Week 4 - H - Adrenal disorders Flashcards
The adrenal glands are surrounding by a protective fatty capsule What is the outer and inner parts of the adrenal glands?
The adrenal glands have the outer adrenal cortex and inner adrenal medulla
What is the adrenal cortex separated into? (outer to inner)
Zona glomerulosa
Zona fasciculata
Zona reticularis
This is the histological appearance of the adrenal cortex regions What is each sections function?
Zona glomerulosa, Mineralocorticoids -Aldosterone
Zona fasciculata, Glucocorticoids - Cortisol
Zona reticularis, Sex steroids (androgen) and glucocorticoids
(Go Find Rex, Make Good Sex)
What is the rate limiting step in the synthesis of corticosteroids in the adrenal cortex?
The conversion of cholesterol to pregnenolone
What regulates the production of aldosterone from the adrenal cortex?
Aldosterone production regulated by renin-angiotensin system and plasma potassium
And regulated by potassium levels - increasing potassium causes an increase in aldosterone produdction
What causes the hypothalamus to secrete more CRH?
Which have a negative feedback effect on the hypothalamus/pituitary secretions:
Androgen produced by zona reticularis?
Cortisol produced by zona fasciculata?
Aldosterone produced by zona glomerulosa?
Stress, illness, time of day
Both Androgen produced by zona reticularis and Cortisol produced by zona fasciculata
How is a falling blood pressure corrected by the renin angiotensin system?
Blood pressure falls
Juxtaglomerular cells of kidney release renin
Renin converts angiotensinogen to angiotensin 1
Angiotensin 1 converted to angiotensin 2 by ACE
Angiotenins 2 stimulates adrenal cortex to secrete aldosterone
Aldosterone causes resorption of Na+ and H2O increasing blood volume –> increasing blood pressure
Just an image of the major cortisol effects
If ACTH cause of cushings, excess androgen as well as excess cortisol
Also redistribution of fat causes more androgen production
What are the 3 main principles of use of corticosteroids?
Suppress inflammation
Suppress immune system
Replacement treatment
What effect does an increased aldosterone have on potassium ions?
Increases potassium excretion
Primary adrenal insufficiency is when the problem is at the adrenal level What are 3 common causes of primary adrenal insufficiency?
Addison’s disease
Congenital Adrenal Hyperplasia (CAH)
Adrenal TB/malignancy
What do androgens go on to form in males and females?
In males becomes testosterone
In females becomes estrogen
Androgen insufficiecny can cause low sex drive and amenorrhea in females
What is the commonest cause of primary adrenal insufficiency? What percentage of the adrenal cortex is usually destroyed by the autoantibodies before symptoms arise? What is the usual antbody?
Addison’s disease
Autoimmune destruction of adrenal cortex >90% destroyed before symptomatic
Autoantibodies positive in 70% (21-alpha hydroxylase antibodies)
What are the clinical features of addisons disease?
Hyperpigmentation
Postural hypotension
Dizziness and low BP
Abdo pain, vomiting
Weight loss
What is the suspicious biochemistry when diagnosing a primary adrenal insufficiency?
Decreased sodium and increased potassium blood levels
Hypoglycaemia (due to the lack of cortisol)
What test is carried out for addisons disease? What is given?
Short synacthen test – stimulation test
– synthetic ACTH is given to see if the adrenal gland responds
What should be measured in a synacthen test?
Give synthetic ACTH (tetracosactide)
- measure cortisol before and 1/2 hour after giving it - addisons excluded if coritsol >550nmol/l
* ACTH levels should be increased (causes skin pigmentation)
* Measure renin/aldosterone levels - increased renin but decreased aldosterone
What should be given as treatment in addison’s disease? (treatment for gluco and mineralo corticoids)
Hydrocortisone as cortisol replacement
- Give IV if acutely unwell
- Usually 15-30mg in daily divided doses to mimic diurnal rhythm
Fludrocortisone as aldosterone replacement– careful monitoring of BP and K
Patients who have Addison’s disease are usually given both glucocorticoid and mineralocorticoid replacement therapy. In patients’ with addison’s disease who present with an illness, how should the treatment be altered?
Double the glucocorticoid dose, keep the fludricortisone dose the same
What is the commonest cause of secondary adrenal insufficiency?
Exogenous steroid use
How does the exogenous steroid use cause an adrenal insufficiency?
Causes a negative feedback on the hypothalamus to not produce CRH and on the pituitary to not produce ACTH
The suppression of the hypothalamic pituitary adrenal axis leading to a decreased organic cortisol production only becomes apparent on withdrawal of the steroids
What is the difference in features of secondary and primary adrenal insufficiency?
There is no tanned skin in secondary as ACTH is decreased
There is no hyperkalamia as aldosterone is regulated by RAAS
Pituitary/hypothalamic disease
Tumours - Surgery/radiotherapy
This can also causes secondary adrenal insufficiency What is used to treat secondary adrenal insufficiency? is fludrocortisone required?
Give hydrocortisone for cortisol replacement
Fludrocortisone is not required to replace aldosterone as it is intact
After a synacthen test, what should the 30 min plasma cortisol level increase to make primary or secondary adrenal insufficiency more likely?
Addison’s disease -
30min cortisol 550mmol/l
as adrenal glands still functioning and can produce cortisol (its just the HPA axis that is gubbed)
Cushings syndrome can be caused by ACTH dependent and independent factors What is the most common cause of Cushing’s syndrome? * What are the ACTHdependent causes?
The commonest cause of Cushing’s syndrome is iatrogenic steroid use
ACTH dependent causes:
* Cushing’s disease (80%): pituitary tumour secreting ACTH - producing adrenal hyperplasia
* ectopic ACTH production (5-10%): e.g. small cell lung cancer
Investigations are divided into confirming Cushing’s syndrome and then localising the lesion. A hypokalaemic metabolic alkalosis may be seen, along with impaired glucose tolerance. How is a cortisol excess established in cushing’s syndrome - what is the screening test?
1st line SCREENING TEST (good outpatient initial test) -
* Overnight 1mg dexamethasone (at midnight) test- measure cortisol at 8am
(there would be no cortisol suppression in Cushing’s)
24hr urinary cortisol is also a good test
If the screening overnight dexamethasone suppression test is abnormal, what is the diagnostic test for Cushing’s syndrome?
If 1st line test is abnormal then carry out the 2nd line DIAGNOSTIC TEST
* Low does 48 hour dexamethasone suppression test (4mg over 48hours (0.5mg/6hr) and measure cortisol levels 6hrs after final dose
What is the expected level of cortisol in a positive cushings low dose dexamethasone?
Greater than 50nmol/l
Always repeat to confirm
ACTH dependent Cushings: * Cushing’s disease (80%): pituitary tumour secreting ACTH producing adrenal hyperplasia * ectopic ACTH production (5-10%): e.g. small cell lung cancer
If the low dose dexamethasone suppression test (4mg over 48) hours comes back with a cortisol >50nmol/l, what can be carried out to differentiate between these two causes?
High dose dexamethasone suppression test (2mg/6hr for 48 hours so 16mg in 48 hours)
* ACTH producing pituitary tumour will likely be suppressed by the high dose test
* Ectopic ACTH producing tumour (eg small cell lung cancer) will not be suppressed by low or high dose dexamethasone suppresion test
Long term steroid treatment suppresses ACTH production (negative feedback to anterior pituitary) causing atrophy of adrenal cortex
Can the steroid treatment suddenly be stopped for iatrogenic cushings?
Cannot stop suddenly
Gradual withdrawal of steroid therapy
How are the ACTH dependent causes of Cushing’s disease treated?
(* Pituitary tumour producing ACTH - Cushing’s disease * Ectopic ACTH production)
How adrenal adenomas causing Cushing’s treated?
* Cushing’ disease - The first-line treatment of Cushing’s disease is surgical resection of ACTH-secreting pituitary adenoma; this surgery involves removal of the tumor via transsphenoidal surgery (TSS)
* Ectopic ACTH production - surgery if tumour is located and hasn’t spread
Adrenal adenomas treated with adrenelectomy
If the patient is not suitable for surgery, what are medical management options of Cushing’s disease?
Metyrapone or ketaconazole - these inhibit steroidgenesis (inhibit cortisol synthesis)
> 90% hypertension cases there is no known cause (‘essential’) < 10% cases are secondary to another disorder eg. renal disease, Cushing’s Presents with hypertension and hypokalaemia
What is this?
Primary aldosteronism
How do patients with Conn’s syndrome present biochemically?
High NaCl,
high water
Low potassium
- presents as fatigue and muscle weakness
Primary aldosteronism is the commonest secondary cause of hypertension
What is the commonest cause of primary aldosteronism?
Bilateral adrenal hyperplasia (60%)
Adrenal adenoma - Conn’s (30%)
Diagnosing primary aldosteronism
Firstly confirm aldosterone excess
- Measure plasma aldosterone and renin and express as ratio (ARR-aldosterone to rennin ratio)
- If ratio raised then investigate further with saline suppression test
How is this measured?
If aldosterone levels fail to suppress by 50% with 2litres of saline, primary aldosteronism is confirmed
When confirming the subtype of cause of primary aldosteronsim (eg bilaterl adrenal hyperplasia or adenoma), how do you carry this out?
Adrenal CT to look for adenoma
Sometimes adrenal vein sampling to confirm adenoma
If an adenoma is found in primary aldosteronism, how is this treated?
Surgical
Only if adrenal adenoma – unilateral adrenalectomy
Cure of hypokalaemia
Cures hypertension in 30-70% cases
Due to the fact that bilateral adrenolectomy is not practical, what is done to treat bilateral adrenal hyperplasia?
Use MR (mineralocorticoid receptor) antagonists (spironolactone or eplerenone)
These are potassium sparing and decrease high blood pressure by promoting excretion of sodium and water
What is the commonest cause of congenital adrenal hyperplasia?
21alpha hydroxylase deficiency (95% of cases)
What is the classical presentation of congenital adrenal hyperplasia in males and females?
In males - Adrenal insufficiency
Often around two to three weeks
Poor weight gain and can presnt like addisons
In females - genital ambiguity
How does a 21-OH deficiency cause congenital ambiguity in females when it is not involved in the pathway?
the enzyme difciecny prevents aldosterone and cortisol being produced, this causes a negative feedback causing more ACTH to be produced and therefore more choesterol is converted to pregnenolone
The excess pregnenolone is converted to androgens causing increased testosterone in the females
What is the treatment of 21-OH deficiency in children?
- Glucocorticoid replacement
- Mineralocorticoid replacement in some
In adults • Control androgen excess • Restore fertility
increased serum catecholamine’s
Classical triad – hypertension, headache, sweating
o Rare tumour of chromaffin cells – cells of the adrenal medulla
What is this?
Pheochromocytoma
Also get palpitations
Why is pheochromocytoma known as the 10% tumour?
10% malignant (more common in extra-adrenal lesions)
10% extra adrenal – called paragangliomas
10% bilateral (up to 50% in familial cases)
10% associated with hyperglycaemia
10% in children
10% familial
What colour do chromaffin cells reduce chrome salts to?
Dark brown
Use potassium dichromate
Pheochromocytoma are often missed however are an important curable form of hypertenison
What are the signs of complications?
Left ventricular failure
Myocardial necrosis
Stroke
Shock
Paralytic ileus of bowel
What are the biochemical abnormalities associated with pheochromocytoma?
Hyperglycaemia - due to adrenaline
Mild hypercalcaemia
May have low potassium
How is pheochromocytoma diagnosed?
Raised urine metanephrines for biochemical test - breakdown product of catecholamines (it has replaced catecholamines test as it is more sensitive)
Diagnosed location of the tumour by a MIBG scan and CT scan
MIBG -meta-iodobenzylguanidine scan to help locate and diagnose certain types of cancer in the body
.(these scans are taken up by sympathetic tissues - indicated functioning, eptopic and metastatic adrenal medullary tumours)
What is the main treatment of pheochromocytomas?
SURGERY with pre-operative medical treatment
alpha and beta blockade (A before B)
- Phenoxybenzamine (alpha 1&2 blocker)
- Propranolol, atenolol or metoprolol (B blocker)
Important the a blockade is given for b-blocker to avoid hypertensive crisis from unopposed alpha-adrenergic stimulation
What are 5 familial conditions associated with pheochromocytomas?
Multiple Endocrine Neoplasia 2 (MEN2) (RET gene)
Von-Hippel-Lindau syndrome (VHL gene)
Succinate dehydrogenase mutations
Neurofibromatosis (NF1 gene)
Tuberose sclerosis (TSC1 or TSC2 gene)
Pheochromocytoma is the commonest adrneal medulla tumour in adults What is the commonest in children?
Neuroblastoma
