Hyperadrenal disorders

Question 1

Essentially, what is Cushing’s

Answer 1

Too much cortisol

Question 2

Describe the effects of excess cortisol on protein and fat synthesis.

Answer 2

Decrease protein synthesis

Increase fat synthesis

Question 3

Explain why people with Cushing’s disease get stretch marks.

Answer 3

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

Question 4

State the clinical features of Cushing’s disease

Answer 4

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.

Question 5

Distinguish between Cushing’s disease and Cushing’s syndrome

Answer 5

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

Question 6

Describe the presentation of Cushing’s

Answer 6

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.

Question 7

List the causes of Cushing’s

Answer 7

o Taking too many steroids.
o Pituitary dependant Cushing’s disease.
o Ectopic ACTH (lung cancer).
o Adrenal adenoma.

Question 8

Describe adrenal adenomas as a cause of Cushing’s

Answer 8

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.

Question 9

What is cortisol

Answer 9

A catabolic steroid

It is also a very good immunosuppressant

Question 10

Describe Cushing’s disease

Answer 10

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.

Question 11

What is key to remember about Cushing’s disease

Answer 11

You lose the circadian rhythm of cortisol release.

Question 12

When patients present with the clinical features of Cushing’s syndrome, what is it important to ask them before starting any investigations

Answer 12

Whether they are taking any oral glucocorticoids.

Question 13

What are the three main tests used to diagnose Cushing’s syndrome?

Answer 13

24-hour urine free cortisol
Blood diurnal cortisol levels (or midnight serum cortisol)
Low dose dexamethasone suppression test

Question 14

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.

Answer 14

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.

Question 15

Summarise the low dose dexamethasone suppression test

Answer 15

§ 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.

Question 16

Why are Cushing’s patients with adrenal adenoma easy to exclude

Answer 16

they will have undetectable ACTH.

Question 17

How can we distinguish between ectopic ACTH from pituitary-dependent Cushing’s disease.

Answer 17

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.

Question 18

Why is the high-dose dexamethasone suppression test no longer required or used

Answer 18

It has too high a false positive rate and also because petrosal sinus sampling is now relatively easy performed.

Question 19

Describe blood diurnal cortisol analysis

Answer 19

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.

Question 20

How do we exclude an ectopic source of ACTH

Answer 20

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.

Question 21

Describe the petrosal sinus test

Answer 21

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.

Question 22

Describe a typical response of a Cushing’s patient to the low dose dexamethasone test

Answer 22

Basal (9am) cortisol- 800mM

End of LDDST- 840 mM

Question 23

Summarise the pharmacological manipulation of steroids to treat Cushing’s

Answer 23

§ Drugs – enzyme inhibitors, receptor blocking drugs.

o E.G. Metyrapone, Ketoconazole.

Question 24

State some surgical treatments for Cushing’s syndrome.

Answer 24

Treatment is dependent on cause
Transsphenoidal Hypophysectomy (for Cushing’s disease)
Bilateral adrenalectomy
Unilateral adrenalectomy for adrenal mass

Question 25

Name two inhibitors of steroid synthesis that can be used to treat Cushing’s

Answer 25

metyrapone; ketoconazole

Question 26

Describe the mechanism of action of metyrapone

Answer 26

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

Question 27

Summarise the mechanism of actions of metyrapone

Answer 27

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

Question 28

What is treatment for Cushing’s focussed on

Answer 28

Post-operative care

Question 29

Why is it important to lower a patient’s cortisol before surgery

Answer 29

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.

Question 30

Describe the impact of surgery on treating patient’s with Cushing’s

Answer 30

The advent of laparoscopic and retroperitoneoscopic has made a big difference to the morbidity of surgery in these patients.

Question 31

What is the major glucocorticoid in rats

Answer 31

Corticosterone

Question 32

Describe the uses of metyrapone

Answer 32

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)

Question 33

Explain the unwanted side effects of metyrapone

Answer 33

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.

Question 34

State the unwanted side effects of metyrapone

Answer 34

Hypertension on long-term administration

Hirsutism
Sedation, hypoadrenalism
Nausea, vomiting, dizziness

Question 35

Why do we see an accumulation of 11-deoxycorticosterone

Answer 35

because it doesn’t have any negative feedback effects on the ACTH axis

Question 36

Summarise the actions of ketoconazole

Answer 36

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

Question 37

Describe the mechanism of action of ketoconazole

Answer 37

Inhibits 17a-hydroxylase

Inhibiting the conversion of pregnenolone to 17a-hydroxypregnenolone and progesterone to 17a-hydroxyprogesterone

Question 38

Describe the uses of ketoconazole

Answer 38

USES (similar to metyrapone)
Cushing’s syndrome
- treatment and control of symptoms prior to surgery

	- orally active

Question 39

Describe the unwanted side effects of ketoconazole

Answer 39

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

Question 40

Why are metyrapone and ketoconazole not really long-term solutions

Answer 40

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

Question 41

What does the type of surgery arranged for Cushing’s depend on

Answer 41

The cause

Don’t have an adrenalectomy if you have a pituitary tumour

Question 42

Describe the surgical route for pituitary surgery

Answer 42

Transphenoidal hypophysectomy

Question 43

What is Conn’s syndrome

Answer 43

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.

Question 44

What is primary hyperaldosteronism?

Answer 44

Hyperaldosteronism caused by an adrenal adenoma

Question 45

What is secondary hyperaldosteronism

Answer 45

hyperaldosteronism caused by something other than a n adrenal adenoma (i.e something not related to the adrenal gland)

Question 46

Describe the diagnosis of Conn’s syndrome

Answer 46

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.

Question 47

What can you test to exclude secondary hyperaldosteronism

Answer 47

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.

Question 48

What imaging modality should be used to look for an adrenal tumour

Answer 48

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

Question 49

What should you ensure before making the diagnosis of Conn’s syndrome

Answer 49

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.

Question 50

What is the usual treatment plan for someone with Conn’s syndrome?

Answer 50

Medical management (spironolactone and eplerenone) 
Surgery to remove the tumour

Question 51

Summarise the mechanisms of action of spironolactone

Answer 51

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).

Question 52

What type of drug is spironolactone

Answer 52

A pro-drug

It is converted into canrenone- which exerts the pharmacological effects

Question 53

Describe the pharmacokinetics of spironolactone.

Answer 53

Orally active
Given daily in single or divided doses
Highly protein-bound and metabolised in the liver

Question 54

Describe the unwanted side effects of spironolactone

Answer 54

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

Question 55

Summarise eplerenone

Answer 55

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
T

Question 56

What are patients with Conn’s also often treated with

Answer 56

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.

Question 57

Summarise the different operations available when an adrenal tumour needs to be removed.

Answer 57

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.

Question 58

If the surgery is successful, what changes should be made

Answer 58

Patients can usually stop potassium supplements and some or all of the anti-hypertensive drugs

Question 59

What should be done if a bilateral adrenal hyperplasia is diagnosed

Answer 59

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.

Question 60

Following an adrenalectomy, what are patients with Cushing’s likely to be

Answer 60

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.

Question 61

What are pheochromocytomas

Answer 61

A secreting tumour (catecholamines) of the adrenal medulla

Question 62

Explain the naming of a pheochromocytomas

Answer 62

Because of its pathological appearance

dusky (phaeo in Greek) colour (chromo)

Question 63

Describe the size of pheochromocytomas

Answer 63

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

Question 64

Summarise the clinical features of a pheo

Answer 64

§ 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.

Question 65

Describe the effects of a pheo

Answer 65

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.

Question 66

State some fatal consequences of phaeochromocytoma.

Answer 66

Myocardial infarction and stroke
It can also cause sudden cardiac death through ventricular fibrillation
It is a MEDICAL EMERGENCY

Question 67

Describe the symptoms of a pheo

Answer 67

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).

Question 68

Describe the steps that must be taken when preparing a phaeochromocytoma patient for surgery.

Answer 68

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.

Question 69

How can we diagnose a phaeochromocytoma

Answer 69

Measuring catecholamines, or the metabolites of catecholamines, the metanephrines, either in the urine or the plasma.

Question 70

Describe the treatment for a phaeo

Answer 70

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.

Question 71

What should we do with young patients who have had a pheo removed

Answer 71

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.

Question 72

Describe the key facts of pheos

Answer 72

o 10% are extra-adrenal (down the sympathetic chain).
o 10% are malignant.
o 10% are bilateral.
o VERY RARE.