Week 4 - H - Adrenal disorders Flashcards by Chris Egubjo

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

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What is the adrenal cortex separated into? (outer to inner)

Zona glomerulosa

Zona fasciculata

Zona reticularis

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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)

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What is the rate limiting step in the synthesis of corticosteroids in the adrenal cortex?

The conversion of cholesterol to pregnenolone

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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

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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

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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

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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

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What are the 3 main principles of use of corticosteroids?

Suppress inflammation

Suppress immune system

Replacement treatment

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What effect does an increased aldosterone have on potassium ions?

Increases potassium excretion

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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

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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

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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)

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What are the clinical features of addisons disease?

Hyperpigmentation

Postural hypotension

Dizziness and low BP

Abdo pain, vomiting

Weight loss

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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)

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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

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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

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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

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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

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What is the commonest cause of secondary adrenal insufficiency?

Exogenous steroid use

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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