Lec #

31 Adrenal Disorders
Dr: Fawaz Ammari
St: Alaa Samarah

12 / 11 / 2007

The adrenal gland and its disorders need tow lectures to be completely covered, but the doctor
compress this lecture to discuss the most important things about it.

Adrenal

glands are triangular shaped glands set above both kidneys in

retroperitoneal cavity and consist of medulla, cortex (90%), and capsule.
Anatomy

There are two adrenal glands that located in retroperitoneal cavity and set
on the superior poles of the kidney
Each about 5 grams
o Larger at birth (5-10g)
o Susceptible to hemorrhage
o Regresses over 6 weeks
Up to 5 cm long, 3 cm wide

Arterial supply (enters circumferentially)

1. Inferior phrenic (main)
2. Aorta and renal arteries
3. Gonadal (in fetus 60% of time)

Venous return
o Right: directly into posterior IVC
o Left: to left renal vein then to Inferior phrenic vein

Lymphatics
o Paraaortic nodes

Nerve supply
o Medulla innervated mainly by sympathetic from T10-L1
o Cortex has no innervation

Histology; the adrenal glands have two major layers:

1. Cortex
o Account for about 90% of adult gland
o Derived from mesoderm
Begins during 5th week of development
Mesothelial cell migration
o The cortex subdivided to 3 layers (zona);
1) Zona Glomerulosa; secrete Aldosterone
2) Zona Fasciculata; secrete cortisol
3) Zona reticularis; secrete androgens
o Zonation occurs until about 18 months of age
2. Medulla
o Derived from neuroectoderm
Neural crest cell migration
Begins during 7th week of development
Primitive medulla by 20th week
o Continues growth until cortex atrophy (18 months)
o The medulla secrete 3 hormones:
1) Epinephrine
2) Norepinephrine
3) Dopamine
The cortical zones and its hormones
1) Zona glomerulosa: it is the outer layer of the cortex that secrete Aldosterone;

Actions of Aldosterone: Helps maintain water and salt balance
1) Increases Na reabsorption; so those patients with excess aldosteron
secretion develop hypernatremia.
2) Increases K+ secretion; so those patients with excess aldosteron
secretion develop Hypokalaemia.
3) Increases H+ secretion

Excess secretion of Aldosterone lead to secondary hypertension and what
we call conns syndrome.
2) Zona fasciculata: it is the middle layer that secretes glucocorticoids (cortisol).

Actions of Cortisol (cortisol is essential for response to stress):
1) Stimulation of gluconeogenesis

Increases protein and lipid catabolism

Decreases glucose utilization

2) Anti-inflammatory effects
3) Suppression of immune response

Inhibits production of IL-2 and T lymphocytes

4) Maintenance of vascular responsiveness to cathecholamines

Required for vasoconstrictor effect of norepinephrine


Excess secretion of cortisol lead to Cushion syndrome

Deficiency of this hormone leads to primary or secondary adrenal
insufficiency.
3) Zona reticularis: it is the inner layer that secretes androgens (DHEA and
androstenedione) which is more important in female than in male;
Excess secretion of androgens in male has no effect but in female this will
cause Hirsutism and irregular menses

The Medulla has sympathetic enervation, and it secrete norepinephrine,

epinephrine, and dopamine, and excess secretion of these hormones will lead to
Pheochromocytoma.

Regulation of Adrenocortical Hormones

The regulation of these hormones secretion depend on negative feedback cycle
that started in hypothalamus by secretion of CRH to anterior pituitary gland that
stimulate it to secrete ACTH which goes with general circulation to adrenal gland
for stimulate its ZF & ZR to secrete their hormones.

ZF & ZR are mainly under the

influence of ACTH and CRH, but the
ZG (aldosteron-secreting layer) are
mainly
influenced
by
RenineAngiotensin system but not affected
by or at minimal influence of ACTH,
so If ACTH deficiency occur the
cortisol
level
will
drop
while
Aldosterone level will not affected.

Note: high level of ACTH lead to

pigmentation which seen in Addisons
diseases (primary hypoadrenalism)
unlike the secondary hypoadrenalism
that
caused
by
pituitaryhypothalamic disorder (low ACTH),
and also note that level of aldosteron
not affected in the secondary
hypoadrenalism
but
affected
in
primary one (decreased).

Biosynthesis of adrenal hormones

Cholesterol
Cholesterol desmolase

17-hydroxylase

Pregnenolone

17-Hydroxypregnenolone

17,20 lyase

DHEA

3 hydroxysteroid
dehydrogenase

Progesterone

17-Hydroxyprogesterone

Androstenedione

21-hydroxylase

11-Deoxycorticosterone

11-Deoxycortisol

Testosterone

11-hydroxylase

Corticosterone

Cortisol

Estradiol

Aldosterone synthase

Aldosterone

All cortical hormones are synthesized from cholesterol by different enzymes in

deferent cortical zones, so as example;
If there are deficiency in Zona fasciculata enzymes  cortisol level will drop
so pituitary gland will be out of inhibitory effect of cortisol (which is actually
not present)  compensatory increase in ACTH  over stimulation of Zona
reticularis  (1) adrenal gland hyperplasia (is Congenital) and (2) excessive
secretion of zona reticularis hormones (if its enzymes are normal).
Dont forget that aldosteron secretion will not influenced by this sequence because
aldosteron secretion controlled by Renine- Angiotensin system not by ACTH.
Again, congenital adrenal hyperplasia (CAH) refers to disorders of adrenal steroid
biosynthesis that result in glucocorticoid deficiency. Because of deficient cortisol
biosynthesis, a compensatory increase in ACTH occurs, inducing adrenal
hyperplasia and overproduction of the steroids that precede blockage of enzyme
production.

We have different types of enzyme deficiencies in congenital adrenal

hyperplasia:
1. 21-hydroxylase deficiency; is the most common one and accounts
for about 95% of cases of CAH.
o In this condition the patients presented with virilization and
salt loss without hypertension.
2. 11-hydroxylase deficiency; accounts for about <5% of cases of CAH.
o In this condition the patients presented with virilization (as 21hydroxylase deficiency) and hypertension (opposite to 21hydroxylase deficiency).
3. 3-hydroxylase deficiency

All the types of enzyme deficiencies are transmitted in an autosomal

recessive pattern.

Aldosteron
Renal juxtaglomerular cells secrete renin in response to a decrease in circulating
volume and/or a reduction in renal perfusion pressure. Renin is the rate-limiting
enzyme that cleaves angiotensinogen to the angiotensin I. Angiotensin I is rapidly
converted to the angiotensin II by angiotensin-converting enzyme (ACE) in the
lungs. Angiotensin II has effects:
1) Is a potent vasopressor.
2) Stimulates aldosterone production (but does not stimulate cortisol
production).
So, the renin-angiotensin-aldosterone system is the major regulator of aldosterone
secretion.
Regulators of aldosterone secretion are:
1) Angiotensin II is the predominant regulator and stimulates aldosterone
secretion as we mention.
2) Hyperkalemia; stimulates aldosterone secretion.
3) Hypernatremia; suppress aldosterone secretion, so if we give large amount of
normal saline the aldosterone level will decrease.
4) ACTH levels also have very minimal influence on aldosterone secretion.
Binding of aldosterone to the mineralocorticoid receptor leads to:
1) Sodium reabsorption in distal tubule  Fluid absorption
2) Potassium excretion.
3) Hydrogen Ion excretion by the renal tubules.
The resultant increase in plasma Na+ and decrease in plasma K+ provide a
feedback mechanism for suppressing renin and, subsequently, aldosterone
secretion.

When aldosteron production falls too low, the kidneys are not able to regulate salt
and water balance, causing blood volume and blood pressure to drop.
Aldosteron secreted in cascade of Renine  (angiotensin1)  (angiotensin 2) 
aldosteron, and the stimulus of this cascade is hypotension (low renal blood flow),
hyponatremia, and hyperkalemia.

Hyperaldosteronism
There are two types of Hyperaldosteronism (excessive secretion of aldosterone)
1. Primary Hyperaldosteronism (conns syndrome); the primary has a problem
in the gland cortex (such as adenoma or carcinoma) that will secrete high
level of aldosteron which associated with low renine.
2. Secondary Hyperaldosteronism; here the problem not lodge in adrenal cortex
but it is due to hypersecreation of renin, and the elevated level of renin end
with hyperaldosteron.



Low renine in primary hyperaldosteronism

High renine in secondary hyperaldosteronism

Those patients with hyperaldosteronism are young and presented with:

1) Secondary hypertension; about 1% of hypertension patients are secondary
to hyperaldosteronism.
2) Hypokalaemia (<3.0).
3) Hypernatremia
4) Alkalosis
So, the symptoms of hyperaldosteronism are mainly related to high blood pressure
and Hypokalaemia;
Hypokalaemia lead to:
1) Polyuria and polydipsia (due to nephrogenic diabetes insipidus).
2) Visual disturbances
Hypokalaemia and hypercalcemia cause
3) Cramps
nephrogenic diabetes insipidus
4) Muscle weakness but in
sever cases the paralysis and tetany can occur.
5) Postural hypotension due to baroreceptor paralysis by Low K+
Mineralocorticoid escape

Due to breakdown of distal tubules ability to absorb sodium

o Sodium retention decreases
o Limits K+ loss

About 1.5kg of excess fluid absorption

o No edema
o Limits HTN

Worse with adenoma, better with hyperplasia

Causes
1) Adenoma:
o Is the most common cause and accounts for about 80%.
o Female affected more than male and the age of onset between 4th5th decades of life
2) Bilateral adrenal hyperplasia
3) Adrenocortical carcinoma (rare)
4) Glucocorticoid remedial aldosteronism
o Aldosterone producing adenoma
o Responsive to renin

Diagnosis
History;
If young patient come with hypertension and manifestations of
hypokalaemia this will give high suspicion of hyperaldosteronism and
we need to prove that by biochemical lab tests.
Laboratory;
1) Low serum K+ (<3.0)
2) Serum aldosterone is high, and we try to suppress this level by
giving normal saline to the patient, and if there is no response
(suppression) this mean that is a primary problem which also
diagnosed if aldosteron level >14 micrograms/d
o In the primary Hyperaldosteronism we lose the laying/standing
elevation of aldosteron bcoz its already elevated.
3) Serum renin
o If >1.0 then unlikely primary hyperaldosteronism
After that we try to interpret the results:
 Elevated aldosterone and elevated renin  there is secondary
hyperaldosteronism (something wrong out of adrenal gland).
 Elevated aldosterone and low renin  there is primary
hyperaldosteronism (the problem within the adrenal gland).
After doing the lab tests and confirm the primary elevation of aldosteron we
must do localization by imaging studies.
Imaging studies
1. CT scan with thin cuts through adrenal (most important and enough)
2. MRI (less sensitive)
3. Adrenal scintigraphy (less accurate)
4. Adrenal vein sampling
o Gold standard
o Measure selective aldosterone levels which elevated on side of
adenoma and suppressed contralateral side.

Treatment

Medical: for Control HTN and correct electrolytes, so we give spironolactone
(aldosteron antagonist), amiloride (k+ sparing agent)
Better for bilateral adrenal hyperplasia
Prepare for surgical treatment
Gynecomastia (with spironolactone)

Surgical: for remove the localized lesion (adenoma/carcinoma)
We may treat the adenoma but the HTN is persist (not cure) in
20-25% of patients, bcoz of chronic changes that develop the
secondary HTN to primary HTN.

Cortisol (glucocorticoid) problems

1. Congenital adrenal hyperplasia due to enzyme deficiency in cortisol
biosynthesis.
2. Cushings Syndrome (excess)
3. Addisons disease (deficiency)

Cushings syndrome and disease

 Cushings Syndrome
o Cushings syndrome results from production of excess cortisol by the
adrenal cortex
o Have endogenic and exogenic causes
 Cushings Disease
o Excess cortisol in the blood due to an ACTH secreting pituitary tumour
(70% of endogenic Cushings syndrome is due to pituitary adenoma).

Action of cortisol is Essential for response to stress

1. protein catabolism and liberation of A.A by muscle
2. Increases plasma glucose levels by;
1) Induction of gluconeogenesis
2) Suppression of glucose utilization
3) Increases glycogenesis
3. Increases lipolysis to provide energy.
4. Anti-inflammatory effects.
5. Suppression of immune response

Inhibits production of IL-2 and T lymphocytes

6. Maintenance of vascular responsiveness to catecholamine
7. Na+ and H2O Retention (Maintains BP).
8. Increased gastric acid production.

Excess Cortisol lead to

1) Over protein catabolism and liberation of amino acids by muscle that lead
to muscle and elastic tissue weakness.
2) amino acids are transformed into glucose and glycogen and then
transformed into fat.
3) Loss of calcium in urine

Epidemiology

Incidence is 2/1 000 000 population (rare), and the exogenic cause is more
than endogenous cause.
The most common cause of cushing is iatrogenic.
Female : Male  3-15 : 1
Onset at 20-40 years old

Manifestation of Cushing
 Those due to changes in protein and fat metabolism;
Central obesity
Moon face
Buffalo hump
Thin skin (paper-like skin) and easy bruising due to rupture of elastic
tissues of skin, this mean that any minimal trauma may cause skin
ecchymosis.
Osteoporosis
Diabetes (polyuria and polydypsia)
 Those due to changes in sex hormones;
Hirsutism (Excess hair growth in female mainly on face)
Irregular menstrual periods
Problems conceiving; mean the female has problem in pregnancy.
Impotence in male
 Those due to salt and water retention;
High blood pressure
Typically, patients will have some, but not all, of
Fluid retention
the clinical manifestations of Cushing syndrome.

Diagnoses: by;
1. History;
Weight gain and fatigue.
Polyuria and polydypsia  Diabetes.
Infertility and impotency.
Cachexia and loss of appetite  tumor (Adrenal carcinoma).
2. Physical exam;
The diagnosis of Cushing
Obesity.
syndrome is principally clinical.
Proximal muscle weakness.

After taking history and doing Physical exam, if the patient has high suspicion of
Cushing we must improve that by measuring cortisol level in both blood and urine.
3. Investigations: there are 3 stages to investigate the patient with Cushing;
a. Screening.
b. Confirmation of the Diagnosis.
c. Differentiation of the Cause.

Screening and Confirmation of the Diagnosis

1. Urinary free cortisol;
Elevated urinary free cortisol excretion on 24-hour urine testing.
2. Diurnal Rhythm;
Normally, there is diurnal variation (fluctuation) in the level of blood
cortisol, is the highest in the morning and lowest in the evening.
This diurnal variation is lost in patient with Cushing syndrome, and
the level of cortisol became elevated all 24 hs without variation.
3. Over night dexamethasone suppression testing;
We give 1 mg of dexamethasone at 11 pm then we measure cortisol
level at 8 am next day;
o In normal; cortisol level depressed below the normal limit
(<50nmol/l).
o In Cushing syndrome; cortisol level still higher than normal
limit.
If the history and physical examination give high suspension of Cushing
syndrome and all these three tests are positive, so the patient definitely has
Cushing syndrome, and after that we look for the cause of elevated cortisol
level by the following tests.

Differentiation of the Cause (finding the etiology)

1) ACTH.
2) High dose Dexamethasone Suppression testing.
3) Localization of the ACTH source by Imaging
1) ACTH
Causes of Cushing Syndrome are grouped to two groups according blood
ACTH level:
1. ACTH-dependent causes;
ACTH level is high
The causes are:
1. Pituitary ACTH-producing tumor (Cushings Disease)
2. Ectopic ACTH-producing tumor
a. Carcinoid tumor.
b. Small cell carcinoma.

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2. ACTH-independent causes (non ACTH-dependent);

ACTH level is low
The causes are:
1. Primary adrenal causes
a. Adrenal adenoma
b. Adrenal carcinoma
2. Glucocorticoid use (factitious or iatrogenic)
2) High dose Dexamethasone Suppression testing
It is used to determine the source of elevated ACTH level in ACTHdependent Cushing syndrome either it is Pituitary ACTH-producing tumor
or Ectopic ACTH-producing tumor.
We give 2 mg Dexamethasone six-hourly for 48 hrs, and then we measure
cortisol level;
If cortisol suppresses to < 50% of baseline then the patient has
Pituitary dependent Cushings disease.
If the Cortisol does not suppress then the patient has ectopic ACTH
production or an adrenal tumour.
However, there is 6-10% of patients may have false positive or false
negative test and is very difficult to reach the diagnoses of them, but they
need more sophisticated investigation which called petrosal vein
sampling.
Petrosal vein sampling:
We introduce catheter through the internal jugular to the
pituitary sinus and we inject CRH to stimulate the secretion of
ACTH.
This investigation is difficult to do and carries high mortality and
morbidity.
3) Localization of the ACTH source
In ACTH-dependent cushing syndrome we try to find the source of
excess ACTH in blood by doing:
1. MRI of sella turcica to see Pituitary ACTH-producing tumor.
NOTE: The Pituitary tumors are too small to be seen by CT and
only detected by MRI.
2.

CT of chest and abdomen to see ectopic source of ACTH

such as small cell carcinoma.

11

In ACTH-independent cushing syndrome we do:

1. CT of adrenal glands
o Adenomas- usually >2cm but <5cm
Low attenuation (lipid content)
Atrophy of opposite gland
o Carcinoma- indistinguishable from adenomas
>5cm
Necrosis, calcifications, irregularity, invasion
2. MRI of adrenal- usually not needed

Laboratory Features
1)
2)
3)
4)
5)
6)
7)
8)

Hypokalaemia due to potassium wasting.

Metabolic Alkalosis.
Hyperglycaemia
Increased Plasma LDH
Very elevated plasma and urinary cortisol
Non-suppression with dexamethasone
Flat CRH response
Very raised plasma ACTH (>110pmol/l)

Causes of Cushings syndrome:

1.

2.

Exogenous steroid use:

PO or topical
Most common cause (overall)
Endogenous causes:
1) Cushings Disease
Primary excretion of ACTH from pituitary gland
95% have identifiable pituitary adenoma either Basophilic or
chromophobe adenoma.
Bilateral adrenocortical hyperplasia in abdomen CT
Cushings disease forms about 70% of endogenous causes of
Cushings syndrome.
Is more common in Female than in Male, F:M about 3:1
2) Ectopic source
Produce ACTH or CRH
Small cell lung carcinoma (most common), Carcinoid tumors,
medullary thyroid, pancreas, ovarian, pheochromocytoma,
small-cell carcinoma of prostate
Form about 15% of endogenous causes of Cushings syndrome.
3) Adrenal adenomas (10%)
4) Adrenal carcinoma (5%)
Most common cause in children
Causes: Exogenous steroid  pituitary adenoma  Ectopic source
 Adrenal adenomas  Adrenal carcinoma
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Pseudo-Cushings disease
Mimic clinical signs and symptoms
Non-endocrine causes;
o Alcoholism
o Major depression
o Morbid obesity
o Acute illness

Treatment:
1) Surgical treatment:
o Surgical treatment of Cushings disease
1. Transphenoidal hypophysectomy
>90% cure rate 1st time, 50% salvage cure 2nd attempt
Exploration even if no obvious adenoma
Complications:
A. Transient postoperative diabetes insipidus.
B. Adrenal insufficiency.
C. CSF rhinorrhea.
D. Meningitis.
2. Transphenoidal irradiation of adrenal gland.
High success rate in kids (80%)
Low success in adults (20%)
3. Bilateral adrenalectomy
Bilateral adrenalectomy was done in the past in any patients with
Cushings disease (be careful, Cushings disease mean that there
is pituitary adenoma, while the adrenal glands are completely
normal) but nowadays it is done only If pituitary surgery failed.
Life-long steroid replacement therapy will be required.
If bilateral adrenalectomy done, sudden and extreme drop of
cortisol level will occur, so the negative feedback effect of cortisol
on pituitary gland will canceled and Rapid growth of pituitary
adenomas occur this is called Nelsons syndrome.
Nelsons syndrome
o Rapid post-operative growth of ACTH-secreting pituitary
adenomas that can be invasive.
o Occur in 10-20% in patients with bilateral adrenalectomy.
o Sever and universal hyperpigementation of the body is one of
the manifestations of Nelsons syndrome.
o Preoperative irradiation decreases incidence.
o Surgical treatment of Adrenal lesions/carcinoma
Removal of primary lesion
Survival based on underlying disease

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o Surgical treatment of Ectopic ACTH lesions

Remove lesion
Survival based on primary disease
May need bilateral adrenalectomy to control symptoms if primary
tumor unresectable
2) Medical treatment:
o Some times the patient may has contraindications for surgery or refuse
surgery or the tumor unresectable, so we move to medical treatment.
o Also used as preparation for surgery or poor operative candidate
o All these drugs interfere with enzyme action in certain step of cortisol
synthesis:
1. Metyrapone; inhibits conversion of deoxycortisol to cortisol
2. Aminoglutethimide;
o Inhibits desmolase enzyme so it will prevent conversion of
Cholesterol to pregnenolone and blocks synthesis of all 3
corticosteroids
o Side effects: N/V, anorexia, lethargy
3. Ketoconazole; an imidazole that blocks cholesterol synthesis
4. Mitotane (O-P-DDD); inhibits conversion to pregnenolone
o Inhibits final step in cortisol synthesis
o Destroys adrenocortical cells (spares glomerulosa cells)

ADRENAL INSUFFICIENCY
Adrenal insufficiency is categorized as primary, secondary or tertiary.
1) Primary (Addisons disease): results from destruction or impairment of
the adrenal cortex
o Thomas Addison described this rare condition in his classical
monograph published in 1855.
o Incidence: 0.8 cases per 100,000
o Prevalence: 4 to 11 cases per 100,000
o Mean age of diagnosis: 40 years
2) Secondary (Central): results from reduced ACTH secretion by the
pituitary gland
3) Tertiary: results from failure of the hypothalamus to produce CRH
(corticotrophin-releasing hormone)

Etiologies:
Primary Insufficiency (Addisons disease):
1. Autoimmunity
Autoimmune Polyglandular Syndrome; this syndrome has two types;
Type I: Addison's disease, chronic mucocutaneous candidiasis,
hypoparathyroidism.

14

2.

3.

4.

5.

6.

7.
8.

Type II (Schmidt's syndrome): Addison's disease, primary

hypothyroidism,
primary
hypogonadism,
insulin-dependent
diabetes.
Infection
Tuberculosis
HIV
Fungal
Infiltrative diseases
Amyloidosis
Sarcoidosis
Hemochromatosis
Neoplasm
Adrenal metastases (lung and breast)
Lymphoma
Hemorrhage or infarct of adrenal gland
Meningococcemia (Waterhouse-Friderichsen)
DIC
Lupus (antiphospholipid antibody)
Anticoagulation
Iatrogenic
Surgical cause as bilateral adrenalectomy.
Medical cause as drugs that inhibit P-450 enzymes (Ketoconazole)
Congenital adrenal hypoplasia
ACTH resistance syndromes

Worldwide, tuberculosis is the most common cause, and in the industrialized nations,
idiopathic or autoimmune adrenal destruction is the most common cause.

Secondary Insufficiency
1. Sudden cessation of exogenous glucocorticoid therapy
Such therapy suppresses HPA axis with adrenal atrophy
Deficiency should be suspected if patient taking > 30mg/d
hydrocortisone (7.5mg/d prednisone or 0.75mg/d dexamethasone)
for >3 weeks followed by sudden cessation.
2. Failure to give stress steroids
3. Inadequate ACTH production
Usually other pituitary hormones deficient, and patients present with
partial or complete hypopituitarism (pan-hypopituitarism)
Isolated ACTH deficiency rare
o Lymphocytic hypophysitis
o Abnormal post-translational processing of POMC to ACTH
4. Removal of ACTH-secreting pituitary adenoma
Function of normal corticotrophs suppressed

15

Manifestations of Adrenal Insufficiency

The symptoms and signs of adrenal insufficiency can be grouped into chronic and
acute syndromes.
o The chronic syndrome is characterized by anorexia, weight loss, fatigue,
and orthostatic hypotension.
o The acute syndrome (Adrenal Crisis) is closely analogous to cardiogenic or
septic shock so symptoms include prostration and all of the signs and
symptoms of the shock syndrome.
In general, primary and secondary adrenal insufficiency has the same
manifestations but there are other specific manifestations for each type as
illustrated in the following table:

Manifestations of Adrenal Insufficiency

Seen in both Primary and Secondary Insufficiency
Weakness
fatigue
mental depression
Anorexia
weight loss
diarrhea
Nausea
vomiting
Postural dizziness
hypoglycemia
Hypotension
Hyponatremia
Mild normocytic anemia
lymphocytosis
eosinophilia

Only seen in Primary Insufficiency

Hyperpigmentation of skin*
Vitiligo
Hyperkalemia
acidosis
elevated creatinine
Salt craving
Symptoms in adrenomyeloneuropathy
Autoimmune thyroid disease

Only seen in Secondary insufficiency

Pallor without marked anemia
Amenorrhea, decreased libido.
Scant axillary and pubic hair.
Secondary hypothyroidism
Prepubertal growth deficit, delayed
puberty and small testicles
Headaches, visual symptoms
Diabetes insipidus

Hypotension and Hyponatremia are more prominent in primary (Addison) adrenal

insufficiency, the explanation is that in Addison disease all adrenal cortex
hormones are low including the Aldosterone hormone so there is hypotension and
hyponatremia, but in secondary adrenal insufficiency Aldosterone level not affected
so Hypotension and Hyponatremia are not prominent as in Addison.
* Hyperpigmentation of skin mainly occurs on the sun-exposed areas (face and
neck), extensor surfaces (friction area) and new scars.
Vitiligo; is autoimmune disease which cause localized depigmented area on the
skin and is associated with other autoimmune diseases such as autoimmune
adrenal insufficiency, pernicious anemia, type 1 diabetes and autoimmune
thyroiditis.

16

 Headaches and visual symptoms may occur in patients with pituitary adenoma
due to increased intracranial pressure and compression on optic chiasm.
Adrenal Crisis
It is top emergency condition that the patient present with shock state, so any
patient comes with shock symptoms and sighs we should think with Adrenal
Crisis after exclusion of anaphylactic, cardiogenic and septic shock.
Manifestations:
Dehydration, hypotension, or shock out of proportion to severity of current
illness
Nausea and vomiting with a history of weight loss and anorexia
Abdominal pain, so-called acute abdomen
Unexplained hypoglycemia and fever
Hyponatremia, hyperkalemia, azotemia, hypercalcemia, or eosinophilia
Hyperpigmentation or vitiligo

DIAGNOSIS
If there is any suspicion of adrenal insufficiency we need to prove that
biochemically;
Basal Cortisol Level
o Avoid random level: low sensitivity
o Check morning cortisol
 Greater than 18 g/dL indicates an intact axis
 Less than 3 g/dL strongly suggests insufficiency
 No further tests
o Intermediate values: perform cosyntropin stimulation test
There are two stimulation tests; tests that induce cortisol secretion:
1. High-Dose Cosyntropin (ACTH) Stimulation Test
This is the most specific test for diagnosing Addison's disease.
Intramuscular or intravenous administration of 250 g of cosyntropin
(exogenous ACTH) then Plasma cortisol levels are measured at 30 and 60
minutes:
o Normal response: peak plasma cortisol level > 18 g/dL
o Subnormal response: peak plasma cortisol level < 18 g/dL, and
this occur in patient with adrenal insufficiency.

Suppression test used to reach the diagnosis of Cushings syndrome.

Stimulation test used to reach the diagnosis of adrenal insufficiency.

Incremental responses (peak - basal values) are of no value

Response is unaffected by the time of day of the test.
All glucocorticoid preparations except dexamethasone cross-react with
cortisol assay; avoid within 24h of testing

17

2. Insulin Tolerance Test (hypoglycemic test)

 Hypoglycemia is a potent stimulant of cortisol secretion.
In this test we induce hypoglycemia by IV injection of insulin and Plasma
glucose and cortisol are measured at 30 mins, 90 mins and 2hs after
injection of insulin
Normally, the cortisol increase above the normal limit but if dont
increase the patient has adrenal insufficiency.
We need to be very conscious in this test because we lower glucose level
to about 40 or less and the patient may enter in sever hypoglycemic state
This test is expensive and contraindicated in patients with coronary
heart disease or seizures.
Other tests used;
Low-Dose Cosyntropin Test (the doctor didnt mention it at all)
Cosyntropin doses as low as 0.5 to 1 ug will give a maximal response
within 15 to 30 minutes
Possibly superior to high-dose test for diagnosing secondary insufficiency
because ACTH level closer to physiologic level
Normal response: peak plasma cortisol level > 18 g/dL
Like high-dose test, low sensitivity when ruling out mild or recent
secondary insufficiency; confirm with more sensitive tests (insulin
tolerance, metyrapone)
Metyrapone Test (the doctor didnt mention it at all)
Metyrapone inhibits conversion of 11-deoxycortisol to cortisol
Give at midnight and measure the concentration of 11-deoxycortisol and
cortisol at 8am
In normal subjects, the plasma 11-deoxycortisol concentration increases
to at least 7ug per dL. In patients with adrenal insufficiency, the increase
is smaller and is related to the severity of the corticotropin deficiency
The Stimulation tests (ACTH and hypoglycemic tests) can diagnose the patients
with adrenal insufficiency but these tests cant differentiate between the primary
and secondary adrenal insufficiency, to differentiate between the primary and
secondary insufficiency we measure circulating plasma ACTH level;
Elevated ACTH level  primary adrenal insufficiency.
Normal or low ACTH level  secondary adrenal insufficiency.

TREATMENT (by replacement therapy):

o The goal in treating adrenal insufficiency is to replace the missing
hydrocortisone and Aldosterone in quantities calibrated to the clinical
situation.
Hydrocortisone can be replaced with oral or intravenous
hydrocortisone.
Aldosterone is replaced with oral fludrocortisone.

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o Unfortunately, most physicians overtreat patients with glucocorticoids and

undertreat them with mineralocorticoids. Because overtreatment with
glucocorticoids results in insidious weight gain and osteoporosis, the minimal
cortisol dose tolerated without symptoms of glucocorticoid insufficiency is
recommended.
1. Glucocorticoids replacement therapy
1. Glucocorticoids replacement therapy in acute adrenal insufficiency
(crises):
1. Initially we give normal saline to the shocked patients to stabilize them.
2. Glucocorticoids; given by intravenous injection
Hydrocortisone (20 mg in the morning and 10 mg in the evening).
prednisolon (5 mg in the morning and 2.5 mg in the evening).
Or cortisone acetate (25 mg in the morning and 12 mg in the
evening.
3. Dextrose 5%; usually used because of possible hypoglycemia.

Clinical improvement and stabilization should be seen in 4-6 hrs

After stabilization of acute adrenal insufficiency, patients with Addison's
disease require lifelong replacement therapy with oral glucocorticoids (oral
hydrocortisone, 40 mg in the morning and 20 mg at 6 PM).

 NOTE: any patient with Addison disease should have wristlet in his hand labeled
by THIS PATIENT ON STEROID REPLACEMENT THERAPY to be dealt carefully by
physicians.
2. Glucocorticoids replacement therapy in chronic adrenal insufficiency:
The aim is to mimic the normal cortisol secretion rate
Most patients can cope with less than 30mg/d of hydrocortisone (usually
15 to 25 mg/day in divided doses)
Doses are usually given on wakening, with a smaller dose in the late
afternoon
Decisions about doses of replacement therapy are largely based on end
points such as weight, well-being, and blood pressure.

During mild stressful conditions (illnesses as diarrhea or pain, fever,

accident or mental stress) patients should double the daily dose but in
sever stressful condition as in surgery the patient converted to IV steroid.
2. Mineralocorticoid replacement therapy (oral fludrocortisone)
In primary adrenal failure, mineralocorticoid replacement is usually also
required in the form of fludrocortisone at 0.05 to 0.2 mg/day.
Adequacy of mineralocorticoid replacement should be assessed by
measuring electrolytes, orthostatics, and plasma renin activity.

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Mineralocorticoid replacement therapy is all too frequently neglected in

patients with adrenal failure.

3. Adrenal androgen replacement therapy

DHEA at 25 to 50 mg/day in both primary and secondary insufficiency
To date, the reported benefit is principally confined to female patients and
includes improvement in sexual function and well-being.

Pheochromocytoma (10% tumor)

This tumor originate from:

1. Adrenal medulla.
2. Or extraadrenal paraganglia cells as Organ Of Zuckerkandl (located
adjacent to the aorta)

Autopsy series is about 1%; this mean that if we have 100 patients with
hypertension we will find 1 of them has pheochromocytoma.
This tumor secrete;
1. Norepinephrine.
2. Epinephrine.
3. Dopamine and other neurohormones; Rarely

Pheochromocytoma has a rule of 10%;

o 10% bilateral
o 10% malignant
o 10% multifocal
o 10% extraadrenal
o 10% occur in children
o 10% familial (neuroectodermal disorders or MEN2)
o 10% normotensive; presented with normal blood pressure.

Presentation

Those patients are young presented with episodic headaches, tachycardia,

diaphoresis (increased sweating)

Hypertension;
o Sustained hypertension
o Sustained hypertension with paroxysm
o Paroxysmal hypertension with intermittent normotension

Nausea and vomiting

Flushing

Raynauds phenomenon

10% present in pheocrisis

50% found as incidentaloma; discovered incidentally by abdominal imaging.

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Diagnosis
1. 24hr urinary catecholamines (Norepinephrine, Epinephrine, Dopamine) and
metabolites (metanephrine, normetanephrine, VMA)
2. Plasma catecholamine or metabolites during episode
o Elevated serum epinephrine suggests pheochromocytoma in medulla or
organ of Zukerkandl

FNA of adrenal gland is contraindicated in pheochromocytoma

patients because it may precipitate hypertensive crisis.

By the previous 2 biochemical tests we measure Plasma and urinary

catecholamines level, if catecholamines increases then the patient has
pheochromocytoma, after that we try to localize the lesion by CT, MRI or
MIBG scan.
3. Localizing studies: CT, MRI, MIBG scan
1) Thin cut CT detects most lesions: 97% intraabdominal
2) MRI:
MRI is particularly useful because 90% of these tumors brighten
with T2-weighted images.
3) MIBG; if CT and MRI fail to reveal an adrenal tumor, radiolabeled
meta-iodobenzylguanidine (MIBG) can be a useful scanning technique
for locating tumors outside of the adrenal gland, such as those in the
organ of Zuckerkandl.

Treatment (the doctor didnt mansion it)

The treatment of pheochromocytoma is surgical

Must medically optimize prior to surgery

o Treat HTN
o Expand intravascular volume
o Control cardiac arrhythmias

Before the surgical procedure about 1-3 wks, -adrenergic antagonist (such
as Phenoxybenzamine, CCB or ACEI)
should be used to avoid
intraoperative hypertensive crisis

PO salt and fluid repletion

May need -blocker as antiarrhythmic. Do not start until after pt -blocked
Metyrosine; decreases catecholamine synthesis
Intraoperativlly; avoid anesthetic agents that precipitate catecholamine
secretion.
o Induce with thiopental/isoflurane
o Phentolamine (short acting -blocker)
o Sodium nitroprusside for BP control

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o Norepinephrine if needed for hypotension

o Lidocaine and esmolol to control arrhythmias.
Medical options: chemo, high dose I131 MIBG, XRT symptomatic relief

Follow up (the doctor didnt mansion it)

6.5% of benign pheochromocytomas recur

50% of malignant dz have residual dz

F/u with biochemical testing

Imaging not routinely necessary

Good luck

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