2016-11-03

Introduction
The adrenal gland has two distinct functionally
parts:
1. The Cortex
2. and the Medulla

Adrenal gland
B E Dhlamini
Chemical pathology
2014

Adrenal Medulla
Adrenal Cortex
The Adrenal Cortex
It is functionally
is essential to life
part of the
It produces 3 sympathetic
classes of steroid nervous system
hormones:
Its pathological
1. Zona glomerulosa
Mineralocorticoids importance is
2. Zona fasciculata - related mainly to
Glucocorticoids the occurrence of
3. Zona reticular- Catecholamine-
Androgens secreting tumours

Mineralocorticoids Renin-angiotensin-aldosterone system

An important Main action of
mineralocorticoid is aldosteron is in the distal
aldosterone. convoluted tubule where
It is secreted in it stimulates :
response to 1. reabsorption of Na+
angiotension II ( 2. excretion of K+
activated by the renin- 3. and excretion of H+
angiotensin systhem)
Due to its effect on Na+ it
Other factor the has central role in
stimulate secretion
determination of ECF renal perfusion
include pressure/Na
conc/plasma volume
1. hyperkalemia, and Blood pressure
2. ECF volume,

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When measuring aldosterone Glucocorticoids

Main glucocorticoid Other function include
Measure the plasma renin at the same time as synthesized is cortisol 1. Gluconeogenesis, by
the concentration of aldosterone, to establish mobilising amino acids and
It is secreted in
whether aldosterone secretion is autonomous response to ACTH increasing their hepatic
or under normal control. which is released by uptake(thus decreased protein
synthesis)
Plasma aldosterone concentration varies with pituitary gland in
2. of Glucose utilisation
posture response to the
hypothalamic 3. Fatty Acid mobilisation and
Calculation of plasma aldosterone : renin ratio catabolism by muscle cells
is a useful screening test. hormone CRH.
4. Inflammatory Responses
The main function is
Correct the plasma potassium before sampling. 5. Metabolic Responses to Stress
mediating the body
response to stress. 6. In High Doses has a weak
Mineralocorticoid effect

Glucocorticoid regulation When measurering Cortisol

It is important to know use of dynamic function
that tests
95% of cortisol in the Random measurements are
blood is bound to protein. rarely of any value in the
diagnosis of adrenal disease,
Plasma cortisol
except that a high
concentrations show a
concentration in a sick
diurnal variation: in the
patient may reasonably be
Morning & at Night. The
taken to exclude adrenal
loss of this diurnal
failure
rhythm is an early feature
of Adrenal Hyperfunction Prednisone use must be
avoided as it interferes with
stress must be kept to a
assays used in analysis of
minimum during
cortisol.
sampling if results are to
be interpreted correctly

Adrenal Androgens Androgen synthesis

The adrenal cortex is also synthesis and

secrete androgens
Dehydroepiandrosterone (DHEA)
Dehydroepiandrosterone Sulphate(DHEAS)
Androstenedione
The clinical effects of excessive adrenal
androgens can be a prominent feature of
adrenal disorders in females

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Measurement of Adrenal androgens

Measurement is of value in
1. The Diagnosis and Management of
Congenital Adrenal Hyperplasia
2. The Investigation of Virilization in Women Disorders of Adrenal gland

Adrenal Hypofunction Adrenal failure

CAUSES CLINICAL FEATURES Insidious onset
COMMON COMMON Non specific clinical features (hypovolemia,
Glucocorticoid Treatment Tiredness, Generalized Weakness, shock, hypoglycemia)
Auto-immune Adrenalitis Lethargy, Anorexia, Nausea, Vomiting,
TB
Weight Loss, Dizziness and Postural Develops acutely and adrenal crisis is a
Hypotension, Pigmentation medical emergency
Loss of Body Hair (Women)
It can be precipitated by stress in patient with
LESS COMMON LESS COMMON incipient adrenal failure.
Adrenalectomy Hypoglycaemia
Secondary Tumor Deposits Depression
Amyloidosis
Haemochromatosis
Histoplasmosis
Adrenal Haemorrhage

Adrenal insufficiency Adrenal failure

Classified as Primary or Secondary on bases of
Primary Secondary
measurement of plasma ACTH concentration
High ACTH value at 9 am Low or normal ACTH
Majority of clinical features of adrenal failure values
are due to lack of mineralocorticoids and Failure to increase
cortisol level after There is an increase of
glucocorticoids
synacthen stimulation cortisol at 6hrs and at 24
Increased pigmentation is a result of the high hrs after synacthen
test
concentration of ACTH, which occurs due to stimulation.
loss of negative feedback by cortisol
If after short synacthen test there is no increase
and adrenal failure is still suspected the long
stimulation test is performed.

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ACTH stimulation test

Adrenal insufficiency diagnosis [synacthen stimulation test]
Unless a patient is on synthetic corticosteroids, a SHORT TEST LONG TEST
plasma Cortisol concentration < 50nmol/l at 9h00 is
effectively diagnostic of Adrenal Failure Procedure: Procedure:
1. Take sample at 9h00 for Day 1 = Inject 1mg depot ACTH im
Concentration > 550 nmol/l excludes the diagnosis measurement of Cortisol Day 2 and 3 = Repeat
If the plasma cortisol lies in between the extremes of 2. Inject 250ug ACTH im/iv Day 4 = Perform short ACTH test
these values an ACTH Stimulation Test must be 3. Take further blood samples
performed to establish the diagnosis. after 30 and 60 min for cortisol

Normal Results: Results:

Cortisol increment of 200nmol/l
with a peak of 550nmol/l
Primary Cortisol Day4 9h00
< 200nmol/l, with no increment ffg
ACTH
SecondaryIncrement in plasma
Cortisol of at least 200nmol/l
above baseline

Treatment of adrenal failure Adrenal hyperfunction

Patient are put on life long treatment, There are two conditions falling under
with hydrocortisone and 9- this category
fludrocortisone. 1. Cushings syndrome
Patient are monitored by measurement 2. Conns syndrome
of renin for mineralocorticoid
replacement.
Measurement of cortisol at different
times of the day to assess cortisol
replacement .

Cushings syndrome Cushings syndrome

In Cushings Syndrome there is over-production
primarily of glucocorticoids.
Mineralocorticoid and androgen over-production
may also occur
Cushings Disease( excess cortisol due to
stimulation by ACTH secreted by pituitary
adenoma) accounts for 60-70% of cases of
spontaneously arising Cushings syndrome
Clinical features are due primarily to the
glucocorticoid effects of excessive cortisol
In very high concentration Cortisol and its
precursors may have some mineralocorticoid
activity(causing hypertension, potassium
wasting and hypokalemic alkalosis)
Increased production of adrenal androgens
may also contribute to the clinical presentation

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Pseudo-cushings syndrome Causes of hypercortisolism

Patient appear cushingoid Physiological Pathological
May have biochemical features of true cushing 1. Pregnancy 1. Cushings syndrome
disease 2. Stress 2. Diabetes mellitus
May occur in patients with severe depression, 3. Chronic excessive 3. Hyperthyroidism
acute illness or alcoholics exercise 4. Severe chronic disease

Alcohol related pseudo-cushings resolve 4. Malnutrition 5. Glucocorticoid

resistance
rapidy on withdrawal of alcohol.
Patient with severe obesity may also look Psychological
cushingoid. 1. Anorexia nervosa
2. Panic disorder
3. Depression

Endogenous
1. ACTH-dependent 85%
Cushings disease (excess
secretion of ACTH from
the anterior pituitary gland
eg adenomas)
Ectopic ACTH/CRH
2. ACTH-independent
15%
Adrenal
adenoma/carcinoma
Micro-/macronodular
hyperplasia
Demonstration of increased
cortisol secretion
Exogenous 24 hr Urinary Cortisol normal < 300 nmol
1. ACTH treatment
Levels are increased with
2. Glucocorticoid
treatment 1. Cushings syndrome
2. and in obesity.
Pseudo-Cushings 3. Pseudo-cushing
1. Major depression Several urine collection increase the
2. Alcoholism sensitivity of the test.
3. Obesity
An incomplete urine collection may result in
underestimation .

Demonstration of increased Demonstration of increased

cortisol secretion
Overnight low dose dexamethasone
suppression test with normal range plasma
cortisol <50nmol/l at 9h00
Dexamethasone bind in the cortisol receptors
in the pituitary and suppress the release of
ACTH and thus cortisol secretion.
Failure to suppress is suggestive of cushings
syndrom but can be due to pseudo-cushing.
False possive occur if patient is taking
drugs(phenytoin or carbamazepine) that
increase Dexas hepatic metabolism
cortisol secretion
Loss of diurnal variation of cortisol secretion
Midnight Cortisol which is normally <100
nmol/l.
Salivary cortisol result have been shown to
give better results than plasmas cortisol( saliva
can be collected at home therefore reducing
the effect of stress on the results).

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The elucidation of the cause
Measurement of ACTH
1. Help to determine the next step in the
investigation of the patients
Low levels suggest adrenal cause of
hypercortisolism
High level may indicate pituitary dependent
or ectopic ACTH secretion.
High Dose Dexamethasone Suppression Test
& corticotrophin- realising hormone test.
1. In cuchings disease, cortisol levels to <
50% of pre-treatment concentration.
2. Failure to suppress suggest ectopic ACTH
production or an adrenal tumour.
Conns syndrome
Hypertension is a consequence of Aldosterone-
induced Na+ retention.
Conns syndrome is an uncommon cause of
hypertension but it is treatable therefore it must be
sort after.
Aldosterone secretion is autonomous in Conns
Syndrome and therefore it is termed Primary
Aldosteronism
Primary aldostoronism may be mimicked by
treatment with carbenoxolone and ingestion of
liquorice( they inhibit 11-hydroxysteroid
dehydrogenase)
Differentiating Primary from
Secondary aldosteronism
In primary aldosteronism plasma sodium
concentration may be normal or high normal
and in secondary aldosteronism it may be
<138mmol/L.
Renin activity measurement will differentiate
between the two condition being high in
secondary and low in primary aldosteronism.
2016-11-03
Conns syndrome
It is characterised by excessive production of Aldosterone
CAUSES CLINICAL FEATURES
Adrenal Adenoma Hypertension
Bilateral Hypertrophy of Muscle Weakness
Zona Glomerulosa Cells (Occasionally paralysis)
Latent tetany and
Glucocorticoid remediable paraesthesia
Aldosteronism Polydipsia and Polyuria
Clinical features are mainly due
to hypokalemia
Secondary aldosteronism
In patients with increased renin activity aldosterone also may
be increased and this condition is known as secondary
aldosteronism ( because adrenal glands are responding to their
trophic stimulus.
Secondary Aldosteronism is far more common and can be
associated with several conditions in which Renin secretion is
increased.
Patient may or may not be hypertensive depending on the
underlying condition.
Condition associated with secondary aldosteronism
COMMON LESS COMMON
Congestive Cardiac Failure RSodium Losing Nephritisenal
Cirrhosis of Liver with ascites Artery Stenosis
Nephrotic Syndrome Bartters and Gitelmans Syndrome
Renin-secreting Tumours
Hypokalemia and aldosteronism
Primary aldosteronism must be suspected in
every patient with hypertension and
hypokalemia( commonest cause of this is use
of loop or thiazied diuretics)
Plasma potassium level may be normal in
patients treated with ace inhibiters.
Hypokalemia of aldosteronism id due to renal
loss of potassium with urine potassium
concentration of >30mmol/24hrs.
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Stages in diagnosis of aldosteronism Stages in diagnosis of aldosteronism

Screening Confirming the Diagnosis Saline Infusion
Involves measuring Aldosterone(pmol/l) and Test, Salt-loading Test, Fludrocortisone Test.
Renin Concentration(mU/l) in the same If the plasma aldosteron remain high then the
sample. diagnosis is confirmed.
RATIO INTERPRETATION ACTION Establishing the Cause Recumbant vs
Standing Aldosterone, Imaging Techniques,
< 70 Diagnosis Excluded Seek other Causes
Selective Blood Sampling
>70<100 Diagnosis Possible Confirmatory Tests

>100 Diagnosis very likely Establish Cause

Aldosterone/Renin ratio Congenital adrenal hyperplasia

Preparation: Collection:
Hypokalaemia is Mid-morning, ambulant It a group of inherited metabolic disorders of adrenal
steroid hormone biosynthesis
corrected for at least 2hrs, seated for
5-15min The clinical features depend on the position of the
Patients must be defective enzyme in the synthetic pathway, which
Avoid stasis and
encouraged to determines the patterns of hormones and precursors
haemolysis
liberalise salt intake that are produced
Interpretation:
Medications which 21a-Hydroxylase deficiency accounts for 95% of all
Advanced age(>65)
significantly affect cases
Time of day, diet, posture
ARR are withdrawn( The incidence is 1 in 12000 live births in UK
Medication
beta blockers, The majority of the remaining 5% are due to deficiency
Potassium of 11b-Hydroxylase
spiranolactone)

Congenital adrenal hyperplasia

21a-hydroxylase converts 11-deoxycortisol to
cortisone and 11DOC to corticosterone
A deficiency results in decreased synthesis of cortisol
and all mineralocorticoids and accumulation of
precursors proximal to the block
21a-Hydroxylase deficiency is often incomplete and
adequate cortisol synthesis can be maintained by
increased ACTH secretion by the pituitary
It is this that causes hyperplasia of the gland
The metabolic block causes accumulation of the
substrate of the enzyme (17a-hydroxyprogesterone)
17-OHP
There is also increased formation of adrenal
androgens

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Congenital adrenal hyperplasia 11-hydroxylase

May present as 3 forms:
1. Simple virilism at birth/neonatal period (mild
deficiency of enzyme and salt wasting is not a
feature)
2. Salt Wasting and Virilism at Birth (Severe
Deficiency of enzyme)
3. Late onset with premature adrenarche,
hirsuitism, and infertility in later life
Decrease Causes decreased conversion of 11-
Deoxycortisol to Cortisone and 11-DOC to
aldosterone
1. Virilisation
2. ACTH-dependant Hypertension
(Mineralocorticoid excess syndrome due to 11-
DOC which has significant mineralocorticoid
activity)
3. Increased plasma levels of ACTH, 17-OHP,
Androstenedione, Testosterone, 11-DOC
4. Low Cortisol and Aldosterone levels
5. Suppressed plasma Renin levels

Disorders of the adrenal medulla

The main interest in Typically presents The consequences of catecholamine excess are
the adrenal medulla with symptoms such many and varied .
for clinical Headache, The classical clinical triad of Hypertension,
biochemistry relates Palpitation, Headache, and Sweating is of limited clinical
to Sweating, utility.
phaeochromocytoma Pallor, Plasma metanephrines or urine metanephrines
s Tremor, and are the currently recommended biochemical
Catecholamine's can Abdominal tests for phaeochromocytoma screening
also be produced by Discomfort
tumours of Hypertension, may
embryological be episodic.
related tissue.

Metabolic pathway of catecholamine

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Factors that affect result.

False positive metanephrines
false positive VMA/HMMA
Food Ice cream
Coffee banana
tea
Vanilla containing
Vanilla containing
substances substance
Drugs THE END
Chlopromazine Following diagnosis,
Methyldopa the site of the tumour
THANK YOU
Naladixic acid is identified by an
phenolsulphophthalein
imaging technique