Disorders of Adrenocortical Dysfunction Flashcards
What are the three stages of Cushing’s Disease investigation?
- Screening Tests, for when the disease is suspected
- Confirmation of the Diagnosis
- 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 possibilities? PART 1
TRUE CUSHING’S SYNDROME
PSEUDOCUSHING’S SYNDROME - common with:
- depression
- alcoholism
- anorexia nervosa
- obesity
If the screening tests for Cushing’s Disease come back positive, there are 3 possibilities that could cause that.
What are these three possibilities? PART 2
EXOGENOUS STEROIDS: found in everyday things such as
- inhalers
- eyedrops
- nasal drops
- skin creams
To remove the possibility of false positives, how do we change the overnight low-dose dexamethasone suppression test?
- Give 4 low-dose tablets a day for 2 days (0.5 mg of dexamethasone six-hourly for 48 hours).
- 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?
CUSHING’S DISEASE:
- pituitary adenoma
ADRENAL TUMOUR:
- benign/ malignant
ECTOPIC ACTH PRODUCTION:
- benign/ malignant
After the low-dose dexamethasone suppression test, how can we differentiate between the different causes?
- high-dose dexamethasone suppression testing
- ACTH
- imaging
Describe the high-dose dexamethasone suppression test.
- High dose of 2 mg of dexamethasone is given every 6 hours for 48 hours.
- If cortisol suppresses to <50% of baseline, patient has Pituitary-Dependent Cushing’s Disease.
- If cortisol does not suppress, patient has ectopic ACTH production or adrenal tumour.
What are some laboratory features of cortisol excess?
- hypokalaemia
- 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.
- 0.1 μg/kg of human CRH is given.
- Blood assayed for ACTH and cortisol at set times: -15, 0, 15, 30, 45, 60, 90, 120 minutes.
Describe what different results of a CRH test indicate.
- If the ACTH doubles, indicates a normal response.
- If the ACTH is suppressed, indicates an adrenal tumour.
- If the ACTH level remains the same, indicates ectopic ACTH production.
- If there is an exaggerated ACTH response, 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?
- Excess cortisol causes patients to be hypertensive, immunosuppressed
- Risk factors for surgery, so given cortisol production blockers (e.g metyrapone/ ketoconazole).
- After surgery, patients require placement of other pituitary hormones until normal production resumed.
What would be the treatment for an adrenal tumour?
- Remove the source of an adrenal tumour.
- Patients will need to have steroid replacement tablets at time of and following surgery.
- Adrenal tumour suppresses the function of the normal gland
What are some of Addison’s clinical features?
- Weakness
- Weight loss
- Postural hypotension
- Myalgia
- Hyperpigmentation
- Hyponatraemia
- Hyperkalaemia
- Acidosis
- Hypercalcaemia
- Hypoglycaemia
- Increased urea and creatinine
- Eosinophilia
What are some causes of Addison’s Syndrome?
- Autoimmune diseases
- Steroid withdrawal
- Metastases
- 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?
- Replace the hormone.
- Use hydrocortisone; it mimics the diurnal rhythm, with last dose being given at 6 PM.
- Use fludrocortisone.
Describe 21-hydroxylase deficiency (classical) CAH.
- Autosomal recessive and HLA-linked.
- Patient cannot make aldosterone or cortisol, so build-up of 17-OH and progesterone
- Excess sex steroids cause virilisation, hirsutism, premature adrenarche, infertility, etc.
- No aldosterone - hyperkalaemia and hypotension.
Describe 11-hydroxylase deficiency (non-classical) CAH.
- Autosomal recessive and HLA-linked.
- Build-up of 11-deoxycortisol and deoxycorticosterone. Forms excess sex steroids
- Deoxycorticosterone has a partial action on the aldosterone receptor.
- So, instead of being hypotensive, patients become hypertensive and hypokalaemic.
How do we investigate for enzyme deficiencies in the making of cortisol and aldosterone?
- Synacthen test.
- 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? PART 1
- 11β- and 21-hydroxylase deficiency uses glucocorticoid therapy (with drugs e.g prednisolone).
- Acts partially on the mineralocorticoid receptor, providing negative feedback to ACTH.
- ACTH levels will fall, and the drive to produce testosterone will stop.
How do we treat enzyme deficiencies in the making of cortisol and aldosterone? PART 2
- Surgery possible to virilised female genitalia
- Treat the mother to prevent foetal virilisation.
How does aldosterone work with negative feedback?
- No direct negative feedback (no aldosterone receptors on the kidney).
- 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.
CONDITION 1
PRIMARY EXCESS:
- Conn’s Syndrome - mostly caused by tumours
- Caused by bilateral adrenal hyperplasia, steroid-treatable hypertension or an aldosterone-producing adrenal carcinoma.
Describe the two conditions in which there is an overproduction of aldosterone.
CONDITION 2 (with hypertension)
SECONDARY EXCESS:
- Could be caused by renal artery stenosis
- If the kidney receives less blood, will release more renin to increase blood volume.
- Can also be caused by a renin-secreting tumour or malignant nephrosclerosis.
Describe the two conditions in which there is an overproduction of aldosterone.
CONDITION 2 (with normal BP)
Associated with 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.
- Tumour of the enterochromaffin cells of the adrenal medulla.
- Produces adrenaline (noradrenaline, dopamine).
- 10% are on both adrenal glands, 10% are cancerous, 10% are found outside the adrenal gland and 10% are inherited.
What are some symptoms of a phaeochromocytoma?
- sweating
- anxiety
- fever
- paroxysmal hypertension
- angor amanii (patient’s perception that they are dying)
- constipation
- abdominal pain
- eosinophilia
- hyperglycaemia
- hypercalcaemia
How would you be able to diagnose a phaeochromocytoma?
Look for:
- eosinophilia
- hyperglycaemia
- hypercalcaemia
- raised urinary metabolites, such as metanephrines and catecholamines
Scan using CT and MRI scanning.
How would you manage a phaeochromocytoma?
Use drugs immediately such as:
- non-competitive α-antagonists (phenoxybenzamine phentolamine)
- non-selective β-blockers (propranolol) (always block α first)
Also:
- fluid resuscitation
- surgery
How is renin released?
→ Afferent arteriole brings blood in glomerulus and senses blood pressure
→ Macula densa in DCT senses salt
→ JG cells produce renin
What happens during hypovolaemia to retain Na+ (mineralocorticoid receptor)?
→ The catalytic site of 11 beta hydroxysteroid dehydrogenase 2 has a saturation point which is set higher than normal cortisol
→ Saturation point is lower than extreme cortisol
→ In extreme cortisol the enzyme gets saturated and cortisol can access the receptor
→ so maximal sodium can be retained
Why does cortisol not usually bind to the mineralocorticoid receptor?
→ Cortisol can bind to the mineralocorticoid receptor
→ 11 beta hydroxysteroid dehydrogenase 2 is part of the mineralocorticoid receptor
→ Cortisol → cortisone by the enzyme (destroyed)
→ Only aldosterone can bind to the receptor
How is the electrical balance retained at the mineralocorticoid receptor?
→ Na+ retained
→ K+ lost
Where does aldosterone bind in the kidney?
Mineralcorticoid receptor
What does the pituitary gland do when there is high cortisol?
Downregulates ACTH
What is the cortisol feedback loop?
→ CRH is released from the hypothalamus
→ goes to pituitary
→ Stimulates ACTH
→ ACTH stimulates adrenal gland to make cortisol
→ Cortisol inhibits hypothalamus
