Disorders Of Adrenocortical Disorders Flashcards
As a recap, what are the actions of cortisol in the body?
INCREASED PLASMA GLUCOSE LEVELS:
increased gluconeogenesis
decreased glucose utilisation
increased glycogenesis
increased glycogen storage
INCREASED LIPOLYSIS:
- provides energy
PROTEINS ARE CATABOLISED:
- releases amino acids
NA+ AND H2O RETENTION:
- maintains BP
ANTI-INFLAMMATORY
INCREASED GASTRIC ACID PRODUCTION
What are the three stages of Cushing’s Disease investigation?
1) Screening Tests, for when the disease is suspected
2) Confirmation of the Diagnosis
3) Differentiation of the Cause
What are the screening tests for Cushing’s Disease?
urinary free cortisol
diurnal rhythm
overnight dexamethasone suppression testing
Describe the overnight low-dose dexamethasone suppression test.
Cortisol is to be measured at 8 AM.
1 mg of dexamethasone is given at 11 PM. The cortisol levels are measured again at 8 AM the next morning.
Cortisol suppression to <50 nmol/l is normal.
If the screening tests for Cushing’s Disease come back positive, there are 3 possibilities that could cause that.
What are these three possible conditions?
TRUE CUSHING’S SYNDROME
PSEUDOCUSHING’S SYNDROME: common with these conditions as they are under stress
depression
alcoholism
anorexia nervosa
obesity
EXOGENOUS STEROIDS: found in everyday things such as
inhalers
eyedrops
nasal drops
skin creams
health food shops
To remove the possibility of false positives, how do we change the overnight low-dose dexamethasone suppression test?
Instead of one dose, we give them 4 low-dose tablets a day for 2 days (0.5 mg of dexamethasone six-hourly for 48 hours).
This means that all the false positives will regulate, so there will be no cortisol left in their bloodstream.
If cortisol is still detectable then the patient has Cushing’s Syndrome.
After the low-dose dexamethasone suppression test, what different diagnoses can be made now, and how can we differentiate between the different causes?
If the test comes back positive now, it could either be:
CUSHING’S DISEASE:
- pituitary adenoma
ADRENAL TUMOUR:
- benign/ malignant
ECTOPIC ACTH PRODUCTION:
- benign/ malignant
We can differentiate between the different causes using:
high-dose dexamethasone suppression testing
ACTH
imaging
Describe the high-dose dexamethasone suppression test.
A high dose of 2 mg of dexamethasone is given every 6 hours for 48 hours.
If the cortisol suppresses to <50% of the baseline, then the patient had Pituitary-Dependent Cushing’s Disease.
If the cortisol does not suppress, then the patient has ectopic ACTH production or an adrenal tumour.
What are some laboratory features of cortisol excess?
hypokalaemia (low potassium in serum)
metabolic alkalosis
hyperglycaemia
For the CRH test, why would we measure CRH levels and not ACTH levels?
ACTH is present in the blood in fragments, making it difficult to measure.
Describe a CRH test, and what different results indicate.
0.1 μg/kg of human CRH is given. The blood is then assayed for ACTH and cortisol at set times: -15, 0, 15, 30, 45, 60, 90, 120 minutes.
If the ACTH doubles, this indicates a normal response.
If the ACTH is suppressed, this indicates an adrenal tumour.
If the ACTH level remains the same, this indicates ectopic ACTH production.
If there is an exaggerated ACTH response, this indicates a pituitary tumour.
Tumours that produce hormones (in this case, ACTH) can be found in different places.
List the different scans/ tests done for each area/ condition to localise the tumour.
PITUITARY TUMOUR:
- MRI or IPSS
ADRENAL TUMOUR:
- CT or MRI
ECTOPIC ACTH PRODUCTION:
octreotide scan
ACTH sampling
What would be the treatment for a pituitary tumour and an adrenal tumour?
FOR THE PITUITARY TUMOURS:
The excess cortisol causes these patients to be hypertensive, immunosuppressed, diabetic, etc. These are risk factors for surgery, so first they are given cortisol production blockers (such as metyrapone or ketoconazole).
Then, after the surgery takes place, patients may require placement of other pituitary hormones until normal hormone production is resumed.
FOR THE ADRENAL TUMOURS:
First, we have to remove the source of an adrenal tumour. The patients will need to have steroid replacement tablets at the time of and following the surgery.
An adrenal tumour suppresses the function of the normal gland, although many will not need the steroid tablets long-term.
What are some of Addison’s clinical features?
tiredness
weakness
anorexia
weight loss
postural hypotension
myalgia
salt cravings
nausea/ vomiting
hyperpigmentation
vitiligo
hyponatraemia
hyperkalaemia
acidosis
hypercalcaemia
hypoglycaemia
increased urea and creatinine
eosinophilia
lymphocytosis
What are some causes of Addison’s Syndrome?
autoimmune diseases
TB
steroid withdrawal
metastases (second, malignant growth from a primary site of cancer)
infiltration (amyloid, haemochromatosis)
Waterhouse-Friedrichsen (bleeding in the adrenal glands)
Apoplexy (bleeding within internal organs)
infection (fungal, viral)
enzyme defect (congenital adrenal hyperplasia, adrenoleukodystrophy, adrenomyeloneuropathy)
drugs
What would be the treatment of Addison’s disease?
Since it is a low amount of cortisol in the body that causes it, we would simply replace the hormone.
We could use hydrocortisone; it mimics the diurnal rhythm, with the last dose being given at 6 PM.
We could also use fludrocortisone.
Describe 21-hydroxylase deficiency (classical) CAH.
It is a rare condition, affecting 1 in 10,000 people. It is autosomal recessive and has an increased incidence in Yupik Eskimos. It is HLA-linked.
The patient cannot make aldosterone or cortisol, so there is a build-up of 17-OH and progesterone in the system. These will be converted to excess sex steroids.
The excess sex steroids cause virilisation (onset of male physical characteristics when not supposed to), hirsutism (male-pattern hair growth in women), premature adrenarche (early sexual maturation), infertility, etc.
Since there is no aldosterone, there is a salt-losing crisis, leading to hyperkalaemia and hypotension.
Describe 11-hydroxylase deficiency (non-classical) CAH.
Even rarer than classical CAH, it occurs in 0.5 in 100,000 live births. It is also autosomal recessive and increased in Moroccan Jews. Again, it is HLA-linked.
The deficiency in the enzyme causes a build-up of 11-deoxycortisol and deoxycorticosterone. Deoxycorticosterone has a partial action on the aldosterone receptor. So, instead of being hypotensive in childhood, patients become hypertensive, as they retain too much salt, and get hypokalaemic.
The excess sex steroids cause virilisation, hirsutism, premature adrenarche, infertility, etc.
How do we investigate for enzyme deficiencies in the making of cortisol and aldosterone?
We can investigate this using a synacthen test. There will be no cortisol rise as there are increased 17-OH and progesterone levels.
How do we treat enzyme deficiencies in the making of cortisol and aldosterone?
Both of the entities comprise of a spectrum of disease, so partial deficiencies complicate matters.
The reactions of 11β- and 21-hydroxylase deficiency lies mainly in the use of glucocorticoid therapy (with drugs such as prednisolone). This will act partially on the mineralocorticoid receptor, providing negative feedback to ACTH. This means that ACTH levels will fall, and the drive to produce testosterone will stop.
There is also surgery possible to virilised female genitalia; we could also treat the mother to prevent foetal virilisation.
How does aldosterone work with negative feedback?
With the control of aldosterone release, there is no direct negative feedback (as there are no aldosterone receptors on the kidney).
However, the actions of aldosterone (such as increasing extracellular fluid and potassium) provides physiological negative feedback to the kidney to switch off renin production (which would ultimately make aldosterone).
Describe the two conditions in which there is an overproduction of aldosterone.
PRIMARY EXCESS:
This is mostly caused by a tumour, and is called Conn’s Syndrome.
It can be caused by bilateral adrenal hyperplasia, steroid-treatable hypertension or an aldosterone-producing adrenal carcinoma.
SECONDARY EXCESS:
- With hypertension:
It could be caused by renal artery stenosis; if the kidney receives less blood, it will release more renin in an attempt to increase blood volume.
It can also be caused by a renin-secreting tumour or malignant nephrosclerosis.
With a normal BP:
It is associated with CCF (congestive heart failure), cirrhosis, nephrotic syndrome and dehydration.
How do we treat Conn’s Syndrome?
removing the primary tumour
spironolactone (blocks mineralocorticoid receptors)
potassium supplementation
Describe phaechromocytoma.
It is a tumour of the enterochromaffin cells of the adrenal medulla. It produces adrenaline (noradrenaline, dopamine).
10% are on both adrenal glands, 10% are cancerous, 10% are found outside the adrenal gland and 10% are inherited.
