Topic

Guide:
I.
II.
III.
IV.
V.
VI.
VII.
VIII.

Historical Background
Anatomy
Adrenal Physiology
Disorders of the Adrenal Cortex
Disorders of the Adrenal Medulla
The Adrenal Incidentaloma
Adrenal Insufficieny
Adrenal Surgery

I. HISTORICAL BACKGROUND
Bartolomeo
Provided the first accurate anatomic account of
Eustachus: 1563 the adrenals
Baron James
Cuvier: 1805

Described the anatomic division of the adrenals

into cortex and medulla

Thomas
Addison: 1855

Described the features of adrenal insufficiency,

which still bears his name

DeCreccio: 1865

Provided the first description of congenital

adrenal hyperplasia (CAH) occurring in a female
pseudohermaphrodite in 1865

Felix Frankel:
1885

First identified pheochromocytomas but they

were not named as such until Ludwick Pick
(1912)

Ludwick Pick:
1912

Term pheochromocytoma
Noted the characteristic chromaffin reaction of
the tumor cells

Adrenaline:
1897

Agent from the adrenal medulla that elevated

blood pressure in dogs
Subsequently named epinephrine in 1897

Cesar Roux:
1926

Performed the first successful adrenalectomies

for pheochromocytoma in Switzerland

Charles Mayo:
1927

Performed one of the first successful

adrenalectomies for pheochromocytoma in the
United States

Harvey Cushing:
1932

Described 11 patients who had moon facies,

truncal obesity, hypertension, and other
features of the syndrome that now bears his
name

Kendall

First synthesized cortisone

Aldosterone:
1952

First identified in 1952

Jerome Conn:
1955

Described the syndrome resulting from

excessive secretion of Aldosterone

Knowsley-
Thornton: 1889

First successful adrenalectomy

Removed a large, 20-pound, adrenal tumor with
the left kidney in a 36-year-old woman in 1889

Perry Sargent:
1914

Performed the first planned adrenalectomy

Flank Approach

Used by Charles Mayo in 1927, he performed

adrenalectomies for pheochromocytoma; and
Roux in Switzerland

Michael Gagner:
1992

Described the first laparoscopic procedure for

the adrenal gland
Since then, laparoscopic adrenalectomy became
standard of care approach for majority of benign
adrenal tumors

Martin Walz

Developed and modernized laparoscopic

posterior retroperitoneal adrenalectomy

II.

ANATOMY

Anatomy
The adrenal glands are paired, retroperitoneal organs
located superior and medial to the kidneys at the level of the
eleventh ribs. The normal adrenal gland measures 5 3 1 cm and
weighs 4 to 5 g. The right gland is pyramidal shaped and lies in close
proximity to the right hemidiaphragm, liver, and infe- rior vena cava
(IVC). The left adrenal is closely associated with the aorta, spleen,
and tail of the pancreas.

Histology
A. Cortex
-
Appears yellow due to high lipid content
-
Accounts for about 80 to 90% of the glands volume.
-
Histologically divided into 3 zones:
(1) Zona Glomerulosa
(2) Zona Fasciculata
(3) Zona Reticularis

Outer are consists of small cells
Zona
Site of production of mineralocorticoid
Glomerulosa
aldosterone
Made up of larger Site of production of
cells that often
glucocorticoids and
Zona
appear foamy due adrenal androgens
Fasciculata
to multiple lipid
inclusions
Cells are smaller
Zona
compared to Zona
Reticularis
fasciculata

B. Medulla
-
10-15% of adrenal gland volume
-
Reddish-brown
-
Produces catecholamines (epinephrine &
norepinephrine)
-
Cells are polyhedral arranged in cords

Referred as chromaffin cells because they stain

specifically with chromium salts









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DR. BANNY C. BAY GENUINO APRIL 30, 2015

ADRENAL GLANDS
Dr. Banny Bay C. Genuino

III. PHYSIOLOGY

IV. DISORDERS OF THE ADRENAL CORTEX

Hyperaldosteronism

Primary (Conns Syndrome)

-
Adenoma (70%)
-
Idiopathic Bilateral Hyperplasia (30%)
-
Adrenocortical carcinoma and glucocorticoid-
suppressible hyperaldosteronism (<1%)

Seconadary

S/Sx: hypertension, hypochalemia

Dxcs:
-
Biochemical
-
Imaging: CT scan/MRI

Aldosterone functions mainly to increase sodium

reabsorption and potassium and hydrogen ion excretion at
the level of the renal distal convoluted tubule.

Once the biochemical diagnosis is confirmed, further
evaluation should be directed at determining which patients have a
unilateral aldosteronoma vs. bilateral hyperplasia, because surgery is
almost always curative for the former, but usually not the latter.
Only 20% to 30% of patients with hyperaldosteronism secondary to
bilateral adrenal hyperplasia benefit from surgery, and as described,
selective venous catheterization is useful to predict which patients
will respond. For the other patients, medical therapy with
spironolactone, amiloride, or triamterene is the mainstay of
management. Glucocorticoid-suppressible hyperaldosteronism is
treated by administering exogenous dexamethasone at doses of 0.5
to 1 mg daily. Treatment with spironolactone may help decrease
glucocorticoid requirements in this condition and avoid symptoms of
Cushings syndrome. Postoperatively, some patients experience
transient hypoaldosteronism requiring mineralocorticoids for up to 3
months. Rarely, acute Addisons disease may occur 2 to 3 days after
adrenalectomy. Adrenalectomy is >90% successful in improving
hypokalemia and about 70% successful in correcting hypertension.


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DR. BANNY C. BAY GENUINO APRIL 30, 2015

Cushings syndrome
-
Symptoms and signs resulting from hypersecretion of
cortisol regardless of etiology

Cushings disease
-

Pituitary tumor (adenoma) bilateral adrenal

hyperplasia and hypercortisolism

Etiology of Cushings Syndrome

ACTH-dependent (70%)

Pituitary adenoma or Cushings disease (~70%)

Ectopic ACTH production* (~10%)

Ectopic CRH production (<1%)

ACTH-independent (20%-30%)

Adrenal adenoma (10%-15%)

Adrenam carcinoma (5%-10%)

Adrenal hyperplasia pigmentedmicronodular cortical

hyperplasia or gastric inhibitory peptide-sensitive
macronodular hyperplasia (5%)
Other

Pseudo-Cushings Syndrome

Iatrogenic exogenous administration of steroids

*From small cell lung tumors, pancreatic islet cell tumors, medullar
thryoid cancers, pheochromoctyomas, and carcinoid tumors of the
lung, thymus, gut, pancreas, and ovary
ACTH = adrenocorticotropic hormone; CRH = corticotrophin-
releasing hormone

Most common cause of Cushings syndrome

EXOGENOUS

Most common cause of endogenous Cushings syndrome

PITUITARY ADENOMA (90%)

Features of Cushings Syndrome
SYSTEM
MANIFESTATION
Weight gain central obesity, buffalo hump,
General
supraclavicular fat pads
Hirsutism, plethora, purple striae, acne
Integumentary
ecchymosis
Cardiovascular
Hypertension
Musculoskeletal Generalized weakness, osteopenia
Neuropsychiatric Emotional lability, psychosis, depression
Metabolic
Diabetes or glucose intolerance, hyperlipidemia
Renal
Polyuria, renal stones
Impotence, decreased libido, mentsrual
Gonadal
irregularities


























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DR. BANNY C. BAY GENUINO APRIL 30, 2015

Hypercotisolism

Cushing described patients with a peculiar fat deposition,

amenorrhea, impotence (in men), hirsutism, purple striae,
hypertension, diabetes, and other features that constitute
the syndrome

Diagnostic studies for confirming Cushings syndrome:

-
OVERNIGHT DST
-
24-HOUR URINARY FREE CORTISOL
-
11:00 PM SALIVARY CORTISOL

Laparoscopic adrenalectomy: adrenal adenomas

Open adrenalectomy: large tumors (6 cm) or

adrenocortical cancers

Bilateral adrenalectomy: primary adrenal hyperplasia

Cushings disease:
-
Transsphenoidal excision of the pituitary adenoma:
successful in 80% of patients
-
Pituitary irradiation:

Persistent or recurrent disease after surgery

Associated with a high rate of

panhypopituitarism

Some patients develop visual deficits

-
Stereotactic radiosurgery

Uses CT guidance

Deliver high doses of radiotherapy to the tumor

(photon or gamma knife) and also bilateral
laparoscopic adrenalectomy

Medical adrenalectomy: (patients who fail to respond to

treatment)
-
KETOCONAZOLE
-
METYRAPONE
-
AMINOGLUTETHIMIDE

Ectopic ACTH production

-
Treating the primary tumor
-
Medical or bilateral laparoscopic adrenalectomy

Palliate patients with unresectable disease

Ectopic ACTH-secreting tumor cannot be

localized

Adrenocortical Cancer

Rare neoplasms: 2 per 1 million worldwide incidence

th
th

Bi-modal age distribution: children and adults (4 and 5

decades of life)

Majority are sporadic

Associated with germline mutations of:

-
p53 (LI-FRAUMENI SYNDROME)
-
MENIN (MULTIPLE ENDOCRINE NEOPLASIA TYPE 1)

Nonfunctioning (50%) Patients with functioning tumors

often present with the rapid

Cortisol-secreting
onset of Cushings syndrome
(30%)
accompanied by virilizing

Androgens (20%)
features. Nonfunctioning tumors

Estrogens (10%)
more commonly present with an

Aldosterone (2%)
enlarging abdominal mass and

Multiple hormones
abdominal or back pain. Rarely,
(35%)
weight loss, anorexia, and
nausea may be present.

What is the most common functioning adrenocortical

cancer = CORTISOL-SECRETING

What is the least common functioning adrenocortical

cancer = ALDOSTERONE

Diagnostics
-
Serum electrolyte levels
-
Urinary catecholamines
-
Dexamethasone suppression test
-
24-hour urine collection for cortisol
-
CT and MRI scans:

SIZE of the adrenal mass on imaging studies is

the single most important criterion to help
diagnose malignancy

The most important predictor of survival in patients with

adrenal cancer is the ADEQUACY OF RESECTION!

Adjuvant setting?

Surgical debulking

Sex Steroid Excess

Virilizing syndromes
-
PLASMA DHEA
-
URINE 17-KETO-STEROIDS
-
GLUCOCORTICOIDS

Feminizing adrenal tumors

-
ESTROGEN LEVEL
-
URINE 17-KETO-STEROIDS

Virilizing tumors produce excessive amounts of the androgen
precursor, DHEA, which can be measured in plasma or urine as 17-
ketosteroids. Patients with feminizing tumors also have elevated
urinary 17-ketosteroids in addition to increased estrogen levels.
Androgen-producing tumors often are associated with production of
other hormones such as glucocorticoids.

Treatment: adrenalectomy

Adrenolytic drugs
-
MITOTANE
-
AMINOGLUTETHIMIDE
-
KETOCONAZOLE


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DR. BANNY C. BAY GENUINO APRIL 30, 2015

Sudden death may occur in patients with

undiagnosed tumors who undergo other surgeries or
biopsy.
-
Symptoms such as anxiety, tremulousness,
paresthesias, flushing, chest pain, shortness of
breath, abdominal pain, nausea, vomiting, and others
are and may be episodic in nature

Dxcs:
-
Biochemical studies (24-hour urine samples for
catecholamines and their metabolites, as well as by
determining plasma metanephrine levels)

Urinary metanephrines

VMA measurements
-
Radiologic studies

CT scan

MRI

MIBG (metaiodobenzylguanidine) specific for

pheochromocytoma

Treatment:
-
Medical

Blood pressure control

o -blockers such as phenoxybenzamine
o -Blockers such as propranolol

Volume repletion
-
Surgical

Adrenalectomy is the treatment of choice for

patients with pheochromocytoma. The chief goal
of surgery is to resect the tumor completely with
minimal tumor manipulation or rupture of the
tumor capsule.

Hereditary Pheochromocytomas

Multiple and bilateral

Unilateral adrenalectomy

Cortical-sparing subtotal adrenalectomy

Laparoscopic subtotal adrenalectomy

Recurrent pheochromocytoma

Autotransplantation of adrenocortical tissue

However, most pheochromocytomas <5 cm in diameter can be
safely resected laparoscopically.

Malignant Pheochromocytomas

12% to 29% of pheochromocytomas

Decreased survival

No definitive histologic criteria defining malignant

pheochromocytomas
-
Malignancy usually is diagnosed when there is
evidence of invasion into surrounding structures or
distant metastases
-
Most common sites: bone, liver, regional lymph
nodes, lung, and peritoneum

Brain, pleura, skin, and muscles may also

occasionally be involved

Pleomorphism, nuclear atypia, and abundant mitotic

figures are seen in benign tumors. Capsular and vascular
invasion may be seen in benign lesions as well.





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DR. BANNY C. BAY GENUINO APRIL 30, 2015

Congenital Adrenal Hyperplasia

A group of disorders that result from deficiencies or

complete absence of enzymes involved in adrenal
steroidogenesis

CONGENITAL ADRENAL LIPOID HYPERPLASIA

-
Most severe form of CAH
-
CHOLESTEROL DESMOLASE DEFICIENCY
-
Disruption of all steroid biosynthetic pathways
fatal salt-wasting syndrome in phenotypic female
patients

21 -HYDROXYLASE most common enzyme deficiency

nd

11 -HYDROXYLASE 2 most common enzyme

deficiency

Dxcs:
-
Karyotype analysis
-
Measurement of plasma and urinary steroids

Imaging:
-
CT
-
MRI
-
NP-59

Treatment:
-
Medically:

Traditionally

Cortisol and mineralocorticoid replacement to

suppress the hypothalamic-pituitary-adrenal axis

The doses of steroids required often are

supraphysiologic and lead to iatrogenic
hypercortisolism
-
Bilateral laparoscopic adrenalectomy

Recently has been proposed as an alternative

treatment

Has been successfully performed in a limited

number of patients for various forms of CAH

V. DISORDERS OF THE ADRENAL MEDULLA
Pheochromocytoma

The 10 percent tumor

-
10% are BILATERAL
-
10% are MALIGNANT
-
10% OCCUR IN PEDIATERIC PATIENTS
-
10% are EXTRA-ADRENAL
-
10% are FAMILIAL

Functional Paraganglioma:
-
Extra-adrenal tumors
-
At sites of sympathetic ganglia in the ORGAN OF
ZUCKERKANDL, NECK, MEDIASTINUM, ABDOMEN,
AND PELVIS

S/Sx:
-
The classic triad: Headache, palpitations, and
diaphoresis
-
Nonspecific
-
Cardiovascular complications
-
Exercise, micturition, defecation precipitating
factors
-
Hypertension: most common clinical sign; can be

Paroxysmal with intervening normotension

Sustained with paroxysms

Sustained hypertension alone.

VI. THE ADRENAL INCIDENTALOMA

Incidentalomas
-
Lesions discovered during imaging performed for
unrelated reasons
-
Excludes tumors discovered on imaging studies
performed for evaluating symptoms of hormone
hypersecretion or staging patients with known cancer
-
Incidence: 0.4% to 4.4%.
MEMORIZE!

VII. ADRENAL INSUFFICIENCY

Etiology of Adrenal Insufficiency
PRIMARY
SECONDARY
Autoimmune (autoimmune polyglandular
disease type I and II)
Exogenous
Infectious TB, fungi, CMV, HIV
glucocorticoid
Hemorrhage spontaneous
therapy
(Waterhouse-Friderichsen syndrome)
Bilateral
and secondary to stress, trauma,
adrenalectomy
infections, coagulopathy, or
Pituitary or
anticoagulants
hypothalamic tumors
Metastases
Pituitary hemorrhage
Infiltrative disorders amyloidosis,
(postpartum
hemochromatosis
Sheehans syndrome)
Adrenoleukodystrophy
Transsphenoidal
Congenital adrenal hyperplasia
resection of pituitary
Drugs ketoconazole, metyrapone,
tumor
aminoglutethimide, mitotane

Most common cause of insufficiency = EXOGENOUS

S/Sx:
-
Stressed patients with any of the relevant risk factors
-
May mimic sepsis, myocardial infarction, or
pulmonary embolus
-
Presents with fever, weakness, confusion, nausea,
vomiting, lethargy, abdominal pain, or severe
hypotension.

Chronic Adrenal Insufficiency

-
Patients with metastatic tumors, may be more subtle
-
Fatigue, salt craving, weight loss, nausea, vomiting,
and abdominal pain
-
Patients may appear hyperpigmented from increased
secretion of CRH and ACTH, with increased -
melanocyte-stimulating hormone side-products.

Diagnostic Studies
-
Laboratory findings: hyponatremia, hyperkalemia,
eosinophilia, mild azotemia, and fasting or reactive
hypoglycemia.
-
PBS: may demonstrate eosinophilia in approximately
20% of patient
-
ACTH stimulation test

ACTH is infused intravenously, and cortisol levels

are measured at 0, 30, and 60 minutes. Peak
cortisol levels <20 g/dL suggest adrenal
insufficiency.

HIGH ACTH LEVELS WITH LOW PLASMA

CORTISOL levels are diagnostic of primary
adrenal insufficiency.

Hydrocortisone interferes with ACTH which is

used in diagnosis of insufficiency

Management:
-
Volume resuscitation
-
Dexamethasone (4 mg) should be administered
intravenously. Hydrocortisone (100 mg intravenously
every 8 hours) also may be used, but it interferes with
testing of cortisol levels.
-
Infection should be sought, identified, and treated.
The ACTH stimulation test should be performed to
confirm the diagnosis
-
Mineralocorticoids (fludrocortisone 0.050.1 mg
daily) may be required once the saline infusions are
discontinued.

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DR. BANNY C. BAY GENUINO APRIL 30, 2015

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DR. BANNY C. BAY GENUINO APRIL 30, 2015

VIII. ADRENAL SURGERY

Open
MIS
Anterior approach
Transabdominal (anterior and
Posterior approach
lateral)
Lateral approach
Retroperitoneal (lateral or
posterior) approach)
Laparoscopic adrenalectomy has rapidly become the
standard procedure of choice for the excision of most benign-
appearing adrenal lesions <6 cm in diameter. The role of
laparoscopic adrenalectomy in the management of adrenocortical
cancers is controversial.

Complications of Adrenal Surgery

Cushings syndrome:
-
Prone to infectious
-
Thrombotic complications

Creation of pneumoperitoneum

Excessive retraction and dissection

Postoperative hemodynamic instability

-
Pheochromocytomas

Adrenal insufficiency after bilateral adrenalectomy and

sometimes after unilat- eral adrenalectomy

Long-term morbidity: NELSONS SYNDROME

-
Nelsons Syndrome = enlargement of pituitary gland
after you remove the adrenals
-
This leads to increased ACTH levels,
hyperpigmentation, visual field defects, headaches,
and extraocular muscle palsies. Transsphenoidal
pituitary resection is the ini- tial mode of therapy, and
external-beam radiotherapy is used in patients with
residual tumor or extrasellar invasion.