Adrenal Disorders Flashcards
What does the adrenal cortex produce?
Corticosteroids
- mineralcorticosteroids (aldosterone)
- glucocorticoids (cortisol)
- sex steroids (androgens and oestrogens)
What is the precursor for corticosteroids?
Cholesterol
What is the effects of angiotensin II on the adrenal glands?
Activation of:
- 3 hydroxysteroid dehydrgenase
- 21 hydroxylase
- 11 hydroxylase
- 18 hydroxylase
How does angiotensin II activate enzymes?
By side chain cleavage
What is the action of aldosterone?
Controls blood pressure, sodium and lowers potassium
What is the effect of ACTH on the adrenal glands?
Activates:
- 3 hydroxysteroid dehydrogenase
- 21 hydroxylase
- 11 hydroxylase
- 17 hydroxylase
What does 17 hydroxylase catalyse?
the conversion of progesterone to 17-OH progesterone
What does 21 hydroxylase catalyse?
- the conversion of progesterone to 11-deoxycorticosterone
What does 11 hydroxylase catalyse?
- 11-deoxycorticosterone to corticosterone or cortisol
What does 18 hydroxylase catalyse?
the conversion of corticosterone to aldosterone
What rhythm does cortisol have?
Diurnal (peaks at 8:30)
What is Addison’s disease?
Primary adrenal failure
Autoimmune disease where the immune system decides to destroy the adrenal cortex
(most commonly: tuberculosis of the adrenal glands)
What is the result of Addison’s disease
The pituitary gland secretes a lot of ACTH and therefore MSH
What are the symptoms of Addison’s Disease?
- Increased pigmentation
- Autoimmune vitiligo
- low blood pressure (no cortisol or aldosterone)
What are the general causes of adrenocortical failure?
- enzymes in the steroid synthetic pathway not working
- adrenal glands are destroyed
What are the causes of adrenocortical failure?
- Tuberculosis Addison’s disease (common worldwide)
- Autoimmune Addison’s disease (common UK)
- Congenital adrenal hyperplasia
What are the consequences of adrenocortical failure?
Increase: - ACTH - pigmentation - plasma K+ Decrease: - blood pressure (can cause death) - salt in urine - glucose (due to glucocorticoid deficiency)
Why does high ACTH levels cause increased pigmentation?
POMC (pro-propio-melanocortin) is a large precursor protein which is cleaved to form ACTH, MSH and endorphins
Where is Pro-propio melanocortin synthesised?
In the pituitary
How do you test for Addison’s disease?
- 9 am cortisol (low)
- ACTH (high)
- short synACTH test
- give 250ug synACTHen (IM)
- measure cortisol response
What results would you expect when doing a short synACTH test in someone with Addison’s disease?
- 9am cortisol, 100nM (270-900)
- administer IM injection of synACTHen
- 9:30am cortisol, 150nM (>600)
Why isn’t aldosterone administered in HRT during adrenal failure?
The half-life of aldosterone is too short for safe 1 x daily administration
What is used to replace Aldosterone in HRT and why?
Fludrocortisone (50-100mcg daily)
Doesn’t exist in natural steroids and therefore the presence slows metabolism significantly.
What is the mechanism of Fludrocortisone?
- binds to both MR and GR
- half life: 3.5 hours
- effects seen for 18 hours
Why isn’t cortisol (hydrocortisone) used in HRT during adrenal failure?
Half-life is too short for 1x daily administration
Causes multiple/late peaks in cortisol which is harmful
What is used instead of cortisol and why?
Prednisolone (1-2 dehydro-hydrocortisone)
- longer half life
- more potent
- 2.3 x binding affinity than cortisol
- replacement dose is 3-4mg 1x daily
What doses of prednisolone are available?
- 1mg, 2.5mg, 5mg
- not enteric coated (slows absorption)
What dosage of prednisolone should be given to a patient?
- depends on the patient (more research required)
- generally: 3.75mg (2-4mg)
- starting is 4mg, aim is to be between 15-25mcg/l at 8 hours
- equivalent to 15-25mg of hydrocortisone daily
What is the risk of replacement prednisolone?
- excess steroid exposure
- sub-clinical Cushing’s disease
What is the general treatment given for adrenal failure?
- Hydrocortisonm 3 x daily (10+5+2.5)
OR - Prednisolone 3mg 1 x daily
- Fludrocortisone 50-100mcg 1 x daily
What is the most common cause of congenital adrenal hyperplasia?
21-hydroxylase deficiency
What hormones will be absent in COMPLETE 21-hydroxylase deficiency?
- aldosterone
- cortisol
How long can you survive with COMPLETE 21-hydroxylase deficiency?
<24 hours
What hormones will be in excess with COMPLETE 21-hydroxylase deficiency?
- Sex steroids
- Testosterone
At what age does COMPLETE 21-hydroxylase deficiency present?
- neonate in a salt losing Addisonian crisis
- Pre-birth (in utero), foetus gets steroids from across the plasma
- Girls may have ambiguous genitalia (due to adrenal testosterone).
What hormones are deficient in PARTIAL 21-hydroxylase deficiency?
- cortisol
- aldosterone
Which hormones are in excess in PARTIAL 21-hydroxylase deficiency?
- sex steroids
- testosterone
At what age does PARTIAL 21-hydroxylase deficiency?
- any age as survival is likely
What is the main problem associated with PARTIAL 21-hydroxylase deficiency?
In later life: - hirsutism in girls - virilisation in girls - precocious puberty in boys due to the adrenal testosterone
What does 11-deoxycorticosterone behave like?
Aldosterone
What can excess 11-deoxycorticosterone cause?
- hypertension
- hypokalaemia
What hormones are deficient in 11-hydroxylase deficiency?
- cortisol
- aldosterone
Which hormones are in excess in 11-hydroxylase deficiency?
- sex steroids
- testosterone
- 11-deoxycorticosterone
What problems are associated with 11-hydroxylase deficiency?
- virilisation
- hypertension
- low potassium
What hormones are deficient in 17-hydroxylase deficiency?
- cortisol
- sex steroids
What hormones are in excess in 17-hydroxylase deficiency?
- 11-deoxycorticosterone
- aldosterone
(mineralcorticoids)
What problems are associated with 17-hydroxylase deficiency?
- hypertension
- low potassium
- sex steroid deficiency
- glucocorticoid deficiency (low glucose)
What are the clinical features of Cushing’s disease?
- excess cortisol
- centripetal obesity
- moon face
- buffalo hump
- proximal myopathy
- hypertension
- hypokalaemia
- red striae, thin skin and bruising
- osteoporosis
- diabetes
What are the causes of Cushing’s disease?
- excess steroid exposure
- pituitary dependent Cushing’s disease
- Ectopic ACTH (from lung cancer)
- Adrenal adenoma secreting cortisol
What are the investigations used to confirm Cushing’s disease?
- 24hour urine collection (for urinary free cortisol)
- blood diurnal cortisol levels
(cortisol highest at 9am, lowest at midnight) - low dose dexamethasone suppression test
What is involved in a low dose dexamethasone suppression test?
- 0.5mg every 6 hours for 48 hours
(dexamethasone=artificial steroid) - normal will suppress cortisol to 0
- ANY cause of Cushing’s will fail to suppress
What values would confirm a diagnosis of Cushing’s disease?
- basal (9am) cortisol, 800nM
- end of low dose dexamethasone test, 680nM
What drugs are involved in the manipulation of steroids?
- Enzyme inhibitors
- Receptor blocking drugs
What is Conn’s syndrome?
Excess aldosterone
Which drugs are inhibitors of steroid biosynthesis?
- metyrapone
- ketoconazole
What is the action of metyrapone?
- The inhibition of 11beta-hydroxylase
- steroid synthesis (in zona fasiculata) is arrested at the 11-deoxycortisol stage
- 11-deoxycortisol has NO negative feedback effects on the hypothalamus and the pituitary gland
What are the main 2 uses of Metyrapone?
- control of Cushing’s syndrome prior to surger
- Control of Cushing’s symptoms after radiotherapy (slow to take effect)
How can metyrapone be used to control Cushing’s syndrome prior to surgery?
- adjust oral dose according to cortisol, aim: serum cortisol = 150-300nmol/l
- improves patients symptoms and promotes better post-op recovery
What are the unwanted side effects of metyrapone?
- hypertension with long term use
- hirsutism
How does metyrapone cause hypertension in the long term?
the excess 11-deoxycorticosterone accumulates in the zona glomerulosa, has aldosterone-like activity causing salt retention and therefore, hypertension.
How does metyrapone cause hirsutism in women?
Increased adrenal androgen production
What is the actions of ketoconazole?
- main use: antifungal (withdrawn due to hepatotoxicity risk)
- at higher concentrations, inhibits steroidogenesis (use in Cushing’s is off label)
What is the mechanism of action of ketoconazole?
Blocks 17alpha-hydroxylase, inhibiting cortisol production
What is ketoconazole used for?
treatment and control of symptoms prior to surgery
orally active
What is the unwanted actions of ketaconazole?
Liver damage (possibly fatal) - monitor liver function weekly (clinically and biochemically)
What are possible treatments of Cushing’s disease?
Depends on the cause Surgical: - pituitary surgery (transsphenoidal hypophysectomy) - bilateral adrenalectomy - unilateral adrenalectomy (for adrenal mass) Medication: - metyrapone - ketoconazole
What are the characteristics of Conn’s disease?
- benign adrenal cortical tumour (zona glomerulosa)
- aldosterone in excess
- hypertension
- hypokalaemia
What are the key aspects of Conn’s syndrome required for diagnosis?
- primary hyperaldosteronism
- renin-angiotensin system is suppressed (to excluse secondary hyperaldosteronism)
What type of drugs are involved in treating Conn’s disease?
Mineralcorticoid Receptor antagonists:
- spironolactone
- elperonone
What is the mechanism of action of spironolactone?
- Converted into several active metabolites, including canrenone - competitive antagonist of the mineralcorticoid receptor
- Blocks sodium resorption and potassium excretion in the kidney tubules
(potassium sparing diuretic)
Describe the pharmacokinetics of spironolactone?
- orally active
- highly protein bound and metabolised in the liver
What are the unwanted actions of spironolactone?
- menstrual irregularities (+progesterone receptor)
- gynaecomastia (-androgen receptor)
What is the difference between spironolactone and epleronone?
Epleronone binds less to andorgen and progesterone receptors, adn therefore is better tolerated.
What are Phaeochromocytomas?
tumours of the adrenal medulla which secretes catecholamines
(adrenaline or nor-adrenaline)
What are the clinical features of a Phaeochromocytoma?
- hypertension (young people)
- episodic severe hypertension post abdominal palpation
- more common nin certain inherited conditions.
- severe hypertension > myocardial infarction or stroke
- high adrenaline > ventricular fib. and death (medical emergency)
What is the management of a Phaeochromocytoma?
- First step: alpha blockade
- may need to be accompanied by IV fluids
- addition of beta blockade to prevent tachycardia
- Need surgery eventually BUT careful prep as anaesthetic can cause a hypertensive crisis
10% of Phaeochromocytomas are …
- extra-adrenal (sympathetic chain)
- malignant
- bilateral
How is Conn’s definitively diagnosed?
The presence of excess aldosterone with suppressed renin
What hormones do you need to double when ill or septic?
- double their prednisolone
IF INCREDIBLY ILL - IV hydrocortisone
Why do you not use fludrocortisone in emergency situations?
Long-acting, therefore takes time to come into action
What do you use instead of fludrocortisone in emergency situations?
- cortisol
- prednisolone
What to test for when TSH is normal, with high blood pressure, and high pulse?
- ADRENALINE
- test for urine catecholamines
