Hyperadrenal Disorders Flashcards
Describe the effects of excess cortisol on protein and fat synthesis.
Excess cortisol:
- Decreases protein synthesis
- Increases fat synthesis*
*Explanation:
- The main aim of cortisol is to increase blood glucose concentraion as it is part of the stress response and stress is metabolically (energy) demanding
- At a physiological level, cortisol promotes lipolysis so that fatty acids can be used in gluconeogenesis
- In order to increase blood glucose levels cortisol opposes the effects of insulin
- This leads to insulin concentration in the blood increasing
- Insulin inhibits lipolysis (and promotes lipogenesis) in adipocytes → increased fat synthesis
Describe the clinical features of Cushing’s syndrome.
- Centripetal obesity (lemon on sticks)
- Moon face and interscapular fat pad (buffalo hump)
- Proximal myopathy
- Cortisol causes muscle protein breakdown
- Red striae, thin skin, easy bruising
- Cortisol causes breakdown of protein in the skin
- Abdominal growth and thin skin → striae (stretch marks)
- Osteoporosis
- Cortisol causes breakdown of bone protein, reducing bone density
- Diabetes
- Hypertension and hypokalaemia
Explain why excess cortisol causes centripetal obesity, moon face and interscapular fat pad.
- Cortisol increases fat synthesis by increasing insulin concentrations
- Central (abdomen and face) adipocytes are much more sensitive to insulin than peripheral adipocytes
- So excess glucose in the blood due to cortisol action is converted to fat and stored in the central adipocytes → LEMON
Explain why excess cortisol causes diabetes.
- Cortisol is opposing the effects of insulin and acting to increase blood glucose concentration
- Because insulin cannot work properly due to the excess cortisol, glucose tolerance is said to be impaired
- This causes high blood glucose concentration → DIABETES
Explain why excess cortisol causes hypertension and hypokalaemia.
- Cortisol can bind to MR as well as GR
- Usually cortisol can’t bind to the MR receptors in the kidneys as it is metabolised by an enzyme (11b-hydroxysteroid dehydrogenase 2)
- At very high levels of cortisol, the enzyme becomes saturated
- Therefore cortisol can bind to the MR and carry out the effects of aldosterone
- Aldosterone causes increased Na+ reabsorption → increased water reabsorption → higher BP
- Increased Na+ reabsorption means increased K+ excretion (due to Na+/K+ pump action)
State four causes of Cushing’s syndrome.
- Taking too many steroids
- Means you already have an excess of steroids which can act in the body to have a similar effect to cortisol (or any other glucocorticoid)
- Pituitary dependent Cushing’s disease
- Pituitary adenoma (of corticotrophs) producing too much ACTH
- Cushing’s disease because cause is known
- Ectopic ACTH from lung cancer
- Some lung cancer cells can start to produce ACTH
- Ectopic = in the wrong place
- Adrenal adenoma secreting cortisol
- Adenoma of the adrenal cortex
What are the three main tests used to diagnose Cushing’s syndrome?
- 24-hour urine collection for urinary free cortisol
- High levels in circulation will mean that some will enter urine - abnormal
- Blood diurnal cortisol levels
- Low dose dexamethasone suppression test
NOTE: These test will identify Cushing’s (i.e. excess cortisol) but will not be helpful in identifying the cause
Describe the results you’d expect from a normal subject AND a patient with Cushing’s syndrome in the 24-hour urine free cortisol and blood diurnal cortisol tests.
You would expect lower cortisol at night in a normal subject and high cortisol in the morning.
- Cortisol is usually highest at 9am and lowest at midnight, if asleep
- This is because cortisol is released in a diurnal (or cicardian) rhythm = daily 24 hour cycle, regulates sleep-wake cycle responds to light and dark in the organism’s environment
In someone with Cushing’s syndrome they would have high cortisol all the time
NOTE: a problem with this test is that the cortisol levels are affected by stress.
Explain the scientific basis of the low dose dexamethasone suppression test.
- Dexamethasone is an artificial steroid (glucocorticoid)
- Giving this extra glucocorticoid should suppress ACTH production due to negative feedback
- Give 0.5mg every 6 hours for 48 hours
- This should herefore lead to redduce cortisol production as there is no ACTH to stimulate the adrena cortex to proudce cortisol
- So in a normal subject undertaking the dexamethasone suppression test, you would expect zero cortisol
- In a Cushing’s patient, cortisol will remain high despite the presence of dexamethasone - cortisol production is no longer regulated by ACTH
NOTE: Any cause of Cushing’s will result in failure of dexamethasone to supresss cortisol production
What results are used to confirm a diagnosis of Cushing’s?
- Basal (9am) cortisol is high - 800 nM or more
- Based on this result you carry out LDDST
- End of LDDST - 680 nM or more
- Confirms Cushing’s
What are two drug types that can be used when you have an excess of a certain steroid hormone?
Enyme inhibition - reduces steroid synthesis
Receptor blocking drugs - reduces effect of steroid on target organs
State two drugs that are used to treat Cushing’s syndrome.
- Metyrapone
- Ketoconazole
NOTE: Both these drugs inhibit steroid biosynthesis
Draw the adrenal steroid synthesis pathway.
NOTE: P450SCC = cholesterol side-chain cleavage enzyme (member of cytochrome P450 superfamily of enzymes)
What is the mechanism of action of metyrapone?
It inhibits the 11β-hydroxylase enzyme
- Disrupts the steroid biosysthesis pathway
What effect does metyrapone have on the steroid synthesis pathway? What are the consequences of this?
It prevents the conversion of:
- 11-deoxycorticosterone → corticosterone
- 11-deoxycortisol → cortisol
- Therefore steroid synthesis in the zona fasciculata (and zona reticularis) is arrested at the 11-deoxycortisol stage
- This means that no/reduced corticosterone or CORTISOL is produced - has consequences:
- ACTH secretion from the anterior pituitary increases (lack of negative feedback from cortisol)
- Plasma deoxycortisol increases
State two uses of metyrapone.
- Control of Cushing’s syndrome prior to surgery
- Adjust dose (oral) according to serum cortisol levels (aim for mean serum cortisol 150-300 nmol/L)
- Treatment improves patient’s symptoms and promotes better post-op recovery (better wound healing, less infection etc. because supraphysiological levels of cortisol have an immunosupressive effect)
- Control of Cushing’s symptoms after radiotherapy (which is usually slow to take effect)
State two negative aspects of metyrapone.
Problem 1
- Metyrapone causes the accumulation of 11-deoxycorticosterone (in the zona gomerulosa
- 11-deoxycorticosterone has mineralocorticoid (aldosterone-like) effects so causes salt retention and HYPERTENSION
- This is on long-term administration (takes time for 11-deoxycorticosterone to accumulate, esp when the precursors are being funnelled towards the sex steroid synthesis pathway as well)
Problem 2
- Metyrapone inhibits two limbs of the steroid synthesis pathway so it funnels the precursors towards the sex steroid synthesis pathway
- This leads to increased adrenal androgens, which has effects such as HIRSUTISM (excessive male-pattern hair growth)
What was ketoconazole originally used for and why is it no longer used for this?
- Ketoconazole was mainly used as an anti-fungal
- It was withdrawn in 2013 due to risk of hepatotoxicity (i.e. it caused liver damage)
What are the effects of ketoconazole on steroid production?
- Ketoconazole inhibits the cholesterol side-chain cleavage enzyme (P450SCC)
- This enzyme converts cholesterol → pregnenolone
- Pregnenolone is the precursor for all the different pathways of steroid hormone production
- This means that it inhibits the production of glucocorticoids, mineralocorticoids and sex steroids
What is ketoconazole used for now?
Treatment of Cushing’s syndrome and control of symptoms prior to surgery (similar to metyrapone)
- At higher concentrations, it inhibits steroidogenesis
- However, this is off-label use - i.e. the drug is being used for a different purpose to the one that is stated on the license/label)
NOTE: Ketoconazole is orally active
State some unwanted actions of ketoconazole.
Liver damage - possibly fatal so it is important monitor liver function weekly: clinically and biochemically
State some surgical treatments for Cushing’s syndrome.
Treatment (i.e. type of surgery) is dependent on cause
- Transsphenoidal Hypophysectomy (for Cushing’s disease)
- i.e. removal of pituitary gland in Cushing’s disease, where the cause is known to be a pituitary adenoma
- Bilateral adrenalectomy
- i.e. removal of both adrenal glands
- Unilateral adrenalectomy for adrenal mass
- i.e. removal of just one adrenal gland if there is a mass/tumour, affecting just one of them
What is Conn’s syndrome?
Benign adrenal cortical tumour
- Tumour of the zona glomerulosa → excess aldosterone
NOTE: Conn’s syndrome = primary hyperaldosteronism
What are the two main features of Conn’s syndrome?
- Hypertension
- Hypokalaemia
Explanation:
- Excess aldosterone leads to excessive Na+ reabsorption
- This is done via the Na+/K+ pump - so the more Na+ that is reabsorbed, the more K+ is excreted
- This leads to hypokalaemia
- The increased Na+ reabsorption creates an osmotic gradient which leads to increased water reabsoprtion
- This results in increased blood volume and hence increased blood pressure - hypertension
What is secondary hyperaldosteronism?
High aldosterone in response to activation of the renin-angiotensin-aldosterone system
What can you test to exclude secondary hyperaldosteronism?
Check for suppression of the renin-angiotensin system
- Measure aldosterone levels in the blood
- If aldosterone is high (hyperaldosteronism), measure blood renin concentration
- Renin levels should be low because its release would be suppressed by the high blood pressure (high renal perfusion pressure) caused by the high aldosterone
Which drugs can be used to treat Conn’s syndrome?
Mineralocorticoid receptor (MR) antagonists:
- Spironolactone
- Epleronone
What is the mechanism of action of spironolactone?
- Spironolactone is converted to several active metabolites in the body, including canrenone
- Canrenone is a competitive antagonist of the MR
- Therefore, it inhibits Na+ reabsorption and K+ excretion in the kidney tubules (potassium sparing diuretic)
State some unwanted effects of spironolactone.
Spironolactone is not very specific to the MR which leads to side effects
- Progesterone receptor agonist → menstrual irregularities Androgen receptor antagonist → gynaecomastia
- Gynaecomastia = enlargement of male breasts due to benign increase in glandular tissue
Name another mineralocorticoid receptor antagonist and explain it’s advantages comapared to spironolactone
Eplerenone
- Similar affinity to the MR compared to spironolactone
- Less binding to androgen and progesterone receptors compared to spironolactone, so better tolerated (i.e. fewer side effects)
What is phaeochromocytoma?
Tumour of the adrenal medulla that is producing excessive amounts of catecholamines (adrenaline and noradrenaline)
What are the features of phaeochromocytoma?
- Hypertension in young people (as you do not usually see hypertension in young people)
- Episodic severe hypertension
- This can be triggered by palpation of the adrenal tumour when doing an abdominal examination
- More common in certain inherited conditions
- e.g. von Hippel-Lindau syndrome = genetic condition associated with tumors arising in multiple organ
What are the clinical features of phaeochromocytoma?
- Severe hypertension can cause myocardial infarction or stroke
- It can cause ventricular fibrillation and death
- Ventricular fibrillation = rapid and disorganised electrical activity in ventricles means that the ventricles quiver instead of pumping blood
- This is because NA/adrenaline can influence the electrical activity of the heart to try to increase heart rate, so it makes sense that excessive NA/adrenaline would lead to a disruption in electrical activity
- Ventricular fibrillation would lead to cardiac arrest (sudden loss of blood flow) and hence death
- Thus this is a MEDICAL EMERGENCY
What is the management plan for phaeochromocytoma?
They would eventually need surgery, but patient needs careful preparation as anaesthetic can precipitate a hypertensive crisis
Therapeutic management prior to surgery:
- Alpha-blockers to prevent the vasoconstriction caused by catecholamines binding to alpha-receptors
- Alpha-blockers cause a drop in blood pressure so they are usually given with IV fluid to prevent hypotension
- Beta-blockers to prevent tachycardia.
- Once all the receptors are blocked, it means that a massive release in adrenaline (and NA) will not be able to have its effects
What percentage of phaeochromocytoma is intra-adrenal?
90%
- 10% of phaeochromocytomas are malignant and 10% are bilateral (affects both adrenal glands)
- 10% are extra-adrenal meaning in the sympathetic chain → excessive sympathetic activation
NOTE: Phaeochromocytoma is a very rare condition
