Transcript Adrenal glands

Adrenal chemistry
Suki Sankaralingam
Consultant Clinical Scientist
MSc Essex University March 2010
Adrenal glands
Adrenal glands
are triangular in
shape
Lie superiorly and
anteriorly to the
kidneys
Each weighs ~4g
Adrenal
glands
Also known as
suprarenal glands
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Adrenal glands and endocrine systems
Cortex (80 -90%)
Makes steroids
under the
influence of ACTH
Medulla (10 -20%)
Nervous tissue
secretes
catecholamines
MSc Essex University March 2010
Adrenal glands and endocrine systems

Adrenal glands

Adrenal cortex – corticosteriod hormones
 Zona glomerulosa - regulated by angiotensin II
 Mineralocorticoids (aldosterone)
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Zona fasciculata – regulated by ACTH
 Glucocorticoids (cortisol)
Zona reticularis - regulated by ACTH
 Androgens (DHEA, DHEAS)
Adrenal medulla – chromaffin cells
 Adrenaline
 Noradrenaline
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Adrenal Steroids and Pathways
Cholesterol
17a
Pregnenolone
17-Hydroxypregnenolone
3
Progesterone
21
Deoxycorticosterone
11
Cotricosterone
L
Dehydroepiandrosterone
3
3
17a
17-Hydroxyprogesterone
21
Deoxycortisol
Androstenedione
17ß
A
Testosterone Oestrone
11
Cortisol
18
Aldosterone
Glucocorticoids
Mineralocorticoids
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Androgens
Enzymes in Steroid Biosynthesis
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Side-chain cleavage enzyme; desmolase (CYP11A1)
3 beta-hydroxysteroid dehydrogenase (3 beta HSD)
17 alpha-hydroxylase/17,20 lyase (CYP17)
21-hydroxylase (CYP21A2)
11 beta-hydroxylase (CYP11B1)
18 hydroxylase (aldosterone synthase CYP11B2)
17 beta-hydroxysteroid dehydrogenase
Aromatase (CYP19)
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The enzyme 17α-hydroxylase (CYP 17) is not present in the outer layer of the cortex
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Steroids and their metabolic by-products are released into the adrenal circulation and inhibit
critical enzymes in subsequent layers through which the blood flows.
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cortisol and androgens cannot be formed in this layer.
no aldosterone can be synthesized by cells below the outer glomerulosa layer.
In the inner layer - 17α-hydroxyprogesterone cannot be converted to cortisol but is shunted
into the formation of androgens.
Mutation or failure of any of these genes can lead endocrine disease
MSc Essex University March 2010
Steroid Hormones

Not encoded in genes, but derived from cholesterol through
enzymatic reactions

Cholesterol is converted to pregnenolone

Pregnenolone moves between mitochondria and endoplasmic
reticulum and is precursor to all steroids
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Includes Glucocorticoids, Mineralocorticoids, Androgens.
MSc Essex University March 2010
Glucocorticoid receptors

Receptors for glucocorticoids (GRs) are usually intracellular, exist in the
cytoplasm, not the nucleus, and are associated with heat shock proteins.

The site of receptor binding on the DNA is known as the glucocorticoid
response element (GRE).
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The structural similarities of the DNA-binding domain of glucocortiocoid,
oestrogen, androgen and progesterone receptors are such that they can all
bind to the same hormone response element, a consensus 15 nucleotide
sequence.

Additionally, cortisol has equal affinity for the aldosterone receptor in the
kidney tubules but its rapid inactivation to cortisone in these cells normally
prevents binding.
Mineralocorticoid- Aldosterone

Promotes
 Retention of sodium
 Excretion of potassium and hydrogen ions mainly in distal and
collecting tubes
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Essential hormone and 30-50 times more potent than deoxycorticosterone
DNA hormone response element binds to intracellular mineralocorticoid
receptor (type1) and glucocorticoid receptors (type2) by means of zinc
domain
Renin-Angiotensin system and circulating potassium are the most important
regulators of aldosterone secretion. The effect of ACTH is short lived
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Hypothalamic-Pituitary-Adrenal axis
Hypothalamus
CRH
Pituitary
POMC
MSH
ACTH
Adrenal
Cortisol
Aldosterone
Androgens
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Renin –Angiotensin-Aldosterone Pathway
Amino Hormones
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Derived from the amino acid tyrosine
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Includes the catecholamines: adrenaline and noradrenaline
Tyrosine
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Adrenaline
Catecholamine synthesis pathway
ADR = adrenaline
DA = dopamine
DBH = dopamine-β-hydroxylase
MAO = monoamine oxidase
MHPG = 3-methoxy-4hydroxyphenylethylene glycol
3-MT = 3-methoxytyramine
NM = normetadrenaline
NORADR = noradrenaline
PHE = phenylalanine
TYR = tyrosine
VMA = vanillylmandelic acid.
Catecholamines
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Noradrenaline is formed in the adrenal medulla
It is further metabolised to adrenaline
The adrenaline produced and released by the adrenal gland
functions as a hormone
It is the elevations of one or both noradrenaline and adrenaline in
the bloodstream that cause the distinctive but variable symptoms of
pheochromocytoma
Pheochromocytomas, similar to adrenal medullary cells, secrete
catecholamines directly into the bloodstream
Pheochromocytomas secrete noradrenaline whereas the
predominant catecholamine secreted by the adrenal medulla is
adrenaline.
Actions of glucocorticoids
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Potent metabolic effects on many tissues
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Anabolic in the liver
 Catabolic in muscle and fat
Regulates the metabolism of protein, carbohydrates and fats
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Diabetogenic
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opposing the action of insulin in peripheral tissues (decreasing glucose
uptake via GLUT4 receptors)
increasing glucose production and release from the liver accomplished
through gluconeogenesis using amino acids (from the catabolic actions
on muscle) as the primary carbon source
Actions of glucocorticoids
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In the cardiovascular system, sustains normal blood pressure by
maintaining normal myocardial function and the responsiveness of arterioles
to catecholamines and angiotensin II.
Inhibits the production of inflammatory factors resulting from injury.
Inhibits fibroblast proliferation and the formation of collagen.
Decreases osteoblast function and new bone formation
Decrease gut calcium absorption and decrease renal calcium reabsorption,
thus adversely affecting calcium balance.
In the CNS, can alter the excitability of neurons, induce neuronal death and
can affect the mood and behaviour of individuals.
Cortisol secretion
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Secreted in a diurnal pattern
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Levels highest in the morning (8 -9AM)
 Lowest around midnight.
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Diurnal pattern
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Changes in people who work alternate shifts and sleep at different times
during the day.
 Disrupted in people who have Cushing’s syndrome.
Actions of adrenal androgens

Role of DHEA and its sulphate in normal physiology – not clearly defined.
 DHEA, DHEAS and androstenedione - ‘weak androgens’
 have a much lower affinity for the androgen receptor than testosterone.
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Adrenal androgens are converted peripherally to the more active
testosterone.
 Males - physiologically insignificant compared to the amount secreted
by the testes
 Females - adrenal-derived testosterone is important in maintaining
normal pubic and axillary hair.
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After the menopause, adrenal androgens may also be an important source
of oestradiol, again due to peripheral conversion.
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Adrenal androgen hypersecretion does not cause any clinical signs in adult
males but is detectable in females by signs of hirsutism and
masculinisation.
Transport of steroids in plasma
Steroid
Cortisol
Aldosterone
Progesterone
Testosterone
Oestradiol
% bound
% bound
to
to
Total
conc.
(nmol/l)
%
unboun
d
CBG
Albumin
SHBG
t1/2in
circulation
(min)
400
4
90
6
0.1
100
0.4
40
20
40
0.1
10
0.6
2.4
17
80
0.6
5
20
2.0
3
40
55
10
0.1
2.0
0
68
30
20
Actions of Catecholamines
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Catecholamines act on their target tissues through G-protein-linked membrane receptors.
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Cardiovascular
 Increase in heart rate
 Increased venous return
 Increased peripheral resistance
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Visceral
 Smooth muscle relaxation and contraction
 Modulation of fluid and electrolyte transport in the gut, kidney, gall bladder
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Metabolic
 Glycogenolysis, lipolysis
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Water and electrolyte metabolism
 Decreased sodium excretion and glomerular filtration
 Effects on renin secretion leads to increased aldosterone production
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Hormone secretion
 Modulates the responses of a number of endocrine systems, including: The renin-angiotensinaldosterone system
 Increased secretion of glucagon and insulin
Metabolism of catecholamines
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Urinary excretion
 Free noradrenaline (~0.5%)
 Conjugated with sulphate (~2%)
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Catechol O-methyl transferase (COMT)
 converts the catecholamines to metadrenaline and normetadrenaline forming about
3% of total excretion
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Monoamine oxidase (MAO)
 produces aldehydes that are immediately metabolised to the corresponding carboxylic
acid or alcohol by aldehyde or alcohol dehydrogenases
 catalyses the metabolism of metadrenaline and normetadrenaline to vanilyl mandelic
acid (VMA, ~65% of excretion) and the corresponding alcohol (methoxy hydroxy
phenyl glycol (MOPG) ~35% of excretion)
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Dihydroxy phenyl glycol (DOPG)
 Noradrenaline released into the circulation is not converted to DOPG.
 Estimates of the excretion of non-metabolised catecholamines (i.e. adrenaline,
noradrenaline , metadrenaline, normetadrenaline) form a better diagnostic test for
pheochromocytomas.
 Measurement of the ratio of DOPG to noradrenaline concentrations in blood may be a
more sensitive way of detecting pheochromocytomas
Adrenal gland disorders
Suki Sankaralingam
Consultant Clinical Scientist
MSc Essex University March 2010
Adrenal gland disorders

Cushing’s syndrome

Adrenal Insufficiency

Congenital adrenal hyperplasia (CAH)

Conn’s syndrome

Phaeochromocytoma
MSc Essex University March 2010
Cushing’s syndrome (CS)
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Most frequently seen in adults between the ages of 20 to 50
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More common in women than men (5:1)
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Rarely, a patient may have an inherited gene mutation, such as
Multiple Endocrine Neoplasia Type 1 or MEN-1, that increases risk of
developing tumors throughout the endocrine system, including pituitary
and adrenal tumors.
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Children with Cushing’s syndrome tend to be obese, develop slowly,
and may remain short.
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Women may have excess hair on their face and chest and menstrual
irregularities.
Causes of Cushing’s syndrome
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Common (~ 99%)
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Uncommon (~ <1%)
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Exogenous therapeutic glucocorticoids
Anterior pituitary adenoma
Ectopic ACTH
Adrenal adenoma
Rare (~ <0.01%)
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Adrenal carcinoma
Ectopic CRH
Alcoholic
Bilateral multinodular hyperplasia
Clinical features of Cushing’s syndrome
Signs and symptoms associated with Cushing’s
syndrome vary but frequently include:
Obesity in the torso with thinner arms and legs
Large rounded face (moon face)
Increased fat in the neck and shoulder area
Thin fragile skin that bruises easily and heals
slowly.
Purplish streaks that look like stretch marks on
their abdomen, thighs, and buttocks.
Muscle weakness
Osteoporosis
High blood pressure
Increased blood sugar
MSc Essex University March 2010
Laboratory Investigations for CS
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Random cortisol and ACTH level – Not recommended. Should avoid identifying aetiology in
the initial screening.
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24 hour urine cortisol (or urine free cortisol) - overall cortisol production can be evaluated. At
lease two measurements recommended due to variability in secretion. Relies on complete collection.
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Note: May be normal in cyclical on mild CS
Falsely low- CrCl <60ml/min, false positive-over collection, excessive fluid intake
Assay interference , reference range should be method specific.
Late night salivary cortisol –Unbound biologically active, Less invasive, collection easy. Two
measurements recommended.
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Not suitable for shift workers, variable sleep patterns
False positive – licorise, tobacco use
Not fully evaluated
Dexamethasone Suppression Test - Dexamethasone is a synthetic steroid that mimics
cortisol in the feedback inhibition of CRH and ACTH production. Patients with Cushing’s syndrome
will not show adequate cortisol suppression after a single low dose of 1mg dexamethasone given
between 23 and 24hrs and sample taken at 9.00am the following morning.
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Levels below 50nmol/L excludes CS
False positive - oestrogen, OCP, anticonvulsants, rifampacin therapy, non compliance
False negative – reduced clearance of dexamethasone in liver and renal failure
Investigations for CS
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Higher doses of 2mg dexamethasone – 0.5mg, six hourly for 48 hours
 To distinguish between an true CS and other causes of Cushing’s syndrom (alcoholism,
poorly controlled diabetes, depression)
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cont…
Cortisol <50nmol/L in blood taken 6 hrs after last dose excludes CS
Cortisol level at midnight – patient needs to be admitted and performed at least 48hrs after
admission.
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CRH stimulation test – mostly used in specialised centres to locate difficult tumours
Corticotrophin releasing hormone (CRH) is injected, and cortisol and ACTH levels are measured at
baseline (before CRH) and at timed intervals after the injection, for example at 30 and 60 minutes. The
normal response is a peak in ACTH levels followed by a peak in cortisol levels. Most patients with
Cushing’s syndrome caused by adrenal tumors or ectopic ACTH-secreting tumors do not respond to
CRH. ACTH levels may also be measured in samples obtained through a catheter placed in the inferior
petrosal sinuses, which carry blood from the pituitary glands, and compared to blood ACTH
concentrations.
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Computed tomography (CT) – used to help locate adrenal, pituitary, and ectopic tumours
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Magnetic resonance imaging (MRI) – sometimes ordered to help evaluate pituitary and adrenal glands
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Ultrasound
Treatment for CS
Treatment is to remove, block, or minimise the body’s exposure to excess
cortisol.
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If due to corticosteroid use
 Minimize the dosage required.
 Never abruptly stop taking these medications - dosages must be changed slowly.
 Patients should consult with their family doctor or endocrinologist if required to adjust
the dose to their needs.
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If due to a a single benign tumour or hyperplasia in one adrenal gland
 Surgical removal of the gland
 May need supplement because of atrophy of the remaining gland which will take some
time to become fully functional.
Nelson’s syndrome – caused by bilateral adrenalectomy. ACTH will be markedly
elevated.
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If due to an ACTH-producing pituitary tumour
 Removal of the tumour will often resolve the excess cortisol.
 If removal not possible - radiation therapy
 If an ectopic ACTH-producing tumour(s) - surgery, radiation, and/or chemotherapy
Addison’s disease
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Affects 1 to 4 people per 100,000
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Found in patients of all ages
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Affects both males and females equally.
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Symptoms may not emerge until about 80% to 90% of the adrenal
cortex has been destroyed.
Causes of Addison’s disease
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Primary adrenal insufficiency (Addison’s)
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due to an autoimmune process (70%).
other causes 30%
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Tuberculosis - common in areas where tuberculosis is more
prevalent
human immunodeficiency virus (HIV).
Bacterial, viral (CMV) and fungal infections adrenal haemorrhage
spread of cancer into the adrenal glands.
rarely, it may be due to a genetic abnormality of the adrenal glands.
Secondary adrenal insufficiency

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decrease production of the pituitary hormone ACTH due to
pituitary damage, a pituitary tumour, or some other cause
corticosteroid therapy (such as prednisone) is abruptly halted.
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With secondary adrenal insufficiency, aldosterone production is
usually not affected.
Clinical features of Adrenal Insufficiency
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The symptoms are non specific. They may emerge slowly, first appearing during times of stress,
then increasing in intensity over a period of several months. Symptoms may include:
Common
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Weakness (~100%)
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Weight loss (~100%)
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Pigmentation (~95%)
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Postural hypotension (~25%)
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Anorexia (~95%)
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Nausea (~95%)
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Abdominal pain (~30%)
Uncommon
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Vitiligo (~20%)
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Salt craving (~15%)
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Hypoglycemia (in adults ~ <1%)
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Aches and pains (~10%)
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About 25% of the time, adrenal insufficiency is diagnosed during an adrenal crisis (also called an
Addisonian crisis). This crisis may be caused by a period of increased stress, trauma, surgery, or
a severe infection. If left untreated it can be fatal. Signs and symptoms may include:
 Kidney failure
 Loss of consciousness
 Low blood pressure
 Severe pain in the lower back, abdomen or legs
 Severe vomiting and diarrhea, leading to dehydration
 Shock
Laboratory Investigations
To determine whether adrenal insufficiency is present
To distinguish between primary and secondary insufficiency
To determine the underlying cause
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Electrolytes – Low sodium (70%) High potassium (35%)
Glucose level - Low
Renal function – Pre uraemic
Cortisol at 9.00am
 low levels confirms the suspicion
 normal level does not exclude
 very high levels excludes adrenal insufficiency.
If the adrenal gland is either not functioning normally or not being stimulated by ACTH, then cortisol
levels will be consistently low.
Cortisol levels are used, along with ACTH and ACTH stimulation tests, to help diagnose adrenal
insufficiency.
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Adrenal antibodies - good marker of autoimmune Addison's disease.

Not routinely done
 Renin activity - elevated in primary adrenal insufficiency
 lack of aldosterone causes increased renal sodium losses. This lowers blood sodium levels
and decreases the amount of fluid in the blood (which lowers blood volume and pressure),
which in turn stimulates renin production by the kidney.
Laboratory Investigations –cont…
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Synacthen stimulation test
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Measuring levels of cortisol in blood before and 30 and 60 minutes after an
injection of 250µg im synthetic ACTH
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If the adrenal glands are functional - cortisol levels will rise in response
to the ACTH stimulation (200nmol above the basal concentration or the
final concentration of at lease 550nmol)
If they are damaged or non-functional - response to ACTH will be
minimal.
ACTH - baseline test to evaluate whether or not the pituitary is producing
appropriate amounts of ACTH.
 low ACTH levels indicate secondary adrenal insufficiency
 high levels indicate primary adrenal insufficiency (Addison’s disease).
Other investigations and treatment

X-rays
 Calcification on the adrenal cortex
-may be due to a tuberculosis

CT or MRI
 Enlarged adrenal glands
-infections, cancers
 Normal or small size adrenal glands
-autoimmune disease , secondary adrenal insufficiency
If the condition is due to an infection
may regain some adrenal function when the infection resolves
replacing the missing hormones (hydrocortisone, fludrocortisone)
In the case of secondary adrenal insufficiency - hormone replacement.
Once suspected, it is imperative that Addison's disease is confirmed biochemically and
treated immediately.
Congenital adrenal hyperplasia
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21-hydroxylase (CYP21A2) deficiency - most common ( 95%)
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Between 1 in 5000 and 1 in 15 000 live births in western countries
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Clinical manifestations - loss of aldosterone and cortisol metabolism with precursors being
shunted into androgen synthesis (vary according to the sex of the patient)
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Total ablation of enzyme activity (e.g. deletion or nonsense mutations) results in ‘saltwasting’ disease (loss of aldosterone) and virilization and ambigous genitalia of a female
infant (increased testosterone production). Salt wasting results in severe dehydration in the
first 14 days of life with hypotension and death if untreated

Mutations resulting in 1–2% normal enzyme activity (e.g. missense mutations) have
virilization but not salt-wasting

Mutations resulting in 20–60% normal enzyme activity give the so-called ‘non-classical’
presentations
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Boys without salt-wasting may present with precocious sexual development
Treatment
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Glucocorticoid therapy (monitored to result in suppression of the high concentrations of 17αhydroxyprogesterone)
Mineralocorticoids (monitored by blood pressure and by assays of plasma renin)
Congenital adrenal hyperplasia –cont…
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11 beta-hydroxylase (CYP11B1) deficiency
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17 alpha-hydroxylase/17,20 lyase (CYP17) deficiency
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Extremely rare (approximately 200 cases in the world literature) and expressed in both adrenal
gland and gonad.
Clinical presentation: hypertension with hypokalemia due to excessive production of
mineralocorticoids; failure of pubertal development in genetic females and genetic males presenting
at puberty with female external genitalia and intra-abdominal testes
3 beta-hydroxysteroid dehydrogenase (3β-HSD2) deficiency
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Very rare incidence of ~1 in 100 000 live births
Clinical presentation: virilisation, similar to CYP21A2 deficiency but with additional hypertension,
perhaps due to increased production of 11-deoxycortisol which has mineralocorticoid actions
Classical form leads to defective production of all steroids.
Clinical presentation: adrenal failure in early infancy; moderate virilization in females; varying
degress of genital ambiguity in males; mild, non-classical form may present with hirsutism and
oligomenorrhea
Side-chain cleavage enzyme; desmolase (CYP11A1) and


StAR protein defect:
Loss of all steroidogenic capacity in adrenal gland and gonad.
Clinical presentation: adrenal failure in early infancy; genetic males have female external genitalia
(loss of androgens); frequently fatal if undiagnosed
CAH

OxidoReductase Deficiency (ORD) –another variant of CAH (first reported in 2004)

Mutation in the electron donor enzyme P450 oxidoreductase (POR)
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cont…..
POR is the electron donor for all microsomal P450 enzymes, including three steroidogenic
enzymes 450c17(17alpha hydroxylase/17,20-lyase), P450c2(21-hydroxylase) and
P450aro(aromatase).
Partial deficiency of 21hydroxylase and 17alpha hydroxylase
Cortisol deficiency – clinically insignificant to life threatening

Two unique features (not seen in other CAH variants)-skeletal malformation and severe genital ambiguity
in both sexes
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Clinical manifestation of ORD
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Clinical diagnosis
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Ambiguous genitalia in both males and females
Primary amenorrhoea and cystic ovaries in females
Poor masculinisation during puberty in males
Maternal virilisation during pregnancy with an affected fetus.
Apparently healthy infant with 21-hydroxylase deficiency on newborn screening
Whose mothers were virilised during pregnancy
Biochemical diagnosis

Detection of steroid abnormalities using GC-MS
Clinical spectrum of 21-OH deficiency
Newborn
Ambiguous genitalia in a female
Absent testes in an apparent male
Severe shock
Failure to thrive
Isolated clitoromegaly
Isolated labial fusion
Childhood
Premature adrenarche
Tall stature and advanced bone age
Adult
Menstrual irregularities
Hirsutism
Short stature
Obesity
Male infertility
Testicular tumours
Conn’s syndrome
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

Most common cause of secondary hypertension
Characterized by excessive secretion of aldosterone from the adrenal
glands.
Also referred to as primary hyperaldosteronism
Excessive aldosterone is produced by

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
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One or more benign adrenal tumours
Hyperplasia
Glucocorticoid – suppressible hyperaldosteronism (autosomal dominant- ACTH dependent)
Idiopathic
cancerous adrenal tumour (rare)
Commonly occurs in adults between the ages of 30 and 50 (although it can
be in anyone)
More common in women than men
Presence of hypokalemia with hypertension - suggests possible primary
hyperaldosteronism.
Resistant to standard hypertension therapies – suspicion of primary
hyperaldosteronism is high
Clinical and Laboratory findings

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
Hypertension (non responsive to 2-3 antihypertensive drugs)
Hypokalemia and inappropriate kaliuria
Alkalosis
Hypernatraemia (rare)
Nonspecific symptoms

frequent urination, increased thirst, weakness, fatigue, temporary paralysis,
palpitations, headaches, muscle cramps, and tingling.
Investigations for Conn’s
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Diagnosing Conn’s syndrome is important
 Few causes of hypertension that is potentially curable
 Secondary aldosteronism must be distinguished from primary aldosteronism.
The ratio of aldosterone to renin is used to screen for primary hyperaldosteronism.
 Patients should be on adequate sodium (100-150 mmol/day) and potassium (50 –
100 mmol/day) prior to test
 Potassium supplement should be stopped 24hrs prior to the test( spironolactone
must be stopped for 6weeks}
 should be off ACE inhibitors, Beta blockers and calcium channel blockers and
diuretics,.
 Sample should be sent to lab within 30 minutes of venepuncture at RT
 Separated and frozen immediately and kept frozen until analysis for renin)
Low renin and high aldosterone - significantly increased ratio (>2000)
 Consistent with primary hyperaldosteronism
Ratio <800 –unlikely of Conn’s
Investigations for Conn’s – cont….

CT/MRI scan of the adrenal glands

benign adrenal tumours are relatively common




Many of them do not secrete aldosterone and are found incidentally during procedures
for other reasons.
Determining hyperplasia can also be tricky because the size of normal adrenal glands
may vary significantly from one person to the next.
If negative CT – saline suppression test to locate the tumour when positive lab result
and high clinical suspicion.
If hyperplasia or an aldosterone-producing tumour is suspected

adrenal venous sampling



Tested for aldosterone, cortisol and aldosterone/ cortisol ratio calculated.
Results from the two adrenal glands compared.
If significantly different - adenoma located in the gland with the highest aldosterone
concentration.
Treatment for Conn’s

Lower blood pressure to normal or near normal levels

Decrease blood levels and resolve electrolyte imbalances

If due to a single benign adrenal tumour – surgical removal.


If the primary hyperaldosteronism is due to a cancerous tumour (rare)


If hypertension does not resolve additional therapy to control BP
organs located next to the affected adrenal gland will need to be evaluated during surgery and
more than the adrenal gland may need to be removed.
If the cause is idiopathic or appears to be due to hyperplasia in both adrenals


surgery not recommended
Treatment with drugs to block the action of aldosterone and with one or more blood pressure
drug therapies.
Mineralocorticoid deficiency

Biochemical features
 Hyponatraemia
 Hyperkalaemia
 Hypercholoraemic metabolic acidosis
 Hypovolaemia
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Causes
 Aldosterone synthase deficiency ()
 Combined with glucocorticoid deficiency
 CAH-21 hydroxylase, 3HSD and desmolase deficiency (autosomal
recessive)
 Adrenoleukodystrophy – X linked
 Autoimmune
 TB, AIDS
Phaeochromocytoma
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Rare tumours (1 per million per annum)
Usually benign
Found in the sexes equally
Incidence between the ages of 20 and 50 years although can occur at any
age
In general,
 10% are bilateral,
 10% are extra-adrenal,
 10% occur in childhood
 10% are malignant.
The majority of pheochromocytomas are sporadic and without known
cause.
Some occur in MEN type 1
Clinical features of phaeochromocytoma
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Common
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Headache (~60%)
Palpitations (~60%)
Anxiety (~50%)
Sweating (~50%)
Abdominal pain (~25%)
Glucose intolerance or diabetes mellitus (~40%)
Hypertension - sustained or paroxysmal with or without postural
hypotension (~50%)
Uncommon
Weight loss (~10%)
Chest pain (~20%)
 Tremor (~5%)
 Pallor (~5%)
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Investigations
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Analysis of catecholamine by HPLC with electrochemical detection
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Urinary and plasma catecholamine metabolites, metanephrines and
normetanephrines - lowest false negatives.
Several stimulation and suppression tests are also available but the safest
are the glucagon stimulation and the clonidine or pentolinium suppression
tests.
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Catecholamine secretion from a pheochromocytoma (but not normal
adrenal medulla) is stimulated approximately 2–5-fold by glucagon
catecholamine secretion from a pheochromocytoma is not suppressed by
clonidine or pentolinium.
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These drugs suppress catecholamine secretion by at least 50% from a normal
adrenal medulla.
MIBG(meta iodo benzyl guanine)
– To locate the tumour
Case studies in adrenal gland disorders
Suki Sankaralingam
Consultant Clinical Scientist
MSc Essex University March 2010
Case 1
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A young female presented to her GP with hirsutism, amenorrhoea for 4
months and weight gain
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Testosterone = 7.9 nnmol/L (0.9 – 3.6)
DHEAS = 14.7 µmol/L (1.2 – 11.0)
UFC= 1740 nmol/L
Dexamethasone suppression = cortisol 900nmol/L
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CT of the abdomen : mass in the left adrenal.
 Proved to be carcinoma of the adrenal cortex
Case 2
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65yr old man was seen in A/E with weight loss, pigmentation and
respiratory distress
Na 144mmol/L
K 2.0 mmol/L
HCO3 >40 mmol/L
Urea 8.6 mmol/L
Creat 120 µmol/L
Cortisol >1600 mmol/L
ACTH 550 ng/L (5-60)
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Diagnosis: ectopic ACTH , oat cell carcinoma of the lungs
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MSc Essex University March 2010
Case 3
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A 48yr old truck driver, who has never been to a GP, presented to the
casualty complaining of abdominal pain, extreme tiredness and recent
history of vomiting.
Na 119
K 5.4
Urea 16.0
Creat 182
Glucose 4.0
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Short synacthen 260nmol/L(basal); 282 (30mins); 285(60 mins)
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Diagnosis: Addison’s
Adrenal antibodies : Positive Autoimmune
Thyroid antibodies : Positive , Thyroid function : Subclinical hypothyroidism
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MSc Essex University March 2010
Case 4
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40 year old female presented with blood pressure of 178/120 mmHg. She has
been on antihypertensive medication including diuretics for 6 months, but her
BP remained uncontrollable.
Blood results 2 weeks after stopping the medication
 Na
145 mmol/L (132 -144)
 K
2.6 mmol/L (3.2 -4.8)
 Cl
95 mmol/L (98 -108)
 HCO3 35 mmol/L (23-33)
Urine K = 75mmol/L
hypokalaemic metabolic alkalosis and inappropriate urinary potassium loss
?Primary hyperaldosteronism
Random Plasma Renin <0.01 pmol/ml/hr (2.1-4.7); Aldosterone 900pmol/L (110-860)
ARR >1000
Adrenal Tumour on CT
MSc Essex University March 2010
Case 5
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12yr male child was admitted with epileptic fits and vomiting over the past 12 hrs. He was
normal prior to that.
On examination there was no indication of meningitis.
His BP 180/120 mm Hg and pulse rate 92 min.
Blood Na = 135mmol/L; K= 4.1 mmol/L; Cl = 98 mmol/L; HCO3 = 25 mmol/L;
mmol/L; Creat =60µmol/L; Glucose=10.5 mmol/L
Urine Na = 50mmol/L; Potassium =40 mmol/L
CSF Total Protein = 0.43 g/L (0.1 – 0.4); Glucose = 6.2 mmol/L (1.7 -3.9)
BP varied between 160/120 and 125/80
Differential diagnosis: Meningitis, encephalitis, hypertension.
Renal angiogram revealed: stenosis of the left renal artery
PRA = 10.2 pmol/ml/hr (2.1–4.7) and Aldosterone = 980pmol/L (110-860)
Consistent with secondary hyperaldosteronism
Before the surgical correction, a mass on the left kidney was noticed by the surgeon.
Urine metadrenaline = 5.0µmol/24hrs (>5.0 for adults)
Further estimation 9.8 and 8.3
Indicated presence of Phaeochromocytoma which was surgically removed.
MSc Essex University March 2010
Urea =4.8
Case 6
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Two weeks old male infant admitted to hospital severely dehydrated and
critically ill
Na = 106mmol/L
K = 6.6mmol/L
Cl = 70mmol/L
HCO3 = 19mmol/L
Urea = 6.5mmol/L
Creat = 50µmol/L
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17-hydroxy progesterone = 950 nmol/L
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Very high 17OHP - ? 21 hydroxylase or 11 beta hydroxylase deficiency
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Hyperkalaemia and hyponatraemia – consistent with 21 hydroxylase deficiency.
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MSc Essex University March 2010
Case 7
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44 year old short male was incidentally discovered with bilateral adrenal tumours on CT
examination for flank pain. The tumours were non malignant.
On subsequent presentation his blood results showed
PRA of 12.8 pmo/ml/hr (2.1-4.7);
Aldosterone 1280 pmol/L (110-860)
BP 134/80 mmHg, Skin was pigmented, no abnormalities on penis size or testicular volume
Electrolytes were within the reference range
ACTH : 149 ng/L (5-60) ; Cortisol 314 nmol/L
Urinary steroid profile : Elevated excretion of ketosteroids except 17hydroxy steroids
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Dexamethasone suppression and ACTH stimulation tests were performed.
Progesterone and 17OHP were markedly elevated. DHEAS and androstenedione were elevated.
11 deoxycortisol and cortisol were within reference while 11 deoxycorticosterone and aldosterone
were elevated
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Results confirmed mild form of CAH
Short stature – due to precocious puperty
Pigmentation – hypersecretion of ACTH
The tumours were due to ACTH
ACTH suppression therapy prevented further growth and to normalise PRA
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MSc Essex University March 2010
Case 8
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33yr old married man was prescribe hydrocortisone (HC) for ulcerative colitis
He started developing gynaecomastia and was referred for endocrine opinion
Gonadotrophins, Oestrogen and androgens were measured.
High oestrogen; FSH/LH were suppressed; Tetosterone was also high
He started menstruating
17OHP was very high with high androgens
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Confirmed CAH – 21 hydroxylase deficiency
When he was on HC, it has suppressed the ACTH which as a result reduced the adrenal
androgens. The ovary then started producing oestrogen.
MSc Essex University March 2010
Case 9
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26yr old waitress was referred to the endocrine clinic for excessive hair growth.
Has been a problem since the age of 16yrs and has got worse and shaving every other
day.
Irregular periods and could be without it for 5 months
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On examination: BP 120/78; BMI 28.4; prominent facial hair and acne; no virilism
TSH=2.1mu/L; FT4 =16.6 pmol/L; Prolactin=232mU/L; FSH=7.4U/L; LH=25.4U/L;
Testosterone = 3.4nmol/L; SHBG=35nmol/L; Oestradiol = 256pmol/L; UFC=322nmol/24hr
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What is the diagnosis?
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PCO or late onset CAH
What test would you do to confirm/rule out LO-CAH?
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Synacthen Stimulation test and measure 17OHP on all three samples
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Basal 17OHP = 6nmol/L
30mins post synacthen = 35nmol/L
60mins post synacthen = 38nmol/L
Confirms late onset CAH
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