The adrenal glands lie alongside the upper part of each kidney. The adrenal gland is alternatively referred to as the suprarenal gland.¹ The right adrenal gland lies between the inferior vena cava and the right crus of the diaphragm, its right border projecting to the right of the vena cava and its upper part coming into contact with the bare area of the liver. Only its lower half has a peritoneal covering. The left adrenal gland is crescent shaped and drapes the medial border of the left kidney above the hilum. Its lower pole is covered in front by the body of the pancreas and the splenic artery. The rest of the gland is covered by peritoneum and forms part of the stomach bed. It lies on the left crus of the diaphragm. The medial border is to the left of the celiac ganglion and overlapped by the left gastric vessels.

Both glands receive a rich blood supply, estimated to be 6 to 7 mL/g/minute from several arterial branches. In contrast, each gland normally has only a single vein. The right vein is only a few millimeters long and enters the vena cava; the left vein is longer and enters the left renal vein. One potential complication of removing the left adrenal gland is the risk of inadvertent ligation of the apical renal arterial branch to the upper pole, which lies in close contact to the inferior border of an adrenal tumor. A complication of removing the right adrenal gland is injury to the vena cava.

The adrenal cortex constitutes approximately 70% of the adrenal gland and is made up of three layers, which are distinct in regard to histology, cellular organization, and their relationship to blood supply. The three layers, from the outside in, are:²

Cortisol binds to α-globulin (transcortin or cortisolbinding globulin),³ a high affinity, low-capacity system. Normally <5% of circulating cortisol is unbound. Small amounts are carried bound to albumin, which is a lowaffinity, high-capacity protein.⁴ Only the unbound cortisol
and its biologically inactive metabolites can be filtered at the glomerulus. The average production rate of cortisol is 12 to 15 mg/m²/day. Cortisol is rapidly metabolized, mainly in the liver. One of the main enzymes that regulates cortisol metabolism is 11 β-hydroxysteroid dehydrogenase. The major metabolites are formed by the reduction of the double bond and ketone groups to produce tetrahydrocortisol, tetrahydrocortisone, cortol, and cortolone.⁴ These metabolites are excreted into the urine in conjugation with glucoronic acid, and account for approximately 60% to 70% of the total cortisol produced. A small amount of cortisol (up to 50 µg per day) is excreted unchanged in the urine and represents the unbound cortisol in plasma that is filtered through the kidney.

Aldosterone has less protein binding than cortisol. An ultrafiltrate of plasma contains as much as 50% of circulating aldosterone, which explains the shorter half-life (20 minutes for aldosterone compared to 2 hours for cortisol) and high metabolic clearance rate. The average secretion rate of aldosterone is 100 to 200 µg per day. Both the kidney and the liver are sites of metabolic clearance, with only a small percentage of aldosterone excreted remaining unchanged in the urine. The major androgens produced by the adrenal cortex are dehydroepiandrosterone (DHEA) sulfate, androstenedione, DHEA, 11-hydroxyandrostenedione, and small amounts of testosterone.

Normal adrenal function is important for modulating: (i) intermediary metabolism and immune responses through glucocorticoid action; (ii) blood pressure, vascular volume, and electrolytes through mineralocorticoid action; and (iii) secondary sexual characteristics (in females) through androgenic action.⁵ The adrenal axis plays an important role in the stress response by rapidly increasing cortisol levels. Cortisol and aldosterone are the two essential hormones, whereas the adrenal androgens are of relatively less physiologic significance in adults. Adrenal disorders include hyperfunction (Cushing’s syndrome) and hypofunction (adrenal insufficiency), as well as a variety of genetic abnormalities of steroidogenesis.

The precursor of all steroids is cholesterol. Part of the cholesterol is synthesized from acetate, but most of it is taken up from low-density lipoprotein in the circulation. A common and important rate-limiting step for the synthesis of all steroid hormones is cleavage of the side chain from cholesterol (C27) to yield pregnenolone (C21), the common branch point for the synthesis of progestins, corticoids, androgens, and, hence, estrogens.⁶ Expression of the side chain cleavage enzyme, cytochrome P450 scc, which converts cholesterol to pregnenolone, is one of the unique features of steroidogenic cells that participate in de novo steroid synthesis. Glucocorticoid production by the adrenal gland is under hypothalamic-pituitary control. Corticotropin-releasing hormone (CRH) is secreted in the hypothalamus in response to circadian rhythm, stress, and other stimuli and travels down the portal system to stimulate adrenal corticotropic hormone (ACTH) release from the anterior pituitary. ACTH is derived from the prohormone, propiomelanocortin, which undergoes complex processing within the pituitary to produce ACTH and a number of other peptides.⁷ Many of these peptides, including ACTH, contain melanocyte-stimulating hormone-like sequences which cause pigmentation when levels of ACTH are markedly elevated. Circulating ACTH stimulates cortisol production in the adrenal gland. The cortisol secreted (or any other synthetic corticosteroid administered to the patient) causes negative feedback to the hypothalamus and pituitary to inhibit further CRH and ACTH release. The set point of this system clearly varies throughout the day according to the circadian rhythm (with maximal activity taking place soon after awakening and the lowest concentrations between 10:00 PM and 2:00 AM), which is usually overridden by severe stress (e.g., trauma, surgery, intense exercise). ACTH is also released during stress, independent of the circulating serum cortisol level. CRH, vasopressin, and norepinephrine act synergistically to increase ACTH release during stress. Endorphinergic pathways also play a role in ACTH regulation. The acute administration of morphine stimulates ACTH release, whereas chronic administration blocks it.

Biosynthesis begins with tyrosine, which can be obtained from the diet or synthesized from phenylalanine. Tyrosine is actively transported from the bloodstream into the adrenal gland, and converted into 3, 4-dihydroxyphenylalanine (DOPA) by the rate-limiting, mitochondrial enzyme, tyrosine hydroxylase. Feedback inhibition is exerted by norepinephrine. Decarboxylation of DOPA to dopamine is catalyzed by the cytosolic enzyme, aromatic L-amino acid decarboxylase. Dopamine, in turn, must be actively transported into granulated vesicles that contain dopamine β-hydroxylase in order to be converted to norepinephrine. For most chromaffin tissue and neurons, the synthesis ends with norepinephrine binding to the granule. In the nonadrenergic neuron, this granule containing norepinephrine is secreted into the synapse during depolarization. As with other chromaffin tissue, the adrenal medulla stores and releases norepinephrine in granules. The adrenal medulla is the body’s primary source of both epinephrine and the cytosolic enzyme, phenyethanolamine N-methyltransferase, which produces epinephrine from norepinephrine. Because phenyethanolamine N-methyltransferase activity is so dependent on glucocorticoids (cortisol in humans), it is also dependent on ACTH and the rest of the hypothalamicpituitary-adrenal (HPA) axis. The ACTH also has a tropic effect on tyrosine hydroxylase activity of the adrenal medulla. For the enzymatic reaction to take place, norepinephrine must be released from its storage granule in the cytoplasm to produce epinephrine, and then transported back into another granule. The storage granules in the adrenal medulla contain epinephrine or norepinephrine,
and the release can be selective. Under normal physiologic conditions, approximately 80% of the catecholamine output from the adrenal medulla is epinephrine.

Pheochromocytomas are catecholamine-secreting tumors of chromaffin tissue and are a rare cause of hypertension.⁸ Less than 0.1% of the hypertensive population has a pheochromocytoma.⁹,¹⁰ The hypertension caused by these tumors is usually curable. Surgery on a patient with an unrecognized pheochromocytoma can be fatal; similarly the administration of β-adrenergic-blocking drugs can have untoward side effects.

These tumors can be associated with other potentially fatal but curable diseases. The high incidence of pheochromocytoma in families as a primary disease, in association with multiple endocrine neoplasia or other familial diseases such as Von Hippel Lindau syndrome and neurofibromatosis I, indicates the need for genetic counseling.¹¹ Approximately 16% of pheochromocytomas will be associated with other endocrine disorders, such as multiple endocrine syndrome 2, which is comprised of medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia.

The incidence of pheochromocytoma as a benign tumor in one of the adrenal glands is 80%. Twenty percent are extra-adrenal, with half located below the diaphragm in areas such as along the aorta, near the urinary bladder, and in the organ of Zuckerkandl; the other half is located above the diaphragm in areas along the aorta, in the lungs or heart, or in the neck or carotid bodies. Ten percent occur in children. In nonfamilial disease, the classical teaching is that 10% of patients have bilateral adrenal tumors and 10% have multiple extra-adrenal tumors; however, in familial disease, more than 80% are bilateral or in multiple sites. The incidence of a malignant pheochromocytoma is 10%. The occurrence of a pheochromocytoma is evenly distributed between the sexes and can occur at any age, although the peak incidence is between the fourth and sixth decades. Catecholamine secretion is responsible for the signs and symptoms of a pheochromocytoma.¹² It is unusual that a tumor will grow large enough or be so invasive as to interfere with the function of the surrounding organs. The manifestations of a pheochromocytoma are primarily the result of the excessive secretion of norepinephrine, epinephrine, and dopamine.¹³ The most common combination is predominantly norepinehrine and epinephrine. Some tumors secrete only norepinehrine, but <10% secrete only epinephrine. Dopamine and its metabolite are more likely to be significantly elevated in children with a pheochromocytoma. The etiology for the increased production and secretion of catecholamines is not clear. It is conceivable that the negative feedback mechanism of norepinephrine on tyrosine hydroxylase is altered so that sensitivity to feedback is decreased, or perhaps metabolism or release is so rapid that feedback does not transpire in the usual manner. Small tumors tend to secrete high levels of circulating catecholamines. With intracellular metabolism being more prevalent in large tumors, high levels of metabolites tend to be released, and free catecholamine secretion is reduced.

Approximately 50% of patients with a pheochromocytoma have sustained hypertension, 45% are normotensive with paroxysms of hypertension, and 5% are normotensive or even hypotensive.¹²,¹⁴ These differences, in part, relate to the patterns of catecholamine secretion; bursts produce hypertensive episodes. Patients with sustained hypertension and some normotensive patients can have high or normal levels of norepinephrine. How sustained levels of high norepinephrine concentrations result in persistent hypertension is not understood. However, if elevated catecholamine secretion persists, α- and β-receptors may become desensitized, or even downregulated. Hemodynamic mechanisms will no longer respond to elevated levels of norepinephrine, and blood pressure will normalize. Catecholamine levels and blood pressure do not usually correlate well, but a significant change in catecholamine concentration will elicit a blood pressure response. Patients with the rare, exclusively epinephrineproducing tumors can present with normotension, or even hypotension, secondary to the vasodilating properties of epinephrine. Orthostatic hypotension is another result of the ganglionic-blocking activity of excessive amounts of catecholamines.

The classic triad of symptoms in patients with a pheochromocytoma consists of episodic headache, sweating, and tachycardia, all of which are largely due to the pharmacologic effects of the catecholamines secreted from these tumors.¹²,¹⁵ Other signs and symptoms include pallor, orthostatic hypotension, visual blurring, papilledema, weight loss, polyuria, polydipsia, increased erythrocyte sedimentation rate, hyperglycemia, psychiatric disorders, and, rarely, secondary erythropoesis consistent with overproduction of erythropoietin. The abnormalities in carbohydrate metabolism are directly related to increases in catecholamine production; these changes resolve after adrenalectomy.

There are two rare presentations of a pheochromocytoma: Episodic hypotension in patients with tumors that secrete only epinephrine and rapid cyclic fluctuations of hypertension and hypotension.¹⁶,¹⁷ The latter group of patients can be treated by fluid repletion and α-adrenergic antagonists. These patients can exhibit significant baseline electrocardiographic (ECG) changes due to the toxic effects exerted on the myocardium by the excessively high levels of catecholamines. Patients may also present with
chest pain and ECG changes suspicious for ischemia. Despite striking repolarization changes, many patients who proceed to coronary angiography preoperatively are found to have no obstruction of their coronary arteries. Anecdotal reports suggest ECG changes to be a manifestation of toxic myocarditis. In addition to the ECG changes mentioned, many patients with a pheochromocytoma are noted to have a long QTc interval which may predispose to ventricular arrhythmias.¹⁸ After removal of the pheochromocytoma, the QTc intervals tend to normalize. An elevated temperature more commonly reflects a catecholaminemediated increase in the metabolic rate and diminished heat dissipation secondary to vasoconstriction. Polyuria is an occasional finding, and rhabdomyolysis with resultant myoglobinuric renal failure may result from extreme vasoconstriction and ensuing muscle ischemia.

The diagnosis of pheochromocytoma is usually suggested by the history in a symptomatic patient or the family history in a patient with familial disease, and can usually be confirmed by measurements of urinary and plasma catecholamines and metabolites and radiologic tests. Specific tests for diagnosing pheochromocytoma are outlined in Table 43.1.

Preparing the patient for surgical removal of a pheochromocytoma entails the institution of α- and β-adrenergic blockade. The reduction in perioperative mortality rates, from as high as 45% to as low as 0% to 3% after the pheochromocytoma is excised, has encouraged the administration of α-antagonists for preoperative therapy which is usually initiated once the diagnosis is established. Phenoxybenzamine, a long-acting (24 to 48 hours), noncompetitive, presynaptic, α-adrenergic antagonist, is typically initiated at least 7 days (usually for 2 to 4 weeks) before surgery and added incrementally until the blood pressure is controlled and paroxysms disappear. The initial dose is usually 10 mg every 12 hours. Most patients require between 80 and 200 mg per day. The combination of α-adrenergic receptor blockade and a liberal salt intake will restore the contracted plasma volume towards normal.¹⁹ Selective α-blockers, such as doxazosin, prazosin and terazosin, have also been used effectively, but their role in preoperative management may be limited to the treatment of individual paroxysms. Nitroprusside, calcium channel blockers (where it was found that treatment extended postoperatively with calcium channel blockers is also effective in treating the clinical manifestations of catecholamine-induced myocarditis and coronary vasospam),²⁰ and angiotensin-converting enzyme inhibitors all can be used to reduce blood pressure in these patients. Intraoperatively, nitroprusside is beneficial in the treatment of hypertensive crises. β-adrenergic blockade is initiated more than 3 days before surgery in patients with persistent tachycardia or reflex tachycardia related to the initiation of α-blockade, or in those having arrhythmias. It is important to initiate α-blockade before β-blockade to avoid the situation of unopposed α-agonism whereby the patient suffers from intense vasoconstriction from the α-adrenergic excess and is at risk for extreme hypertension as well as a dramatic increase in myocardial workload. Low doses often suffice; a reasonable starting dose is 10 mg propranolol, three to four times per day, and is increased as needed to control the pulse rate. Labetolol, a β-adrenergic antagonist with some α-blocking activity, is effective as a second-line medication, but can increase the blood pressure if used alone, presumably because of its β-blocking effect being much more pronounced than its α-blockade. The pharmacologic adrenergic blockade helps to blunt the intense surges in blood pressure that occur during surgery and tumor manipulation.