uses of Metyrapone and Ketoconazole?
Cushing’s syndrome
Treatment and control of symptoms prior to surgery
What are the side/adverse effects of Ketoconazole?
Liver damage - can be fatal
Monitor liver function weekly - clinically and biochemically
What is the action of Osilodrostat?
Similar to Ketoconazole, blocks several enzymes in the steroid synthesis pathway
Inhibits 17 and 11 -hydroxylase
What is the treatment of Cushing’s?
Depends on the cause
Pituitary surgery (trans-sphenoidal hypophysectomy)
Bilateral adrenalectomy
Unilateral adrenalectomy (in the case of an adrenal mass)
What is Conn’s syndrome?
Benign adrenal cortical tumour (zona glomerulosa)
Excess aldosterone
Hypertension and hypokalaemia
What are the consequences of Conn’s syndrome, biochemically?
Increases renal sodium reabsorption
Increases renal potassium excretion
Increases blood pressure (sodium & water retention)
What is the diagnosis of Conn’s syndrome?
Primary hyperaldosteronism
Renin-angiotensin system should be suppressed (high blood pressure means no renin release)
How is Conn’s syndrome treated?
MR antagonist:
Spironolactone, epleronone
(MR = mineralocorticoid receptor)
When is Spironolactone used and what is its mechanism of action?
Used for primary hyperaldosteronism
Competitive antagonist of the mineralocorticoid receptor (MR)
Blocks sodium reabsorption and potassium excretion
What are the side/adverse effects of Spironolactone?
Gynaecomastia (activates androgen receptors)
What is Eplerenone?
Another MR antagonist
Similar affinity to Spironolactone
Less affinity for androgen receptors than spironolactone (less gynaecomastia)
What is a Phaeochromocytoma?
A tumour of the adrenal medulla (responsible for secretion of catecholamines)
What are catecholamines?
Group of hormones responsible for the “fight-or-flight” response (raising blood pressure, blood glucose, heart rate, dilates air passages etc…)
Adrenaline and noradrenaline
What are the clinical features of a phaeo (Phaeochromocytoma)?
Hypertension in young people
Episodic severe hypertension
More common in certain inherited conditions
What are the potential complications caused by a phaeo?
Severe hypertension can lead to myocardial infarction or stroke
High adrenaline can cause ventricular fibrillation and death
This means Phaeochromocytomas are a medical emergency
What is the management for a phaeo?
Eventually, surgery is required
Requires careful preparation as anaesthetics can precipitate a hypertensive crisis
What is the first therapeutic step in the managements of a phaeo?
Alpha blockade (alpha receptors in arteries cause vasoconstriction)
Note: patients may require intravenous fluid as alpha blockade commences
What should patients be given in addition to an alpha blockade in management of a phaeo?
Beta blockade
Helps to prevent tachycardia
