CHAPTER

39

The Adrenal Glands
Quan-Yang Duh, MD
and

Michael W. Yeh, MD

History Anatomy and Embryology Normal Histopathology Biochemistry and Physiology Inborn Errors of Metabolism: Congenital Adrenal Hyperplasia Adrenal Insufficiency Diseases of the Adrenal Cortex Diseases of the Adrenal Medulla The Incidentally Discovered Adrenal Mass (“Incidentaloma”) Metastases to the Adrenal Gland Technical Aspects of Adrenalectomy

Medicine for their groundbreaking work on the adrenocortical hormones. The Austrian-born endocrinologist Hans Selye first described the stress response in mammals in 1936 and made major contributions to understanding of the hypothalamic-pituitary-adrenal (HPA) axis. Roger Guillemin, Andrew Schally, and Rosalyn Yalow were awarded the Nobel Prize in 1977 for characterizing the peptide hormones of the brain that underlie the HPA axis as we now understand it.1,2

ANATOMY AND EMBRYOLOGY General and Developmental Aspects
The adrenal glands are paired, mustard-colored structures that are positioned superior and slightly medial to the kidneys in the retroperitoneal space (Fig. 39-1). They are flattened and roughly pyramidal (right) or crescent shaped (left) and weigh approximately 4 g each. The adrenals are among the most highly perfused organs in the body, with blood flow of 2000 mL/kg/min, behind only the kidney and the thyroid. In most respects the cortex and medulla can be considered two completely distinct organs that happen to colocalize during development. The two portions have disparate embryologic origins. The primordial cortex arises from the coelomic mesodermal tissue near the cephalic end of the mesonephros during the fourth to fifth week of gestation. Biosynthetic activity can be detected as early as the seventh week. The cortical cell mass dominates the fetal adrenal at 4 months of development, and steroidogenesis reaches its maximum during the third trimester. The adrenal medulla arises from ectodermal tissues of the embryonic neural crest. It develops in parallel with the sympathetic nervous system, beginning in the fifth to sixth week of gestation. From their original position adjacent to the neural tube, neural crest cells migrate ventrally to assume a para-aortic position near the developing adrenal cortex. There, they

HISTORY
The adrenal glands were first described by the Italian anatomist Bartolomeo Eustachi in 1563. The German comparative anatomist Albert von Kölliker (1817-1905), who noted the presence of adrenals in a number of vertebrate species, is credited with first identifying two distinct portions of the adrenal gland, namely, the cortex and medulla. Although Thomas Addison described the clinical features of primary adrenal failure in 1855, it was not until nearly a century later that the adrenal hormones were fully isolated and characterized. Adrenaline (or epinephrine) was first isolated from adrenal extract at the turn of the century. Steroid hormones were crystallized from cortical extract (cortin) by Swiss and American investigators in the 1930s, but their highly similar chemical structures made isolation of the individual compounds challenging. Edward Kendall, Tadeus Reichstein, and Philip Hench jointly received the 1950 Nobel Prize in Physiology or

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Right and left inferior phrenic arteries Inferior vena cava

Right adrenal gland Right adrenal vein

Left adrenal gland

Left inferior phrenic vein

Left inferior adrenal artery

Right renal artery and vein

Left adrenal vein

Left kidney

Left renal artery and vein

A

Inferior vena cava

Abdominal aorta

Figure 39-1 Anatomy of the adrenal glands. A, Left and right adrenal glands in situ.

differentiate into the chromaffin cells that make up the adrenal medulla.3 This course of embryologic development yields certain surgically relevant sequelae. Both cortical and medullary tissue can be found at extra-adrenal sites (Fig. 39-2). The range of potential sites is wider for chromaffin tissue than for cortical tissue, presumably because of the longer path of migration for the former. Pheochromocytomas may arise in extra-adrenal sites more commonly than previously thought (see later). When extra-adrenal, pheochromocytomas are also called paragangliomas.

by its proper capsule, in addition to sharing Gerota’s fascia with the kidneys. The adrenal capsules are immediately associated with the perirenal fat.

Vasculature
Knowledge of the macroscopic vascular anatomy of the adrenal glands is essential for proper surgical management. It is important to conceptualize that although the arterial supply is diffuse, the venous drainage of each gland is usually solitary. The arterial supply arises from three distinct vessels: the superior adrenal arteries from the inferior phrenic arteries, the small middle adrenal arteries from the juxtaceliac aorta, and the inferior adrenal arteries from the renal arteries. Of these, the inferior is the most prominent and is commonly a single identifiable vessel. The left adrenal vein is approximately 2 cm long and drains into the left renal vein after joining the inferior phrenic vein. The right adrenal vein is typically as short as it is wide (0.5 cm) and drains directly into the vena cava. This configuration presents a surgical challenge that will be revisited in the technical section of this chapter. In up to 20% of individuals, the right adrenal vein may drain into an accessory right hepatic vein or into the vena

Relationships
The right adrenal gland abuts the posterolateral surface of the retrohepatic vena cava. The right adrenal fossa is bounded by the right kidney inferolaterally, the diaphragm posteriorly, and the bare area of the liver anterosuperiorly. The left adrenal gland lies between the left kidney and aorta, with its inferior limb extending farther caudad toward the renal hilum than the right adrenal. The other relationships of the left adrenal gland are the diaphragm posteriorly and the tail of the pancreas and splenic hilum anteriorly. Each adrenal gland is enveloped

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Stomach

Spleen Adrenal gland

Pancreas Liver

Adrenal gland Kidney

Inferior vena cava Duodenum Kidney

Pancreas Stomach Liver

Inferior vena cava Spleen Adrenal gland Kidney Diaphragm Diaphragm Adrenal gland

B

C
Figure 39-1, cont’d B, Relationships of the left adrenal gland. C, Relationships of the right adrenal gland.

Adrenal T1 Medullary Cortical

cava at or near the confluence of such a vein.4 Vigilance toward this variant and others (Fig. 39-3) may reduce the likelihood of intraoperative venous hemorrhage during right adrenalectomy.

NORMAL HISTOPATHOLOGY
The cortex is approximately 2 mm thick and accounts for greater than 80% of the mass of the gland. It is made up of three layers (Fig. 39-4). The outer zona glomerulosa is a thin layer of relatively small cells with moderately eosinophilic, lipid-poor cytoplasm. It has an undulating inner border and normally does not form a complete circumferential layer. The majority of the adrenal cortex is formed by the zona fasciculata, a middle layer composed of long radial columns of large, clear, lipid-laden cells. The inner zona reticularis is made up of small nests of compact, eosinophilic cells. The adrenal medulla con-

Figure 39-2 Sites of extra-adrenal cortical and medullary tissue.

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Right hepatic vein Adrenal

Middle and left hepatic veins

Right hepatic vein Adrenal

Middle and left hepatic veins

Territory of potential venous confluence (multiple veins may be present)

Adrenal vein

Kidney

Kidney

Renal Inferior vein vena cava Territory

Renal Inferior vein vena cava Normal (single vein directly into IVC) Middle and left hepatic veins

A
Middle and left hepatic veins

B

Right hepatic vein Adrenal

Right hepatic vein Adrenal

Adrenal vein Kidney Kidney

Adrenal vein

Inferior Renal vein vena cava IVC/renal vein “trifurcation”

Inferior Renal vein vena cava Renal vein confluence

C

D
Figure 39-3 Variations in right adrenal vein anatomy. A, Territory of potential right adrenal vein confluence.

B, Normal (>80%)—single vein directly into the inferior vena cava (IVC). C, IVC/renal vein “trifurcation.” D, Renal vein confluence.

sists of clusters and short cords of chromaffin cells, which are large, polyhedral, and packed with basophilic secretory granules. Catecholamines within these granules yield a brown-colored reaction when treated with chromium salts, thus giving the cells their name. In contrast to the cortex, the adrenal medulla is richly endowed with autonomic nerve fibers and ganglion cells. Sympathetic fibers

synapse directly with the chromaffin cells and constitute an interface between the nervous and endocrine systems.5 The microvasculature of the adrenal gland functionally unifies the cortex and medulla. The adrenal arteries arborize extensively before entering the capsule to form a subcapsular plexus. Blood flows centripetally through

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Right hepatic vein Adrenal

Middle and left hepatic veins

Right hepatic vein Adrenal

Middle and left hepatic veins

Adrenal vein

Adrenal vein

Kidney

Kidney

Renal Inferior vein vena cava High single vein

Renal Inferior vein vena cava IVC/right hepatic vein “trifurcation” Middle and left hepatic veins

E
Right hepatic vein Adrenal

F

Adrenal vein

Kidney

Inferior Renal vein vena cava Right hepatic vein confluence

G
Figure 39-3, cont’d E, High single vein into the IVC. F, IVC/right hepatic vein “trifurcation.” G, Right hepatic vein

confluence.

capillaries in the zona glomerulosa and zona fasciculata before forming a deep plexus within the zona reticularis. From there, steroid-enriched postcapillary blood enters the medulla, where cortisol drives expression of phenylethanolamine-N-methyltransferase (PNMT). PNMT is responsible for conversion of norepinephrine to epinephrine. This microvascular arrangement is essentially a portal system between the cortex and the medulla.

BIOCHEMISTRY AND PHYSIOLOGY Adrenal Steroid Biosynthesis
Adrenal steroid biosynthesis begins with transport of cholesterol to the inner mitochondrial membrane by the steroidogenic acute regulatory protein (StAR) (Fig. 39-5).6 Cholesterol then undergoes a series of oxidative reac-

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latter being active in humans. Aldosterone is generated by oxidation of corticosterone at the carbon 18 position by CYP11B2 localized to the zona glomerulosa. CYP17 expression is confined to the zona fasciculata and zona reticularis, thus accounting for synthesis of glucocorticoids and adrenal sex steroids in these regions.

Steroid Hormone Physiology and Metabolism
Steroid hormones belong to a general class of lowmolecular-weight, lipophilic signaling molecules that act by entering cells and binding to intracellular receptors. This group of hormones also includes thyroid hormone, retinoids, and vitamin D. Hormone binding results in alterations in gene expression that show a delayed and prolonged response when compared with the changes induced by peptide hormones, which act by binding to cell surface receptors. In the circulation, endogenous steroid hormones are largely bound to highly specific binding globulins. Serum levels of these proteins (and hence free hormone levels) can be altered by certain physiologic and disease states such as pregnancy, nephrotic syndrome, and cirrhosis. Metabolism of both endogenous and pharmacologic steroids generally proceeds via hydroxylation, sulfonation, or conjugation (or any combination of these processes) to glucuronic acid in the liver, followed by urinary excretion. The regulation and physiologic actions of individual steroid hormones are discussed in the following sections.

A

Capsule

Glomerulosa Faciculata

Glucocorticoids
Reticularis

B
Figure 39-4 Normal adrenal histopathology. A, Low-power view showing the adrenal cortex (C) and medulla (M). B, Mediumpower view demonstrating individual layers of the adrenal cortex. The thickness of the zona glomerulosa varies along its length. (Photomicrographs courtesy of Anthony Gill, MD).

tions catalyzed predominantly by membrane-associated enzymes belonging to the cytochrome P-450 (CYP) family. Cleavage of the cholesterol side chain yields the hormonally inactive compound pregnenolone, the immediate precursor to adrenal steroid hormones. Serial oxidation by CYP17 (moving “rightward” on the chart) converts pregnenolone and progesterone into the major adrenal sex steroids dehydroepiandrosterone (DHEA) and androstenedione. Additional enzymatic steps confined to the gonads (not shown) generate testosterone, estrone, and estradiol from androstenedione. Oxidation of pregnenolone and 17-hydroxypregnenolone at the carbon 3 position by 3β-hydroxysteroid dehydrogenase, followed by the action of CYP21A2 and CYP11B1 (moving “downward” on the diagram), yields the major mammalian glucocorticoids corticosterone and cortisol, with only the

Release of corticotropin-releasing factor (CRF) into the hypothalamic-pituitary portal system by hypothalamic neurons results in secretion of adrenocorticotropic hormone (ACTH) by the anterior pituitary. Synthesis of pro-opiomelanocortin (POMC), the large precursor peptide to ACTH, is also up-regulated. ACTH binds to a G protein–coupled receptor on the adrenocortical cell surface and stimulates glucocorticoid secretion, among other effects. Steroidogenesis is acutely up-regulated via increased StAR-mediated cholesterol transport and pregnenolone synthesis by CYP11A1 (cholesterol side chain cleavage enzyme). Chronically, ACTH increases transcription of all steroidogenic enzymes and supports maintenance of normal adrenal cell mass. ACTH is released in a pulsatile fashion that normally displays a circadian rhythm. The highest levels of ACTH, and thus cortisol, are generally detected on waking, with levels gradually declining through the day to reach a nadir in the early evening. This pattern must be considered when evaluating patients for glucocorticoid deficiency or excess. Negative feedback by glucocorticoids occurs at both the hypothalamic and pituitary levels. Glucocorticoid hormones have broad-ranging effects on almost all organ systems in the body. As a rule, they generate a catabolic state that characterizes the body’s response to stress. The hormones are so named because they cause alterations in carbohydrate, protein, and lipid metabolism that have the net effect of increasing blood

StAR

Cholesterol transport to inner mitochondrial membrane
19 1 2 3 10 4 5 6 11 9 8 7 12

21 18 13 14 20 17

16 15

HO

Cholesterol carbon numbering Reactions confined to zonae fasciculata and reticularis
CH3 C=O CH3 C=O OH O

Cholesterol CYP11A1 Side chain cleavage

CYP17

CYP17

HO

HO

HO

Pregnenolone 3βHSD
CH3 C=O

17-hydroxy pregnenolone 3βHSD
CH3 C=O

Dehydroepiandrosterone (DHEA) 3βHSD
O

CYP17

OH

CYP17

O

O

O

Progesterone CYP21A2
CH2OH C=O

17-hydroxy progesterone CYP21A2
CH2OH C=O OH

Androstenedione

O

O

Deoxycorticosterone CYP11B1
CH2OH C=O HO

11-deoxycortisol CYP11B1
CH2OH C=O HO OH

O

O

Corticosterone CYP11B2
CH2OH C=O HO

Cortisol

O

Aldosterone Reaction confined to zona glomerulosa

Figure 39-5 Adrenal steroid biosynthesis. Reactions confined to the zone glomerulosa are shaded turquoise; those

confined to the zonae fasciculata and reticularis are shaded orange. Human mineralocorticoids are indicated in yellow, glucocorticoids in green, sex steroids in blue.

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glucose concentrations. Hepatic glucose output is elevated by up-regulation of gluconeogenesis, and net glycogen deposition occurs. Glucose uptake by peripheral tissues is directly inhibited. Glucocorticoids stimulate lipolysis with the release of free fatty acids into the circulation, and a general state of insulin resistance is induced that results in protein catabolism. Fatty acids and amino acids serve as energy sources and substrate for gluconeogenesis. In the cardiovascular system, glucocorticoids exert a permissive and enhancing effect on catecholamine signaling by sensitizing arterial smooth muscle cells to β-adrenergic stimulation and increasing catecholamine concentrations in neuromuscular junctions.7 Cardiac contractility and peripheral vascular tone are thus maintained, which explains why the hemodynamic collapse that accompanies acute adrenal insufficiency can be remedied by glucocorticoid administration. Glucocorticoids are potent anti-inflammatory and immunosuppressive agents that act at many levels. Acutely, glucocorticoids reduce circulating lymphocyte and eosinophil counts while increasing neutrophil counts. Lymphocyte apoptosis is promoted, cytokine and immunoglobulin production is decreased, and histamine release is suppressed. Glucocorticoids also reduce prostaglandin synthesis via inhibition of phospholipase A2. Additional pathologic effects of glucocorticoids are discussed later in the section on glucocorticoid excess.

synthesized in both the adrenal and liver) is regulated by ACTH and other incompletely understood mechanisms. Of the three, androstenedione is produced in the smallest quantities. The physiologic effects of adrenal sex steroids are generally weak in comparison to the gonadal sex steroids, particularly in males. In females, peripheral conversion of DHEA and DHEA-S to more potent androgens, including androstenedione, testosterone, and dihydrotestosterone, supports normal pubic and axillary hair growth and may play a role in maintaining libido and a sense of well-being.

Catecholamine Biosynthesis and Physiology
Synthesis of catecholamines in the adrenal medulla begins with the hydroxylation of tyrosine, a rate-limiting step that generates dihydroxyphenylalanine (L-dopa) in the cytosol (Fig. 39-6). Decarboxylation of L-dopa generates dopamine, which is taken up by neurosecretory granules and β-hydroxylated to form norepinephrine. Epinephrine is created by the action of PNMT, which unlike the other enzymes involved in catecholamine synthesis, is localized to the chromaffin cells of the adrenal medulla and organ of Zuckerkandl. Sympathetic stimulation of the adrenal medulla results in depolarization of the chromaffin cell membrane and release of stored catecholamines into the circulation. Basal levels of adrenal catecholamine secretion are normally low, although large (up to 50-fold) increases in levels may be observed in response to major physiologic or psychological stressors. Target tissue responses are mediated by α- and β-adrenergic receptors. α-Adrenergic receptors display greater affinity for norepinephrine than for epinephrine, and the opposite is true for β-adrenergic receptors. Stimulation of β1-receptors in the myocardium results in an increase in heart rate and contractility. Stimulation of β2-receptors results in smooth muscle relaxation in tissues such as the uterus, bronchi, and skeletal muscle arterioles. α1-Receptors mediate vasoconstriction in tissues such as the skin and gastrointestinal tract. α2-Receptors exist in presynaptic locations in the central nervous system, where they mediate attenuation of sympathetic outflow. The net effect of adrenal catecholamine release is to augment blood flow and delivery of oxygen to the brain, heart, and skeletal muscle (which are essential for the “fight or flight” response) at the expense of other organ systems.

Mineralocorticoids
Release of aldosterone from the zona glomerulosa is principally regulated by angiotensin II and the blood potassium level. The renin-angiotensin-aldosterone axis is responsive to delivery of sodium to the distal convoluted tubule of the kidney. Low sodium delivery, which occurs in states such as hypovolemia, shock, renal artery vasoconstriction, and hyponatremia, stimulates the release of renin from the juxtaglomerular apparatus. The prohormone angiotensinogen is synthesized by the liver and is cleaved to inactive angiotensin I by renin. Further cleavage of angiotensin I by angiotensin-converting enzyme in the lungs and elsewhere yields angiotensin II, a potent vasoconstrictor and stimulator of aldosterone release. Aldosterone release is also highly sensitive to minute changes in the blood potassium level. Hypokalemia reduces aldosterone release by suppressing renin secretion and also by acting directly at the zona glomerulosa. Hyperkalemia has the opposite effect. Aldosterone regulates circulating fluid volume and electrolyte balance by promoting sodium and chloride retention in the distal tubule. Potassium and hydrogen ions are secreted into urine. Acutely, expansion of extracellular fluid volume and a rise in blood pressure are observed after aldosterone infusion. Negative feedback occurs primarily via an increase in sodium delivery to the distal tubule, which suppresses release of renin.

Catecholamine Clearance
Catecholamines are potent, short-acting compounds with a plasma half-life on the order of 1 minute. Their presence in synapses and the circulation is controlled by tight negative regulation via both reuptake and degradation. Degradation pathways merit some discussion because they generate the metabolites commonly measured in the biochemical evaluation of pheochromocytoma (discussed later). Epinephrine and norepinephrine are inactivated by one or both of the following enzymes: monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) (see Fig. 39-6). Initial methylation by COMT yields meta-

Adrenal Sex Steroids
Secretion of the adrenal androgens androstenedione, DHEA, and DHEA-S (the sulfonated derivative of DHEA,

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SYNTHESIS
HO CH2

COOH CH NH2

Tyrosine Tyrosine hydroxylase
HO COOH HO CH2 CH NH2

Dihydroxyphenylalinine (L-dopa) DOPA decarboxylase
HO

HO

CH2

CH2

NH2

Dopamine Dopamine β-hydroxylase
HO OH HO CH CH2 NH2

Phenylethanolamine N-methyltransferase
HO

HO OH CH CH2 NH CH3

Norepinephrine Catechol-O-methyl transferase Monoamine oxidase
HO OH HO CH CH2 NH2 HO OH CH O C OH

Epinephrine Monoamine oxidase Catechol-O-methyl transferase

CH3O

CH3O OH HO CH CH2 NH CH3

Normetanephrine

3,4-Dihydroxymandelic acid Catechol-O-methyl transferase
CH3O OH HO CH O C OH

Metanephrine

Monoamine oxidase

Monoamine oxidase

Vanillylmandelic acid (VMA) DEGRADATION

Figure 39-6 Catecholamine biosynthesis and metabolism. Synthetic steps are shaded orange; degradative steps are shaded turquoise. Major catecholamines are indicated in green, major metabolites in yellow.

nephrine and normetanephrine, which can be detected in both plasma and urine. Their relatively stable plasma levels, which contrast with the high-amplitude fluctuations seen in plasma epinephrine and norepinephrine levels, make them attractive diagnostic markers.8 The sequential action of MAO and COMT generates the major final product vanillylmandelic acid. Catecholamine metabolites are excreted in urine, sometimes after sulfonation or conjugation to glucuronic acid in the liver.

INBORN ERRORS OF METABOLISM: CONGENITAL ADRENAL HYPERPLASIA
Congenital adrenal hyperplasia (CAH) is a relatively common inherited disorder that provides insight into mechanisms of steroid biosynthesis and negative feedback. Although six enzyme defects are known to cause CAH, more than 90% are caused by CYP21A2 deficiency

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Table 39-1

Properties of Endogenous and Commonly Used Pharmacologic Glucocorticoids
IV/PO* COMMON TRADE NAME RELATIVE POTENCY DAILY PHYSIOLOGIC DOSE DOSING INTERVAL

COMPOUND

Cortisol = hydrocortisone Cortisone Prednisone Prednisolone Methylprednisolone Dexamethasone†

Both PO PO PO Both Both

Cortef (PO) Solu-Cortef (IV) — — — Medrol (PO) Solu-Medrol (IV) Decadron

1× 0.8× 4× 4× 5× 25×

20 mg 25 mg 5 mg 5 mg 4 mg 1 mg

q8-12h q8-12h q24h q24h q24h q24h

*Oral and intravenous dosages are similar. † Does not cross-react with the cortisol assay.

(also known as 21-hydroxlase deficiency), which is discussed here. Several phenotypes of this disorder have been described. In 75% of cases, classic CYP21A2 deficiency is manifested as a salt-wasting form, where impaired 21-hydroxylation of progesterone results in aldosterone deficiency. In addition, impaired 21-hydroxylation of 17-hydroxyprogesterone results in cortisol deficiency. The saltwasting form is manifested within the first few months of life as hypovolemia, hyperkalemia, and hyperreninemia. Reduced negative feedback leads to an increase in ACTH secretion and accumulation of steroid hormone precursors upstream of CYP21A2. Shunting of precursors toward oxidation at carbon 17 generates an excess of adrenal androgens, which leads to ambiguous genitalia in newborn girls. In a minority of cases, CYP21A2 deficiency is manifested as a simple virilizing form, in which aldosterone synthesis is intact. The diagnosis of CAH is made by biochemical screening for elevated plasma levels of 17-hydroxyprogesterone, followed by confirmatory genetic and provocative biochemical testing. Treatment centers around glucocorticoid and mineralocorticoid replacement, as well as surgical correction of genital anomalies in girls.9

result from ACTH-induced melanogenesis.10 Hormonal insufficiency secondary to intrinsic adrenal disease arises from three general mechanisms: congenital adrenal dysgenesis/hypoplasia, defective steroidogenesis, and adrenal destruction. Of these, adrenal destruction from autoimmune causes is the most common, followed by infectious adrenalitis (tuberculous, fungal, or viral), adrenal replacement by metastatic tumor, and adrenal hemorrhage (Waterhouse-Friderichsen syndrome). The latter occurs in the setting of septicemia from meningococcus or other organisms and is more common in pediatric and asplenic patients.11

Secondary Adrenal Insufficiency
Secondary adrenal insufficiency is a relatively common disorder that results from ACTH deficiency and often occurs in the setting of pharmacologic steroid withdrawal. Patients receiving high supraphysiologic doses of glucocorticoids (greater than the equivalent of 20 mg prednisone daily, Table 39-1) for more than 5 days and those receiving low supraphysiologic doses for more than 3 weeks are at risk for suppression of the HPA axis. Surgical cure of Cushing’s syndrome (see later) likewise results in glucocorticoid withdrawal. The rate of recovery from HPA axis suppression varies in accordance with the duration and severity of the previous glucocorticoid excess, and the need for glucocorticoid supplementation may last several years.12 Other less common causes of secondary adrenal insufficiency include panhypopituitarism secondary to neoplastic or infiltrative replacement, granulomatous disease, and pituitary hemorrhage/infarction. Pituitary infarction may occur in the setting of severe postpartum hemorrhage (Sheehan’s syndrome).

ADRENAL INSUFFICIENCY Primary Adrenal Insufficiency (Addison’s Disease)
Addison originally described 10 patients with “anemia . . . feebleness of the heart action . . . [and] a peculiar change of color in the skin” associated principally with tuberculous destruction of the adrenal glands. This rare disease is most commonly manifested as weakness and fatigue, anorexia, nausea or vomiting, weight loss, hyperpigmentation, hypotension, and electrolyte disturbances (hyponatremia and hyperkalemia). Hyperpigmentation, previously thought to be caused by elevated levels of POMC and its cleavage product α-melanocyte–stimulating hormone, is now believed to

Adrenal Insufficiency in the Critically Ill
A growing body of literature suggests that critically ill patients with sepsis or systemic inflammatory response syndrome may be affected by acute reversible dysfunction of the HPA axis. The incidence of the disorder is

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approximately 30% in critically ill patients, although this figure may be higher in those with septic shock. Whether these patients incur increased mortality because of adrenal insufficiency remains to be defined. Proposed mechanisms of reversible HPA axis dysfunction include adrenal ACTH resistance and decreased responsiveness of target tissues to glucocorticoids. Glucocorticoid supplementation in septic patients has been the topic of at least 14 randomized, controlled trials. In these studies there appears to be an inverse relationship between survival benefit and glucocorticoid dose, with physiologic (i.e., replacement) doses yielding a median relative survival benefit of 1.33 and high supraphysiologic doses demonstrating significant harm. Although the data remain controversial, the most recent evidence suggests that patients with vasopressordependent septic shock may benefit from 5- to 7-day courses of glucocorticoids in the dose range of 400 mg/ day or less of hydrocortisone or equivalent.13

Suspected adrenal insufficiency

8 AM serum or salivary cortisol Serum cortisol ≤15 µg/dL or salivary cortisol ≤5.8 ng/mL Serum cortisol >15 µg/dL or salivary cortisol >5.8 ng/mL

Adrenal insufficiency possible

Adrenal insufficiency unlikely

250 µg ACTH (cosyntropin) stimulation test Post cortisol <18 µg/dL Post cortisol ≥18 µg/dL

Adrenal Crisis
Acute adrenal insufficiency, or adrenal crisis, is a lifethreatening condition that typically occurs in individuals with already marginal adrenocortical function who are subjected to a significant acute physiologic stressor such as infection or trauma. Sudden complete loss of adrenal function, as occurs with Waterhouse-Friderichsen syndrome and certain hypercoagulable states, can also occur with adrenal crisis. Clinical findings include shock, abdominal pain, fever, nausea and vomiting, electrolyte disturbances, and occasionally, hypoglycemia. Mineralocorticoid deficiency resulting in an inability to maintain sodium and intravascular volume is the primary pathogenetic mechanism, although diminished cardiovascular responsiveness to catecholamines secondary to glucocorticoid deficiency also plays a role. Treatment of adrenal crisis centers around large-volume (>2 L) intravenous (IV) resuscitation with isotonic saline and glucocorticoid administration in the form of either hydrocortisone (100 mg IV every 6-8 hours) or dexamethasone (4 mg IV every 24 hours). Dexamethasone is long acting and carries the advantage of not interfering with biochemical assays of endogenous glucocorticoid production. Ironically, mineralocorticoid replacement is not an early priority because the sodium- and fluid-retentive effects of mineralocorticoids do not occur until several days after administration. Fluid and electrolyte balance can be rapidly achieved by saline infusion.14
Adrenal insufficiency possible Adrenal insufficiency unlikely

8 AM serum ACTH Increased ACTH Decreased or normal

Primary adrenal insufficiency

Secondary adrenal insufficiency

Figure 39-7 Algorithm for the diagnosis of adrenal insufficiency. The adequacy of cortisol production is initially assessed with morning cortisol measurement. Patients with low or borderline values undergo provocative adrenocorticotropic hormone (ACTH) stimulation testing, with serum cortisol being measured before and 30 to 60 minutes after the administration of ACTH. Failure to mount a adequate response to ACTH establishes the diagnosis of adrenal insufficiency in most cases. The cause of adrenal insufficiency is then investigated with morning ACTH measurement.

Diagnosis and Treatment of Adrenal Insufficiency
As is true for most endocrine disorders, diagnosis of adrenal insufficiency depends on maintaining sufficient clinical suspicion for the disease. The clinical manifestations are discussed earlier. Surgeons are most likely to encounter patients with adrenal insufficiency in the intensive care unit, the trauma suite, or the operating room when treating patients with steroid-dependent

chronic illnesses. Routine and provocative biochemical testing is necessary to confirm the diagnosis (Fig. 39-7). The first step is to document inadequate cortisol production, which can be done by measuring morning levels of cortisol in serum or saliva. In most patients, a morning serum cortisol concentration greater than 15 µg/dL or a morning salivary cortisol concentration greater than 5.8 ng/mL effectively excludes adrenal insufficiency. These cutoff values are deliberately set high to maximize sensitivity at the expense of specificity for this screening test. Patients whose values fall below these thresholds undergo provocative testing with exogenous ACTH (cosyntropin). A high-dose cosyntropin stimulation test is performed by administering 250 µg of cosyntropin and

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Table 39-2

Appropriate Perioperative Glucocorticoid Regimens for Patients With Secondary Adrenal Insufficiency Caused by Chronic Pharmacologic Steroid Use
DEGREE OF SURGICAL STRESS EXAMPLES DAILY GLUCOCORTICOID DOSE

Minor Moderate Major

Procedures under local anesthesia, most outpatient procedures, inguinal hernia repair Routine abdominal, peripheral, vascular, or orthopedic surgery Resection of gastrointestinal cancer, cardiopulmonary bypass

Hydrocortisone, 25 mg or equivalent Hydrocortisone, 50-75 mg or equivalent Hydrocortisone, 100-150 mg or equivalent

Adapted from Salem M, Tainsh RE Jr, Bromberg J, et al: Perioperative glucocorticoid coverage. A reassessment 42 years after emergence of a problem. Ann Surg 219:416-425, 1994.

measuring serum cortisol levels 30 to 60 minutes later. A positive test (i.e., a stimulated cortisol level of less than 18 µg/dL) is strongly suggestive of adrenal insufficiency. Likewise, a normal test greatly reduces the likelihood of the diagnosis, although false-negative results may occur in patients with mild, new-onset, or secondary adrenal insufficiency. Higher cutoff values (25 µg/dL) have been recommended for evaluation of critically ill patients.15 After the diagnosis of adrenal insufficiency has been made, a morning ACTH level is determined to differentiate between primary and secondary adrenal insufficiency. Treatment of adrenal crisis is discussed earlier. The goal of maintenance therapy for chronic adrenal insufficiency is to replace physiologic glucocorticoid and mineralocorticoid levels. Daily adult cortisol production is in the range of 10 to 20 mg, which can be replaced by the long-acting, orally bioavailable agent prednisone at a dose of 5 mg/day. Typical mineralocorticoid replacement consists of fludrocortisone, 0.1 mg/day. Commensurate increased dosages of glucocorticoids are needed during periods of minor and major physiologic stress, such as mild infections (minor), as well as trauma, significant infections, burns, or elective surgery (major).

DISEASES OF THE ADRENAL CORTEX Primary Hyperaldosteronism
Epidemiology and Clinical Features Primary hyperaldosteronism, or unregulated release of excess aldosterone from one or both adrenal glands, was first described by Jerome Conn, an endocrinologist at the University of Michigan, in 1954. Primary hyperaldosteronism is classically manifested as resistant hypertension and hypokalemia, although recent reports have revealed that the majority of patients may be normokalemic, depending on the population screened. Hypokalemia is probably a manifestation of severe or late-stage disease. The prevalence of primary hyperaldosteronism has been the topic of considerable debate. Until recently it was generally believed to affect roughly 1% of patients with hypertension. Widespread application of the aldosterone-renin ratio, discussed later, as a screening test in certain centers led to reports of a 10% to 40% prevalence of primary hyperaldosteronism among hypertensives.17 There is some consensus that these higher figures reflect strong referral bias and that the actual prevalence in unselected hypertensive patients is probably 7% or less. Nonselective use of the aldosterone-renin ratio to identify patients with primary hyperaldosteronism is known to significantly decrease the fraction of patients with surgically correctable disease (unilateral aldosteronoma), although the absolute number of surgically treatable cases increases.18 The mean age at diagnosis of primary hyperaldosteronism is roughly 50, and the disease has a mild male predilection. Most patients are asymptomatic, although those with significant hypokalemia may complain of muscle cramps, weakness, or paresthesias. Patients typically have moderate to severe hypertension that is refractory to medical therapy. It is common for them to require two to four antihypertensive medications. Responsiveness to spironolactone may be seen, a feature that is predictive of a good response to surgical treatment. Primary hyperaldosteronism is a potentially curable cause of significant cardiovascular disease. A recent study comparing 124 subjects with biochemically confirmed primary hyperaldosteronism and hypertensive controls matched for age and systolic blood pressure revealed

Perioperative Steroid Administration
Recommendations concerning glucocorticoid administration during elective surgery have been based primarily on uncontrolled, retrospective studies. The need for supraphysiologic doses of glucocorticoids in this setting has generally been overstated. Patients with secondary adrenal insufficiency as a result of chronic glucocorticoid treatment of autoimmune or inflammatory conditions have a 1% to 2% risk for hypotensive crisis without perioperative glucocorticoid coverage. To prevent this rare but hazardous complication, chronic glucocorticoid users are, at the least, maintained on their usual glucocorticoid dosage throughout the perioperative period. Supplementation above this level is given in short courses according to the guidelines listed in Table 39-2.16 Patients undergoing unilateral adrenalectomy are given supplemental glucocorticoids only if the underlying diagnosis is Cushing’s syndrome.

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Table 39-3

Causes of Primary Hyperaldosteronism*
SELECTIVE SCREENING NONSELECTIVE SCREENING

Aldosterone-producing adenoma Bilateral adrenal hyperplasia (idiopathic hyperaldosteronism) Aldosterone-producing adrenocortical carcinoma Familial hyperaldosteronism Type 1 (glucocorticoid-remediable aldosteronism) Type 2 (non–glucocorticoid-remediable aldosteronism)

60% 35% <1% <1% <1%

30% 65% <1% <1% <1%

*Rates of specific pathologies are highly dependent on the pattern of screening (selective versus nonselective).

that primary hyperaldosteronism is associated with a significantly increased risk for stroke, myocardial infarction, atrial fibrillation, and left ventricular hypertrophy.19 These data add to existing evidence that the adverse cardiovascular sequelae of primary hyperaldosteronism are greater than those caused by blood pressure elevation alone. Successful removal of an aldosteronoma leads to regression of many of these adverse physiologic changes. The most common causes of primary hyperaldosteronism are unilateral aldosterone-producing adenoma (aldosteronoma) and bilateral adrenal hyperplasia (also termed idiopathic hyperaldosteronism, Table 39-3). In the past, aldosteronoma was present in more than 60% of cases, but that figure has decreased substantially as nonselective screening with the aldosterone-renin ratio has been applied. This phenomenon may reflect increased detection of hyperplasia, which is characterized by milder biochemical abnormalities than occurs with aldosteronoma.

Biochemical Diagnosis and Localization The goal of diagnostic testing is to identify and lateralize aldosteronomas. There is some consensus that biochemical screening should be performed in all patients with hypertension and unexplained hypokalemia, as well as those with hypertension sufficiently resistant to medical therapy to warrant investigation for secondary hypertension. Establishing the diagnosis of primary hyperaldosteronism begins with determining the ratio of plasma aldosterone to plasma renin activity (expressed here as ng/dL divided by ng/mL•h, Fig. 39-8). This test is performed after discontinuation of interfering medications such as spironolactone, angiotensin-converting enzyme inhibitors, diuretics, and β-adrenergic blockers. Variable cutoff values have been used in the literature, but a cutoff of 30 yields a sensitivity of approximately 90%.20 A subset of patients with essential hypertension will have suppressed renin levels, which may result in false elevations of the aldosterone-renin ratio. Thus, inclusion of an absolute aldosterone concentration of greater than 15 mg/dL increases the specificity of initial screening. Patients who test positive and are younger than 30 years are genetically screened for glucocorticoid-remediable aldosteronism (familial hyperaldosteronism type 1), especially if they have a family history of early-onset hypertension. This

rare autosomal dominant condition results in abnormal regulation of aldosterone synthesis by ACTH and can be treated medically. Confirmatory biochemical testing is aimed at demonstrating inappropriately high (nonsuppressible) aldosterone levels by creating a state of hypervolemia/sodium excess. This is done with IV saline loading (2-3 L of isotonic saline given over a 4- to 6-hour period, followed by measurement of plasma aldosterone) or oral salt loading (200 mEq = 5000 mg sodium daily over a 3-day period, followed by measurement of 24-hour urine aldosterone excretion). Some centers administer high-dose fludrocortisone (0.1 mg every 6 hours) during oral salt loading to increase the specificity of suppression testing, but this method has not been widely adopted. After the diagnosis has been confirmed, localization is performed with anatomic imaging, selective venous sampling, and sometimes functional scanning. The fact that most aldosteronomas are smaller than 15 mm in maximum dimension poses some challenge to localization. Thin-cut (3 mm) adrenal computed tomography (CT) is the preferred initial localization test (Fig. 39-9). In patients younger than 40 years, the finding of a solitary adrenal mass 1 cm or greater in size and a normal contralateral adrenal gland is sufficient to proceed to surgery. Unilateral adrenalectomy yields successful clinical outcomes in approximately 95% of such cases. The next step in the localization algorithm is selective adrenal venous sampling. This test relies on simultaneous measurement of cortisol and aldosterone levels in the peripheral circulation, as well as the left and right adrenal veins (Fig. 39-10). Greater than a fivefold elevation in cortisol concentration in a sample relative to peripheral blood indicates successful cannulation of an adrenal vein (positive control). Lateralization is indicated by an unbalanced ratio of aldosterone to cortisol in the left and right adrenal veins, with a fourfold greater ratio on one side than on the other identifying the culprit gland. Considerable controversy exists over which patients undergo this study, an invasive procedure with a 90% technical success rate in experienced hands.21 There is consensus that adrenal venous sampling should be applied in all cases in which the biochemical diagnosis of primary hyperaldosteronism has been confirmed and thin-cut adrenal CT reveals either no abnormalities or bilateral abnormalities. Of the remaining patients who have a unilateral mass on CT, a small but not insignificant fraction (2%-10%) will

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Ratio <30 Biochemical diagnosis

PAC/PRA Ratio >30

Discontinue interfering medications*

Suppression of urine aldosterone

24-hr urine free aldosterone Urinary potassium excretion Oral or IV sodium loading No suppression Probable primary hyperaldosteronism Unilateral adrenal mass >1 cm, normal contralateral adrenal, age ≤40 years

Thin cut adrenal CT Nonlateralizing CT Consider for age >40 years Consider repeat testing Failed study Adrenal vein sampling

Localization

Nonlateralizing (bilateral adrenal hyperplasia)

Lateralizing (aldosteronoma)

Management

Observation, consider repeat testing if suspicion remains

Medical management

Adrenalectomy

*Including spironolactone, ACE inhibitors, diuretics, β-blockers.

Figure 39-8 Algorithm for diagnosis, localization, and management of primary hyperaldosteronism. PAC, plasma

aldosterone concentration in ng/dL; PRA, plasma renin activity in ng/mL•h. Initial screening with the PRA/PAC ratio is performed, followed by confirmatory testing with sodium loading. After the biochemical diagnosis has been established, noninvasive localization is attempted with CT. Patients with clear CT evidence of a unilateral abnormality can proceed to adrenalectomy with a greater than 90% cure rate. Adrenal vein sampling is performed in patients with equivocal CT findings and older patients, especially those older than 60, because nonfunctional cortical adenomas are found in 4% or more of this population and can cause false-positive CT localization.

represent false-positive localization and have persistent hyperaldosteronism after unilateral adrenalectomy. In these patients the adrenal mass represents a nonfunctioning cortical adenoma and the true underlying diagnosis is either a contralateral microaldosteronoma or bilateral adrenal hyperplasia, the latter of which is not surgically remediable. Because patients 40 years or older are more likely to have nonfunctioning adrenal cortical adenomas, some authors have advocated adrenal venous sampling in all older patients. Yet others have recommended universal application of this test in the workup of primary hyperaldosteronism. Practically speaking, approximately 20% to 30% of patients being evaluated for primary hyperaldosteronism undergo adrenal venous sampling when it is applied to select patients. The utility of the test is

limited by its low success rate in most reports (40%-80%), with the most common reason for incomplete adrenal venous sampling being failure to cannulate the right adrenal vein. Frequently, however, sufficient lateralizing information is provided during adrenal venous sampling to guide surgical treatment, even when the study is not bilaterally selective.22 Functional scanning with radiolabeled 131I-6-β-iodomethylnorcholesterol (NP-59) may be considered as a third-line localization test for patients without conclusive lateralizing information on either CT or adrenal venous sampling. The sensitivity of NP-59 scanning is low in small tumors. Most aldosteronomas are small to begin with, and those with negative CT scans represent the smallest subset of tumors. For these reasons, NP-59 scanning does not generally aid management in primary hyperaldosteronism.

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Surgical Management and Outcomes Laparoscopic adrenalectomy is the preferred procedure for the management of aldosteronoma and most other adrenal tumors.23 Cure of primary hyperaldosteronism is defined by clinical and biochemical end points. Reductions in blood pressure, antihypertensive medication requirements, and plasma/urine aldosterone levels and resolution of hypokalemia (if previously present) are observed as soon as 24 hours after successful surgery. Overall cure rates range from 75% to 95% at subspecialty centers, depending on the specific criteria for cure that are used. In general, more than 80% of patients can expect either normalization of blood pressure or a significant reduction in antihypertensive medication requirements (typically from three to four medications down to one). In some patients, depending on the degree of preoperative sodium overload, blood pressure may take several weeks to improve. Our practice is to stop all antihypertensive medications immediately after surgery, with the exception of β-blockers, which must be tapered to avoid a rebound phenomenon. In patients who continue to be hypertensive in the short term, medications may be added back temporarily as needed until blood pressure gradually reaches a new equilibrium over time. A subset of patients with the following preoperative features demonstrates reduced benefit from surgical treatment: male, age older than 45 years, family history of hypertension, long-standing hypertension, and no response to spironolactone.24 These characteristics indicate a component of essential hypertension and, in some cases, irreversible cardiovascular alterations resulting from chronic disease. Based on these features, patients need to be counseled about what they can expect to gain from surgery.

A

B
Figure 39-9 Appearance of aldosteronoma on anatomic imaging. A, Venous phase, contrast-enhanced CT demonstrating a 2-cm left aldosteronoma. B, Late arterial phase, coronal CT demonstrating a 1.7-cm left aldosteronoma (arrow) and a normal right adrenal gland (arrowhead).

Cushing’s Syndrome
Epidemiology and Clinical Features The clinical features of glucocorticoid excess were first documented by Harvey Cushing in 1912. He described a young woman of “extraordinary appearance” in whom obesity, hirsutism, amenorrhea, easy bruising, and extreme muscle weakness developed. The principal differential diagnosis to be considered when evaluating patients for Cushing’s syndrome is obesity, an increasingly common condition. A subset of signs and symptoms, including easy bruising, muscle weakness, hypertension, plethora (a red facial appearance caused by thinning of the skin), and hirsutism, may allow discrimination between Cushing’s syndrome and obesity based on clinical features (Fig. 39-11). The most common cause of Cushing’s syndrome is pharmacologic glucocorticoid use for the treatment of inflammatory disorders. Endogenous Cushing’s syndrome is rare, with 5 to 10 individuals affected per million. Of these, the majority of affected individuals (75%) will have Cushing’s disease, that is, glucocorticoid excess caused by an ACTH-hypersecreting pituitary adenoma. The remainder will be split between primary adrenal Cushing’s syndrome (15%) and ectopic ACTH syndrome (<10%), the latter of which most

commonly arises from either neuroendocrine tumors or bronchogenic malignancies in the thorax. Cushing’s syndrome is a lethal disease. The physiologic derangements resulting from glucocorticoid excess, including hypertension (present in >70% of cases), hyperglycemia, and truncal obesity, ultimately yield a fivefold excess in mortality, primarily secondary to cardiovascular complications.25 Thus, all efforts need to be made to identify and appropriately treat patients with Cushing’s syndrome.

Biochemical Diagnosis and Localization Diagnosis of Cushing’s syndrome relies on demonstration of inappropriate cortisol secretion or loss of physiologic negative feedback. Normally, cortisol release follows a predictable circadian rhythm, with the peak reached approximately 1 hour after waking and the nadir around midnight. Thus, inappropriate cortisol secretion can be detected as either elevated cortisol release over a 24-hour period or a higher than expected level in the late evening.

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Right: Cortisol 328 Aldosterone 13 A/C ratio = 0.04

Left: Cortisol 275 Aldosterone 4414 A/C ratio = 16

Right: Cortisol 1201 Aldosterone 2646 A/C ratio = 2.2

Left: Cortisol 1996 Aldosterone 3897 A/C ratio = 2.0

Peripheral: Cortisol 44 Aldosterone 72

Peripheral: Cortisol 64 Aldosterone 57

A

B

Right: Cortisol 33 Aldosterone 29 A/C ratio = ?

Left: Cortisol 204 Aldosterone 452 A/C ratio = 2.2

Peripheral: Cortisol 43 Aldosterone 27

C
Figure 39-10 Possible outcomes of adrenal vein sampling for primary hyperaldosteronism. Aldosterone is expressed in ng/dL, cortisol in µg/dL. A, Successful study lateralizing strongly to the left adrenal. B, Successful study, nonlateralizing. Stimulation with adrenocorticotropic hormone yielded high adrenal vein cortisol levels. C, Failed study. The right adrenal vein was not cannulated.

Traditionally, lack of negative feedback has been assessed by dexamethasone suppression testing and other types of provocative tests, many of which are cumbersome and require inpatient hospitalization. The recent advent of late evening salivary cortisol testing has provided an attractive and feasible alternative to suppression testing. More than 90% of circulating cortisol is bound to plasma proteins. Unbound cortisol can be detected in urine and saliva, and assessment of these body fluids forms the basis of biochemical screening for Cushing’s syndrome (Fig. 39-12). Twenty-four-hour urine collection for determination of urinary free cortisol is performed at least twice for initial screening. Unequivocally elevated levels prompt immediate further testing to determine the cause/subtype of Cushing’s syndrome (i.e., primary

adrenal cause versus a pituitary cause versus ectopic ACTH syndrome). Patients with moderately elevated 24hour urinary cortisol levels undergo confirmatory testing with two late evening (bedtime) cortisol measurements. A high cutoff value of 550 ng/mL carries a sensitivity of 93% and a specificity of 100%.26 Primary adrenal Cushing’s syndrome, also termed ACTH-independent Cushing’s syndrome, is caused by autonomous adrenal cortisol production and is therefore generally associated with an undetectable ACTH level (<5 pg/mL) because of feedback inhibition. The underlying pathology is variable, with a solitary adrenal adenoma found in approximately 90% of cases, adrenocortical carcinoma in less than 10%, and bilateral micronodular or macronodular hyperplasia in less than 1%. Nearly all

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A B

C
Figure 39-11 Clinical manifestations of Cushing’s syndrome. A, Moon facies, plethora, and excess supraclavicular

fat in a woman with Cushing’s syndrome. B, Buffalo hump in a woman with Cushing’s syndrome. C, Purple abdominal striae in a man with Cushing’s syndrome.

these lesions, except micronodular hyperplasia, are readily apparent on CT.27 Hypercortisolemia associated with normal or elevated ACTH levels is indicative of ACTH-dependent Cushing’s syndrome, which is most commonly caused by a pituitary corticotroph microadenoma (Cushing’s disease). Suspicion of ACTH-dependent Cushing’s syndrome prompts pituitary imaging and high-dose dexamethasone suppression testing (i.e., serum or urine cortisol measurement after the administration of 2 mg of dexamethasone every 6 hours over a 48-hour period). Dexamethasone is chosen because it does not cross-react with present biochemical assays for cortisol. Corticotroph adenomas are commonly suppressed in response to high-dose dexamethasone administration, whereas ectopic ACTH sources are completely lacking in feedback inhibition. Slightly more than half of corticotroph microadenomas are visible on pituitary magnetic resonance imaging (MRI). Detection of a

pituitary mass larger than 6 mm in diameter in a patient with ACTH-dependent Cushing’s syndrome that is suppressed with high-dose dexamethasone justifies proceeding to pituitary surgery.28 In the absence of a demonstrable mass, bilateral inferior petrosal sinus ACTH sampling with CRF stimulation is pursued. Demonstration of a central-to-peripheral ACTH gradient in a study performed by a skilled practitioner is sufficient to diagnose Cushing’s disease. Absence of a clear gradient prompts CT imaging of the chest/abdomen and occasionally somatostatin receptor scintigraphy to identify an ectopic ACTH source.

Surgical Management and Outcomes Perioperative and postoperative glucocorticoid administration is obviously essential in the care of patients with Cushing’s syndrome. For patients undergoing adrenalectomy for Cushing’s syndrome, perioperative “stress dose”

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Normal Biochemical diagnosis

24-hr urine free cortisol 1-3 normal Late evening salivary cortisol 2 <550 ng/dL

2

>3-fold elevation

>550 ng/dL

Cushing’s syndrome unlikely

Probable Cushing’s syndrome

Undetectable ACTH-independent disease

ACTH

Detectable ACTH-dependent disease

CT of adrenals Localization

Mass >6 mm Suppression

Pituitary MRI, high-dose dexamethasone suppression test No mass Bilateral inferior petrosal sinus sampling

Gradient detected

No gradient

Chest/Abd CT, somatostatin receptor scintigraphy

Management

Adrenalectomy 90% effective

Transsphenoidal pituitary microsurgery 75% effective Failure Bilateral adrenalectomy

Resection

Ectopic ACTH (<10%)

Primary adrenal Cushing’s syndrome (15%)

Cushing’s disease (75%)

Figure 39-12 Algorithm for the diagnosis, localization, and management of endogenous Cushing’s syndrome. A biochemical diagnosis can be established with either an unequivocally elevated 24-hour urine free cortisol level (greater than a threefold elevation) or an elevated late evening salivary cortisol. Most cases of Cushing’s syndrome are caused by Cushing’s disease (pituitary corticotroph microadenoma), in which plasma adrenocorticotropic hormone (ACTH) is elevated. An undetectable ACTH level establishes the diagnosis of ACTH-independent Cushing’s syndrome and prompts adrenal imaging. Bilateral adrenalectomy is considered for patient’s with Cushing’s disease not cured by transsphenoidal surgery.

steroids (hydrocortisone, 100 mg IV every 8 hours for 24 hours) are recommended. In the most common scenario of resection of a solitary adrenal Cushing’s adenoma, steroids can usually be tapered to physiologic replacement levels over the course of several weeks. However, a subset of patients with Cushing’s syndrome of greater duration and severity will have lasting HPA axis suppression that requires glucocorticoid supplementation for longer periods, sometimes for more than 1 year. It is our

practice to routinely administer perioperative antibiotics for 24 hours to patients undergoing adrenalectomy for Cushing’s syndrome because of their elevated risk for surgical site infection. Management of patients who undergo pituitary surgery for Cushing’s disease is variable. In some centers, glucocorticoids are withheld during the immediate postoperative period to provide a window during which early remission may be assessed.29 A subnormal morning

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cortisol level on postoperative day 1 or 2 is indicative of cure. Glucocorticoid supplementation is then resumed, usually for at least 6 months, until the HPA axis recovers. Because of the significant risk for postoperative adrenal crisis in patients with Cushing’s syndrome of all subtypes, glucocorticoid supplementation is ideally managed in conjunction with an experienced endocrinologist. Adrenalectomy is more than 90% effective in the treatment of primary adrenal Cushing’s syndrome. Failures may result from local and occasionally distant tumor recurrence in the case of malignant disease. Pituitary microsurgery for Cushing’s disease, typically performed via a transnasal transsphenoidal approach, is approximately 75% successful in experienced hands. Remission rates may be improved by reoperation or pituitary irradiation in patients whose basal cortisol levels do not fall appropriately after initial surgery. Laparoscopic bilateral adrenalectomy is considered for patients in whom pituitary surgery has failed.30

Special Case: Subclinical Cushing’s Syndrome The term subclinical Cushing’s syndrome has been used to describe patients with incidentally discovered adrenal masses (see The Incidentally Discovered Adrenal Mass, later) who display biochemical evidence of cortisol hypersecretion without overt signs or symptoms of Cushing’s syndrome. This disease entity has been incompletely characterized with respect to its physiologic consequences and natural history. Clear-cut definitions for the diagnosis of subclinical Cushing’s syndrome, such as cutoff values for biochemical tests and objective assessment guidelines for the presence or absence of clinical features, are lacking. Some reports indicate that hypertension, dyslipidemia, and impaired glucose tolerance are highly prevalent in individuals with subclinical Cushing’s syndrome.31 However, adrenalectomy for this entity has not been consistently demonstrated to yield health benefits. Progression to overt Cushing’s syndrome occurs in less than 10% of cases. Thus, at present, patients found to have subclinical hypercortisolism are monitored for the development of adverse cardiovascular and metabolic features. Therapy is primarily medical and directed at the subset of patients with progressive disease. However, lower biochemical thresholds for surgical treatment need to be considered for larger tumors (i.e., those 3-4 cm in diameter).

Figure 39-13 CT demonstrating a 10-cm left adrenocortical carcinoma. Note the areas of central necrosis.

biochemically detected by measurement of 24-hour urine testosterone, DHEA, and DHEA-S. Although laparoscopic adrenalectomy remains the preferred procedure for the majority of sex steroid–secreting tumors, the high probability of malignancy merits close radiographic and intraoperative inspection for evidence of invasion or metastasis, or both. Open adrenalectomy is performed for malignant tumors.

Adrenocortical Carcinoma
Adrenocortical carcinoma is a rare tumor with an annual incidence of approximately one per million. Almost all cases occur in patients 40 to 50 years of age, although there is a minor peak in children younger than 5. Adrenocortical carcinomas demonstrate no significant gender predilection. They are frequently very large at initial evaluation (mean tumor size, 9-12 cm), and they generally carry a poor prognosis. Historically, 5-year survival rates have been in the 15% to 20% range, although improved survival rates of 25% to 60% have been reported during the past several years.33 More than half of adrenocortical carcinomas are functional. Cushing’s syndrome is most commonly seen, followed by virilization. Radiographic evaluation is primarily performed with CT, which typically reveals a heterogeneous mass with irregular/ indistinct borders, central necrosis, and invasion of adjacent structures (Fig. 39-13). Metastases to the lymph nodes, liver, and lungs may be found. Treatment of adrenocortical carcinoma centers around radical open surgery. Complete resection can be achieved in up to 70% of patients in experienced hands. Management frequently involves en bloc resection of adjacent organs or regional lymphadenectomy (or both). Particular care must be taken when dealing with right-sided adrenocortical carcinomas larger than 9 cm because direct tumor extension into the inferior vena cava and some-

Sex Steroid Excess
Adrenal tumors causing clinical features of sex steroid excess are rare. The majority of such tumors are virilizing (as opposed to feminizing), and they may initially be seen at a late stage in association with an advanced adrenal malignancy. Virtually all feminizing tumors are malignant, whereas approximately a third of virilizing tumors are malignant. Of adrenocortical carcinomas, 20% cause virilization, with the majority of these cases occurring in children. An additional 24% of adrenocortical carcinomas will display mixed features of Cushing’s syndrome and virilization.32 Virilizing tumors may be

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times the right heart may be observed. Tumors demonstrating intravascular extension may need to be resected while the patient is on cardiopulmonary bypass to reduce the likelihood of lethal intraoperative tumor embolization. Patients who undergo incomplete resection of adrenocortical carcinomas have extremely limited life expectancy (median survival, <1 year). Even those who undergo successful surgery are prone to the development of local recurrence and metastases, which typically occur within 2 years. The principal chemotherapeutic agent for the treatment of adrenocortical carcinoma is mitotane (o,p-DDD, or 1,1-dichloro-2-[o-chlorophenyl]-2-[p-chlorophenyl] ethane), a derivative of the insecticide DDT that is a direct adrenocortical toxin. Mitotane has been used clinically both as an adjuvant to surgery and as primary therapy in individuals with unresectable or metastatic disease. The rarity of adrenocortical carcinomas has made systematic assessment of mitotane’s efficacy difficult. On balance, mitotane treatment does not appear to improve survival in patients who have undergone complete resection, but it may offer a moderate survival advantage in patients with unresectable or metastatic disease.34 Its use is limited by significant gastrointestinal and neurologic toxicity. Conventional cytotoxic chemotherapy and external beam radiation therapy currently play little role in the management of adrenocortical carcinoma, although some efficacy has been demonstrated with cisplatinbased regimens.

to have the disease.36 The differential diagnosis of pheochromocytoma is extensive and encompasses such diverse processes as hyperthyroidism, hypoglycemia, coronary artery disease, heart failure, stroke, drug-related effects, and panic disorder. Pheochromocytoma has been described as a “biologic time bomb” because of the potentially lethal cardiovascular effects of the bioactive compounds secreted by these tumors. Thus, despite the challenges in diagnosis, clinicians need to aggressively screen for this disease and seek appropriate treatment for affected patients. Previously, pheochromocytoma was dubbed the “10% tumor” for the reason that 10% are bilateral, 10% malignant, 10% extra-adrenal, and 10% familial. Recent discoveries regarding the genetic underpinnings of pheochromocytoma have challenged these old axioms.37

DISEASES OF THE ADRENAL MEDULLA Pheochromocytoma
Epidemiology and Clinical Features The first account of pheochromocytoma was published in 1886 by Felix Frankel, who described a young woman suffering from intermittent attacks of palpitations, anxiety, vertigo, and headache. Autopsy revealed bilateral adrenal tumors that stained brown when treated with chromium salts. The characteristic positive chromaffin reaction lends these adrenomedullary tumors the name pheochromocytoma (“dusky-colored tumor” from the Greek phaios, or dusky). Successful surgical management of pheochromocytoma was initially described in 1926 by both César Roux and Charles Mayo.35 Pheochromocytoma affects approximately 0.2% of hypertensive individuals. Males and females are affected equally. The peak incidence in sporadic cases lies between the ages of 40 and 50, whereas familial cases tend to be manifested earlier. A subset of patients have the classic triad of headache, diaphoresis, and palpitations, although almost all patients will display at least one of these symptoms. Hypertension is present in 90% of cases and may be episodic or sustained. The principal challenge in making the diagnosis of pheochromocytoma arises from the fact that essential hypertension is common and the clinical features suggestive of pheochromocytoma are nonspecific. In fact, only 0.5% of patients with hypertension and suggestive features will ultimately prove

Biochemical Diagnosis and Localization Establishment of a biochemical diagnosis of pheochromocytoma rests on detection of elevated levels of catecholamines and their metabolites in body fluids. Measurement of 24-hour urine levels of these compounds has long been the cornerstone of biochemical testing, and they remain the most reliable tests available today. In 2002, measurement of free (unconjugated) metanephrines in plasma was introduced as an alternative screening tool for pheochromocytoma.8 Plasma free metanephrine testing carries an extremely high sensitivity that approaches 99% and, being a one-time blood test, is more convenient than 24-hour urine testing. However, the specificity of plasma free metanephrine testing is 89% at best, with specificities at most laboratories likely to lie in the 85% range or below. Given that pheochromocytoma is a rare diagnosis that is sought within a large pool of hypertensive individuals, false-positive test results are a major problem. In fact, it is estimated that false-positive tests outnumber true-positive tests as much as 30 to 1 when plasma free metanephrine testing is used as a principal screening tool.38 Therefore, the primary utility of plasma free metanephrine testing is to exclude pheochromocytoma when the test is negative (Fig. 39-14). When positive, confirmatory testing with 24-hour urinary levels of catecholamines and their metabolites is required. Many drugs and conditions, including sympathomimetics (present in many cold remedies), phenoxybenzamine (frequently initiated when suspicion of pheochromocytoma is raised), acetaminophen (which interferes with the plasma free metanephrine assay), many psychotropic drugs (notably tricyclic antidepressants), and major physical or psychological stressors, are capable of confounding catecholaminebased testing, thus further contributing to the problem of false-positive results. Tests performed during episodes of acute pain, critical illness, or urgent hospitalization may be misleading. The presence of confounding factors, including manifestations or treatment of competing diagnoses, is extremely common in the population being screened. Clearly, biochemical testing is ideally performed when the patient is as free as practically possible of all confounding factors.

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Negative

Plasma free metanephrines Positive

Discontinue interfering medications*

Biochemical diagnosis

24-hr urine metanephrines and catecholamines Negative/equivocal Negative Repeat 24-hr urine metanephrines and catecholamines

Positive

Positive

Normetanephrine suppressed

Mild to moderate elevation Normetanephrine NOT suppressed Clonidine suppression test

Age <50 years or suggestion of multifocality CT/MRI Localization

MIBG

Age >50 years, single site

Management

Observation, consider repeat testing if suspicion remains

Preoperative conditioning

Surgery *Including sympathomimetics, phenoxybenzamine, acetaminophen, many psychotropic drugs.

Figure 39-14 Algorithm for the diagnosis, localization, and management of pheochromocytoma. Initial plasma free

metanephrine testing can effectively exclude the diagnosis if negative. Twenty-four-hour urine collection for catecholamines and their metabolites is generally performed twice, with cutoffs approximately twice the upper limit of normal being criteria for positivity (see Table 39-4). Clonidine suppression testing can be used for the small fraction of patients in whom the diagnosis remains uncertain after urine testing. Localization with CT or MRI follows biochemical confirmation of the diagnosis, with MIBG performed for younger patients and those otherwise at risk for multifocal disease. Phenoxybenzamine is given in escalating doses for at least 2 weeks before surgery.

The operating characteristics of catecholamine-based plasma and urine tests are listed along with corresponding cutoff values in Table 39-4. Cutoff values for 24-hour urine tests are deliberately set high to maximize specificity; in fact, these values are approximately double the upper 95% reference range in most laboratories. A urine collection may be considered positive if total metanephrines or any single catecholamine fraction (epinephrine, norepinephrine, or dopamine) is elevated above its cutoff value. This approach maintains high specificity and yields an acceptable sensitivity of 88%.38 Importantly, it takes into account the fact that pheochromocytomas both synthesize and metabolize catecholamines and that tumors may possess heterogeneous secretory “profiles,” depending on their relative expression of synthetic and degradative enzymes (see Fig. 39-6).

Two 24-hour urine collections for catecholamines and their metabolites are sufficient to make (or exclude) the diagnosis of pheochromocytoma in almost all cases. Clonidine suppression testing, or measurement of plasma free normetanephrine levels after the oral administration of 0.3 mg of clonidine, may help clarify equivocal test results. Anatomic localization may be performed with MRI or CT. MRI is slightly more sensitive, but CT often yields better anatomic definition for operative planning (Fig. 39-15). Scintigraphy with 131I- or 123 I-labeled metaiodobenzylguanidine (MIBG, Fig. 39-16) is performed in select patients in whom multifocal disease is suspected. MIBG scanning is highly specific for pheochromocytoma but carries a sensitivity of only 77% to 90%. Positron-emission tomography (PET) with the use of novel 18F-labeled catecholamine

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Table 39-4
TEST*

Cutoff Values for the Biochemical Diagnosis of Pheochromocytoma
CUTOFF VALUE (mol) CUTOFF VALUE (g) DEFINITIONS SENSITIVITY (%) SPECIFICITY (%)

Plasma free metanephrine Plasma free normetanephrine Urinary total metanephrines Urinary epinephrine Urinary norepinephrine Urinary dopamine Urinary total metanephrines and catecholamines

0.3 nmol/L 0.6 nmol/L 6.6 µmol/day 191 nmol/day 1005 nmol/day 4571 nmol/day —

59 µg/L 110 µg/L 1.3 mg/day 35 µg/day 170 µg/day 700 µg/day

Paired test, positive if either or both values are elevated

99 71 29 50 8

85-89 99.6 99.6 99.6 100 99

Grouped test, positive if any one of following three urinary values are elevated: total metanephrines, epinephrine, norepinephrine, dopamine 7.9 mg/day 112 µg/L Positive result = elevated level after clonidine and fall of less than 40

88

Urinary vanillylmandelic acid Clonidine suppression test Plasma free normetanephrine

40 µmol/day 0.61 nmol/L

64 96

95 100

*When performed twice, 24-hour urine testing of urinary total metanephrines and catecholamines (grouped test) is both highly sensitive and highly specific.

analogues is probably more sensitive but remains largely investigational.39

Perioperative Care Throughout the first half of the 20th century, perioperative mortality rates in the treatment of pheochromocytoma ranged from 26% to 50%. At the new millennium, the mortality rate in most specialty centers is approximately 2%. This dramatic improvement can largely be ascribed to advances in pharmacology, physiology, anesthesia, and perioperative medical care. The adverse perioperative hemodynamic changes that are most commonly observed with pheochromocytoma are intraoperative hypertension and postoperative hypotension. Intraoperative hypertension may be caused by stimulation of catecholamine release by anesthetic induction agents, as well as direct manipulation of the tumor. Postoperative hypotension may be profound. It results from a state of hypovolemia created by the presence of excess circulating catecholamines. Sudden withdrawal of this stimulus after tumor removal leads to peripheral arteriolar vasodilation, in addition to a dramatic increase in venous capacitance, which together may precipitate cardiovascular collapse. In their early report of a large, successful case series, investigators at the Mayo Clinic described the use of intraoperative α-adrenergic blockade, followed by aggressive volume repletion and administration of α-adrenergic agonists in the immediate postoperative period.40 The principles of contemporary perioperative care remain much the same. As soon as the biochemical diagnosis of pheochromocytoma has been confirmed, α-adrenergic blockade is initiated to protect against hemodynamic lability. Our practice is to start with phenoxybenzamine, 10 mg twice daily. The dosage can

be titrated upward every 2 to 3 days to a maximum of 40 mg three times daily to achieve normalization of heart rate and blood pressure. The period of preoperative conditioning lasts at least 2 weeks to allow adequate reversal of α-adrenergic receptor down-regulation. This restores sensitivity to vasopressor agents, which can then be used to treat the patient postoperatively. Phenoxybenzamine is a nonspecific, noncompetitive (irreversible), long-acting (half-life of 24 hours) α-adrenergic antagonist. Although its use is associated with the side effects of postural hypotension and significant nasal congestion, it is generally favored over α1-selective agents such as prazosin and doxazosin. Nasal congestion can actually serve as a useful indicator of adequate blockade. Furthermore, phenoxybenzamine provides the most complete α-blockade among available agents, and its pharmacokinetics permits serum drug levels to decay in parallel with catecholamine levels postoperatively. β-Blockers may be administered after adequate αblockade has been achieved in the subset of patients with persistent tachycardia. β-Blockers are never the first agent administered because a decrease in peripheral vasodilatory β-receptor stimulation results in unopposed αadrenergic tone, which may exacerbate hypertension. Preoperative volume expansion with isotonic fluids has been advocated in the past. However, in our experience the need for volume expansion is significantly reduced when aggressive preoperative α-blockade has been achieved because the resultant increase in venous capacitance restores euvolemia. Clinical suspicion of hypovolemia needs to remain high in the postoperative period, and patients need to be aggressively resuscitated if they become hypotensive or oliguric. Some patients may require vasopressors after tumor removal, especially if preoperative α-blockade is incomplete.

Chapter 39 The Adrenal Glands

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A

B

C
Figure 39-15 Appearance of pheochromocytoma on anatomic imaging. A, Venous phase, contrast-enhanced CT scan demonstrating a right adrenal pheochromocytoma. The heterogeneity in the inferior vena cava represents swirling of contrast, not tumor thrombus or invasion. B, Coronal T2-weighted MRI demonstrating a left adrenal pheochromocytoma with central cystic change. C, Left anterior oblique magnetic resonance angiographic reconstruction demonstrating a right adrenal pheochromocytoma.

Surgical Management and Outcomes Successful operative treatment of pheochromocytoma is dependent on close communication between the surgeon and anesthesiologist. Needless to say, invasive hemodynamic monitoring is required, and fluid management must be meticulous. Manipulation of the tumor needs to

be minimized, and the anesthetic team must be prepared to administer supplemental IV α- and β-blockers, as well as vasopressors, when necessary. Surgery is curative in greater than 90% of pheochromocytoma cases. Although these tumors are highly vascular and tend to adhere to adjacent structures (Fig.

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Section VIII Endocrine

A

C

B
123 I-MIBG scan of the abdomen demonstrating an isolated left adrenal pheochromocytoma. Physiologic radiotracer uptake is noted in the liver, right colon, and transverse colon. B, Whole-body 131I-MIBG scan demonstrating a large left para-aortic extra-adrenal pheochromocytoma. Physiologic radiotracer uptake is noted in the liver, salivary glands, and bladder. C, 131I-MIBG scan of the abdomen demonstrating malignant pheochromocytoma with local recurrence in the left adrenal bed and liver metastases.

Figure 39-16 Appearance of pheochromocytoma on functional imaging (MIBG scanning). A,

39-17), the great majority of them can be removed successfully via a laparoscopic approach. Laparoscopic resection is contraindicated when preoperative imaging demonstrates local invasion. Advances in surgical technique have resulted in reduced operative complication rates. Specifically, functional image-guided focused exploration has replaced bilateral adrenal and retroperitoneal exploration and has led to diminished rates of solid organ injury.41

Molecular Genetics of Pheochromocytoma A number of recent reports describing novel germline mutations have demonstrated that familial pheochromocytoma is much more common than previously thought. Before the year 2000, pheochromocytoma was known to be associated with multiple endocrine neoplasia type 2

syndromes (40%-50% penetrant), von Hippel-Lindau syndrome (10%-20% penetrant), and neurofibromatosis type 1 (1%-5% penetrant). The discovery that neuroendocrine cells of the carotid body proliferate in response to hypoxic stimuli led to the identification of mutations in the succinate dehydrogenase gene family in kindreds affected with pheochromocytoma/paraganglioma. Succinate dehydrogenase, which is made up of four subunits, is localized to the mitochondria and catalyzes essential steps in oxidative phosphorylation. Germline mutations in the B and D subunits, which are inherited in an autosomal dominant fashion, have been identified in approximately 10% of apparently sporadic pheochromocytoma cases.42 Thus, there is new consensus that 21% to 30% of pheochromocytomas are familial. Familial cases occur at an earlier age and are

Chapter 39 The Adrenal Glands

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A

vival rates at 5 years range from 20% to 45%. No histopathologic criteria for determining malignancy have demonstrated the ability to accurately predict the clinical course. Thus, malignancy is defined by the development of metastases (i.e., tumor implants distant from the primary mass in locations where neuroectodermal tissue is not normally found). The latter criterion distinguishes metastatic disease from possible multifocal primary disease. The most common sites of metastasis are the axial skeleton, lymph nodes, liver, lung, and kidney. Treatment of both primary and recurrent disease centers on surgical resection, which even in the absence of cure has significant palliative benefits.44 Malignant pheochromocytomas are minimally responsive to radiotherapy and chemotherapy. High-dose 131I-MIBG radionuclide therapy has been used to treat malignant and metastatic pheochromocytoma. Moderate initial response has been observed, but long-term benefit is uncommon. Chronic medical management of catecholamine excess is performed with α1-selective blockers because of their favorable side effect profile.

THE INCIDENTALLY DISCOVERED ADRENAL MASS (“INCIDENTALOMA”) Epidemiology and Differential Diagnosis
Incidentally discovered adrenal masses, also termed clinically inapparent adrenal masses or “incidentalomas,” are discovered through imaging performed for unrelated/ nonadrenal disease. Their existence as a clinical entity is a by-product of advanced medical imaging. Incidentalomas were first described in the early 1980s, when CT scanners became more prevalent in developed nations, and they have become a common clinical problem as the use of CT and MRI has become widespread. Incidentalomas are found in 2.1% of autopsies and 1% to 4% of abdominal imaging studies.45 The prevalence rises to greater than 4% in patients older than 60 years. The differential diagnosis of an adrenal mass is extensive and includes both secreting and nonsecreting neoplasms (Fig. 39-18). In patients with a history of malignancy, metastatic disease is the most likely cause of adrenal masses, particularly when bilateral (see Metastases to the Adrenal Gland, later). In those without a clear history of malignancy, at least 80% of incidentalomas will turn out to be nonfunctioning cortical adenomas or other benign lesions that do not require surgical management. Thus, in most patients, the most important aspect of management is to distinguish the subset of adrenal masses that are likely to have a clinical impact from the large proportion that will not.

B
Figure 39-17 Gross appearance of pheochromocytoma. A, Open

resection of a left para-aortic extra-adrenal pheochromocytoma (depicted in Fig. 39-16B) via an infracolic approach. The patient’s head is to the right. The tumor is being rotated medially by the surgeon’s hand to reveal the left ureter, indicated by forceps. B, Left adrenal pheochromocytoma. (A, Courtesy of Stan Sidhu, PhD.)

more likely to be multifocal. Succinate dehydrogenase B mutation carriers have high rates of extra-adrenal (abdominal or thoracic) pheochromocytomas and malignant disease, whereas succinate dehydrogenase D carriers tend to have multiple tumors and hormonally inactive paragangliomas of the head and neck. The lifetime penetrance of succinate dehydrogenase mutations is estimated to be greater than 75%.43 Genetic counseling and testing is encouraged for patients in whom pheochromocytoma is diagnosed before the age of 50.

Clinical Evaluation and Surgical Management
The workup for adrenal incidentaloma integrates hormonal evaluation with size criteria. The principles and methods of hormonal evaluation are discussed earlier in the tumor-specific sections and are generally applicable to incidentalomas. However, one conceptual difference

Malignant Pheochromocytoma Depending on the underlying genotype, anywhere from 2.5% to 40% of pheochromocytomas are malignant. Sur-

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Section VIII Endocrine

10% 5% 5% 5% 5% 9%

1%

60%

Nonfunctioning adenoma Pheochromocytoma Cortisol producing adenoma Aldosteronoma Adrenocortical carcinoma Adrenal cyst Ganglioneuroma Myelolipoma

Figure 39-18 Differential diagnosis of adrenal incidentaloma in patients without a history of malignancy. Approxi-

mate proportions of the various pathologies are shown.

is that the biochemical thresholds that prompt operative treatment are somewhat lower in patients with an initial radiographic manifestation (incidentalomas) than in those with an initial clinical manifestation. This results from the fact that tumor size, which correlates strongly with risk for malignancy, contributes an additive effect in favor of surgical management. Evaluation begins with history taking, with a focus on previous malignancy, hypertension, and symptoms of glucocorticoid or sex steroid excess. Biochemical investigations for hormonally active tumors are followed by consideration of size criteria (Fig. 39-19). In a general sense, surgery is recommended for hormonally active tumors and those that carry a significant risk for malignancy. Adrenocortical carcinomas represent less than 2% of adrenal tumors measuring 4 cm or less and roughly 6% of those measuring 4 to 6 cm. Tumors larger than 6 cm carry a greater than 25% risk for malignancy. Because studies have consistently found that CT and MRI underestimate adrenal tumor size by approximately 20% (an effect that is exaggerated in smaller tumors), our practice is to remove all incidentalomas measuring 5 cm or greater and to strongly consider removal of those measuring 3 to 5 cm.46 Factors that need to be considered in surgical decision making for this latter group include suspicious imaging characteristics (heterogeneity, high attenuation, or irregular margins), the patient’s age and surgical risk, growth on interval imaging, and patient preference. If observation is chosen, patients undergo repeat imaging in 6 to 12 months given the fact that 5% to 25% of adrenal masses may increase in size. CT-guided fine-needle aspiration is rarely helpful in the evaluation of adrenal masses and may be hazardous. The diagnosis of primary adrenal malignancy cannot be reliably based on cytologic criteria alone. Therefore, the use of fine-needle aspiration is generally confined to patients with a history of extra-adrenal malignancy in whom the clinician seeks to establish the diagnosis of metastatic disease. In all cases, pheochromocytoma must be excluded before attempting such a procedure to avoid precipitating potentially fatal hypertensive crisis. As with the other disease processes that have been discussed, most adrenal incidentalomas can be removed laparoscopically, except for those displaying obvious

malignant features on imaging. No upper size limit to this approach has been established, and tumors measuring 15 cm have been successfully removed laparoscopically by experienced surgeons.

METASTASES TO THE ADRENAL GLAND Epidemiology and Clinical Features
The adrenal glands are common sites of metastasis because of their rich vascular supply. In fact, autopsy studies reveal that adrenal involvement eventually develops in approximately 25% of patients with carcinoma. In half these cases, the metastatic disease is bilateral. The primary cancers that most often spread to the adrenals are those of the lung, gastrointestinal tract, breast, kidney, pancreas, and skin (melanoma).47 Patients with isolated adrenal metastases represent a very small subset of the total. However, these individuals are of particular interest to the surgeon and oncologist because growing evidence indicates that resection of isolated adrenal metastases may improve survival. The principal determinant of survival in these patients is the disease-free interval. Patients in whom metachronous isolated adrenal metastases develop more than 6 months after the initial cancer have better survival rates than those with synchronous adrenal metastases.

Clinical Evaluation and Surgical Management
Evaluation of patients with isolated adrenal metastases must involve careful exclusion of extra-adrenal disease with CT or MRI (including the head in cases of breast cancer or melanoma and triphasic contrast-enhanced CT evaluation of the liver plus 3-mm slices through the lungs for gastrointestinal malignancies), as well as bone scan and PET when appropriate. Patients with isolated bilateral adrenal metastases (Fig. 39-20) must be evaluated for adrenal insufficiency secondary to replacement of all normal adrenal tissue with tumor, which may occur in up to 30% of such patients. This is best done by measurement of morning cortisol and ACTH. Cortisol insufficiency must be adequately treated before surgery to avoid perioperative adrenal crisis.

Chapter 39 The Adrenal Glands

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Adrenal incidentaloma

Hormonal evaluation

24-hr urine metanephrines and catecholamines

Low-dose (1 mg) dexamethasone suppression test

PAC/PRA if hypertensive

Functioning adrenal tumor?

Yes

No Size criteria, risk/benefit assessment <3 cm Consider tumor size 3-5 cm Consider case-specific factors: • Suspicious imaging features • Young patient • Few surgical risk factors • Interval tumor growth • Patient preference No Yes >5 cm

Management

Interval CT in 6 months

Adrenalectomy

Figure 39-19 Algorithm for management of an adrenal incidentaloma. Adrenalectomy is recommended for all

patients with functional tumors. For nonfunctioning tumors, the risk for malignancy is assessed according to size. Tumors larger than 5 cm on CT carry a greater than 25% risk for malignancy and need to be removed. Those smaller than 3 cm can be safely observed. Case-specific factors must be considered for intermediate-sized tumors. PAC, plasma aldosterone concentration; PRA, plasma renin activity.

The great majority of adrenal metastases are well encapsulated and thus amenable to laparoscopic resection. Complete adrenal metastasectomy has yielded a mean survival of 20 to 30 months in most series,48 as compared with 12 months for patients with incomplete resection and 6 months for patients not undergoing surgical therapy.

TECHNICAL ASPECTS OF ADRENALECTOMY Choice of Operative Approach
In our practice, approximately 90% of adrenalectomies are performed laparoscopically. Laparoscopic adrenalectomy affords many advantages over conventional open surgery, including reduced length of hospitalization, reduced pain, decreased operative blood loss, and a lower rate of postoperative complications.49 Similar degrees of benefit are observed with transabdominal and

posterior retroperitoneal laparoscopic approaches. Because of the wider operative field and greater versatility afforded by the lateral transabdominal technique, it is our favored approach and is discussed in greater detail later. The lateral transabdominal approach can be used to handle very large tumors, and previous abdominal surgery does not alter the success rate significantly when the procedure is performed by an experienced surgeon. The overall conversion rate to open adrenalectomy is less than 5% in large series. As discussed earlier, open adrenalectomy is performed for primary adrenal tumors demonstrating features suggestive of malignancy, such as large size (>8 cm), clinical feminization, hypersecretion of multiple steroid hormones, or any of the following imaging attributes: local/ vascular invasion, regional adenopathy, and metastases. For open adrenalectomy, we also prefer a transabdominal approach, which is performed via a subcostal incision as discussed later.

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Section VIII Endocrine

Figure 39-21 Patient positioning for left lateral transabdominal

laparoscopic adrenalectomy.

Figure 39-20 Isolated bilateral 7-cm adrenal metastases from

colorectal cancer causing adrenal insufficiency. The patient had undergone previous right colectomy and right hepatectomy. Bilateral adrenal metastasectomy was performed laparoscopically.

surgeon is reliant on gravity to serve as a retractor in providing the necessary exposure. Having the patient securely fixed to the table permits the often extreme positioning with respect to pitch (Trendelenburg/reverse Trendelenburg) and roll (tilting left/right) that is necessary during the operation.

Laparoscopic Lateral Transabdominal Adrenalectomy
Patient Preparation and Positioning Draw sheets and a full-length beanbag are placed on the operating table in advance. It is important that the table be capable of flexion and have a kidney rest that can be elevated. The patient is initially positioned supine for induction of anesthesia and placement of a urinary catheter. Intermittent pneumatic compression devices are applied to the legs. Placement of an orogastric or nasogastric tube for gastric decompression is frequently helpful, particularly when treating left-sided lesions. The patient is then turned on the side (80-degree lateral decubitus position), with the side bearing the lesion facing upward (Fig. 39-21). At this point the patient is carefully positioned in the cephalocaudal dimension such that the 10th rib is directly over the breakpoint in the table. The table is flexed and the beanbag rigidified in a position that supports the buttocks and back while leaving the umbilicus (an important surface landmark) exposed. Flexing the table and raising the kidney rest serve to widen the space between the costal margin and the iliac crest and to drop the iliac crest away from the plane of the laparoscopic instruments. Wide cloth tape is used to secure the patient to the table at the chest, hips, and lower extremities. Great care must taken to protect bony prominences and points of potential peripheral nerve compression in the extremities. The surgical preparation is carried from the nipple line to the pubis and from the umbilicus to the midline of the back. Careful positioning is essential for technical success in laparoscopic adrenalectomy. As discussed later, the

Technique: Left Adrenal Initial peritoneal access is achieved 2 cm inferior to the costal margin in the midclavicular line (Palmer’s point). This can be performed with either the Veress or Hasson technique. We generally use four 11-mm radially dilating (noncutting) trocars, which allows free exchange of the laparoscope, fan retractor, dissecting devices, and clip applier as needed. The ports are equally distributed along the costal margin, with the posterior port placed as far lateral/posterior as permitted by the position of the colon (Fig. 39-22). It is advisable to leave at least 5 cm (4 fingerbreadths) between each port to minimize external interference of the laparoscopic instruments. For tissue dissection, we use the hook monopolar cautery and an energy-based tissue sealing/dividing device. The lateral attachments of the spleen are taken down first, with the goal of rotating the left upper quadrant viscera anteromedially. Splenic mobilization is continued until the greater curvature of stomach becomes visible at its apex, at which point the spleen and tail of the pancreas are allowed to fall anteriorly with rightward tilting of the table and gentle use of the fan retractor. In many patients, the splenic flexure of the colon must be mobilized caudally by dividing the splenocolic ligament. We use an “open book” technique that involves developing the cleftlike plane just medial to the adrenal gland and lateral to the aorta (Fig. 39-23). The left-hand page of the book is composed of the spleen, tail of the pancreas, and greater curvature of the stomach. The right-hand page of the book consists of the kidney and adrenal tumor. The left crus of the diaphragm is a useful landmark that leads the surgeon to the left inferior phrenic vein. As mentioned in the anatomy section of this chapter, the left inferior phrenic vein courses along the medial aspect of

Chapter 39 The Adrenal Glands

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Pancreas Stomach Spleen

Left inferior phrenic vein Adrenal

Kidney

Figure 39-22 Port placement for right laparoscopic adrenalectomy. In this figure the patient is lying right-side up with the head toward the right. The marked line denotes the costal margin. Ports are placed approximately 2 cm inferior to the costal margin, spaced about 4 fingerbreadths apart.

Adrenal vein

A
Stomach Spleen

Colon

Left renal vein Pancreas Left inferior phrenic vein Adrenal

the left adrenal gland before joining with the left adrenal vein. By developing the cleft of the open book, moving in a superior-to-inferior direction, the adrenal vein is encountered at the inferomedial aspect of the adrenal gland. The small adrenal arteries that lie within this plane can be handled with energy-based coagulation. The left adrenal vein is carefully dissected out, clipped (leaving two clips on the patient side), and divided. The inferior tip of the left adrenal gland may extend quite low and approach the renal hilum within millimeters. However, because the left adrenal vein is rather long (2 cm), it is not generally necessary to expose the renal vasculature during left adrenalectomy. The adrenal gland is liberated by completing the dissection circumferentially and posteriorly and taking the specimen off the superior pole of the kidney and posterior abdominal wall. These attachments are deliberately divided last because they aid in suspending the adrenal gland on the lateral/superior wall of the operative field, thereby providing exposure of the medial vascular plane during the critical initial portion of the procedure. The tumor is placed in a resilient catchment device, morcellated, and extracted. If noncutting trocars are used, only the skin need be closed.

Kidney

B

Colon

Adrenal vein

Figure 39-23 Technique of left laparoscopic adrenalectomy. The spleen and pancreatic tail have been mobilized and retracted anteromedially to expose the adrenal gland. The cleft of the “open book” is developed in a superior-to-inferior direction to identify the inferior phrenic vein and adrenal vein.

Technique: Right Adrenal Laparoscopic right adrenalectomy is, in some respects, a mirror image of the procedure just described. During right adrenalectomy, the left-hand page of the open book is made up of the kidney and adrenal tumor, and the right-hand page consists of the bare area of the liver (Fig. 39-24). To gain access to the appropriate plane, the right triangular ligament of the liver must first be completely mobilized and the liver allowed to rotate anteromedially. On the right side, the colon usually lies well inferior to the operative field. When developing the space between

the adrenal gland and inferior vena cava superiorly to inferiorly, the surgeon must be mindful of adrenal vein variants, as illustrated in the anatomy section of this chapter (see Fig. 39-3). The right adrenal vein is a potentially perilous structure to manage because it is short, wide, variable, and confluent with thin-walled, large capacitance vessels (the inferior vena cava in >80% of cases, followed by the renal vein and uncommonly the right hepatic vein) that can bleed briskly if directly injured (e.g., by cautery), lacerated from undue traction on adjacent structures, or sheared by clips. A significant second

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Section VIII Endocrine

Figure 39-24 Technique of right laparoscopic adrenalectomy. The liver has been mobilized and retracted medially to expose the adrenal gland and inferior vena cava. The space just medial to the adrenal gland is developed to identify the adrenal vasculature.

adrenal vein may be found in up to 10% of patients. By methodically dissecting one layer at a time and moving in a superior-to-inferior direction, all potential adrenal vein variants can be encountered in controlled fashion. The adrenal vein must be dissected out delicately, definitively ligated (again usually with two clips on the patient side), and then divided. Loss of control of the adrenal vein stump needs to be avoided; if it occurs, conversion to an open procedure may be necessary. Of note, the junction of the inferior vena cava and right renal vein is frequently difficult to identify. In vivo, the transition is a gradual curve rather than the 90-degree takeoff depicted in anatomy texts. Therefore, it cannot be used as a reliable anatomic landmark for identification of the adrenal vein.

Figure 39-25 Patient positioning for open right adrenalectomy.

Patients who undergo laparoscopic adrenalectomy recover rapidly. Most patients, including approximately half of those treated for pheochromocytoma, are able to leave the hospital on the first postoperative day. In the treatment of adrenal tumors, successful outcomes hinge on excellent perioperative medical management as much as technical skill, particularly in cases of pheochromocytoma and Cushing’s syndrome. These considerations are discussed earlier in the disease-specific sections.

Open Anterior Transabdominal Adrenalectomy
Patient Preparation and Positioning Neuraxial blockade (use of an epidural catheter) is routinely used for intraoperative and postoperative anesthetic/analgesic management. The patient is positioned supine, with the ipsilateral side slightly elevated on a bolster (Fig. 39-25). A urinary catheter, orogastric or nasogastric tube, and intermittent pneumatic compression devices are placed. The surgical preparation is carried from the nipple line to the pubis and down to the table on either side. Technique: Left Adrenal We prefer to use a subcostal incision, which may be extended across the midline (chevron) with or without a vertical upper midline extension to achieve wide exposure. The left adrenal can be exposed by entering the lesser sac through the gastrocolic ligament and incising

Complications and Postoperative Care Potential technical complications include venous hemorrhage and bleeding from solid organ capsular injuries. Small amounts of bleeding can often be managed by coagulation or direct pressure with rolled Kittner gauze. Hollow viscus injuries are uncommon but may be associated with procedures performed in patients who have previously undergone major abdominal surgery. Pancreatic injuries and fistulas have been reported with leftsided procedures but are rare complications, as are port site hernias and port site metastases in cases of malignancy. Patients undergoing laparoscopic adrenalectomy for Cushing’s syndrome are at risk for surgical site infections, including port site infections in 5% to 10% of cases and, rarely, subphrenic abscesses requiring catheter drainage, as a result of their catabolic and immunosuppressed state.

Chapter 39 The Adrenal Glands

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Gallbladder Liver

Right adrenal vein

Pancreas Duodenum Inferior vena cava Transverse colon

Figure 39-26 Open right adrenalectomy. The right lobe of the liver and the hepatic flexure of the colon have been completely mobilized. The retroperitoneum is entered and the duodenum and head of the pancreas reflected medially (Kocher maneuver) to expose the adrenal gland and inferior vena cava.

the retroperitoneum inferior to the tail of the pancreas or by rotating the spleen, pancreatic tail, and stomach anteromedially as described in the section on laparoscopic adrenalectomy. The latter approach is used in our practice. The splenic flexure of the colon is mobilized inferiorly and the plane medial to the adrenal gland developed. The adrenal vein is isolated, tied in continuity, and divided. The small adrenal arteries can be ligated or electrocoagulated and the specimen removed after circumferential dissection is completed.

Technique: Right Adrenal Open right adrenalectomy begins with complete mobilization of the right lobe of the liver, including the lateral attachments and the falciform ligament. The adrenal can be exposed by rotating the liver medially or, more commonly, retracting the inferoposterior segments cephalad with long, padded retractors (liver, renal vein, Deaver, or Harrington types). The retroperitoneum is entered by

performing a Kocher maneuver (Fig. 39-26) and the inferior vena cava exposed by medial reflection of the duodenum. The plane between the adrenal gland and inferior vena cava is developed first. Vascular structures, which may be numerous in highly angiogenic tumors, are ligated sequentially. The adrenal vein is isolated, securely tied, and divided. Loss of control of the adrenal vein stump may be managed with the application of a side-biting (Satinsky) vascular clamp. As discussed earlier, open adrenalectomy is generally performed in cases of suspected or known malignancy. Locally invasive right-sided adrenal tumors can be challenging to manage given their frequent invasion of adjacent venous structures (Fig. 39-27). It is our practice to involve an experienced vascular or liver surgeon in the management of tumors with extensive venous invasion. Locally invaded organs, most commonly the kidney, are resected en bloc with the primary mass. Complete radical resection is a critical determinant of survival in patients with malignant adrenal

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Section VIII Endocrine

Figure 39-27 Open resection of a right adrenocortical carcinoma invading the inferior vena cava. The patient’s head is to the left. The liver (white arrowhead) is retracted cephalad. The white arrow indicates the tumor and the black arrow indicates the inferior vena cava, which is encircled with vessel loops.

A

tumors; in some cases this can be achieved only if immediate venous reconstruction is performed (Fig. 39-28).

Complications and Postoperative Care Technical complications of open adrenalectomy include venous hemorrhage, tumor embolization in patients with intravascular tumor extension, and solid organ injury. Postoperative complications are similar to those associated with other major abdominal procedures. Most patients experience return of bowel function within 3 to 4 days and are able to leave the hospital on postoperative day 5 to 7.

Selected References
Axelrod L: Perioperative management of patients treated with glucocorticoids. Endocrinol Metab Clin North Am 32:367-383, 2003.
A thorough review of existing nonsystematic studies on steroid use that provides clear guidelines and the rationale behind them.

B
Figure 39-28 Open resection of a right adrenocortical carcinoma

Gifford RW Jr, Kvale WF, Maher FT, et al: Clinical features, diagnosis and treatment of pheochromocytoma: A review of 76 cases. Mayo Clin Proc 39:281-302, 1964.
A landmark account of the biochemical, pharmacologic, and physiologic advances that allowed collaborators at the Mayo Clinic to treat 76 patients with pheochromocytoma while experiencing only one death.

necessitating vascular reconstruction. A, The infrahepatic inferior vena cava has been replaced with a polytetrafluoroethylene graft. The liver can be seen superiorly and the colon inferiorly. B, Ex vivo specimen consisting of the right adrenal tumor with the kidney resected en bloc. The renal vein is indicated by the arrow. Forceps have been placed through the resected segment of inferior vena cava.
A critical analysis of biochemical test operating characteristics in the diagnosis of pheochromocytoma.

Grumbach MM, Biller BM, Braunstein GD, et al: Management of the clinically inapparent adrenal mass (“incidentaloma”). Ann Intern Med 138:424-429, 2003.
A summary statement from the National Institutes of Health Consensus Development Program with recommendations on incidentaloma workup and indications for surgery.

Lindholm J, Juul S, Jorgensen JO, et al: Incidence and late prognosis of Cushing’s syndrome: A population-based study. J Clin Endocrinol Metab 86:117-123, 2001.
Documents the excess mortality associated with Cushing’s syndrome.

Milliez P, Girerd X, Plouin PF, et al: Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 45:1243-1248, 2005.
A compelling report on the adverse effects of primary aldosteronism in which affected patients are compared with controls matched for systolic blood pressure.

Kudva YC, Sawka AM, Young WF Jr: Clinical review 164: The laboratory diagnosis of adrenal pheochromocytoma: The Mayo Clinic experience. J Clin Endocrinol Metab 88:4533-4539, 2003.

Chapter 39 The Adrenal Glands

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Minneci PC, Deans KJ, Banks SM, et al: Meta-analysis: The effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med 141:47-56, 2004.
A useful analysis of various steroid regimens in the treatment of critically ill patients with relative adrenal insufficiency.

Neumann HP, Bausch B, McWhinney SR, et al: Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346:1459-1466, 2002.
A landmark report documenting a surprisingly high rate of familial pheochromocytoma and calling attention to the significance of succinate dehydrogenase mutations.

Ng L, Libertino JM: Adrenocortical carcinoma: Diagnosis, evaluation and treatment. J Urol 169:5-11, 2003.
A multi-institutional descriptive report on this rare disease.

Nobel Lectures, Physiology or Medicine 1942-1962. Amsterdam, Elsevier, 1964.
An account of the clinical discoveries and advances in organic chemistry that led to identification, isolation, and artificial synthesis of adrenal cortical hormones. A full transcript can be found at http://nobelprize. org.

Nobel Lectures, Physiology or Medicine 1971-1980. Amsterdam, Elsevier, 1992.
Documents the formidable challenges surmounted in the identification of peptide hormones, found in such minute concentrations, and development of the radioimmunoassay necessary for their detection. A full transcript can be found at http://nobelprize.org.

Plouin PF, Duclos JM, Soppelsa F, et al: Factors associated with perioperative morbidity and mortality in patients with pheochromocytoma: Analysis of 165 operations at a single center. J Clin Endocrinol Metab 86:1480-1486, 2001.
One of the largest single-institution series on surgical management of pheochromocytoma documents the evolution in clinical care over more than 2 decades.

Welbourn RB: Early surgical history of phaeochromocytoma. Br J Surg 74:594-596, 1987.
Describes the initial achievements of American and European surgeons in the successful treatment of pheochromocytoma.

Young WF, Stanson AW, Thompson GB, et al: Role for adrenal venous sampling in primary aldosteronism. Surgery 136:12271235, 2004.
A large single-institution series documenting the unreliability of CT alone in localizing aldosteronomas. The discussion that follows the main text is particularly informative.

References
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