SCTL Adrenal Disorders

Objectives:
At the end of the module, students should be able to
1. discuss the common pathologies affecting the adrenal gland.
2. explain the symptoms and signs associated with adrenal disorders.
3. explain the principles of biochemical tests in the investigations of adrenal disorders.
Case 2
A 17-year-old girl is referred to the endocrine clinic with a 2-month history of tiredness and lethargy.
She has noticed that she becomes dizzy when she stands up. On examination, she has pigmentation on
the buccal mucosa and palmar creases and in an old appendicectomy scar. Her blood pressure is
120/80 mmHg lying down, but falls to 90/50mmHg when she stands up.
Investigations
Serum: Sodium
Potassium
Urea

128 mmol/L
5.4 mmol/L
8.5 mmol/L

Blood glucose (fasting)

2.5 mmol/L

Short ACTH stimulation test:

Plasma cortisol:
0900 hour
30 min after ACTH
60 min after ACTH
Plasma ACTH (0900)

150 nmol/L
160 nmol/L
160 nmol/L
500 ng/L (normal < 50ng/L)

Anti-adrenal antibodies are detectable at high concentration.

Activity 2
1. List the causes of Addisons disease. What is the most common cause.
Primary adrenal insufficiency
Addisons disease occur when adrenal cortex is damaged and does not produce hormones in
adequate quantities.

Secondary adrenal insufficiency

Adrenal insufficiency occur when pituitary gland is damaged. Corticotrophs in anterior
pituitary gland secretes ACTH which stimulates adrenal cortex to secrete cortisol. Inadequate
production of ACTH leads to insufficient production of cortisol.
Other causes of Addisons disease
Tuberculosis
Other infections of the adrenal glands
Spread of cancer to the adrenal glands
Bleeding into the adrenal glands.
The most common cause is primary adrenal insufficiency
2. Describe the symptoms and signs of adrenal hypofunction (Addisons disease).
Low blood pressure - Normally, cortisol causes blood pressure to rise, by increasing cardiac
output and increased peripheral vascular tone decreased level of
cortisol causes low blood pressure that falls further standing, causing
dizziness or fainting.
Low blood glucose- Cortisol usually inhibits glucose uptake and metabolism, decreases protein
synthesis, and increases release of amino acids from muscle. Therefore,
decreased level of cortisol causes hypoglycemia.
Darkening of skin due to ACTC is a proopiomelanocortin gene also producing melanocyte
stimulating hormone causing hyperpigmentation of the skin.
3. What is postural hypotension. Explain why the patient has postural hypotension. Relate it to
aldosterone function. Revise the regulation of aldosterone secretion.
Postural hypotension is a form of low blood pressure (hypotension) due to a change in body position
(posture) when a person moves to a more vertical position such as from lying down to sitting or
standing. The change in position causes a temporary reduction in blood flow and therefore a shortage
of oxygen to the brain. This leads to dizziness and sometimes, loss of consciousness.
It is due low of aldosterone hormone secretion. As aldosterone function to increase the reabsorption of
sodium and thus water follow, so that the blood presure can be increased when it is lower than the
normal blood pressure. So, when there is low aldosterone secretion, less sodium is conserved, thus
less water is conserved, lowing the plasma level and finally lowering the blood pressure.
Regulation of aldosterone secretion:

4. Interpret the serum electrolytes and urea result above. Explain the pathophysiology behind it.
Serum: Sodium
Potassium
Urea

128 mmol/L
5.4 mmol/L
8.5 mmol/L

The sodium level is lower than normal as the normal level which is 135-145 mmol/L. It is because the
low level of aldosterone secretion, lower the conservation of sodium in blood.
The potassium level is higher than the normal which ranges from 3.5 to 5.0 mmol/L. It is due to the
low aldosterone level decrease the activation of sodium-potassium pump on the basolateral side, thus
lower the potassium excretion.
The urea (BUN) level is higher than the normal which ranges from 2.5 to 8 mmol/L. It is because of
the negative feedback to increase back the low aldosterone and cortisol level, thus increasing the
conservation of urea.

5. Explain why the patient has hypoglycaemia. Relate to cortisol function.

Cortisol stimulates several processes that collectively serve to increase and maintain normal
concentration of glucose in blood. In Addisons disease, there is lack of cortisol production.
That explains how the patient develops hypoglycaemia.
6. Patient has hyperpigmentation. Explain its pathophysiology. Discuss the regulation of cortisol
secretion.
Hyperpigmentataion of the skin and mucous membranes often precedes all other symptoms
by months to years. It is caused by the stimulant effect of excess adrenocorticotrophic
hormone (ACTH) on the melanocytes to produce melanin. ACTH accumulation is caused by

the adrenal gland is not functioning efficiently to produce cortisol. The hyperpigmentation is
caused by high levels of circulating ACTH that bind to the melanocortin 1 receptor on the
surface of dermal melanocytes. Other melanocyte-stimulating hormones produced by the
pituitary and other tissues include alpha-MSH (contained within the ACTH molecule), betaMSH, and gamma-MSH. When stimulated, the melanocyte changes the color of pigment to a
dark brown or black.
Hyperpigmentation is usually generalized but most often prominent on the sun-exposed areas
of the skin, extensor surfaces, knuckles, elbows, knees, and scars formed after the onset of
disease. Scars formed before the onset of disease (before the ACTH is elevated) usually are
not affected. Palmar creases, nail beds, mucous membranes of the oral cavity (especially the
dentogingival margins and buccal areas), and the vaginal and perianal mucosa may be
similarly affected.
7. Discuss ACTH stimulation test and interpret the patients result. Differentiate between
primary and secondary hypoadrenalism.
The ACTH test (also called the cosyntropin test, tetracosactide test or Synacthen test) is a
medical test usually ordered and interpreted by endocrinologists to assess the functioning of
the adrenal glands stress response by measuring the adrenal response to adrenocorticotropic
hormone (ACTH). During the test, a small amount of synthetic ACTH is injected, and the
amount of cortisol, and sometimes aldosterone, the adrenals produce in response is measured.
This test may cause mild to moderate side effects in some individuals. The ACTH stimulation
test is recognized as the gold standard assay of adrenal insufficiency, although this test is
primarily used to determine the presence of Addison's disease and pituitary impairment. The
test is extremely sensitive (97% at 95% specificity) to primary adrenal insufficiency, but less
so to secondary adrenal insufficiency (57-61% at 95% specificity); while secondary adrenal
insufficiency may thus be dismissed by some interpreters on the basis of the test, additional
testing may be called for if probability of secondary adrenal insufficiency is particularly high.
Cortisol stimulation
In healthy individuals, the cortisol level should double from a baseline of 20-30 g/dl within
60 minutes. For example, if the serum cortisol level was 25 g/dl before the stimulation, it
should reach at least 50 g/dl.
Interpretation for primary adrenal insufficiency, Addison's disease
In Addison's disease, baseline cortisol is well below 10 g/dl and rises no more than 25
percent.
Interpretation for secondary adrenal insufficiency
ACTH may dramatically stimulate cortisol from the low baseline value encountered in
patients suffering from secondary adrenal insufficiency. Stimulation resulting in a greater than
14-fold increase in serum concentration over 30 minutes has been reported, although more
typically serum cortisol levels will double or triple from baseline. The lower the baseline
cortisol, the more likely it is that the patient's cortisol will increase by a large amount.

Primary insufficiency - there is an inability of the adrenal glands to produce enough steroid
hormones (Addison's disease is the name given to the autoimmune cause of this
insufficiency). Glucocorticoid and often mineralocorticoid hormones are lost.[1]
Secondary insufficiency - there is inadequate pituitary or hypothalamic stimulation of the
adrenal glands
Thus, the patient may suffer from primary hypoadrenalism

8. Why is the time of the day important in doing this test?

In the morning, where the patient must have fast for 6-9 hours

Case 3
A 35-year-old woman is found to have a blood pressure of 190/110 mmHg by her GP at a routine
health check. He prescribes a thiazide diuretic but a week later she returns to the doctor complaining
of severe muscle weakness and constipation. The doctor immediately refers her to the endocrine clinic
and an urgently orders for serum potassium level and it is found to be 2.6 mmol/L. The diuretic is
stopped and her blood pressure medication is changed to prazosin and potassium supplement is started
for her. After 3 weeks, her potassium concentration is only 3.0 mmol/L. A 24-hour urine collection
contains 70 mmol potassium. A diagnosis of Conns syndrome is made and she is admitted to the
hospital for further investigation.
Investigation:
Plasma aldosterone:
0900 h, recumbent
1300 h, ambulant

1320 pmol/L (normal 100-450 pmol/L)

510 pmol/L

Plasma rennin activity

0900 h,

<0.5 pmol/ mL / min (normal 1.1 2.7 pmol/mL/min)

Activity 3
1. What is Conns syndrome?
It is an aldosterone producing adenoma.
2. List the causes of Conns syndrome. What is the most common cause?
The syndrome is due to:

Solitary adrenal (Conn) adenoma, 35%

Bilateral (micronodular) adrenal hyperplasia, 60%

Glucocorticoid remediable aldosteronism (dexamethasone-suppressible hyperaldosteronism),

<1%
rare forms, including disorders of the renin-angiotensin system, <1%

3. Discuss the signs and symptoms of Conns syndrome.

Signs :

High blood pressure

Low blood potassium (hypokalemia)

Low blood acid

Symptoms :

Headache, vision problems (due to high blood pressure)

fatigue, muscle cramps, muscle weakness, numbness, temporary paralysis, (due to

kypokalemia)

polyuria, polydipsia (due to reduced ability of kidney to concentrate urine)

4. Conns syndrome may be an uncommon cause of hypertension. Discuss the pathophysiology of

hypertension in Conns syndrome. Relate to aldosterone function.
In conns syndrome, a benign adenoma in one of the adrenal glands produces and secretes
an excessive level of aldosterone. This promotes sodium reabsorption at the renal tubules
of the kidney, which cause water to follow which then causes an increased in total blood
volume hence resulting in hypokalemia as sodium is reabsorbed, potassium is pumped
out.
5. What is a diuretic? Discuss why the patient develop severe weakness and constipation
following treatment with diuretic. Revise the role of potassium in cellular function.
It is a drug that can increase the volume of urine produced by promoting the excretion of salt and
water from the kidneys.
Why patient develop severe weakness and constipation following treatment with diuretic?
-

Diuretic causes an excessive amount of potassium to be excreted out through urine. Thus, this
leads to hypokalemia (decrease amount of potassium in blood). The ratio of intracellular to
extracellular potassium concentration determine the cellular resting membrane potential and
influences the function of excitable tissues such as nerves and skeletal muscles. Following
treatment with diuretics, low level of potassium in blood interupt with the normal action
potential mechanism which is crucial for muscle contraction. Due to that, the muscle unable
to contract and this will results in severe weakness (owing to the disturbation of action
potential in skeletal muscle) and constipation (owing disturbation of action potential in
smooth muscle of intestines) .

Role of potassium in cellular function.

-

A. Muscle contraction: through sodium-potassium pump that helps in regulating muscle

contraction and regulating heartbeat.

B. Blood pressure: Dietary supplement with postassium is believed to lower blood pressure
by balancing the negative effects of salts. The kidney helps to control blood pressure by
controlling the amount of fluid stored in the body. This uses a delicate balance of sodium and
potassium concentration to pull the water across the wall of cells from the bloodstream into
the collecting channel of the kidneys (excretion).

C. Enzyme production: Potassium is needed as cofactor for the activation of an important

enzyme involved in carrying out body processes such as carbohydrate metabolism, and
pyruvate kinase.

D. Bone health: Potassium reduced the amount of calcium being pulled from the bone in
order to maintain the correct acid-base balance based in a complex interactions between
concentration of potassium, sodium, calcium, and phosphorus within the boned and the
interstitial fluid surrounding the bone.

6. Stopping diuretics and supplementation with potassium does not increase the potassium level.
Explain.
- This is because the patient is diagnosed with Conns Syndrome which mean that there will be an
excessive secretion of aldosterone, thus this leads to an excessive reabsorption of sodium and
excessive excretion of potassium. The postassium supplementation and stopping of diuretics will not
rise the potassium level as the main cause of underlying disease is not yet treated.
7. Interpret the investigation result. Differentiate between primary and secondary
hyperaldosteronism. Revise the regulation of aldosterone secretion.
Interpretation of investigation result
From the investigation, it can be concluded that the level of aldosterone in the patients plasma is very
high because it is 1320 pmol/L in the morning while the patient is lying down, when the normal level
is 100-450 pmol/L. This could be due to the excess secretion of aldosterone. In the afternoon, when
the patient is able to walk, the level decreases but is still considered a high level at 510 pmol/L.
Aldosterone is affected by upright posture and therefore samples are taken lying down and then
repeated after being upright for a few hours.
The plasma rennin activity is less than 0.5 pmol/mL/min when the normal value is from 1.1 to 2.7
pmol/mL/min, which is very low and could be due to the sodium retention which leads to plasma
volume expansion and elevated blood pressure. The increased blood pressure will lead to an increased
glomerular filtration rate and cause a decrease in rennin releases from the granular cells of the

juxtaglomerular apparatus in the kidney. The decreased rennin levels and the reactive down-regulation
of angiotensin II are unable to down-regulate the constitutively formed aldosterone, leading to an
elevated plasma aldosterone: plasma rennin activity ratio.
Primary hyperaldosteronism

Due to the defect of the adrenal glands where they excrete excessive aldosterone

Caused by an adrenal adenoma, Conns syndrome

Usually treated with surgery by removal of adrenal glands or medicines

Secondary hyperaldosteronism

Abnormality that indirectly results in pathology through a predictable physiologic pathway

i.e. a renin-producing tumour leads to increased aldosterone

Treated with medicines and limiting salt intake

Primary and secondary hyperaldosteronism have common symptoms.

Regulation of aldosterone secretion
Aldosterone is produced exclusively in the zona glomerulosa under a separate control pathway from
that of cortisol. Although ACTH does play a role in regulation of zona glomerulosa function,
angiotensin II is the most important regulator of aldosterone secretion.
The zona glomerulosa, like the rest of the adrenal cortex, requires ACTH to prevent atrophy of the
tissue. ACTH can stimulate aldosterone production, but prolonged high levels are required. As in the
zon fasciculata and reticularis, the effects of ACTH are mediated by cAMP.
The major stimulus for aldosterone synthesis is angiotensin II.
Angiotensinogen is synthesized and released by the liver. Angiotensinogen in serum is cleaved to
form angiotensin I by renin, synthesized by the juxtaglomerular apparatus of the kidney. Angiotensin I
is then converted to the active octapeptide angiotensin II by Angiotensin Converting Enzyme.
Cleavage by renin is the rate limiting step for the production of angiotensin II.




8. Why is plasma aldosterone higher in recumbent and lower 4 hours after ambulation?
Definition: Recumbent: Lying down, Ambulation: Movement

1. Principle of aldosterone secretion: Aldosterone is activated by angiotensin 2 and

Potassium ion. Angiotensin 2 is activated by rennin. Rennin is secreted form
juxtaglomerular apparatus when perfusion is low (BP low). (Recall Rennin-AngiotensinAldosterone System: Refer diagram)


2. Recumbence (lying down) -> BP is low, while ambulance (moving) -> BP increase.
Hence renin secretion decrease as patient undergo ambulation. This explains the decrease
in aldosterone concentration in plasma.

Case History 4
A 75-year-old woman presents with anxiety, palpitation and sweating. Her pulse is 80/min, regular
and blood pressure 160/100 mmHg. She has previously been investigated for abdominal pain, for
which no cause have been found. Thyroid functions test are normal. The doctor orders a 24-hour urine
collection and the result is as shown.
Urine Test Result.
Urine hydroxymethoxymandelic acid (HMMA)
Urine adrenaline
Urine noradrenaline

99 mol/24h (ref range < 35)

1.0 mol/24h (ref range < 0.1)
0.38 mol/24h (ref range < 0.57)

A CT scan of abdomen shows a mass arising from the left adrenal gland, and isotopic scan of the
adrenals, shows a single left adrenal mass.
The patient is diagnosed to have phaeochromocytomas.

Activity 4

1. What is phaeochromocytomas? Revise the anatomy of adrenal gland and the hormones
secreted by different layers of the adrenal gland.
Pheochrmocytomas is an uncommon tumour of adrenal medullary tissue that causes
production of excessive amounts of catecholamine.


Glomerulosa
-secrete Aldosterone
-have 18 hydroxylase
-regulated by Angiotensin II and potassium level (if increase in blood )
Fasiculata
-secrete cortisol
-have 17 hydroxylase
-have 11 hydroxylase that is activated by ACTH
Reticularis
-secrete androgen
-have 17 hydroxylase
-have 17 hsd

2. Explain why the patient has palpitation and sweating. Relate to action of adrenaline and
noradrenaline.
Palpitation
Excessive catecholamine (epinephrine and norepinephrine) bind to adrenergic receptor (Beta-1) on the
heart (myocardium) which result in sympathetic response.
These give effects:

increased force of contraction (inotropic)

increased rate of contraction (chronotropic)

increased excitability (predisposes to arrhythmia)

increased AV nodal conduction velocity

Sweating
Excessive catecholamine (epinephrine and norepinephrine) bind to adrenergic receptor (Alpha-1) on
the sweat gland which result in sympathetic response.
These give effect:

increased sweating (diaphoresis)

3. Explain the pathophysiology of hypertension in this patient.

-

Pheochromocytomas produce high levels of chemicals called catecholamines.

Catecholamines act on both the alpha and beta adrenergic receptors. Catecholamines are
released in times of stress. They make your heart beat faster with greater force and narrow the
blood vessels, causing a rise in blood pressure and also increase in blood flow.

These tumors commonly produce: epinephrine (adrenaline), norepinephrine and dopamine -three compounds that are among the strongest known for increasing blood pressure.

The body normally uses tiny amounts of these chemicals to respond to dangerous or stressful
situations. Even in small amounts, all three have large effects on blood pressure.

Because pheochromocytomas produce large amounts of each of these hormones, the effects
on blood pressure are typically very dramatic.

Almost all patients with pheochromocytomas have elevated blood pressure, and the hallmark
of high blood pressure caused by this condition is extreme blood pressure swings during the
day.

4. Interpret the investigation result. Discuss the metabolism of cathecolamines.

Cathecolamine are amine group of organic benzene ring that have two hydroxyl side group
and side chain amine. This includes dopamine, norepinephrine and epinephrine.

Chromaffin cells of adrenal medulla have enzyme to synthesize epinephrine.

Amino acid tyrosine is taken up and converted to norepinephrine and epinephrine.

Norepinephine and epinephrine are stored in electron-dense granules which also contain ATP
and several neuropeptides.

Secretion of these hormones is stimulated by acetylcholine released from preganglionic

sympathetic fibers innervating the medulla (via GPCR ! Gq !Ca2+ ! exocytosis).

Many types of "stressors" stimulate such secretion, including exercise, hypoglycemia and
trauma.

Following secretion into blood, the catecholamines bind loosely to and are carried in the
circulation by albumin and perhaps other serum proteins.

Chromaffin cells are the structural and functional equivalents of the postganglionic neurons in
the sympathetic nervous system.

The preganglionic sympathetic fibres of the splanchnic nerves, which release acetylcholine are
the principle regulators of adrenomedullary hormone secretion.

Importantly, most of this metabolism occurs independently of exocytotic release, and only a
small fraction of catecholamine metabolites is formed from circulating catecholamines.

Failure to recognize these facts probably reflects another misconception that vesicular stores
of catecholamines exist in a static state until a stimulus evokes release into the extracellular
space.

In fact, vesicular stores of catecholamines exist in a highly dynamic equilibrium with

catecholamines in the surrounding cytoplasm.

Avid and rapid active transport from cytoplasm into vesicles, mediated by vesicular
monoamine transporters, counterbalances passive outward leakage from vesicles.

Although only a small fraction of the catecholamines in the cytoplasm escapes vesicular
sequestration, that fraction represents a major source of catecholamine metabolites.

References:
1. Stephen J. McPhee & Gary D. Hammer. Pathophysiolgy of Disease. An Introduction to
Clinical Medicine, 6th Edition, 2010. Chapter 21, Disorders of Adrenal Cortex.
2. William J Marshall & Stephen K Bangert. Clinical Chemistry. 5th Edition, 2004. Chapter 8.
Disorders of Adrenal Glands.

Prepared By:
Prof Dr Noor Aini Abd Hamid