Chapter 79. Adrenal Glands

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Jeremy Irvan, M.D.

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Greenfield's Surgery: Scientific Principles and Practice
Chapter 79: Adrenal Glands

Author(s): John A. Olson
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ANATOMY
The adrenal glands are bilateral, retroperitoneal, endocrine organs located adjacent to the superior pole of
each kidney. These glands appear grossly as flat, triangular structures each weighing approximately 4 g.
Each adrenal gland is composed of two distinct endocrine organs, the cortex and medulla. The outer adrenal
cortex is bright yellow and nodular, whereas the adrenal medulla is red-brown in color and is sandwiched
between the thin layers of the cortex. The adrenals are embedded in retroperitoneal perinephric fat but can
be identified as distinct structures by their golden brown, nodular appearance. The right adrenal gland abuts
the inferior vena cava medially and lies in close proximity to the diaphragmatic crus posteriorly and the liver
anteriorly. The left adrenal gland resides between the kidney and aorta, immediately deep to the tail of the
pancreas and spleen.
Embryologically, fetal and definitive adrenal cortices arise from coelomic mesoderm near the urogenital
ridge during the fourth to sixth weeks of gestation. Postnatally, the fetal cortex involutes, leaving only the
definitive cortex to differentiate into the three adult zonae, the glomerulosa, fasciculata, and reticularis. The
adrenal medulla develops from the neural crest during the fifth gestational week and migrates along
paraaortic and paravertebral routes to join the developing cortex. Ectopic adrenal cortex and medulla may be
found anywhere along their respective paths of embryologic migration. Most neural crest tissue regresses,
however, extra-adrenal neural crest derivatives may be found along the retroperitoneum and at the aortic
bifurcation (organ of Zuckerkandl).
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The adrenal cortex is composed of three distinct zones. The outer zona glomerulosa, located just beneath the
fibrous gland capsule, is the site of mineralocorticoid production. The middle zona fasciculata, composed of
linear arrays of large, foamy cells with lipid inclusions, is the predominant site of glucocorticoid and adrenal
sex steroid biosynthesis. The inner zona reticularis is the primary location of synthesis of adrenal androgens.
Both the zona fasciculata and zona reticularis respond to stimulation by adrenocorticotropic hormone
(ACTH). The adrenal medulla is smaller than the cortex. Cells of the adrenal medulla appear as
homogeneous sheets, with large, irregular, atypical-looking nuclei. The cytoplasm of these cells has
numerous secretory granules containing catecholamines, neuron-specific enolase, and chromogranin.
Catecholamines in these granules precipitate chromium salts, which is the basis for the term chromaffi n
cells.
Caption:
FIGURE 79.1 (A) Arterial (dark shaded) and venous (light shaded) anatomy of the adrenal glands. (B)
Schematic showing outer adrenal cortex (light shaded) and inner adrenal medulla (dark shaded).
The adrenal glands have an extensive vascular supply derived from branches of the inferior phrenic artery
superiorly, the aorta medially and the renal artery inferiorly. Venous return from the right adrenal gland
empties directly into the inferior vena cava through a wide but short central vein. Venous drainage from the
left adrenal gland empties into a smaller vein that shares a common trunk with the left phrenic vein.
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Together they join the left renal vein (Fig. 79.1).
BIOCHEMISTRY AND PHYSIOLOGY
Adrenal Cortex
Adrenocortical steroid hormones, glucocorticoids, mineralocorticoids, and androgenic steroids are all
synthetic derivatives of cholesterol that are either extracted from plasma or synthesized intracellularly (Fig.
79.2). In mitochondria of cells in the adrenal cortex, cholesterol is converted by desmolase (CYP11A1) to
delta-5-pregnenolone, the common parent compound for all adrenal cortex steroids. Pregnenolone is then
shunted to the three biosynthetic pathways, each compartmentalized within the adrenal according to
synthetic capabilities within each zone. In the zonae fasciculata and reticularis, pregnenolone is either
converted to progesterone by 3-beta-hydroxysteroid dehydrogenase or is oxidized at position 17 by 17-alpha
hydroxylase (CYP17) to form 17-hydroxypregnenolone. In the zona fasciculata, progesterone is
hydroxylated by CYP17 at position 17 to form 17-hydroxyprogesterone. Subsequently,
17-hydroxyprogesterone is sequentially hydroxylated at the 21 position by 21-beta hydroxylase (CYP21A2)
and at position 11 by 11-beta hydroxylase (CYP11B1) to form cortisol. In the zona reticularis, the
androgenic steroids dehydroepiandrostenedione (DHEA) and androstenedione are made from
17-hydroxypregnenolone and 17-hydroxyprogesterone, respectively. Collectively, the glucocorticoid and
androgenic steroids are known as 17-hydroxy corticosteroids and 17-hydroxy ketosteroids. In the zona
glomerulosa, progesterone is not hydroxylated at the 17 position owing to the lack of enzyme at this
location. Instead aldosterone is made from progesterone by a sequential series of hydroxy- lation steps at
position 21 by CYP21A2, position 11 by CYP11B1, and position 18 by aldosterone synthase (CYP11B2 and
P450c11as). The zona glomerulosa is well suited to aldosterone biosynthesis because of the relative lack of
17-hydroxylase and the exclusive expression of aldosterone synthase, required for the conversion of
corticosterone to aldosterone.
Cortisol
Cortisol is the predominant glucocorticoid in humans. Production and release of cortisol is tightly regulated
by a complex feedback relationship between the hypothalamus, corticotrophs of the anterior pituitary, and
cells of the adrenal cortex zonae fasciculata and reticularis. This endocrine system is called the
hypothalamic-pituitary-adrenal (HPA) axis. Communication within the HPA axis is mediated by synthesis
and secretion of corticotrophin-releasing hormone (CRH) by the hypothalamus and ACTH production by
corticotrophs of the anterior pituitary (Fig. 79.3). ACTH is a cleavage product of a precursor polipeptide,
proopiomelanocortin (POMC) that is built of 241 amino acid residues within corticotroph cells of the
anterior and intermedate lobes of the pituitary. Several derivatives of POMC are important biologically
active substances, including ACTH. Under stimlation of hypothalamic CRH stimulus, POMC can be
cleaved into ACTH and !-lipotropic hormone in the anterior lobe. ACTH acts directly on the adrenal to
regulate cortisol production by cells within the zonae fasciculata and reticularis. Feedback loops involving
cortisol, hypothalamic CRH, and pituitary ACTH keep the concentration of cortisol in plasma within a
narrow range of 10 to 15 "g/dL. Typical daily production of cortisol in humans ranges between 10 to 30 mg
and can increase to as high as 300 mg per day under conditions of maximal stress.
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Caption:
FIGURE 79.2 Steroid biosynthetic pathways in the adrenal cortex. Steroids and precursors are shown in
square boxes. Enzymes are shown in stippled boxes. Enzyme gene symbol designations are: CYP11A1,
desmolase; CYP17, 17! hydroxylase (±17,20 lyase*); 3" HSD, 3" Hydroxysteroid dehydrogenase;
CYP21A2, 21 hydroxylase; CYP11B1, 11" hydroxylase; CYP11B2, Aldosterone synthase. Inset: Basic
steroid ring structure. The four basic carbon rings are designated A, B, C, and D. Individual carbons at
sites of steroidegenic enzyme activity are designated numerically.
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Caption:
FIGURE 79.3 Schematic of hypothalamic-pituitary-adrenal axis for cortisol. Regulatory feedback
relationships are designated with arrows.
In circulation, cortisol is protein bound to transcortin and albumin with a small percentage of free cortisol
available to target tissues. The half-life of cortisol in circulation is 90 minutes. Cortisol is metabolized in the
liver to the inactive metabolites dihydrocortisol and tetrahydrocortisol, which become conjugated to
glucuronidate and excreted in the urine. These urinary metabolites, collectively known as
17-hydroxycorticosteroids, as well as free cortisol, can be measured in the urine.
Cortisol binds to specific intracellular cytoplasmic receptors, causing translocation of activated receptor-
ligand complexes to the nucleus. Biologic effects result from transcriptional activation of genes and may be
grouped into intermediary metabolism, immunomodulation, and regulation of intravascular volume (Table
79.1). Important effects of cortisol on intermediary metabolism center on raising blood glucose directly and
indirectly by providing substrate for gluconeogenesis by the liver. These effects include (a) stimulation of
glucagon and inhibition of insulin-stimulated glucose uptake by cells; (b) decrease in peripheral protein
synthesis and increase in proteolysis, thus delivering gluconeogenic amino acids to the liver; and (c)
stimulation of peripheral lipolysis. In effect, cortisol acts anabolically in vital organs to preserve glucose
supply and catabolically in peripheral tissues to mobilize gluconeogenic substrates. Cortisol also possesses
profound antiinflammatory and immunosuppressive activities. Impairment of cellular immunity is due to
inhibition of interleukin production, impairment of monocyte and neutrophil chemotaxis despite raised
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leukocyte counts, and reduction of T-cell activation. Humoral immunity is inhibited by inhibition of T-cell
stimulation of B cells and by direct inhibition of B-cell proliferation and activation. These
immunomodulatory effects may also underlie the impairment of normal wound healing seen in states of
cortisol excess. Cortisol also regulates intravascular volume through renal retention of sodium and maintains
blood pressure through inotropic and chronotropic effects on the heart as well as by increasing peripheral
vascular resistance. In bone, glucocorticoids promote osteopenia by inhibition of bone formation by
osteoblasts.
TABLE 79.1 SYSTEMIC EFFECTS OF CORTISOL

Function Normal amounts Excessive amounts
Metabolic
Protein Proteolysis Muscle wasting
Glucose Gluconeogenesis Hyperglycemia
Low-use peripheral lipolysisLimb thinness
Fat
Central lipogenesis Truncal obesity
Mucosal cells Ulceration
Gastrointestinal
Prostaglandin Pancreatitis(&quest;)
Chronotropic, inotropic
Cardiovascular Hypertension
Vascular resistance
Renal Sodium resorption Hypertension
Bone Osteoblastic development Osteoporosis
Circulating cells
Inflammatory and immuneSoluble mediators Infection
Antigen processing
Fibroblasts Striae
Wound healing
Epithelial cell Dehiscence
Aldosterone
Aldosterone is the principle mineralocorticoid in humans. Aldosterone secretion by the cells of the adrenal
zona glomerulosa is regulated by the renin-angiotensin system and by plasma potassium (Fig. 79.4).
Aldosterone is also regulated to a lesser degree by ACTH and plasma sodium concentration.
Juxtaglomerular myoepithelial cells lining afferent arterioles of the kidney sense renal blood flow and
pressure, and they secrete renin in response to decreased perfusion. Renin enzymatically activates
angiotensinogen to the inactive decapeptide precursor, angiotensin I. Angiotensin I is converted to
angiotensin II by angiotensin converting enzyme in the lung. Angiotensin II has three major effects: (a)
arteriolar vasoconstriction; (b) renal sodium retention; and (c) increased aldosterone biosynthesis, each of
which results in sodium retention and potassium excretion by the kidney. These effects work together to
maintain arterial blood pressure as well as blood volume. Physiologic conditions that stimulate the renin-
angiotensin cascade and aldosterone release include dehydration, upright posture and hemorrhage.
Inhibitory factors include volume repletion. Postural changes in renin-angiotensin and aldosterone are
mediated by the sympathetic nervous system.
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Caption:
FIGURE 79.4 Regulatory relationships of renin, the angiotensins, and their sites of production and
enzymatic conversion.
Under normal circumstances, aldosterone secretion is controlled by total body sodium and potassium levels.
Excess sodium intake suppresses renin activity and leading to decreased aldosterone levels and increased
renal excretion of sodium. Conversely, sodium depletion stimulates the renin-angiotensin system and
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aldosterone production, which promotes sodium retention by the kidney. Increased potassium intake directly
decreases renin release and aldosterone production; decreasing potassium intake increases renin release.
Humans with normal sodium intake typically produce 100 to 150 mg of aldosterone per day.
In circulation, aldosterone is bound to albumin and transcortin with a small percentage of free aldosterone
available to target tissues. The half-life of aldosterone in plasma is 15 minutes. Aldosterone is metabolized
rapidly in the liver and conjugated to glucuronidate, which is excreted in the urine. In liver failure,
metabolism of aldosterone is impaired leading to elevated levels and fluid retention.
Aldosterone is the major regulator of extracellular fluid volume and potassium homeostasis (Table 79.2).
Aldosterone binds to high affinity aldosterone receptors in target tissues, including cells of the distal
convoluted tubule in the kidney (the major site of action), the salivary glands, and colonic mucosa (minor
sites). Stimulation of these cells results in retention of sodium and excretion of potassium. Retention of
sodium in the kidney leads to passive reabsorption of water and an increase in extracellular fluid volume. To
balance aldosterone-mediated retention of positively charged sodium ions the kidney epithelium releases
intracellular potassium into the distal convoluted tubule for excretion in the urine. Hydrogen ion is also
released causing acidification of the urine.
Adrenal Androgens
Adrenal C-19 androgenic steroids, include DHEA and delta-4 androstenedione, are synthesized in cells of
the zona reticularis. These steroids promote secondary sexual characteristics in men and virilization in
women. DHEA is the major adrenal androgen, while androstenedione is relatively minor. Both are relatively
weak androgens and exert their effects on target tissue after local tissue conversion to testosterone. Unlike
gonadal androgens, adrenal androgens are regulated by ACTH, not gonadotropins, and can therefore be
inhibited by glucocorticoid administration.
TABLE 79.2 EFFECTS OF ALDOSTERONE SECRETION

Tubular action Normal amounts Excessive amounts
Hypertension
Increased resorption of sodium Protects against low-volume statesPositive sodium balance
Hyporeninemia
Hypokalemia
Metabolic alkalosis
Decreased resorption of potassiumProtects against hyperkalemia Hyperglycemia
Nocturia, polyuria
Muscle weakness
Adrenal Medulla
Catecholamines of the adrenal medulla include epinephrine, norepinephrine, and dopamine. These
vasoactive hormones are synthetic derivatives of the amino acid tyrosine (Fig. 79.5). The biosynthetic
pathway that converts tyrosine to active catecholamines involves four sequential enzymatic reactions: (a)
tyrosine is converted to L-dihydroxyphenylalanine (dopa) by tyrosine hydroxylase; (b) dopa is converted to
dopamine by aromatic-L-amino acid decarboxylase; (c) dopamine is converted to norepinephrine by
dopamine beta hydroxylase; and (d) norepinephrine is converted to epinephrine by phenylethanolamine-
N-methyltransferase (PNMT). Epinephrine is the major (80%) catecholamine stored in the adrenal medulla,
followed by norepinephrine (20%) and dopamine (<1%). Tissue expression of the enzyme PNMT is limited
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to cells of either the adrenal medulla or organ of Zuckerkandl, located near the aortic bifurcation, thus most
extraadrenal pheochromocytomas produce norepinephrine, rather than epinephrine.
A complex regulatory network governs synthesis and secretion of catecholamines. Factors that increase
catecholamine release include splanchnic nerve stimulation, stress, and glucocorticoids. The metabolic
milieu within the adrenal medulla also greatly influences catecholamine synthesis by regulating enzymatic
activity: glucocorticoids, phospholipids, cyclic adenosine monophosphate, adenosine triphosphate, protein
kinase, and magnesium increase activity of PNMT and decrease catecholamine negative feedback.
Catecholamines are stored and secreted from granules within cells of the medulla in association with the
matrix protein chromogranin. Chromogranin A is measurable in the blood and their measurement may
support the biochemical testing for pheochromocytoma, as well as other functional neuroendocrine tumors.
Caption:
FIGURE 79.5 Catecholamine biosynthetic and metabolism pathways. Precursors, catecholamines, and
metabolites are shown in square boxes. Enzymes are shown in stippled boxes. Enzyme gene symbol
designations are: TH, tyrosine hydroxylase; AADC, aromatic-L-amino acid decarboxylase; DBH, dopamine
" hydroxylase; PNMT, phenylethanolamine-N-methyltransferase; COMT, catechol-O-methyltransferase;
MAO, monoamine oxidase. VMA, 3-methoxy-4-hydroxy-mandelic acid. TABLE 79.3 CATECHOLAMINE
EFFECTS
Receptor class Normal amounts Excessive amounts
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Chronotropic, inotropic Tachycardia

!1 Sweat glands Sweating
Decreased glucose use Hyperglycemia
!2 Smooth muscle relaxation Hypotension
Smooth muscle contraction
Hypertension
#1 Gluconeogenesis
Glycogenolysis
Hyperglycemia
Suppressed insulin effects
#2 Smooth muscle contraction aPallor
a
Platelet aggregation.
Catecholamines act on target tissues through membrane-bound receptors. Pharmacologic distinction of

adrenergic receptors is made based on their relative responsiveness to natural and artificial bioamines.
Alpha-adrenergic receptors show highest affinity for norepinephrine, less for epinephrine, and least for
isoproterenol. Beta-adrenergic receptors are most responsive to isoproterenol and least to norepinephrine. In
addition, specific antagonists recognize each receptor class: alpha-receptors are antagonized by
phentolamine and phenoxybenzamine, and beta-receptors are blocked by propranolol and related
compounds. Beta-adrenergic receptor subtypes include beta-1, which is present in cardiac muscle, adipose
tissue, and small intestine, and beta-2 receptors, which are found in vascular, tracheal, and uterine smooth
muscle, skeletal muscle, and liver. Alpha-adrenergic receptors are similarly subdivided: alpha-1 receptors
mediate vasoconstriction whereas alpha-2 receptors modulate presynaptic norepinephrine release and
platelet aggregation. (Table 79.3)
Metabolism of catecholamines occurs through three mechanisms: by specific uptake by sympathetic

neurons, by nonspecific uptake and degradation by peripheral tissues, and by excretion in the urine.
Catecholamines are metabolized in liver and kidney by two enzymes, monoamine oxidase and catechol-
O-methyltransferase (Fig. 79.5). In these tissues, monoamine oxidase and catechol-O-methyltransferase
convert epinephrine or norepinephrine to normetanephrine, and metanephrine, 3,4- dihydroxy-mandelic
acid, and 3-methoxy-4-hydroxy-mandelic acid. These inactive metabolites are excreted by the kidney and
are measurable in the urine either as free compounds or as conjugates of glucuronide or sulfate.
DISEASES OF THE ADRENAL CORTEX
Hypercortisolism
The term hypercortisolism refers to the physiologic state of glucocorticoid excess. This disorder is rare, with
an estimated incidence of 10 per million population. The most common cause of hypercortisolism is the
administration of exogenous steroids as immunosuppressive therapy for inflammatory disorders or after
organ transplantation. Endogenous hypercortisolism, or Cushing syndrome, in all cases is caused by
increased adrenal production of cortisol, which may be ACTH dependent (ACTH elevated) or independent
(ACTH suppressed). Some patients with major depression or chronic alcoholism have abnormally high
cortisol secretion and may appear to have clinical and biochemical features of Cushing syndrome. Pseudo-
Cushing syndrome responds to treatment of the underlying disorder.
Cushing syndrome is ACTH dependent in 80% to 90% of cases. Such ACTH-dependent hypercortisolism is
most often (80% to 90% of cases) caused by an ACTH-secreting pituitary adenoma (termed Cushing
disease). Ectopic ACTH- producing nonendocrine tumors (mostly non-small cell lung cancer and bronchial
carcinoids) represent 10% to 20% of cases of ACTH-dependent Cushing syndrome. All causes of
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ACTH-dependent Cushing syndrome involve bilateral adrenal hyperplasia in response to ACTH

stimulation.
Of patients with endogenous Cushing syndrome, 10% to 25% have ACTH-independent disease caused by a
primary adrenal cause. A solitary adrenal adenoma is present in 80% to 90% of these patients and is often
associated with atrophy of both adjacent and contralateral adrenocortical tissue. Nodular cortical hyperplasia
of both glands causes the remaining cases of primary adrenal Cushing syndrome. Although nodular
hyperplasia represents a diffuse process, one or more distinct nodules may simulate adenomas. Rarely
tumors secrete CRH ectopically, leading to ACTH-independent (though ACTH is elevated) Cushing
syndrome with secondary adrenal hypertrophy.
Signs and Symptoms
Clinical features of cortisol excess are listed in Table 79.1. Truncal obesity (orange on toothpicks),
accumulation of fat around the head and neck (moon facies and buffalo hump), and muscle wasting are
present in most patients. Patients often have purple striae and purpura on the abdomen and extremities.
Hirsutism may be present in women. High blood pressure is common and is usually moderate, although
malignant hypertension has been observed. Muscle weakness and bone pain, particularly backache, are also
common. Weakness is caused part to proximal muscle wasting but also to hypokalemia. Osteoporosis is
common and pathologic fractures are observed in advanced cases. Neurologic symptoms, including
headache, emotional lability, depression, and even psychosis may be observed. Glucose intolerance is
common but can often be managed by alterations in diet alone. The serum potassium level may be low
secondary to the weak mineralocorticoid properties of cortisol.
Autonomous glucocorticoid production without specific signs and symptoms of Cushing syndrome is
termed subclinical Cushing syndrome. This condition is being diagnosed with increased frequency because
of the detection of adrenal incidentalomas by routine CT. A substantial percentage of incidentalomas are
hormonally active, with 5% to 20% of the tumors producing glucocorticoids. The estimated prevalence of
subclinical hypercortisolism is 79 cases per 100,000 persons, substantially higher than classic Cushing
syndrome. Depending on the amounts of glucocorticoids secreted by the tumor, the clinical spectrum ranges
from slightly attenuated diurnal cortisol rhythm to atrophy of the contralateral adrenal gland. Patients with
subclinical Cushing syndrome lack the classical stigmata of hypercortisolism but have a high prevalence of
obesity, hypertension, and type 2 diabetes.
Diagnosis
The investigation of suspected Cushing syndrome should answer two questions: (a) Does the patient have
hypercortisolism&quest; (b) If the answer is yes, then what is the cause&quest; It is worthwhile to
emphasize that the diagnosis of Cushing syndrome is biochemical. Radiologic investigations should not be
undertaken until Cushing syndrome has been confirmed and its likely etiology characterized biochemically.
Hypercortisolism insensitive to suppression by administration of exogenous glucocorticoid is the sine qua

non of Cushing syndrome. The low-dose dexamethasone suppression test is the best test in patients with
suspected Cushing syndrome. For this test, 1 mg of dexamethasone is administered orally at 11 PM and
plasma cortisol is obtained at 8 AM the following day. Normal individuals suppress cortisol to below 5
"g/dL. Patients with Cushing syndrome fail to suppress below 5 "g/dL. False-positive test results occur in
10% to 15% of cases with the overnight test and occur especially in patients with obesity or alcoholism or in
those taking estrogens or phenytoin. Measurement of free cortisol (not metabolites) in three consecutive
24-hour collections of urine is also a good screening test for Cushing syndrome. Collections should include
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concurrent creatinine measurement to evaluate the completeness of the collection. A 24-hour urinary free
cortisol level greater than 100 "g is diagnostic of Cushing syndrome. This test may be less sensitive than the
low-dose dexamethasone suppression test in mild hypercortisolism. Plasma cortisol levels can normally
vary considerably during a 24-hour period, so a single random plasma cortisol level is not helpful in
establishing a diagnosis of Cushing syndrome.
Once the presence hypercortisolism is established, the next task is to determine ACTH-dependent (pituitary
or ectopic source) from ACTH-independent (primary adrenal) causes. Measurement of basal ACTH by
immunoradiometric assay is the best test to make this distinction. Plasma ACTH levels are normally
between 10 and 100 pg. Suppression of the absolute level of ACTH below 5 pg per mL is nearly diagnostic
of adrenocortical neoplasms, which secrete high levels of cortisol and inhibit ACTH release by the pituitary.
Patients with pituitary neoplasms and secondary bilateral adrenocortical hyperplasia have ACTH levels that
may range from the upper limits of normal (15 pg. per mL) to 500 pg per mL. The highest plasma levels of
ACTH (more than 1000 pg per mL) are in patients with ACTH-producing nonendocrine tumors such as
non-small cell lung cancer.
Although 80% to 90% of patients with ACTH-dependent Cushing syndrome have Cushing disease, a high
dose dexamethasone suppression test may be required to exclude ectopic ACTH syndrome.
Hypercortisolism caused by to ACTH-secreting pituitary adenomas is suppressed at least partially by high
dexamethasone, whereas hypercortisolism caused by adrenal tumors and ectopic ACTH-producing tumors is
not suppressed. For this test 2 mg dexamethasone is administered orally every 6 hours for 2 days, and a
24-hour urine collection for free cortisol is taken during the second day. About 90% of patients with
pituitary source Cushing disease have a 50% reduction in urine free cortisol. The specificity of the test can
be improved to 100% for diagnosing pituitary disease if more than 90% suppression in urinary free cortisol
is used.
Biochemical testing of suspected Cushing syndrome is followed by radiologic studies. Pituitary adenomas
are best imaged with gadolinium-enhanced MRI of the sella turcica, which has a sensitivity approaching
100%, although small pituitary microadenomas may be missed. Patients with ACTH-independent Cushing
syndrome require thin-section CT or MRI of the adrenal, which identifies adrenal abnormalities with more
than 95% sensitivity. CT or MRI of the chest may identify a source of ectopic ACTH and should be
undertaken in patients with elevated ACTH and hypercortisolism that cannot be suppressed by high-dose
dexamethasone.
Despite the accuracy of biochemical testing and radiographic localization, a pituitary versus ectopic source
of ACTH sometimes cannot be determined. Bilateral inferior petrosal sinus sampling is the best test to settle
this issue. Simultaneous bilateral petrosal sinus and peripheral blood samples are obtained before and after
peripheral intravenous injection of 1 "g per kg CRH. An inferior petrosal sinus to peripheral plasma ACTH
ratio of 2.0 at basal stimulated or of 3.0 after CRH administration is 100% sensitive and specific for pituitary
adenoma. Comparison of right and left inferior petrosal sinus ratios may also lateralize the adenoma.
The laboratory approach to the diagnosis of Cushing syndrome is summarized in Algorithm 79.1. A careful
history and physical examination form the basis for suspecting this condition. A low-dose dexamethasone
suppression test and/or urinary free cortisol measurement provide initial evidence for the diagnosis. Plasma
ACTH determination and the high-dose dexamethasone suppression test are then used to identify the
underlying cause of excess cortisol production by the adrenal cortex. Imaging studies support the cause of
Cushing syndrome suggested by biochemical testing and localize the site for subsequent treatment.
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Caption:
ALGORITHM 79.1 Diagnosis of hypercortisolism. ACTH, adrenocorticotropic hormone; IRMA,
immunoradiometric assay; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron
emission tomography.
Treatment
ACTH-dependent Cushing syndrome is best treated by removing the source of ACTH excess. In the case of
Cushing disease, transsphenoidal resection of the pituitary microadenoma is successful in 80% or more of
cases. If a microadenoma is not found, then hemihypophysectomy may be performed with the understanding
that fertility may be impaired. Pituitary irradiation is a good treatment option when fertility is desired, when
a tumor is not found or is unresectable, or cure is not achieved by transsphenoidal resection of a tumor.
Debulking of unresectable primary lesions or recurrences with or without bilateral adrenalectomy may
provide palliation in some patients. Treatment of ectopic ACTH syndrome involves removal of the primary
lesion. Medical adrenalectomy with metyrapone, aminoglutethimide, and mitotane has been used to
suppress production of corticosteroid in inoperable cases for both pituitary and ectopic sources of ACTH.
Bilateral adrenalectomy is a good option for patients intolerant of mitotane.
ACTH-independent Cushing syndrome is best treated by removal of the adrenal tumor and affected gland.
Small lesions, less than 6 cm. in diameter, may be resected laparoscopically. Lesions larger than 6 cm or
those suspected of being carcinoma require an anterior open approach. Resection of cortisol-producing
benign adrenal adenomas is curative and prognosis is good following resection. Cortisol-producing
adrenocortical carcinomas recur frequently following adrenalectomy, heralded by the reemergence of
hypercortisolism. Micronodular pigmented hyperplasia and macronodular adrenal hyperplasia may involve
both adrenal glands. These conditions are cured only by bilateral adrenalectomy. Medical adrenalectomy
with mitotane or agents interfering with cortisol production is not currently recommended.
Whether patients with subclinical Cushing syndrome should undergo adrenalectomy is unclear.
Adrenalectomy for subclinical Cushing is reasonable in young patients (<50 years), in patients with
suppressed plasma ACTH, and in patients with a recent history of weight gain, substantial obesity, arterial
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hypertension, diabetes mellitus, and osteopenia. Truly asymptomatic patients with normal plasma ACTH
concentrations and the elderly or unfit may be observed. Demonstration of the benefits of surgery versus
conservative treatment in patients with subclinical Cushing syndrome will require a randomized prospective
trial.
All patients who undergo adrenalectomy for Cushing syndrome require perioperative and postoperative
glucocorticoid replacement, since the contralateral gland is suppressed. Replacement therapy with
hydrocortisone, 12 mg/m2 per day, may be required as long as 2 years postoperatively. Adequacy of
replacement is monitored clinically. The duration of replacement therapy is guided by normalization of the
ACTH stimulation test.
Hyperaldosteronism
Hyperaldosteronism is a syndrome of hypertension and hypokalemia caused by autonomous adrenal

secretion of the mineralocorticoid aldosterone. Hyperaldosteronism may be primary, as a result of an adrenal
neoplasm with suppressed plasma renin, or may be secondary, as a result of elevated plasma renin. Primary
hyperaldosteronism is twice as common in women as in men, and it usually occurs between the ages of 30
and 50 years. Screening of hypertensive patients with plasma aldosterone and plasma renin activity (PRA)
has suggested that primary hyperaldosteronism may be the underlying cause of up to 15% of cases of
essential hypertension.
An aldosterone-producing adrenal adenoma (Conn syndrome) is the source of primary hyperaldosteronism

in 60% to 70% of cases. Idiopathic bilateral adrenal hyperplasia causes the remaining cases of primary
hyperaldosteronism. Adrenocortical carcinoma is a rare cause of primary hyperaldosteronism. Autosomal
dominant glucocorticoid-suppressible hyperaldosteronism is a rare cause of hyperaldosteronism resulting
from the fusion of the ACTH-responsive 11-beta hydroxylase gene promoter to the aldosterone synthase
gene in cells of the adrenal cortex.
Secondary hyperaldosteronism is a physiologic response of the renin-angiotensin system to decrease renal

perfusion renal artery stenosis, cirrhosis, congestive heart failure, and normal pregnancy. The adrenal cortex
functions normally and secretes aldosterone in response to the elevated plasma renin and angiotensin caused
by these conditions. Secondary hyperaldosteronism responds to treatment of the underlying cause.
Signs and Symptoms
Clinical manifestations of primary hyperaldosteronism are attributable to hypersecretion of aldosterone by

the adrenal gland (Table 79.2). Aldosterone-mediated retention of sodium and excretion of potassium and
hydrogen ion by the kidney causes moderate diastolic hypertension. Edema is absent. Hypokalemia occurs
spontaneously in 80% to 90% of patients with primary hyperaldosteronism but may be normal.
Hypokalemia is easily provocable in the remaining patients. Potassium depletion frequently causes
symptoms of muscle weakness and fatigue, polyuria and polydipsia, as well as impaired insulin secretion
and fasting hyperglycemia. Primary hyperaldosteronism should be suspected in hypertensive patients with
spontaneous hypokalemia (serum concentration <3.5 mEq/L), moderate hypokalemia (serum potassium
concentration <3.0) during diuretic therapy despite concomitant use of oral potassium or potassium-sparing
diuretics, or refractory hypertension without explanation.
Diagnosis
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The clinical hallmarks of primary hyperaldosteronism are (a) diastolic hypertension without edema; (b)
suppression of plasma renin in the face of volume depletion; and (c) hypersecretion of aldosterone that fails
to suppress with intravascular volume expansion. Diagnostic evaluation must establish primary
hyperaldosteronism, discern surgically correctable adrenal adenoma from medically treatable idiopathic
hyperplasia, and localize an adrenal tumor (Algorithm 79.2).
Demonstration of an elevated plasma aldosterone concentration (PAC) in the setting of suppressed PRA is
the best test to establish primary hyperaldosteronism. The ratio in normal subjects and patients with
essential hypertension is 4 to 10 compared with more than 30 in most patients with primary
hyperaldosteronism. A PAC of greater than 20 ng/dL and a PAC/PRA ratio of greater than 30 are diagnostic
for aldosteronoma with almost 90% sensitivity. A serum potassium value less than 3.5 mEq/L and urinary
potassium excretion greater than 30 mEq per day also support a diagnosis of primary hyperaldosteronism.
Hypokalemia and inappropriate kaliuresis are often but not always present as well. Before biochemical
evaluation, patients need to be potassium repleted and have an adequate sodium intake. Medications
including ACE inhibitors and spironolactone should be withheld for at least 4 weeks before study.
Caption:
ALGORITHM 79.2 Diagnosis and management of hyperaldosteronism. PRA, plasma renin activity; PAC,
plasma aldosterone concentration; CT, computed tomography; AVS, bilateral adrenal venous sampling.
An elevated PAC/PRA ratio alone does not establish the diagnosis of primary hyperaldosteronism, which
must be confirmed by demonstrating inappropriate aldosterone secretion with salt loading. This involves a
24-hour urine collection for sodium and aldosterone after 3 days of a high-sodium diet. The 24-hour urinary
excretion of aldosterone should be less than 14 "g. per 24 hours after a high-salt diet. An intravenous saline
infusion test or captopril challenge test is also a reliable method to confirm primary hyperaldosteronism.
These tests are not usually required.
After the diagnosis of primary hyperaldosteronism is made, distinction must be made between an
aldosteronoma and idiopathic adrenal hyperplasia. The first test measures aldosterone in blood collected at 8
AM from a patient who has been supine overnight. Laboratory studies are repeated 4 hours later after the
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patient has been upright. Aldosterone secretion in patients with an aldosteronoma is unaffected by postural
changes (<20 ng/dL), whereas, in patients with idiopathic adrenal hyperplasia, plasma aldosterone levels are
elevated 33% (>20 ng/dL) or more by postural changes.
High-resolution adrenal computed tomography (CT) is the best test for localization of an adrenal tumor (Fig.
79.6). CT will detect an aldosterone-producing adenoma in 90% of cases overall. The presence of a
unilateral adenoma greater than 1 cm on CT and supportive biochemical evidence of an aldosteronoma are
generally all that is needed to make the diagnosis in most patients over 40 years of age. The contralateral
adrenal gland must be examined in patients presumed to have an aldosterone-producing adenoma to ensure
that bilateral hyperplasia is not present. Magnetic resonance imaging (MRI) is less effective and more costly
but may be useful during pregnancy or in situations in which intravenous contrast medium injection is
undesirable. The test of 6-[beta](131I)-iodo-methyl-19-norcholesterol (NP-59) scintigraphy identifies
functional tumors and discriminates aldosteronoma from adrenal hyperplasia with an overall accuracy of
approximately 75%, but requires a tumor of sufficient size (>1 cm) for imaging to be dependable.
Adrenal vein sampling to lateralize the source of aldosterone production is useful in patients with
hyperaldosteronism when there is no adrenal abnormality on CT or MRI or when both adrenal glands are
abnormal but asymmetric. Further, patients older than 40 years, in whom the possibility of a nonfunctioning
adenoma is statistically higher, may benefit from routine sampling. Percutaneous transfemoral cannulation
of both adrenal veins is performed and intravenous ACTH (50 "/hr) is administered. Simultaneous adrenal
vein blood samples for aldosterone and cortisol are taken before and after ACTH injection, and their ratios
are determined. The PAC is markedly higher (at least fourfold) on the side of an adenoma, whereas there is
little or no left–right gradient present in cases of bilateral adrenal hyperplasia. A 10-fold gradient of cortisol
in adrenal veins to a peripheral sample ensures adequacy adrenal vein cannulation. This study is greater than
90% accurate and has been shown to alter management in 30% to 50% of patients, even in those with an
apparent unilateral adenoma. This test is technically difficult and may be unsuccessful in 25% of patients.
Emerging data suggest that adrenal vein sampling may be superior to CT in differentiating the source of
aldosterone production in patients with hyperaldosteronism.
Caption:
FIGURE 79.6 Computed tomography scan of right adrenal aldosteronoma. Short arrow shows
aldosteronoma. Long arrow shows normal contralateral adrenal gland.
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Caption:
FIGURE 79.7 Aldosteronoma within right adrenal gland shown in Figure 79.8.
Treatment
Surgical removal of an aldosterone-secreting adenoma (Fig. 79.7) results in durable improvement of

hypertension and hypokalemia in 70% to 90% of patients. Laparoscopic adrenalectomy is the preferred
approach to remove these tumors. Morbidity and mortality following these procedures are almost negligible.
Preoperative spironolactone or eplerenone and potassium are given to replenish potassium stores and correct
alkalosis before anesthesia. Preoperatively, a significant fall in blood pressure with aldosterone receptor
antagonists predicts a successful outcome after adrenalectomy. Response to adrenalectomy is also influenced
by the duration and severity of hypertension and by the presence of histologic changes in the kidney. Age
greater than 50 years, male sex, and the presence of multiple nodules within the adrenal is also associated
with a poor response to surgery.
Management of idiopathic adrenal hyperplasia is medical because fewer than 20% to 30% of patients with
this disease are cured by adrenalectomy. Idiopathic adrenal hyperplasia is treated with spironolactone or
with newer aldosterone antagonist eplerenone. Other potassium sparing diuretics may be used including
triamterene and amiloride. Treatment of glucocorticoid-suppressible hyperaldosteronism includes
dexamethasone 0.5 to 1.0 mg daily. Glucocorticoids are used in small doses to avoid Cushing syndrome.
Congenital Adrenal Hyperplasia
The congenital adrenal hyperplasias are autosomal recessive conditions resulting from inherited defects of
one or several of the enzymes necessary for cortisol biosynthesis (Fig. 79.8). Cortisol deficiency leads to
ACTH overproduction and secondary hyperplasia of the adrenal cortex with shunting of cortisol precursors
into adrenal androgen pathways. Peripheral tissues convert the excess adrenal androgens to testosterone,
which causes virilization of the patient.
Most cases (>90%) of congenital adrenal hyperplasia are secondary to deficiency of 21-hydroxylase
(CYP21A2) resulting from mutation of the gene on the short arm of chromosome 6. Two forms of this
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deficiency are recognized; partial or complete. The complete form is characterized by androgen excess at
birth, with virilization, hypovolemia, hyponatremia, hyperkalemia, and hyperpigmentation. The partial form
is characterized by virilization only and may present in adolescence or adulthood.
Of the remaining causes of congenital adrenal hyperplasia, 11-beta-hydroxylase deficiency (CYP11B1) is

the second-most common cause, followed by 3-beta-hydroxydehydrogenase and 17-hydroxylase (CYP17)
deficiency. Congenital lipoid adrenal hyperplasia is the most severe form of congenital adrenal hyperplasia
and is often fatal (Table 79.4).
Caption:
FIGURE 79.8 Schematic representation of the mechanism underlying congenital adrenal hyperplasias.
Enzymatic defects in the adrenal gland prevent normal production of cortisol with resulting loss of negative
feedback to the hypothalamus and pituitary. Chronic adrenocorticotropic hormone stimulation of the
adrenal gland shunts steroid precursors through androgenic and mineralocorticoid pathways, leading to the
overproduction of androgens and mineralocorticoids. The most common deficiencies are CYP21A2
(21-hydroxylase), CYP11B1 (11"-hydroxylase), and 3-"-HSD (3-"-hydroxysteroid dehydrogenase). TABLE
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79.4 CONGENITAL ADRENAL HYPERPLASIAS

Aldosterone 3!-Hydroxysteroid
21-Hydroxylase11!-Hydroxylase 17"-Hydroxylase Lipoid
Disease synthase dehydrogenase
deficiency deficiency deficiency hyperplasia
deficiency deficiency
Defective gene CYP21 CYP11B1 CYP11B2 CYP17 HSD3B2 STAR
Ambiguous
Females Females No Males Males Males
genitalia
Salt wasting
Addisonian crisis Present Rare Absent Present Present
only
Incidence (general
1:10–18,000 1:100,000 Rare Rare Rare Rare
population)
Hormones
Corticosterone
Glucocorticoids Reduced Reduced Normal Reduced Reduced
normal
MineralocorticoidsReduced Elevated Reduced Elevated Reduced Reduced
Reduced (males)
Androgens Elevated Elevated Normal Reduced Reduced
Elevated (females)
Reduced Reduced in
Estrogens Normal Reduced Reduced Reduced
(females) females
Physiology
Blood pressure Reduced Elevated Reduced Elevated Reduced Reduced
Na balance Reduced Elevated Reduced Elevated Reduced Reduced
K balance Elevated Reduced Elevated Reduced Elevated Elevated
Acidosis Present Absent Present Absent Present Present
±
DOC, 11- Corticosterone DOC
Elevated metabolites17-OHP
deoxycortisol 18-hydroxy- corticosterone DHEA, 17$5preg None
corticosterone
OHP, hydroxyprogesterone; DOC, deoxycorticosterone; DHEA, dehydroepiandrostenedione.
(Modified from White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev.
2000;21:245–291.)
Signs and Symptoms
Prenatal adrenal virilization in females produces ambiguous external genitalia (female

pseudohermaphrodism). The ovaries, fallopian tubes, and uterus develop normally and patients are fertile.
Postnatal congenital adrenal hyperplasia causes virilization of females and precocious puberty of males.
Females develop hirsutism, polycystic ovaries, and irregular menses. Male patients exhibit secondary sexual
characteristics by age 2 or 3 years. Fertility is often impaired. Both sexes experience rapid somatic growth
and short stature. Virilization, salt wasting, and hyperpigmentation are variably present with the non-21-
hydroxylase forms of congenital adrenal hyperplasias.
Diagnosis
Elevated plasma 17-hydroxyprogesterone is the most characteristic abnormality found in 21-hydroxylase

deficiency. Both plasma cortisol and 24-hour free urinary cortisol excretion are variably reduced. Diagnosis
of other forms of the disease involves demonstration of elevated levels of enzyme substrate: corticosterone
and 11-deoxycortisol for 11-beta hydroxylase; dehydroepiandrosterone and 17 delta-5 hydroxypregnenolone
for 3-beta hydroxydehydrogenase; and deoxycorticosterone and corticosterone for 17 beta-hydroxylase
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deficiency (Table 79.4).
Treatment
The treatment of 21-hydroxylase deficiency is glucocorticoid and mineralocorticoid replacement. Clinical

management is often complicated by inadequately treated hyperandrogenism or iatrogenic hypercortisolism,
or both. New treatment approaches under investigation include combination therapy to block androgen
action and inhibit estrogen production, and bilateral adrenalectomy in the most severely affected patients.
Female patients with ambiguous genitalia may require surgical correction as infants. Treatment of
congenital adrenal hyperplasias caused by other enzyme deficiencies includes steroid and electrolyte
replacement and surgical correction of the external genitalia in affected female infants.
Virilizing and Feminizing Adrenal Tumors
Excess production of adrenal androgens by an adrenal adenoma or carcinoma can produce virilizing features
either alone or more commonly in addition to Cushing syndrome. Development of an adrenal virilizing
tumor in women causes hirsutism and masculinization. Males with these tumors may present late with signs
and symptoms of tumor enlargement or distant metastases develop. Virilizing tumors secrete androgen
precursor, dehydroepiandrosterone, which can be measured either directly in plasma or in urine as a
17-ketosteroid. Feminizing adrenal neoplasms are extremely rare. Abdominal CT is subsequently used to
localize the lesion. Resection of tumor and involved adrenal gland is the primary treatment for patients with
adrenal virilizing tumors. Tumor recurrence is heralded by return of virilization or by detection of increased
17-ketosteroids in the urine. Tumor debulking or inhibition of steroidogenesis with aminoglutethimide or
mitotane may be useful in controlling signs and symptoms in patients with metastatic disease.
Adrenocortical Carcinoma
Adrenocortical carcinoma is a rare malignancy with an estimated incidence of 0.5 to 2 cases per million per
year. Presentation peaks in the first and fifth decades of life. The prevalence is higher in females than in
males (1.4 to 2:1). The cause of adrenocortical carcinoma is unknown, although somatic mutations in P53
and inheritance of this tumor in patients with germline mutations in P53 (Li Fraumeni syndrome) implicate
this tumor suppressor gene in its pathogenesis. 1
Signs and Symptoms
Adrenocortical carcinoma is a very aggressive malignancy, and most patients (up to 75%) present with
locoregionally advanced or distant disease. Syndromes of adrenal hormone overproduction are frequent (up
to 60%) and may include hypercortisolism, hyperaldosteronism, or virilization. Patients with rapidly
progressive Cushing syndrome or mixed presentations with signs of both Cushing syndrome and virilization
should be suspected of having adrenocortical carcinoma. Nonfunctioning adrenocortical carcinomas present
most commonly as abdominal pain or mass with vague symptoms of nausea, weight loss, and fatigue.
Diagnosis
Patients with suspected adrenocortical carcinoma should have biochemical testing to identify hormone
overproduction followed by staging investigations including cross-sectional imaging and bone scans.
Contrast-enhanced CT of the abdomen and chest is important to preoperatively diagnose local tumor
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invasion and metastatic lesions as well as to confirm a functioning contralateral kidney (Fig. 79.9). In the
absence of distant metastases or local invasion, preoperative distinction between large adenomas and
carcinomas can be difficult, although large (>6 cm) adrenal masses that extend to nearby structures on CT
scanning should be approached as carcinomas. Biopsy of adrenal lesions suspected of being adrenocortical
carcinoma is unnecessary and should be avoided. The risk of seeding and the inability of histologic
examination to distinguish between adenoma and carcinoma underlie this approach. Biopsy of extraadrenal
lesions may be performed to confirm metastatic disease.
A definitive diagnosis of adrenocortical carcinoma requires pathologic demonstration of tumor invasion to

adjacent organs or spread to lymph nodes or distant sites. Practically, any adrenal neoplasm larger than 6 cm
or weighing more than 100 g should be considered malignant. Histologic features of tumor necrosis,
hemorrhage, and local invasion are gross pathologic evidence of carcinoma, while cells with large,
hyperchromatic nuclei and more than 20 mitoses per high-power field suggest malignancy.
Caption:
FIGURE 79.9 Computed tomography scan of right adrenocortical carcinoma showing invasion of liver and
inferior vena cava. Note that a contralateral kidney is present and functioning. TABLE 79.5 STAGING:
AMERICAN JOINT COMMITTEE ON CANCER STAGING OF ADRENOCORTICAL
CARCINOMA, WITH 5-YEAR SURVIVAL RATES
Stage Criteria
Tumor
T1 Tumor <5 cm, no invasion
T2 Tumor >5 cm, no invasion
T3 Tumor with invasion to fat
T4 Tumor with organ invasion
Lymph nodes
N0 No lymph node metastasis
N1 Lymph node metastasis present
Metastasis
M0 No distant metastasis
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M1 Distant metastasis present

Stage groupTNM 5-year survival rate
I T1 (<5 cm) N0M030%–45%
II T2 (>5 cm) N0M012%–57%
T1-2, N1, M0
III 5%–18%
T3N0M0
Any T, any N, M1
IV 0
T3–4N1M0
Treatment
Surgical resection is the mainstay of treatment for all stages of adrenocortical carcinoma. Complete
resection of locally confined tumor is the only chance for cure from adrenocortical carcinoma. However,
distant or local spread is evident in 65% of cases at presentation and a minority of patients is resectable with
curative intent. Recurrence rates after surgery range from 38 to 85%, depending on stage at presentation
(Table 79.5).
Many patients with adrenocortical carcinoma present with metastatic disease, involving the lung, lymph
nodes, liver, or bone. Resection or surgical debulking of locally advanced or metastatic lesions may provide
symptomatic relief for select patients, especially those with low-grade, slow-growing, hormonally
productive cancers. Symptomatic recurrent or metastatic disease is best treated by resection when feasible.
Chemotherapy for adrenocortical carcinoma usually includes mitotane, although no controlled studies have
established its efficacy in this disease. Partial responses to mitotane occur in less than a third of patients, and
survival is unchanged. Adjuvant chemotherapy with mitotane after complete resection for adrenocortical
carcinoma is unproven and toxic so that many oncologists reserve its use for recurrent, unresectable or
metastatic disease. Cisplatin in combination with mitotane or doxorubicin and 5-fluoruracil have been
applied in metastatic disease with partial responses noted.
The prognosis of adrenocortical carcinoma is poor. Median survival following diagnosis for all patients is
approximately 18 months. Overall survival following resection for all stages of adrenocortical cancer is 15%
to 47% at 5 years. Stage-specific 5-year survival is 30% to 45% for stage I, 12% to 57% for stage II, 5% to
18% for stage III, and 0 for stage IV disease.
DISEASES OF THE ADRENAL MEDULLA
Pheochromocytoma
Pheochromocytomas are functional adrenal tumors that arise from neuroectodermal cells of the adrenal
medulla or in certain extraadrenal sites. These tumors are uncommon, occurring in 0.005% to 0.1% of
persons, but occur with increased frequency in hypertensive populations (0.2% incidence) and in heritable
endocrine tumor syndromes. The peak incidence of pheochromocytoma occurs during the fourth and fifth
decades of life, and men and women are affected about equally. The rule of tens is a useful way to
characterize pheochromocytoma: tumors are bilateral in 10% of cases, extraadrenal in 10%, familial in 10%,
multicentric in 10%, and malignant in 10% and occur in children in 10% of cases.
Approximately 10% of pheochromocytomas are extraadrenal, although most (98%) are still located within
the abdomen. Extraadrenal pheochromocytomas can occur at any site in the abdomen where chromaffin
tissue is located and have been found in the paravertebral ganglia, the organ of Zuckerkandl, and the urinary
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bladder. Clues to the presence of extraadrenal pheochromocytoma are predominance of norepinephrine

because extraadrenal sites lack the enzyme necessary to convert norepinephrine to epinephrine.
Familial pheochromocytoma is a component of two autosomal dominant syndromes: von Hippel-Lindau

syndrome and multiple endocrine neoplasia (MEN)-2. Patients with von Hippel-Lindau syndrome have
pheochromocytoma (usually bilateral), retinal angiomas, cerebellar hemangioblastoma, epididymal
cystadenoma, renal and pancreatic cysts, and renal cell carcinoma. Patients with MEN 2A develop
pheochromocytoma (usually bilateral), medullary carcinoma of the thyroid (MTC), and primary
parathyroid hyperplasia. Patients with MEN 2B develop pheochromocytoma (usually bilateral), MTC,
mucosal neuromas, intestinal ganglioneuromatosis, and have a characteristic marfanoid body habitus.
Pheochromocytoma also occurs in neurofibromatosis type 1 and familial paraganglioma. The frequency of
pheochromocytoma in these disorders is 10% to 20% in von Hippel-Lindau syndrome, 50% in MEN-2, and
0.1 to 5.7% with neurofibromatosis type 1.
In some families, patients with pheochromocytomas have no other clinical abnormalities, suggesting the
existence of a separate disease limited to the formation of adrenal medullary tumors. In a study of three
generations of an affected kindred, a novel mutation was found in the von Hippel-Lindau gene even though
there were no other clinical manifestations of this disorder. Patients with bilateral pheochromocytoma,
young patients with pheochromocytoma, and patients with paraganglioma should be screened for MEN2
and von Hippel-Lindau syndrome.
The etiology and pathogenesis of pheochromocytoma is unknown. A genetic component seems certain
because pheochromocytoma occurs not only as a part of familial syndromes but also as an isolated disorder
because of mutation in the RET gene or the MEN2 gene. Familial pheochromocytoma as well as sporadic
pheochromocytoma occurs also with mutations in the succinate dehydrogenase complex, subunit B, iron
sulfur protein (SDHB). Either germline or somatic mutations in the SDHD gene is another cause of
pheochromocytoma. 2
Signs and Symptoms
Symptoms of pheochromocytoma are attributable to the effects of excessive circulating catecholamines on

target tissues (Table 79.3). The classic triad of symptoms in patients with a pheochromocytoma is episodic
headache, sweating, and tachycardia. Hypertension is common with pheochromocytoma and is sustained in
roughly half of patients, is paroxysmal in one third, and is absent in one fifth. Orthostatic hypotension
results from diminished plasma volume and blunted autonomic reflexes. Other symptoms include
palpitations, anxiety, and tremulousness. Cardiovascular sequelae include myocardial infarction, cardiac
dysrhythmias, and stroke. Gastrointestinal motility is also impaired. Asymptomatic patients with functioning
tumors are rare, and nonfunctioning tumors are distinctly uncommon. Sudden death has been reported in
patients with pheochromocytoma who have undergone surgical procedures or childbirth.
Diagnosis
Elevation of catecholamines and their metabolites in either urine or blood is essential for the diagnosis of
pheochromocytoma. Determination of plasma-fractionated metanephrines is probably the best test for
diagnosis of pheochromocytoma. Alternatively, measurement catecholamines and their metabolites in a
single 24-hour urine collection may be performed to make or exclude this diagnosis. Measurement of
plasma catecholamines is not as useful in distinguishing patients with pheochromocytoma from those with
essential hypertension. Measurement of plasma chromogranin A is nonspecific and a poor diagnostic but
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potentially helpful confirmatory test.
Many medications alter or interfere with measurement or either plasma or urine catecholamines. Such
medications should be discontinued to ensure accurate testing. These drugs include acetaminophen,
labetolol, clonidine withdrawal, tricyclic antidepressants, antipsychotics and ethanol. To control blood
pressure, other antihypertensives such as calcium channel blockers may be substituted.
In normotensive or mildly hypertensive patients with elevated plasma catecholamine levels (1,000 to -2,000
pg/mL), a clonidine suppression test may be used to distinguish from pheochromocytoma. An oral 0.3-mg
dose of clonidine suppresses centrally mediated release of catecholamines to less than 500 pg/mL within 2
to 3 hours but does not affect release of catecholamines by a pheochromocytoma.
Biochemical confirmation of the diagnosis should be followed by radiologic evaluation to locate the tumor.
Pheochromocytomas are best imaged with CT or MRI. Contrast-enhanced CT readily detects tumors 1 cm
and larger and has sensitivity of 87% to 100% for pheochromocytoma (Fig. 79.10A). MRI is similarly
sensitive, and a T2-weighted image brightness three times greater than liver is highly specific for
pheochromocytoma (Fig. 79.10B, C). MRI is useful in suspected malignant pheochromocytoma to evaluate
for inferior vena cava thrombus or liver invasion.
Functional nuclear imaging with iodine-131-metaiodobenzylguanidine (131-I MIBG) is a useful adjunct to

cross sectional imaging for pheochromocytoma (Fig. 79.10D). MIBG resembles norepinephrine and is taken
up by adrenergic tissues including pheochromocytoma. An MIBG scan can detect tumors not detected by
CT or MRI or multiple tumors when CT or MRI is positive. Multiinstitutional experience with this
technique has demonstrated an overall sensitivity of 77% to 87% and a specificity of 96% to 100%. This test
is usually not necessary for sporadic pheochromocytoma unless urinary or plasma catecholamines and
metabolites are marginally elevated, or if malignant or extraadrenal pheochromocytoma is suspected. 131-I
MIBG scanning is also useful to screen patients with metastatic pheochromocytoma for high dose 131I
MIBG therapy. 111-In-pentetreotide scintigraphy may also identify pheochromocytoma and can be used
therapeutically as with 131-I MIBG.
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Caption:
FIGURE 79.10 Imaging of pheochromocytoma (arrows). (A) Computed tomography scan shows
well-circumscribed left adrenal mass. (B) T2-weighted magnetic resonance imaging shows the mass to be
heterogeneously bright consistent with pheochromocytoma. (C) and (D) Coronal contrast enhanced MRI
and near-simultaneous 131I-metaiodobenzylguanine (131 I-MIBG) scanning show location of the
pheochromocytoma and relationship to surrounding structures.
Treatment
Surgical resection is the only cure for pheochromocytoma. When the diagnosis of pheochromocytoma has
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been established and localization studies are completed, preoperative preparation of the patient centers on
blood pressure control. Usually 1 to 3 weeks before operation alpha-adrenergic blockade is performed fi rst
with phenoxybenzamine, starting at 10 mg twice a day and increasing by 10 to 20 mg per day until blood
pressure normalizes. Side effects of alpha blockade include postural hypotension, reflex tachycardia, nasal
congestion, and an inability to ejaculate. Preoperative alpha blockade also reverses the relative hypovolemia
that is usually present in patients with pheochromocytoma and also prevents severe blood pressure swings
during intraoperative manipulation of the tumor. Metyrapone added preoperatively to phenoxybenzamine
can achieve a greater degree of sympathetic blockade.
Beta-adrenergic blockade with propranolol added after alpha blockade can manage patients who develop
tachycardia or who have inducible cardiac arrhythmias or ischemia. Propranolol may enhance pressor
response to endogenous norepinephrine and thus should not be given until adequate alpha blockade has been
established. Propranolol can also produce profound bradycardia, myocardial depression, and congestive
heart failure. Newer drug regimens to manage hypertension in pheochromocytoma include selective alpha-
1-adrenergic antagonists (terazosin and doxazosin) and calcium channel blockers (nifedipine and
nicardipine).
Patients with pheochromocytoma can be expected to have blood pressure volatility and high intravascular
volume requirements during and immediately after surgery. Elderly patients or those with history of heart
disease may require pulmonary catheter insertion and arterial line placement for careful monitoring of blood
pressure and arterial pH. Anesthetic agents may trigger the release of catecholamines from
pheochromocytomas. The anesthetic plane is now considered more important than the choice of agent, and
both enflurane and isoflurane have been used successfully. Magnesium administration during surgery is an
effective way to control blood pressure in patients with pheochromocytoma. Intraoperative hypertension is
best treated with a sodium nitroprusside drip, and cardiac arrhythmias are best managed with short-acting
beta-blockers (esmolol) or lidocaine.
Formerly, an anterior approach through either a midline or bilateral subcostal incisions was used exclusively
to resect pheochromocytomas. Today, CT, MRI, and nuclear scans permit preoperative localization of tumor
in 95% or more of cases, so that the surgical approach may be more directed using a laparoscopic approach.
Regardless of approach, important common principles include minimal handling of the tumor, early
isolation and ligation of the adrenal vein, and avoidance of capsular rupture. Recurrence following resection
of benign pheochromocytoma is infrequent, and its presence indicated malignancy.
Recurrent, malignant pheochromocytoma can include locally advance disease or metastasis to bone, liver,
lymph nodes, lungs, and the central nervous system. Treatment of malignant pheochromocytoma involves
resection of metastases when feasible and medical control of hypertension. Radiation therapy may be
helpful to ameliorate pain from bony metastases. Ablative therapy with 131-I MIBG may also produce
partial responses and palliation of hormonal symptoms. Radiofrequency ablation of hepatic and bone
metastases can be effective in selected patients. Combination chemotherapy with cyclophosphamide,
vincristine, and dacarbazine can also be effective. Overall 5-year survival for patients with malignant
pheochromocytoma ranges from 36% to 60%.
Metastasis to the Adrenal Glands
The adrenal glands are frequent sites for metastases from many cancers. Carcinoma of the lung and breast
account for most adrenal metastases; however, virtually any cancer including melanoma, lymphoma, and
kidney and ovarian carcinoma can spread to the adrenals. Autopsy series of patients with carcinoma show
that the adrenal glands are involved in more than 25% of cases. Among cancer patients, 50% to 75% of
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newly discovered adrenal masses represent metastases. Usually, either a primary site is obvious, or
widespread disease is apparent. Biopsy of adrenal masses in patients with a history of carcinoma may be
performed after pheochromocytoma is excluded. Resection of isolated adrenal metastases in select patients
with long disease free intervals from lung cancer, renal cell carcinoma and melanoma can be considered,
although subsequent extraadrenal disease usually develops. Median survival after complete resection of
isolated adrenal metastases from a variety of tumors ranges from 13 to 60 months with actuarial 2- and
5-year survival of 40% to 50% and 20%, respectively.
Incidental Adrenal Mass
Clinically inapparent adrenal masses (also called adrenal incidentalomas) have become commonplace over
the past 20 years with the increased use of abdominal imaging such as CT and MRI. The estimated
prevalence of incidental adrenal neoplasms varies by population studied and method of detection.
Unsuspected adrenal masses are detected by CT in between 0.6% and 1.9% of healthy patients, a figure that
is somewhat lower than the estimated prevalence of up to 8.7% based on unselected autopsy data. Patients
with a prior history of malignancy have a prevalence of adrenal masses of up to 4.4%. Adrenal masses
increase in frequency with advancing age, ranging from 3% in midlife to 10% in the elderly. The
combination of an aging population and increased application of abdominal imaging promises to create a
significant public health challenge.
Over the past 10 years, increased awareness of morbidity associated with subclinical hormone
overproduction as well the increased availability of minimally invasive, laparoscopic adrenalectomy has
resulted in a lower threshold for treatment of adrenal masses. The goal of evaluation is to distinguish and
remove those adrenal masses that are functioning or likely to be malignant versus those that are neither and
may be observed.
Expectations of the yield for the workup of adrenal masses may be informed by epidemiologic reports and
reports of pathologic findings in resected incidentalomas. Epidemiologic data indicate that up to 6.5% of
incidentalomas are pheochromocytoma, 7% produce aldosterone, 0.035% produce cortisol, and 0.06% is
carcinoma. A recent review of 44 reports describing over 3,000 such cases reported that 41% were cortical
adenomas, 19% were metastases from other primary cancers, 10% were adrenocortical carcinomas, and 8%
were pheochromocytomas, with the remainder including myelolipomas and cysts.
Diagnosis
The evaluation of incidental adrenal masses, previously considered controversial, can now be standardized.
Two simple questions must be answered: Is it functional&quest; Is it malignant&quest; The diagnostic
approach should proceed to answer these questions sequentially (Table 79.6). Current opinion is that all
asymptomatic patients with adrenal masses should be screened for pheochromocytoma, hypercortisolism,
and hyperaldosteronism (Algorithm 79.3).
All patients require a complete history and physical examination, biochemical evaluation of pertinent
hormones, and select imaging studies. Attention must be paid to episodes of hypertension, tachycardia, and
anxiety that suggest pheochromocytoma. Physical findings such as muscle wasting, purple striae, hirsutism,
and gynecomastia may suggest either Cushing syndrome or a virilizing tumor. Secondary metastases from
underlying malignancy must be considered and evaluated with appropriate history, physical examination,
and select tests including mammograms in women and chest radiography in all patients, especially smokers.
Biochemical testing should routinely exclude pheochromocytoma, hypercortisolism, and
27 of 42 1/18/11 6:36 PM
hyperaldosteronism. Pheochro- mocytoma is evaluated either by 24-hour urine collection for

catecholamines, metanephrines, and 3-methoxy-4-hydroxy-mandelic acid, or by plasma fractionated
metanephrines. Subclinical or clinically apparent Cushing syndrome is best evaluated with the overnight 1
mg dexamethasone suppression test. Hyperaldosteronism is best assessed by concurrent measurement of
serum or plasma aldosterone and PRA.
Imaging studies usually include cross-sectional imaging with either CT or MRI. CT is the best test for
identifying and characterizing most adrenal masses. Using a fast scanner and 1-m scanning intervals, both
adrenal glands can be identified in 97% to 99% of patients and lesions as small as 5 mm can be readily
identified. Currently, attenuation values expressed in Hounsfield units (HU) have better performance than
size or other criteria to differentiate adenomas from adrenal malignancy and nonadenomas such as
pheochromocytoma. Adenomas are usually lipid rich and have attenuation values less than 18 HU on
unenhanced CT, a threshold with high sensitivity and specificity (85% to 95% and 93% to 100%,
respectively). Generally, further workup is unnecessary when an adrenal lesion has an attenuation of less
than 10 HU suggesting lipid-rich adrenal adenoma. A notable exception is lipid poor adenoma, which has
higher HU density. In these cases, rapid washout of intravenous contrast suggests an adenoma. Using a 10-
to 15-minute delayed enhanced CT, a washout value of 50% to 60% of the initial enhancement is used to
distinguish adenoma from nonadenoma.
TABLE 79.6 DIAGNOSIS: SUMMARY OF TESTS FOR EVALUATION OF INCIDENTAL

ADRENAL MASS
Question Best test Alternative test Diagnosis
Plasma fractionated 24-hr urine for catecholamines,
Pheochromocytoma
metanephrines metanephrines, VMA
1 mg dexamethasone
Is it 24-hour urine for cortisol Hypercortisolism
suppression test
functioning&quest;
Serum potassium
Plasma renin/plasma 24-hour urine for potassium Hyperaldosteronism
aldosterone ratio
Cortical adenoma
Adrenocortical
Carcinoma
Is it Computed tomography
Magnetic resonance imaging Pheochromocytoma
malignant&quest;
Myelolipoma
Cyst
Fine Needle Aspiration Metastasis
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Caption:
ALGORITHM 79.3 Diagnosis and management of the incidental adrenal mass. PRA, plasma renin activity;
PAC, plasma aldosterone concentration; HTN, hypertension; CT, computed tomography; MRI, magnetic
resonance imaging; FNA, fine needle aspiration.
MRI can differentiate adenomas, metastases and pheochromocytomas, although the best MRI technique
for evaluating adrenal masses is complex and controversial. Adenomas usually show a loss in signal
intensity on chemical shift MRI because of high lipid content. Malignant masses tend to be bright on
T2-weighted images because of higher fluid content. Secondary metastases to the adrenal are hypointense to
liver on T1-weighted images and are brighter than liver on T2-weighted images. Metastases also typically
show strong contrast enhancement. Pheochromocytomas most often have low lipid content and high water
content, giving low T1 signal intensities and very bright T2 signal intensities. Comparison of the adrenal
mass to liver and spleen intensities on various sequences adds to specificity and sensitivity of the test.
Masses that appear cystic may be aspirated under CT guidance. Fine-needle aspiration biopsy may be of
value in patients with known extraadrenal malignancy; however, it is not indicated in the evaluation of
primary adrenal neoplasms and is contraindicated if pheochromocytoma is suspected.
Treatment
Resection is indicated for all functioning adrenal incidentalomas and those suspected of harboring primary
adrenal cancer. Size cutoff for resecting adrenal incidentalomas has drifted to include smaller and smaller
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lesions. The prevalence of primary adrenal carcinoma in adrenal incidentalomas is related to mass size. The
risk of primary adrenal carcinoma is less than 2% in lesions under 4 cm while the incidence rises to 25% for
lesions larger than 6 cm. Lesions larger than 6 cm and smaller lesions with suspicious criteria on imaging
should be resected. Lesions smaller than 4 cm with benign imaging characteristics should be followed. For
lesions between 4 and 6 cm, either resection or observation is acceptable. Decisions should not be based on
size alone, but also on imaging characteristics including CT attenuation values. Resection of secondary
adrenal malignancy is not generally recommended except for highly select patients.
Adrenal Insufficiency
Adrenal insufficiency reflects inadequate glucocorticoid and mineralocorticoid production by the adrenals,
either secondary to suppression of the HPA axis or by destruction or removal of the adrenal glands. The
most common causes of primary adrenal insufficiency are autoimmune adrenalitis, infection, and gland
replacement with metastatic disease. Chronic exogenous steroid use with HPA suppression and surgical
resection of adrenal glands are important causes of secondary adrenal insufficiency.
Clinical signs and symptoms usually do not become manifest until at least 90% of the gland is destroyed.
Adrenal insufficiency usually occurs gradually unless the patient experiences stress which may precipitate
acute crisis.
Signs and Symptoms
Acute adrenal insufficiency usually manifests as shock in a patient with undiagnosed chronic adrenal
insufficiency who has been subjected to physiologic stress. Similarly, patients with established adrenal
insufficiency caused by exogenous steroid use may experience crisis if they do not increase glucocorticoid
replacement during times of stress or illness. Symptoms of adrenal insufficiency reflect glucocorticoid and
mineralocorticoid deficiencies. Signs and symptoms of acute insufficiency include fever, nausea, vomiting,
refractory hypotension, and lethargy (Table 79.7). Acute adrenal insufficiency is a medical emergency and
should be suspected in stressed patients with a history of either adrenal insufficiency or exogenous steroid
use. Chronic adrenal insufficiency presents more subtly, with fatigue, weight loss, anorexia, nausea and
vomiting, abdominal pain, and diarrhea.
TABLE 79.7 DIAGNOSIS: SYMPTOMS AND SIGNS OF ACUTE ADRENAL INSUFFICIENCY

Symptoms
Lethargy
Confusion or disorientation
Nausea and vomiting
Abdominal pain
Signs
Hypotension
Hyponatremia, hyperkalemia, azotemia,
Hypoglycemia
Fever
Anemia
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Diagnosis
Laboratory findings of adrenal insufficiency include hyponatremia, hyperkalemia, azotemia, and fasting or
reactive hypoglycemia. Hypercalcemia may also be present. The rapid ACTH stimulation test is the best test
for both acute and chronic adrenal insufficiency. Synthetic ACTH (250 "g) is administered intravenously,
and plasma cortisol levels are measured 30 and 60 minutes later. Normal peak cortisol response should
exceed 20"g/dL. Measurement of ACTH by IRMA is then used to distinguish primary from secondary and
tertiary adrenal insufficiency. High plasma concentration of ACTH (>200 pg/dL) and low plasma cortisol
(<10 mg/dL) are diagnostic of primary adrenal insufficiency. Low levels of plasma ACTH indicate
secondary (pituitary) or tertiary (hypothalamic) adrenal insufficiency.
Treatment
Acute adrenal insufficiency is based on clinical suspicion before laboratory confirmation is available.
Intravenous volume replacement with isotonic fluids and immediate intravenous steroid replacement therapy
with 4 mg dexamethasone is essential. A rapid ACTH stimulation test is then performed to establish the
diagnosis of adrenal insufficiency after resuscitation and corticosteroid replacement. Hydrocortisone
acetate is detected in laboratory measurement for cortisol so dexamethasone should be used for replacement
of glucocorticoid function until ACTH testing is complete. Thereafter, 100 mg of hydrocortisone is
administered intravenously every 6 to 8 hours and is tapered to standard replacement doses as the patient's
condition stabilizes. Mineralocorticoid replacement is not required until oral intake resumes. Chronic
adrenal insufficiency requires both corticosteroid and mineralocorticoid replacement. Usual daily dosing is
12 mg/m2 of hydrocortisone and 0.05 to 0.10 mg fludrocortisone.
Patients who have known adrenal insufficiency or who have received supraphysiologic doses of
corticosteroid for at least 1 week in the year preceding surgery should receive perioperative stress-dose
corticosteroids. Administration of 100 mg hydrocortisone the morning of major surgery followed by 100 mg
of hydrocortisone every 8 hours during the perioperative 24 hours is usually more than sufficient. Steroids
can be rapidly tapered to replacement levels as the patient's condition permits.
Adrenalectomy.
Surgical approaches to the adrenal glands include the laparoscopic approach, the anterior transabdominal
approach, and less commonly, the combined thoracoabdominal approach or posterior retroperitoneal
approach. Either adrenal gland can be removed using any of these approaches. The choice of approach
depends on the suspected pathology, the size of the adrenal lesion, and the expertise of the surgeon. Small
benign appearing tumors that are localized with confidence by imaging studies are resected using a
laparoscopic or posterior approach. Posterior retroperitoneal adrenalectomy, once the most common method
of adrenalectomy is less commonly used since most lesions amenable to this approach can be removed
laparoscopically. Large adrenal masses and those that may harbor malignancy should be resected using an
anterior approach to adequately explore the entire abdomen and gain sufficient exposure for safe resection.
Very large adrenocortical carcinomas may require a thoracoabdominal approach for en bloc resection with
involved adjacent structures.
Laparoscopic adrenalectomy.
Laparoscopic adrenalectomy is now the preferred approach to most small, benign adrenal lesions including
functioning and nonfunctioning adenomas and pheochromocytomas. Enthusiasm for the laparoscopic
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approach is based on the expectation of decreased postoperative pain, faster rehabilitation, and fewer
complications. Numerous studies have shown the efficacy and safety of this procedure for tumors up to 6
cm. Larger lesions can be approached by experienced surgeons in select circumstances. Importantly,
expertise in open adrenalectomy is absolutely necessary for the laparoscopic surgeon to convert to an open
procedure and promptly rectify any intraoperative laparoscopic complications.
Laparoscopic adrenalectomy begins with induction of general anesthesia, placement of a urinary catheter
and orogastric tube, and positioning of the patient in the lateral decubitus position with the affected side up.
Exposure is facilitated by extension of the operating table at the patient's waist. A total of three or four
intraperitoneal ports (one camera, one retractor particular for the right side, and two working ports) are
placed at least 5 cm apart in a transverse line from the lateral edge of the rectus sheath to the midaxillary
line between the costal margin and iliac crest (Fig. 79.11A). Four-quadrant exploration of the peritoneal
cavity is first performed with the videoscope through the medialmost port, and the videoscope is then
transferred to the middle port. A retractor is placed through the medialmost port to retract the viscera
medially. Operating instruments are alternately placed within the abdomen through the lateral ports.
Laparoscopic adrenalectomy proceeds similar to the open anterior approach. Right adrenalectomy begins
with mobilization of the liver to open the retroperitoneum and allow retraction of the right lobe of anteriorly
and medially using the most medial port. The adrenal gland is then identified posterolateral to the inferior
vena cava and superior to the kidney. Dissection usually begins by developing the plane between right
adrenal and inferior vena cava using careful blunt dissection, with small vessels sequentially coagulated
using electrosurgical or harmonic energy. The right adrenal vein is identified, carefully dissected and then
doubly clipped and divided (Fig. 79.12A). Dissection then continues circumferentially around the gland
with additional small vessels coagulated or clipped. The adrenal gland subsequently is placed in a bag and
removed through an expanded port.
Left adrenalectomy is performed with mirror-image patient and port site orientation as right adrenalectomy.
After port placement, dissection begins with mobilization of the splenic flexure of the colon and spleen from
the left retroperitoneum. Subsequent medial retraction of the spleen, tail of the pancreas, and stomach is
accomplished with the fan or similar retractor if necessary. Often after full mobilization, no retractor is
necessary, and thus only 3 ports are needed. The left adrenal gland is identified in perinephric fat at the
superior renal pole. Intraoperative laparoscopic ultrasound can be useful for this on the left side, particularly
in Cushing syndrome with the associated increased truncal fat. Once identified, left adrenal gland dissection
proceeds circumferentially around the gland, with identification, ligation and division of the left adrenal vein
at the inferiormost aspect of the dissection (Fig. 79.12B). Care is needed to identify and avoid the inferior
phrenic vein, which courses along the medial aspect of the left adrenal gland. Following circumferential
dissection, the gland is removed.
Anterior approach.
Anterior, open adrenalectomy begins with positioning the patient in reverse Trendelenburg position with
elevation of the right flank. An ipsilateral or bilateral subcostal incision allows access to either adrenal and
facilitates exploration of the abdomen (Fig. 79.11B). The abdomen is opened and explored for evidence of
metastatic disease, including biopsy or excision of suspicious lesions. Resection of the right adrenal gland
proceeds with full mobilization and anteromedial retraction of the right hepatic lobe (Fig. 79.13A). It is
important to fully expose the retrohepatic inferior vena cava. In order to uncover the inferior vena cava, the
right kidney and the right adrenal gland, the hepatic flexure and transverse colon and are retracted inferiorly,
usually without need for extensive mobilization. A Kocher maneuver of the duodenum is seldom necessary
as the adrenal gland is superior to this area. The retroperitoneal space is entered behind the liver to expose
32 of 42 1/18/11 6:36 PM
the adrenal gland. Dissection of the gland proceeds from its inferomedial aspect, where small feeding
arteries are individually clipped and divided. The vena cava is carefully dissected along its lateral border,
which allows identification of the right adrenal vein where it drains directly into the inferior vena cava from
the anterior aspect of the adrenal gland. The adrenal vein is ligated and divided close to the vena cava. If
necessary because of hemodynamic changes during an operation for a pheochromocytoma, the adrenal vein
is identified and ligated early to avoid catecholamine surges and blood pressure fluctuations during
manipulation of the gland. Once the adrenal vein is ligated, arterial feeding vessels are clipped and divided
sequentially, beginning at the superolateral aspect of the gland and continuing medially.
Resection of the left adrenal gland requires mobilization of the spleen, tail of pancreas and left colon. The
left colon is freed from its peritoneal attachments and is reflected inferiorly. The spleen is then delivered
from the left upper quadrant medially, and the splenocolic ligament is divided. The spleen, stomach, and
pancreatic tail are retracted medially en bloc to expose the left kidney and adrenal (Fig. 79.13B). The left
adrenal vein is ligated and divided at its junction with the left renal vein. The gland is dissected and the
arterial vessels are ligated and divided sequentially, beginning at the superolateral aspect of the gland and
continuing medially.
33 of 42 1/18/11 6:36 PM
34 of 42 1/18/11 6:36 PM
Caption:
FIGURE 79.11 Incisions for right adrenalectomy. Shown are typical incisions for (A) laparoscopic
approach, (B) open, anterior approach, (C) posterior, open approach, and (D) thoracoabdominal approach.
Incisions for left adrenalectomy are positioned opposite.
Thoracoabdominal approach.
The thoracoabdominal approach is used for large adrenal lesions with invasion of surrounding structures
including the liver and diaphragm on the right side, and the spleen, pancreatic tail, stomach, and diaphragm
on the left. The patient is positioned with the ipsilateral flank raised and arm extended cephalad. Incision is
made in the tenth or eleventh intercostal space beginning at the posterior axillary line and is extended
toward the midline of the abdomen (Fig. 79.11C). Retractors are placed and subsequent adrenalectomy is
performed as for the anterior approach.
Posterior approach.
With the advent of laparoscopic adrenalectomy, the posterior approach is infrequently used. When
laparoscopic adrenalectomy is not an option, typically because of extensive prior transperitoneal operations,
the posterior approach is better tolerated and allows faster postoperative recovery compared with the
anterior approach. A posterior approach becomes increasingly more difficult as tumor size increases and is
not recommended for excision of large pheochromocytomas, adrenal tumors greater than 6 cm, or adrenal
carcinoma.
35 of 42 1/18/11 6:36 PM
Caption:
FIGURE 79.12 Laparoscopic adrenalectomy. Shown are intraoperative views of exposed right (A) and left
(B) adrenal pheochromocytomas (pheo) in a patient with multiple endocrine neoplasia (MEN)-2A. Note
clips on each adrenal vein. IVC, inferior vena cava.
The patient is placed prone on the operating table and flexed at the waist, which allows the abdominal
contents to fall away from the retroperitoneum. The incision is made from the midline at the tenth rib and is
extended inferolaterally to the superior border of the posterior iliac crest (Fig. 79.11D). Dissection proceeds
through the subcutaneous fat and latissimus dorsi muscle to the lumbodorsal fascia. This fascia is incised
longitudinally, and the underlying sacrospinalis muscle. The sacrospinalis muscle is retracted medially, and
the twelfth rib and vascular bundle are resected as far medially as possible. The twelfth intercostal nerve is
preserved and gently retracted superiorly. The retroperitoneum is entered and the diaphragm is bluntly
elevated from Gerota's fascia, the pleura are separated from the diaphragm, and the diaphragm is then
divided. Gerota's fascia is incised, and the kidney is retracted inferiorly to expose the adrenal gland. The
36 of 42 1/18/11 6:36 PM
arterial blood supply is controlled first by clipping and ligating numerous arterial vessels, which course
posteriorly. The adrenal vein, located deep to the arteries, is ligated as it is encountered. On the right, the
adrenal vein exits from the anterior aspect of the gland and courses to the inferior vena cava. Once the
adrenal vein is divided the gland is then freed circumferentially from its lateral to medial aspect. The
inferior border of the gland is dissected last to maintain attachment to the kidney and allow inferior
retraction of the gland. Finally, repair of the diaphragm and any incidental pleural defects, reapproximation
of the lumbodorsal fascia, and closure of the skin.
37 of 42 1/18/11 6:36 PM
Caption:
FIGURE 79.13 Anterior approach to right (A) and left (B) adrenalectomy. Note position of phrenic vein in
relationship to the left adrenal vein and tumor.
References
1. OMIM Online Mendelian Inheritance in Man [database online] &num;202300. Baltimore, MD: Johns
Hopkins; 2005. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi&quest;id5202300. Access
June 9, 2005.
2. OMIM Online Mendelian Inheritance in Man [database online] &num;171300. Baltimore, MD: Johns
Hopkins; 2005. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi&quest;id5171300). Access
June 9, 2005.
Bravo EL, Tagle R. Pheochromocytoma: state-of-the-art and future prospects. Endocr Rev.
2003;24:539–553.
Brunt LM, Lairmore TC, Doherty GM, et al. Adrenalectomy for familial pheochromocytoma in the
laparoscopic era. Ann Surg. 2002;235: 713–720.
Findling JW, Raff H. Diagnosis and differential diagnosis of Cushing syndrome. Endocrinol Metab Clin
North Am. 2001;30:729–747.
Harrison LE, Gaudin PB, Brennan MF. Pathologic features of prognostic significance for adrenocortical
carcinoma after curative resection. Arch Surg. 1999;134:181–185.
Kalady MF, McKinlay R, Olson JA Jr, et al. Laparoscopic adrenalectomy for pheochromocytoma. A
comparison to aldosteronoma and incidentaloma. Surg Endosc. 2004;18:621–625.
Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is
best&quest; JAMA 200220;287:1427–1434.
Magill SB, Raff H, Shaker JL, et al. Comparison of adrenal vein sampling and computed tomography in the
differentiation of primary aldosteronism. J Clin Endocrinol Metab. 2001;86:1066–1071.
Mansmann G, Lau J, Balk E, et al. The clinically inapparent adrenal mass: update in diagnosis and
management. Endocr Rev. 2004;25: 309–340.
Mulatero P, Stowasser M, Loh KC, et al Increased diagnosis of primary aldosteronism, including surgically
correctable forms, in centers from five continents. J Clin Endocrinol Metab. 2004;89:1045–1050.
Ng L, Libertino JM. Adrenocortical carcinoma: diagnosis, evaluation and treatment. J Urol. 2003;169:5–11.
NIH state-of-the-science statement on management of the clinically inapparent adrenal mass

(“incidentaloma”). NIH Consens State Sci Statements 2002;19:1–25.
Orth DN. Adrenal insufficiency. Curr Ther Endocrinol Metab. 1994;5: 124–130.
Pacak K, Linehan WM, Eisenhofer G, et al. Recent advances in genetics, diagnosis, localization, and
treatment of pheochromocytoma. Ann Intern Med. 2001;134:315–329.
38 of 42 1/18/11 6:36 PM
Reincke M. Subclinical Cushing syndrome. Endocrinol Metab Clin North Am. 2000;29:43–56.
Shen WT, Sturgeon C, Duh QY. From incidentaloma to adrenocortical carcinoma: the surgical management
of adrenal tumors. J Surg Oncol. 2005;89: 186–192.
Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med. 2003;349:776–788.
Stojadinovic A, Ghossein RA, Hoos A, et al. Adrenocortical carcinoma: clinical, morphologic, and
molecular characterization. J Clin Oncol. 2002;20: 941–950.
Werbel SS, Ober KP. Acute adrenal insufficiency. Endocrinol Metab Clin North Am. 1993;22:303–328.
White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev.
2000;21:245–291.
Young WF Jr. Minireview: primary aldosteronism—changing concepts in diagnosis and treatment.

Endocrinology 2003;144:2208–2213.
Chapter Links
Chapter: 79
Adrenal Glands
ANATOMY
BIOCHEMISTRY AND PHYSIOLOGY
Adrenal Cortex
Cortisol
Aldosterone
Adrenal Androgens
Adrenal Medulla
DISEASES OF THE ADRENAL CORTEX
Hypercortisolism
Signs and Symptoms
Diagnosis
Treatment
Hyperaldosteronism
Signs and Symptoms
Diagnosis
Treatment
Congenital Adrenal Hyperplasia
Signs and Symptoms
Diagnosis
Treatment
Virilizing and Feminizing Adrenal Tumors
Adrenocortical Carcinoma
Signs and Symptoms
Diagnosis
Treatment
DISEASES OF THE ADRENAL MEDULLA
Pheochromocytoma
39 of 42 1/18/11 6:36 PM
Signs and Symptoms

Diagnosis
Treatment
Metastasis to the Adrenal Glands
Incidental Adrenal Mass
Diagnosis
Treatment
Adrenal Insufficiency
Signs and Symptoms
Diagnosis
Treatment
Adrenalectomy.
Laparoscopic adrenalectomy.
Anterior approach.
Thoracoabdominal approach.
Posterior approach.
References
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SCORE | General Surgery Resident Curriculum Portal https://portal.surgicalcore.

Jeremy Irvan, M.D.

Greenfield's Surgery: Scientific Principles and Practice

Chapter 79: Adrenal Glands

Together they join the left renal vein (Fig. 79.1).

BIOCHEMISTRY AND PHYSIOLOGY

TABLE 79.1 SYSTEMIC EFFECTS OF CORTISOL

TABLE 79.2 EFFECTS OF ALDOSTERONE SECRETION

Chronotropic, inotropic Tachycardia

Catecholamines act on target tissues through membrane-bound receptors. Pharmacologic distinction of

Metabolism of catecholamines occurs through three mechanisms: by specific uptake by sympathetic

DISEASES OF THE ADRENAL CORTEX

ACTH-dependent Cushing syndrome involve bilateral adrenal hyperplasia in response to ACTH

Signs and Symptoms

Hypercortisolism insensitive to suppression by administration of exogenous glucocorticoid is the sine qua

Hyperaldosteronism is a syndrome of hypertension and hypokalemia caused by autonomous adrenal

An aldosterone-producing adrenal adenoma (Conn syndrome) is the source of primary hyperaldosteronism

Secondary hyperaldosteronism is a physiologic response of the renin-angiotensin system to decrease renal

Signs and Symptoms

Clinical manifestations of primary hyperaldosteronism are attributable to hypersecretion of aldosterone by

Surgical removal of an aldosterone-secreting adenoma (Fig. 79.7) results in durable improvement of

Congenital Adrenal Hyperplasia

Of the remaining causes of congenital adrenal hyperplasia, 11-beta-hydroxylase deficiency (CYP11B1) is

79.4 CONGENITAL ADRENAL HYPERPLASIAS

Signs and Symptoms

Prenatal adrenal virilization in females produces ambiguous external genitalia (female

Elevated plasma 17-hydroxyprogesterone is the most characteristic abnormality found in 21-hydroxylase

deficiency (Table 79.4).

The treatment of 21-hydroxylase deficiency is glucocorticoid and mineralocorticoid replacement. Clinical

Virilizing and Feminizing Adrenal Tumors

Signs and Symptoms

A definitive diagnosis of adrenocortical carcinoma requires pathologic demonstration of tumor invasion to

M1 Distant metastasis present

DISEASES OF THE ADRENAL MEDULLA

bladder. Clues to the presence of extraadrenal pheochromocytoma are predominance of norepinephrine

Familial pheochromocytoma is a component of two autosomal dominant syndromes: von Hippel-Lindau

Signs and Symptoms

Symptoms of pheochromocytoma are attributable to the effects of excessive circulating catecholamines on

potentially helpful confirmatory test.

Functional nuclear imaging with iodine-131-metaiodobenzylguanidine (131-I MIBG) is a useful adjunct to

Metastasis to the Adrenal Glands

Incidental Adrenal Mass

Biochemical testing should routinely exclude pheochromocytoma, hypercortisolism, and

hyperaldosteronism. Pheochro- mocytoma is evaluated either by 24-hour urine collection for

TABLE 79.6 DIAGNOSIS: SUMMARY OF TESTS FOR EVALUATION OF INCIDENTAL

Signs and Symptoms

TABLE 79.7 DIAGNOSIS: SYMPTOMS AND SIGNS OF ACUTE ADRENAL INSUFFICIENCY

NIH state-of-the-science statement on management of the clinically inapparent adrenal mass

Young WF Jr. Minireview: primary aldosteronism—changing concepts in diagnosis and treatment.

Signs and Symptoms

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