Disorders of Adrenal Function Flashcards
Adrenal Gland
Where is the adrenal gland?
what are the two parts of the adrenal gland?
What are the three layers of oine part and what is released from there?
what does the other part release?
The adrenal gland sits on top of the kidney and is composed of two main parts. The cortex on the outside and the medulla in the middle.
The cortex is subdivided into three layers, from outside going in:
- Zona glomerulosa – Secretes the mineralocorticoids e.g. aldosterone
- Zona fasiculata – Secretes the glucocorticoids e.g. cortisol
- Zona reticularis – Secretes the sex steroids e.g. testosterone
The medulla releases adrenaline and noradrenaline.
Actions of Cortisol
what are glucocorticoids essential for?
How do they increase plasma glucose levels?
what does cortisol do to fat stores?
why can excess cause weight gain?
What does cortisole do to muscles? How does this link to the liver?
other effects of cortisol (3)
Overall glucocorticoids are essential for the response to stress.
Glucocorticoids increase plasma glucose levels through:
• Increasing gluconeogenesis
• Decrease glucose utilisation (GLUT 4 expression inhibited)
• Increase glycogenesis
• Increase glycogen storage
Cortisol increases lipolysis, which provides energy (glycerol can be fed into gluconeogenic pathway)
BUT really due to hyperglycaemia, insulin usually takes over this bit and so overall you get lipogenesis, which is why people with excess cortisol gain weight.
Cortisol increases protein catabolism in muscle, which releases amino acids which can be made available to the liver for use in gluconeogenesis -> which is why people with excess cortisol often have hyperglycaemia.
- Na+ and H2O retention, which maintains BP
- Anti-inflammatory effects of cortisol
- Increased gastric acid production – to prevent infection
Cushing’s
how does cushing’s syndrome come about?
How does cushing’s disease come about?
symtoms of cushing’s syndrome (3 key symtoms with their own characteristics)
Cushing’s syndrome is the clinical features of chronic exposure to excessive levels of cortisol. The incidence is 2/1,000,000 in the population. Ratio makes incidence significantly higher in females than males and typical age of onset is 20-40 years of age.
So as stated Cushing’s Syndrome is having excess cortisol in the blood.
Cushing’s Disease is having excess cortisol in the blood due to an ACTH secreting pituitary tumour.
Symptoms and Signs of Cushing’s Syndrome include:
- Changes in protein and fat metabolism (due to effects of high insulin and proteolysis) o Change in body shape o Central obesity o Moon face o Buffalo hump o Thin skin, easy bruising o Oesteoporosis (brittle bones) o Diabetes (as cortisol promotes insulin resistance)
- Changes in sex hormones (as ACTH causes release of androgens) o Excessive hair growth o Irregular periods o Problems conceiving o Impotence
- Salt and water retention (due to cortisol acting on mineralocorticoid receptor)
o High blood pressure
o Fluid retention
Investigation of Cushing’s Disease
what are the 3 stages?
what are the different tests done during these stages?
why do we do a urinary free cortisol test over 24 hours?
Investigation of Cushing’s Disease
The way we investigate someone who we believe may have Cushing’s is in three stages:
- Screening: Test urinary free cortisol (we could test at midnight, when cortisol should be at its lowest but generally we do a 24hr urinary cortisol test.
o This is because cortisol rises and falls over the day) and look at diurnal rhythm (to see how it changes) - Confirmation of the Diagnosis: for confirmation we would do an overnight dexamethasone suppression test
- Differentiation of the Cause: True Cushing’s or pseudo or exogenous. Where in the pituitary is it coming from? Where in body if ectopic?
As mentioned above, cortisol is released in a circadian rhythm pattern, i.e. it is an endogenous pattern (innate) that runs on about a 24/25hr cycle (so related to day length). This is why we would do a urinary free cortisol test where we test urinary cortisol over 24hrs. Cortisol is highest in early morning and lowest at midnight.
Dexamethasone test:
what will excess cortisol lead to the decrease of in the feedback loop?
What is dexamethasone? what would happen if we take it?
what is the Overnight Low Dose Dexamethasone Suppression Test?
how much is given and when?
when is cortisol measured?
how is cushing’s confirmed?
what are the 3 differentials diagnosis if cortisol is still present?
what is the High Dose Dexamethasone Test?
How much is given and when and for how long?
how is cushing’s disease confirmed and why?
if cortisol doesnt go down, what is the diagnosis?
how do you distinguish between the two remaining diagnoses? what levels do you look at and why?
The normal axis is shown below and there is a negative feedback loop, meaning that cortisol DECREASES both CRH release from the hypothalamus and ACTH from the anterior pituitary.
Dexamethasone is a drug version of cortisol, hence if we give it to someone who is normal and healthy the dexamethasone should inhibit the release of CRH and ACTH from hypothalamus and pituitary respectively.
ACTH levels would fall and as a result cortisol levels would also fall.
Overnight Low Dose Dexamethasone Suppression Test:
This is done first, where cortisol is measured at 8am, then 1mg of dexamethasone is given at 11pm. The person goes to sleep and then cortisol is measured the next morning at 8am.
If cortisol has been suppressed to less than 50nmol/l, the person is normal.
However, if cortisol is detectable after the low dose dexamethasone test, the person has Cushing’s.
There are then three possibilities for causing this (differential diagnosis):
- Patient has Cushing’s disease, in which case it would be a pituitary adenoma that is releasing high levels of ACTH resulting in high cortisol
- The patient has an adrenal tumour (neoplasia), that is secreting cortisol. This could be a benign tumour or malignant one.
- The patient has an ectopic source of ACTH production, this means that a tumour somewhere outside of the normal glandular tissue is secreting ACTH, a typical place is the lung.
High Dose Dexamethasone Test
So now is time for our high dose dexamethasone suppression testing, in order to find what the cause is. We may also use imaging for this.
The high dose given will be 2mg of Dexamethasone, every 6 hours, for 48 hours. If cortisol suppresses to less than 50% of the baseline (i.e. what it was when it was last measured), then the patient has (pituitary dependent) Cushing’s Disease.
This is because the negative feedback loop is still in-tact, the problem is that it is working at a much greater baseline level, so if the pituitary is given a small kick we won’t see much.
But when it is given the massive kick of dexamethasone, this is so much it is enough for it to respond and turn down ACTH production.
HOWEVER, if cortisol hasn’t been suppressed by this much, then the patient has an ectopic ACTH production OR an adrenal tumour.
So how do we distinguish between the two?
The key is that an adrenal tumour will be secreting high levels of cortisol, it is completely unregulated by ACTH (i.e. tumour is just doing its own thing!). Because of the high levels of cortisol (and the negative feedback loop being intact) it will result in decreased CRH and crucially ACTH release into the blood.
Therefore, we know that in an adrenal tumour ACTH will be low.
Conversely an ectopic tumour that is producing ACTH, it also will be doing its own thing (not being controlled by CRH), but because it is actually releasing ACTH, levels of ACTH in the body will be high!
So, we simply distinguish the two by:
o Adrenal tumour – ACTH low
o Ectopic tumour – ACTH high
There are also some key laboratory features we are likely to see in someone with Cushing’s
what other 3 clinical lab features will you see and why?
There are also some key laboratory features we are likely to see in someone with Cushing’s
o Hypokalaemia (low K+)
o Metabolic Alkalosis
o Hyperglycaemia (caused by effects of cortisol on increasing gluconeogenesis)
The reason we get the hypokalaemia and metabolic alkalosis is because at very high levels, cortisol can bind to the mineralocorticoid receptor in the kidneys.
Usually the enzyme 11-beta hydroxysteroid dehydrogenase will convert cortisol to inactive cortisone so it can’t do this.
But as said, at high levels, the enzyme gets overwhelmed and cortisol will bind, therefore there will be the effects of aldosterone!
• Remember that ACTH is derived from POMC (pro-opiomelanocortin), as well as many other hormones.
CRH Test
when is blood tested?
what does an exaggerated response indicate? why?
what does a flat response indicate? why?
Here a small amount of CRH is given and blood is then assayed for ACTH and cortisol at specific intervals, over 2 hours.
- An exaggerated response (i.e. very high ACTH and cortisol) would suggest pituitary Cushing’s disease (makes sense as it is working at very high level)
- A flat response (i.e. little increase in ACTH or cortisol) would suggest an ectopic ACTH production.
o This is because the ectopic source is producing high ACTH, but it is doing so at a set level that is not being up-regulated by CRH or down-regulated by anything. So, its levels will not be increased by giving CRH.
Localisation
how do we test pituitary? what is IPSS?
how do we test adrenal?
how do we test ectopic? (2 methods)
We want to localise and see exactly even more specifically where the problem is (e.g. where in the pituitary is this tumour? Where in the body is the ectopic tumour?).
- For Pituitary we’d use MRI and IPSS (intra petrosal sinus sampling, here we just looking at ACTH in blood in specific veins in skull, can tell us which side of pituitary the tumour is on)
- For adrenal we’d use CT or MRI
- For ectopic we’d use octreotide scan (type of nuclear medicine) OR we would do ACTH sampling (where we basically test blood ACTH in different parts of body in order to try and locate the tumour)
Treatment
what is the treatment for high cortisol? give two drug names
other treatments? what may some patients need following treatment?
what if the source of high cortisol was due to adrenals? what will they need at the time and after tretament for a short while?
The treatment for this high cortisol (due to pituitary) is cortisol production blockers, e.g. Metyrapone or Ketoconazole.
Could also do DXT three field or gamma knife (radiotherapy)
Following treatment, patients may require replacement of other pituitary hormones too.
If the source of very high cortisol is adrenal, we just have to remove the tumour. Patients will need to have steroid replacement tablets at the time and following surgery.
- This is because the adrenal tumour suppresses the function of the normal gland, fortunately many will not need the steroid tablets long term.
Addison’s
what is this due to?
Clinical features
causes of addiosn?
Example of primary adrenal failure is Addison’s, this is where there is chronic low blood cortisol.
Clinical features of Addison’s include: o Tiredness o Weakness o Anorexia o Weight loss o Postural hypotension o Hyperkalaemia o Acidosis o Salt craving
Causes of Addison’s include: • Autoimmune (MOST COMMON) • TB • Steroid withdrawal • Infection • Enzyme defect -> e.g. Congenital Adrenal Hyperplasia (CAH) • Drugs
For LOW cortisol, we can diagnose using two tests - what are they?
What synacthen?
What is the short test and which disease can it indicate?
What is the long test? and what disease can this inidicate? when do we test in the long test?
what are the 2 phases with this test? what would you expect at both phases?
what is the insulin tolerance test? who do we not give it to and what do we do instead?
what is the treatment for hypo-cortisol? the two drugs and their functions
For LOW cortisol, we can diagnose using two tests, the synacthen test or stress test.
For hypo-activity of cortisol we have the Synacthen test. Synacthen is like synthetic ACTH.
There is a short synacthen test (250mcg) where we give synacthen and see how much ACTH we produce over the next hour or so. This can be used to diagnose primary adrenal failure -> Because there will not be a rise in cortisol if there is primary adrenal failure.
We can also do a long synacthen test (1mg), to see if there is pituitary disease. Here we give a high intramuscular shot of synacthen. For the first hour (we would test at end of 1st hour) the levels would be low, this is because if there is pituitary disease the adrenals would be shrunken so they wouldn’t work very well. But the dose given in the long synacthen test, the dose is so large that over 24hrs we get a little adrenal growth.
o So, in the synacthen test we have two phases, we look at first hour to see ACTH levels and then the next day.
o So, if you see at the end of first hour there is no response but on the second day there is, it suggests the gland isn’t working because the pituitary gland isn’t telling it what to do. You just need to give it a large kick to wake up.
The better test however is the insulin tolerance test = to induce stress by making them hypoglycaemic (wouldn’t give in elderly, epileptics or people with ischemic heart disease, instead we’d use glucagon). Here we’d use the same parameters as before (low dose, then high dose). And see the response in levels of cortisol and ACTH.
Insulin Tolerance
Treatment for hypo-cortisol is simple -> replace it
Hydrocortisone (mimics diurnal rhythm)
Fludocortisone (replaces aldosterone)
21- Hydroxylase Deficiency (classical) CAH
Congenital Adrenal Hyperplasia (CAH)
how common is this?
genetics wise - what kind of disorder?
What is 21HD needed for? what if this is defficient?
why is there excess sex steroid and what is the consequence of this?
why do you get hyperkalaemia and hypotension?
This is the most common form of CAH, it is an autosomal recessive disorder that is HLA linked.
21HD is needed to make cortisol, so a lack of it impairs cortisol synthesis. So there becomes a build-up of 17-OHP which gets shuttled into making more sex steroids.
It is also needed for aldosterone synthesis, so a deficiency will also impair its synthesis.
Excess sex steroids result in
Hirsutism, virillisation (genetalia effected), infertility, premature adrenarche (early maturity)
No aldosterone = salt losing crisis -> hyperkalaemia and hypotension
11-beta hydroxylase deficiency
genetics wise - what kind of disorder?
how common is this?
why do you get hypertension and hypokalaemia?
Investigation for these diseases? 2 tests and what do you expect?
11-beta hydroxylase deficiency is non-classical and far less common. It is also autosomal recessive.
Here you get a similar issue, with an inability to produce cortisol and aldosterone. So again, there is shuttling to sex steroids and instead of aldosterone you get synthesis of a substance called DOC.
No aldosterone, but high DOC which is an agonist at mineralocorticoid receptors -> hypertension and hypokalaemia
Investigation for these diseases would be
o Synacthen test: would be no cortisol rise
o Increased 170HP progesterone levels
Prednisolone suppression
Treatment
Treatment
Fludrocortisone is used only in 21-hydroxylase deficiency to replace absent mineralocorticoid activity.
Aldosterone
Where is aldosterone produced? where does it act on and via what? what else binds here?
what can activate the RAAS system?
renin pathway?
2 effects of angiotension II
how is negative feedback take place as no aldosterone receptors?
Aldosterone is produced in the zona glomerulosa of the adrenal cortex and acts on the kidney via the mineralocorticoid receptor (nuclear receptor), this receptor also binds glucocorticoids (cortisol) with equal affinity.
Blood flows into the glomeruli of the kidneys via the afferent arterioles. A number of things may activate the RAAS system.
o Low blood pressure (decrease in renal perfusion)
o Low Na+ (low Na+ in the in the macula densa! This is just before the DCT!)
o High sympathetic activity
Any of the above will lead to renin release, renin is an enzyme
- Renin will convert angiotensinogen to angiotensin I
- ACE will convert angiotensin I to angiotensin II
- Angiotensin II has its own effects on vasoconstriction, but it also acts on adrenal cortex to cause release of Aldosterone
- Aldosterone will increase Na+ absorption and hence water retention. Also, will lead to increase loss of K+
There are no aldosterone receptors on the kidney, so it can’t negatively feedback, instead it will be turned off by reducing the stimulating factors (e.g. low BP)
