Hyperadrenal disorders Flashcards
Essentially, what is Cushing’s
Too much cortisol
Describe the effects of excess cortisol on protein and fat synthesis.
Decrease protein synthesis
Increase fat synthesis
Explain why people with Cushing’s disease get stretch marks.
They are putting on a lot of fat quickly, which stretches the skin.
Because protein synthesis is switched off, you can’t make the protein required for skin growth so the skin tears
State the clinical features of Cushing’s disease
o Too much cortisol. o Centripetal obesity. o Moon face, buffalo hump. o Proximal myopathy. o Hypertension and hypokalaemia. o Red striae, thin skin and bruising. o Osteoporosis and diabetes.
Distinguish between Cushing’s disease and Cushing’s syndrome
Cushing’s disease is specific to a pituitary tumour producing uncontrolled excess quantities of ACTH.
Cushing’s syndrome is when the cause is uncertain or different to that of Cushing’s disease
Cushing’s syndrome can be caused by Cushing’s disease
Describe the presentation of Cushing’s
Patients become gradually unwell, as the cortisol level slowly rises. Initially, the main effect is on the diurnal rhythm of cortisol secretion which becomes less pronounced. The total exposure of the body’s cells to cortisol increases. This causes a gradual increase in appetite, and patients put on weight. Fat synthesis is promoted over protein synthesis and patients develop muscle weakness, with a proximal myopathy becoming apparent.
In addition, the skill heals poorly, and wounds can take a long time to heal
The combination of reduced protein synthesis with rapidly increasing girth causes stretch marks which may be red.
List the causes of Cushing’s
o Taking too many steroids.
o Pituitary dependant Cushing’s disease.
o Ectopic ACTH (lung cancer).
o Adrenal adenoma.
Describe adrenal adenomas as a cause of Cushing’s
Tumours of the zona fasciculata of the adrenal cortex may secrete unregulated amounts of cortisol.
This will result in Cushing’s syndrome, which is clinically very similar in appearance to Cushing’s disease, except that there is no increase in pigmentation because, unlike Cushing’s disease, the ACTH is suppressed.
What is cortisol
A catabolic steroid
It is also a very good immunosuppressant
Describe Cushing’s disease
Tumour of the corticotrophs of the pituitary gland
Normal corticotrophs secrete ACTH in a pulsatile manner and with a diurnal rhythm so that they are most active in the morning.
A tumour of the corticotrophs is not under such regulation, but secreted a fixed large amount of ACTH, which results in a loss of diurnal rhythm.
The consequent total exposure of the patient to glucocorticoids is thus increased, although the plasma level of cortisol may be within the normal reference.
Thus a random cortisol in unhelpful in making the diagnosis.
What is key to remember about Cushing’s disease
You lose the circadian rhythm of cortisol release.
When patients present with the clinical features of Cushing’s syndrome, what is it important to ask them before starting any investigations
Whether they are taking any oral glucocorticoids.
What are the three main tests used to diagnose Cushing’s syndrome?
24-hour urine free cortisol
Blood diurnal cortisol levels (or midnight serum cortisol)
Low dose dexamethasone suppression test
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.
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.
Summarise the low dose dexamethasone suppression test
§ 0.5mg 6-hourly for 48 hours.
§ Normal = dexamethasone supresses cortisol to zero due to feedback inhibition.
§ Cushing’s = ANY cause will fail to suppress
Dexamethasone is a potent steroid that exerts negative feedback on ACTH.
Why are Cushing’s patients with adrenal adenoma easy to exclude
they will have undetectable ACTH.
How can we distinguish between ectopic ACTH from pituitary-dependent Cushing’s disease.
In the past, the high-dose dexamethasone suppression test was used to make this distinction. This is because a pituitary corticotroph adenoma remarkably retains some feedback control so that when very high-dose dexamethasone is administered there would be some suppression in cortisol production that would not occur with malignant ectopic ACTH.
Why is the high-dose dexamethasone suppression test no longer required or used
It has too high a false positive rate and also because petrosal sinus sampling is now relatively easy performed.
Describe blood diurnal cortisol analysis
o 2) Blood diurnal (varying levels depending upon time of day) cortisol analysis.
§ Normal = cortisol high in morning and low at night.
§ Cushing’s = cortisol high all the time.
Take sample when the patient is asleep- tell them that you are scheduling the test for the morning.
How do we exclude an ectopic source of ACTH
Compare the level of ACTH in the petrosal sinuses with that of the peripheral circulation. This can not only confirm that the pituitary is indeed the source of the problem, but also on which side of the pituitary the tumour is.
Unlike other pituitary tumours, Cushing’s tumours are often so small at presentation that they cannot be seen on an MRI scan.
Describe the petrosal sinus test
Blood is taken from the veins draining the pituitary and a dose of corticotrophin-releasing hormone (CRH) is administered. A corticotroph adenoma exhibits an exuberant response to CRH, and the resultant release of ACTH can be measured in the catheter.
Prolactin levels can also be measured to ensure the correct positioning of the catheters.
Describe a typical response of a Cushing’s patient to the low dose dexamethasone test
Basal (9am) cortisol- 800mM
End of LDDST- 840 mM
Summarise the pharmacological manipulation of steroids to treat Cushing’s
§ Drugs – enzyme inhibitors, receptor blocking drugs.
o E.G. Metyrapone, Ketoconazole.
State some surgical treatments for Cushing’s syndrome.
Treatment is dependent on cause
Transsphenoidal Hypophysectomy (for Cushing’s disease)
Bilateral adrenalectomy
Unilateral adrenalectomy for adrenal mass
Name two inhibitors of steroid synthesis that can be used to treat Cushing’s
metyrapone; ketoconazole
Describe the mechanism of action of metyrapone
Inhibits the 11B-hydroxylase enzyme
Therefore:
It prevents the conversion of:
· 11-deoxycorticosterone à corticosterone
· 11-deoxycortisol à cortisol
This means that no corticosterone or cortisol is produced
Summarise the mechanism of actions of metyrapone
inhibition of 11b-hydroxylase (refer also to first year notes on steroid biosynthesis)
steroid synthesis in the zona fasciculata [and reticularis] is arrested at the 11-deoxycortisol stage
11-deoxycortisol has no negative feedback effect on the hypothalamus and pituitary gland- so ACTH is raised
What is treatment for Cushing’s focussed on
Post-operative care
Why is it important to lower a patient’s cortisol before surgery
Cortisol suppresses peripheral protein synthesis, rates of wound healing after surgery are slowed, so that large scars can result in hospital stays.
Also cortisol is an immuno-suppressant- so the patient would have an even greater risk of infection during surgery.
Describe the impact of surgery on treating patient’s with Cushing’s
The advent of laparoscopic and retroperitoneoscopic has made a big difference to the morbidity of surgery in these patients.
What is the major glucocorticoid in rats
Corticosterone
Describe the uses of metyrapone
Control of Cushing’s syndrome prior to surgery.
- adjust dose (oral) according to cortisol (aim for mean serum cortisol 150-300 nmol/L)
- improves patient’s symptoms and promotes better post-op recovery (better wound healing, less infection etc)
Control of Cushing’s symptoms after radiotherapy (which is usually slow to take effect)
Explain the unwanted side effects of metyrapone
deoxycorticosterone accumulates in z. glomerulosa; it has aldosterone-like (mineralocorticoid) activity, leading to salt retention and hypertension.
Increased adrenal androgen production HIRSUTISM
in women
Metyrapone inhibits two limbs of the steroid synthesis pathway so it funnels the precursors towards the sex steroid synthesis pathway.
State the unwanted side effects of metyrapone
Hypertension on long-term administration
Hirsutism
Sedation, hypoadrenalism
Nausea, vomiting, dizziness
Why do we see an accumulation of 11-deoxycorticosterone
because it doesn’t have any negative feedback effects on the ACTH axis
Summarise the actions of ketoconazole
main use as an antifungal agent – although withdrawn in 2013 due to risk of hepatotoxicity
at higher concentrations, inhibits steroidogenesis – off-label use in Cushing’s syndrome
Describe the mechanism of action of ketoconazole
Inhibits 17a-hydroxylase
Inhibiting the conversion of pregnenolone to 17a-hydroxypregnenolone and progesterone to 17a-hydroxyprogesterone
Describe the uses of ketoconazole
USES (similar to metyrapone)
Cushing’s syndrome
- treatment and control of symptoms prior to surgery
- orally active
Describe the unwanted side effects of ketoconazole
Liver damage - possibly fatal - monitor liver function weekly, clinically and biochemically
Nausea, vomiting, abdominal pain
Alopecia
Gynaecomastia, oligospermia, impotence, decreased libido
Ventricular tachycardias
These unwanted effects are due to loss of sex steroids, glucocorticoids and mineralocorticoids
Why are metyrapone and ketoconazole not really long-term solutions
As they can cause nausea and are associated with abnormal liver function tests on prolonged use. However, they can be used as a stop-gap while arranging surgery
What does the type of surgery arranged for Cushing’s depend on
The cause
Don’t have an adrenalectomy if you have a pituitary tumour
Describe the surgical route for pituitary surgery
Transphenoidal hypophysectomy
What is Conn’s syndrome
A benign adrenal cortical (zona glomerulosa) tumour but sometime could be a bilateral adrenal hyperplasia
§ Produces aldosterone in excess.
§ Leads to hypertension and hypokalaemia – due to water retention, aldosterone enhances sodium reabsorption and potassium excretion in the kidneys.
What is primary hyperaldosteronism?
Hyperaldosteronism caused by an adrenal adenoma
What is secondary hyperaldosteronism
hyperaldosteronism caused by something other than a n adrenal adenoma (i.e something not related to the adrenal gland)
Describe the diagnosis of Conn’s syndrome
Tumours originating in the zona glomerulosa are not under control of RAS and consequently can secrete large amounts of unregulated aldosterone. Once the diagnosis is biochemically confirmed, by repeated measurement of raised plasma aldosterone concentrations in the presence of suppressed renin levels (usually induced by a saline infusion), then imaging should be undertaken.
What can you test to exclude secondary hyperaldosteronism
Check for suppression of the renin-angiotensin system
Measure aldosterone and if that’s high, measure the renin and that should be low because if would be suppressed by the high blood pressure.
What imaging modality should be used to look for an adrenal tumour
A CT of the adrenals will demonstrate the absence or presence of a tumour. When found tumours are usually smaller than 1cm in diameter. Even in the presence of a tumour, one should then proceed with selective venous sampling of both adrenals, to ensure that the source of excess aldosterone is unilateral, and to confirm that a unilateral adrenalectomy will be effective.
If on the angiogram the aldosterone is found to be coming from both adrenals, this would suggest bilateral adrenal hyperplasia
What should you ensure before making the diagnosis of Conn’s syndrome
To make the measurements on patients who have been taken off any drug treatments for hypertension because these can alter the aldosterone:renin ratio
In particular, beta blockers cause a fall in renin so patients on beta blockers can have a high aldosterone:renin ratio even if they don’t have Conn’s.
Patients with suspected Conn’s syndrome should be referred to a clinical centre where Conn’s syndrome is commonly managed.
What is the usual treatment plan for someone with Conn’s syndrome?
Medical management (spironolactone and eplerenone) Surgery to remove the tumour
Summarise the mechanisms of action of spironolactone
Primary hyperaldosteronism (Conn’s syndrome)
Converted to several active metabolites, including canrenone, a competitive antagonist of the mineralocorticoid receptor (MR).
Blocks Na+ resorption and K+ excretion in the kidney tubules (potassium sparing diuretic).
What type of drug is spironolactone
A pro-drug
It is converted into canrenone- which exerts the pharmacological effects
Describe the pharmacokinetics of spironolactone.
Orally active
Given daily in single or divided doses
Highly protein-bound and metabolised in the liver
Describe the unwanted side effects of spironolactone
Spironolactone is very non-specific (to mineralcorticoid receptor0so it has several side effects
Progesterone receptor agonist à menstrual irregularities
Androgen receptor antagonist à gynaecomastia
GI tract irritation
Contra-indications:
· Renal and hepatic disease
Summarise eplerenone
Also a mineralocorticoid receptor (MR) antagonist
Similar affinity to the MR compared to spironolactone
Less binding to androgen and progesterone receptors compared to spironolactone, so better tolerated
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What are patients with Conn’s also often treated with
anti-hypertensive agents because it can be difficult to adequately control their raised blood pressure.
They are also often on potassium supplements in view of the profound potassium loss in this condition.
Summarise the different operations available when an adrenal tumour needs to be removed.
An alternative to laparoscopic adrenalectomy is the retroperitoneoscopic adrenalectomy. This technique has the advantage of avoiding the visceral innervation of the peritoneal cavity and is used by many large centres around the world.
The retroperitoneoscopic approach was found to be associated with earlier oral intake ad lower analgesic requirement. Most significantly, the length of hospital stay was found to be reduced by a mean of 43 hours.
If the surgery is successful, what changes should be made
Patients can usually stop potassium supplements and some or all of the anti-hypertensive drugs
What should be done if a bilateral adrenal hyperplasia is diagnosed
Removing both adrenals would be effective but is not recommended.
Because this would result in patients requiring lifelong cortisol and fludrocortisone (a mineralcorticoid) replacement, and missing occasional doses can result in an Addisonian crisis, which may be fatal.
Aldosterone antagonists such as spironolactone or eplerenone are effective in these patients.
Following an adrenalectomy, what are patients with Cushing’s likely to be
Addisonian for up to a year.
The contralateral adrenal, while normal, would have become suppressed because the high cortisol level would have inhibited pituitary ACTH release by negative feedback.
Consequently, the normal adrenal often atrophies, and it can take up to a year to recover fully.
For this reason, patients should be put on hydrocortisone replacement until recovery occurs.
What are pheochromocytomas
A secreting tumour (catecholamines) of the adrenal medulla
Explain the naming of a pheochromocytomas
Because of its pathological appearance
dusky (phaeo in Greek) colour (chromo)
Describe the size of pheochromocytomas
Tend to be larger than adrenal cortical tumours, and when they secrete catecholamines, the effects of increased alpha and beta adrenoreceptor stimulation occur- which can be dangerous
Summarise the clinical features of a pheo
§ Clinical features of a phaeo include:
o Hypertension in young people.
o Episodic SEVERE hypertension (after abdominal palpation – squeezes more adrenaline out).
§ Different to Conn’s hypertension as this is episodic in the older population.
§ Can cause MI or stroke.
§ Can cause VF and death if not treated.
· Thus is classed as a MEDICAL EMERGENCY.
o More common in certain inherited conditions.
Describe the effects of a pheo
Alpha receptors cause vasoconstriction, and beta receptors cause myocardial irritability.
The most dangerous nature of a pheo is its tendency to behave as a syncytium, with degranulation from a large number of these cells causing the release of a large number of catecholamines at the same time.
This can cause a dangerous surge of adrenaline, which can cause a sudden increase in BP that may result in a cerebral haemorrhage, stroke, myocardial infarctions, arrhythmias and sudden death. The suspicion of finding such a tumour should thus be treated as an emergency.
State some fatal consequences of phaeochromocytoma.
Myocardial infarction and stroke
It can also cause sudden cardiac death through ventricular fibrillation
It is a MEDICAL EMERGENCY
Describe the symptoms of a pheo
Palpitations, panic attacks, episodic severe hypertension, sweating and cold extremities.
In between attacks, patients are often completely normal and the diagnosis can thus be readily missed.
Typically, functional symptomatic phaeochromocytomas are large (usually more than 2cm by the time they cause symptoms).
Describe the steps that must be taken when preparing a phaeochromocytoma patient for surgery.
Anaesthetic could precipitate a hypertensive crisis.
You give the patient an alpha-blocker to prevent the vasoconstriction caused by adrenaline binding to alpha-receptors.
Alpha-blockers cause a drop in blood pressure so they are usually given with a bit of fluid.
Then you give beta-blockers to prevent tachycardia.
Once all the receptors are blocked, it means that a massive release in adrenaline will not be able to have its effects.
How can we diagnose a phaeochromocytoma
Measuring catecholamines, or the metabolites of catecholamines, the metanephrines, either in the urine or the plasma.
Describe the treatment for a phaeo
The patient needs to be made safe by alpha and beta receptor blockade
Traditionally, alpha blockade is carried out with phenoxybenzamine, and beta blockade using propranolol.
Once these receptors are fully blocked, the tumour can be removed surgically, ideally laparoscopically, or, more recently, retroperitoneally.
The latter approach has been used since 2009, results in the least morbidity and more rapid discharge, and is probably now the gold standard operation for adrenal surgery.
What should we do with young patients who have had a pheo removed
young or family history of pheos
refer to genetic clinic to consider genetic causes such as MEN2 or one of the mutations of succinate dehydrogenase subunits (SDH-D Or -B) or neurofibromatosis.
Describe the key facts of pheos
o 10% are extra-adrenal (down the sympathetic chain).
o 10% are malignant.
o 10% are bilateral.
o VERY RARE.
