Disorder of the Adrenal Cortex (MKEB2404)

8/14/2019 Disorder of the Adrenal Cortex (MKEB2404)

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Disorder of the Adrenal Cortex


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Cortisol metabolism

Circulates in the plasma both in free and boundform

Free form-biologically active form ~5%

Bound form ( cortisol binding globulins andalbumin) ~95%

Cleared from the circulation-conjugation toglucuronide in the liver and excretion in the urine

Free form filtered in the renal glomerulus andappears in the urine as free cortisol


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Clinical Features

Central obesity,

hypertension,

glucose intolerance,plethoric faces,

purple striae,

hirsutism ,

menstrual dysfunction,

muscle weakness ,

bruising and osteoporosis.


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General Biochemistry

Hypokalaemia with inappropriate kaliuresis

glucose intolerance;

metabolic alkalosis


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Investigation of Cushing's

syndromeIatrogenic :

All the following tests do NOT apply to

iatrogenic cause.The biochemical picture is SUPPRESSEDCORTISOL due to the exogenous steoroid.

Careful history taking is mandatory.If iatrogenic cause has been excluded,proceed to:


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Screening tests

This is used to exclude the suspicion

rapidly. Two tests are recommended for

screening

the 'overnight dexamethasone suppression

test' and

the '24 hours urinary free cortisol output'.Either one is good for such purpose, but no

need to do both.


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Overnight dexamethasone test

Dexamethasone 1 mg orally at 11 pm.

Serum cortisol at 8 am in the following

morning.

Interpretation: Normal individual, serum

cortisol is suppressed to less than 50

nmol/L.Failure to suppress is suggestive of

Cushing's syndrome


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24 hours urinary free cortisol

Measure free cortisol in a 24-hour urine

collection

A normal value excludes the diagnosis

High value is suggestive of Cushings

syndrome.


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False positive conditions for both

screening testsobesity, alcohol abuse, acute stress(infection, operation...)... etc.

The cortisol levels in these conditions maynot be suppressed by just 1 mg ofdexamethasone (but would be suppressed ifhigher).

Hence one needs a confirmatory test toconfirm.


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Confirmatory test:

Low dose dexamethasone suppression test (LDDX)

A positive screening result requires confirmation to establish the

diagnosis.

The serum cortisol level in false positive conditions would be

suppressed by LDDX

(9:00 am serum cortisol < 140 nmol/L after dexamathasone 0.5

mg six-hourly for 48 hours) while a genuine endogenous

Cushing's syndrome would not.

Plasma cortisol should suppress


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What is the aetiology ?

High dose dexamethasone suppression test(HDDX)

Dexamethasone 2 mg 4 times a day for two days(compare to LDDX).

Suppressed morning serum cortisol level to morethan 50% of the basal level after the two days is

seen in Cushings disease (pituitary adenoma) butnot in adrenal tumour or ectopic ACTH cases. i.e.the degree of automony of secreting cortisol ishigher in the latter two conditions.


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CRH Test

Useful to differentiate between Cushinsdisease and ectopic ACTH production

CRH (100ug i.v.) In Cushing's disease plasma ACTH

increases by 50% over base line after 60

minutes and cortisol increases by 20% Ectopic secretion and adrenal tumours noresponse


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Glucocorticoid (+/- mineralocorticoid)

Deficiency: Adrenal InsufficiencyCauses

A primary disease at the adrenal level, destruction of

over 90 % of the cortex (Addison's disease)A destructive process at the hypothalamic-pituitary

level, leading to CRH or ACTH deficiency, or both

(e.g. part of a pan-hypopituitarism)

Prolonged suppression of the H-P-A axis byexogenous or endogenous glucocorticoids (i.e.

Cushing's syndrome, iatrogenic or endogenous).


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Clinical Features

Glucocorticoid deficiency:Weakness, hypoglycaemia, weight loss, GIdiscomfort.

Mineralocorticoid insufficiency:

Na wasting, hyponatraemia (often the only clue),hypovolaemia, overt or postural hypotension, hyperK, mild metabolic acidosis.

In primary adrenal insufficiency, feedback increase in

ACTH & MSH - hyperpigmentation.Patches of vitiligo sometimes accompany"autoimmune adrenalitis".


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Secondary adrenal insufficiency

Nosymptoms of aldosterone insufficiency(intact renin-aldosterone system)

No hyper-pigmentation (no increasedACTH / MSH)

May have other pituitary hormone

deficiencies:- hypogonadism, hypothyroidism


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Adrenal crisis

This is a medical emergency but difficult torecognise clinically

High fever, dehydration, nausea, vomiting,hypotension --> shock, hyperK, HYPO Na,haemoconcentration.

This could be fatal if not diagnosed/treated

promptly.Hence, one should always consider adrenalinsufficiency in all cases of un-explainedhyponatraemia with or without hyperkalaemia.


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Investigation of suspected

adrenal insufficiencyBasal Cortisol level

Random, am or pm cortisol level is NOT useful in

excluding the diagnosis!The failing gland may secrete cortisol falling into

the 'reference range' but unable to response to

stress. It is dangerous to rely on a random

cortisol level to exclude the diagnosis - always

use a stimulation test (short synacthen test) to

exclude.


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Short Synacthen Test

Take blood for basal serum cortisol, thengive synacthen (tetracorsactrin- synthetic

ACTH analogue) 250 mg intramuscularlyor intravenously. Take another serumcortisol at 30 min and one specimen at 60min.

Interpretation

Normal response: basal or post-stimulatedserum cortisol level > 550 nmol/L


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Prolonged synacthen test

Use to distinguish primary adrenal

insufficiency from pituitary failure and

prolonged glucocorticoid suppression (the'sleeping' adrenal gland will response after

prolonged ACTH stimulation).


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Prolonged ACTH stimulation

Day 1: Inject 1mg depot ACTH i.m. Days 2 and 3: repeat

Day 4: perform short ACTH test

Results Primary adrenal insufficiency: Plasma cortisol at

9h on day 4


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RAS

Renin-Angiotensin System: Main controller. The immediate

controlling factor is Angiotensin II which is in turn controlled

by Renin..

Renin is synthesized and released by the juxtaglomerular

apparatus in response to renal perfusion pressure (decreased

pressure causes increased secretion and vice versa). This

enzyme converts liver-produced angiotensinogen (glycoprotein)

to angiotensin II (decapeptide) which in turn is converted toangiotensin II (octapeptide) by angiotensin converting enzyme

(ACE, located mainly in walls of small blood vessels of lung).


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Angiotensin II

Angiotension II has four major actions: (1) arteriolar

vasoconstriction, (2) aldosterone release, (3) inhibition of

renin release, (4) stimulation of liver synthesis of renin

substrate (angiotensinogen).

Renin secretion is controlled by: (1) renal perfusion

pressure, (2) sodium concentration at macula densa, (3)

sympathetic nervous system (activates renin through b-

receptors), (4) angiotensin II.


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Mechanisms of mineralocorticoid action

Binding to the receptor in the cytosol

Movement of the complex hormone-receptor

into the nucleus

Alteration of the rate of transcription of

mineralocorticoid-responsive genes

Changes in the level of mRNAs and their

protein products


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Biological effects of

mineralocorticoids

Activation of Na influx into the cells (via

apical membrane)

Increasing of the number of luminal Nachannels (1 hour)

Activation of aldosterone-activated

kinase that increases Na channels activity(6-24 hours)


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Mineralocorticoid Excess:

Conn's SyndromeCause

Adrenal aldosterone producing adenoma

(APA)

Idiopathic hyperaldosteronism with bilateral

adrenal hyperplasia (BAH)


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General biochemistry

Hypokalaemia with inappropriate kaliuresis,

impaired glucose tolerance, metabolic

alkalosis


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Stages of diagnosis

Screening

Diagnosis

Establishment of cause


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Screening

Suppressed plasma renin activity (PRA)

The primary defect in Conns syndrome is

autonomous production of aldosterone withfeedback inhibition of plasma renin activity

Plasma aldosterone/renin ratio

Increased in Conns syndrome


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Confirmation

Serum aldosterone response to salt loadIn primary hyperaldosteronism (Conns

syndrome), secretion of aldosterone is

relatively autonomous.Plasma volume is already expanded;

therefore, an additional salt loading (volume

expansion) has only minimum effects onaldosterone concentration


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How to distinguish between

adenoma and BAH?In normal subject, erect aldosterone (at

12:00 noon) is greater than supine

aldosterone (8:00 am) because uprightposture tends to lower blood pressure,

which in turn stimulates more renin

production.BAH follows this pattern but adenoma

shows the reverse (the "paradoxical drop").


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Disorder of the Adrenal Cortex (MKEB2404)