Acs0538 Disorders Of The Adrenal Glands


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Acs0538 Disorders Of The Adrenal Glands

  1. 1. © 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 38 Disorders of the Adrenal Glands — 1 38 DISORDERS OF THE ADRENAL GLANDS L. Michael Brunt, M.D., F.A.C.S. The adrenal glands may be affected by a variety of different patho- activity (PRA). A PAC-to-PRA ratio greater than 25 to 30, in con- logic conditions. Although not among the most common disorders junction with suppressed PRA (< 0.2 to 0.5 ng/ml/hr) and a PAC encountered by surgeons, functioning adrenal tumors that pro- higher than 15 ng/dl, is consistent with primary hyperaldostero- duce excessive amounts of adrenal hormones are remarkable for nism.3 The diagnosis may be confirmed by means of suppression the range of clinical syndromes they give rise to. In this chapter, the testing with either oral salt loading or intravenous administration clinical presentation, diagnostic evaluation, and management of of saline. With oral salt loading, hypokalemia is corrected and the the various adrenal tumors are reviewed, and the workup of inci- patient is placed on a high-salt diet for 3 days. On day 3, a 24-hour dentally discovered adrenal masses (adrenal incidentalomas) is urine collection is obtained for measurement of sodium, potassi- outlined. The technical details of adrenalectomy (both open and um, creatinine, and aldosterone concentrations. Patients with pri- laparoscopic) are discussed in detail elsewhere, as are the anatom- mary hyperaldosteronism should have a 24-hour urine aldosterone ic relations of the adrenal glands to surrounding structures and the value higher than 12 μg/24 hr.1 Plasma aldosterone levels should arterial and venous blood supply [see 5:26 Adrenalectomy]. be higher than 10 ng/dl after I.V. salt loading. Once the diagnosis of primary hyperaldosteronism has been confirmed biochemically, the next step is to identify the cause or Disorders of the Adrenal Cortex determine the subtype [see Table 1]. Historically, aldosterone- PRIMARY HYPERALDOSTERONISM Clinical Evaluation Primary hyperaldosteronism is suspected Primary hyperaldosteronism (Conn syndrome) is now known to Measure plasma aldosterone concentration, be a much more common cause of hypertension than was previ- and assess plasma renin activity. PAC:PRA ously thought, occurring in as many as 8% to 12% of hypertensive ratio > 25–30, with PAC > 15 ng/dl and patients.1 The diagnosis of primary hyperaldosteronism should be PRA < 0.2–0.5 ng/ml/hr, is consistent with considered in any patient who has hypertension of early onset, primary hyperaldosteronism. hypertension that is difficult to control, or hypertension with Confirm diagnosis by means of suppression testing with oral or IV salt loading. hypokalemia [see Figure 1]. Although the classic presentation is that of hypertension with hypokalemia, many patients with primary hyperaldosteronism have a normal or low-normal serum potassi- um level; indeed, current data suggest that as many as 60% of patients diagnosed with this condition—and perhaps more—were Aldosterone is Aldosterone is not suppressible normokalemic at the time of diagnosis.2 The hypertension that suppressible (urinary aldosterone > 12 µg/24 hr; results from primary hyperaldosteronism is moderate to severe and plasma aldosterone > 10 ng/dl) may be refractory to standard antihypertensive medications. Patient does not have primary hyperaldosteronism. Perform CT of adrenal with thin Symptoms are nonspecific and may include headache caused by (3 mm) cuts. the hypertension. Most of the other symptoms observed are attrib- utable to hypokalemia; these include muscle weakness, cramps, fatigue, and, if the hypokalemia is severe, polydipsia, polyuria, noc- turia, and even paralysis. The pathophysiology of primary hyperaldosteronism primarily Patient has unilateral Patient has microadenoma (< 1 cm), macroadenoma (> 1 cm) bilateral nodules, or normal adrenals consists of increased aldosterone secretion by the adrenal gland, and is young (< 40–50 yr) or is older (> 40–50 yr) which leads to increased sodium retention, expansion of intravas- cular fluid volume, and suppression of renin secretion by the kid- Perform laparoscopic Perform adrenal vein sampling. ney. Aldosterone also promotes the exchange of sodium for potas- adrenalectomy. sium and hydrogen ion in the distal tubule, which leads to potassi- um depletion and alkalosis.The alkalosis may be aggravated by the movement of hydrogen ion into the cells to replace intracellular potassium. Significant potassium depletion may also be accompa- Lateralization (aldosterone:cortisol > 4 times No lateralization higher on one side than on the other) is is apparent nied by mild glucose intolerance. apparent Treat medically. Investigative Studies Perform laparoscopic adrenalectomy. The initial biochemical evaluation for suspected primary hyper- aldosteronism should consist of measurement of the plasma aldo- Figure 1 Algorithm illustrates diagnostic evaluation of the sterone concentration (PAC) and assessment of plasma renin patient with suspected primary hyperaldosteronism.
  2. 2. © 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 38 Disorders of the Adrenal Glands — 2 Table 2 Adrenal Vein Sampling Results in a Patient Table 1 Subtypes of Primary Hyperaldosteronism with Primary Hyperaldosteronism Aldosterone-producing Familial hyperaldosteronism adenoma Sampling Aldosterone Cortisol Level Aldosterone- Aldosterone Type I (glucocorticoid- Site Level (ng/dl) (μg/dl) Cortisol Ratio Ratio* Idiopathic hyperaldosteronism remediable) Aldosterone-producing adrenal Type II (aldosteronoma or Right adrenal carcinoma idiopathic) vein 480 346.7 1.38 Left adrenal 33,765 1,448 23.3 16.9 vein secreting adenomas (aldosteronomas) have accounted for approx- imately 60% of cases, and idiopathic hyperaldosteronism from Inferior vena 67.0 24.1 2.78 cava bilateral cortical hyperplasia has accounted for the bulk of the remaining cases. In the past few years, however, this picture has *Defined as the aldosterone-cortisol ratio in the left adrenal vein divided by the aldos- begun to change: several series in which hypertensive patients were terone-cortisol ratio in the right adrenal vein. The results show a lateralizing source of screened on the basis of aldosterone-to-renin ratios found that increased aldosterone production from the left adrenal gland. only 30% to 50% of patients with primary hyperaldosteronism had aldosteronomas, whereas 50% to 70% had bilateral adrenal small adrenal nodules and is therefore the preferred imaging hyperplasia.2 It is important to distinguish between these two con- modality for this purpose [see Figure 2]. Magnetic resonance ditions because aldosteronomas are treated surgically and idio- imaging may also be used, but it is more costly, and the images pathic hyperaldosteronism is treated medically. Aldosterone-pro- can be harder for clinicians to interpret. Findings on CT or MRI ducing carcinomas are rare and account for fewer than 1% of may include a unilateral macroadenoma (> 1 cm) or microade- cases of primary hyperaldosteronism. noma (< 1 cm) with a normal contralateral adrenal gland, bilat- Glucocorticoid-remediable hyperaldosteronism (also known as eral adrenal nodules or bilateral adrenal thickening, and bilater- familial hyperaldosteronism type 1) is a rare type of hyperaldo- al normal glands. steronism that is inherited in an autosomal dominant pattern.This Patients with a unilateral macroadenoma and a normal con- condition is due to a chimeric gene that results from fusion of two tralateral adrenal gland may be considered for adrenalectomy, components: (1) the promoter region for the enzyme 11β-hydrox- without any need for further testing. For all other patients, adren- ylase (CYP11B1), which catalyzes the conversion of deoxycortisol al vein sampling is recommended to differentiate aldosteronoma to cortisol, and (2) the gene that codes for aldosterone synthesis from idiopathic hyperaldosteronism. In this procedure, aldo- (CYP11B2). As a result, aldosterone synthesis is primarily depen- sterone and cortisol levels are measured from both adrenal veins dent on activation by adrenocorticotropic hormone (ACTH) and and from the inferior vena cava. ACTH is usually infused during is suppressed by exogenous glucocorticoid administration.3 Its the procedure to minimize stress-related fluctuations in cortisol extreme rarity notwithstanding, familial hyperaldosteronism type and aldosterone levels. An aldosterone-to-cortisol ratio that is at 1 has been associated with a significant increased risk of hemor- least four to five times greater on one side than on the other is con- rhagic stroke. Familial hyperaldosteronism type 2 is associated sidered diagnostic of a unilateral source of increased aldosterone with the development of both aldosteronomas and idiopathic production (i.e., an aldosteronoma) and constitutes an indication hyperaldosteronism. for adrenalectomy [see Table 2]. The initial step in subtype determination should be to per- Adrenal vein sampling is a technically demanding procedure form cross-sectional imaging to look for an adrenal adenoma. that should be carried out only by radiologists who have consider- Aldosteronomas are generally small, typically measuring no able experience with it. The value of this procedure was demon- more than 1 to 2 cm in diameter. Thin-section imaging with strated in a 2004 study of 194 patients with hyperaldosteronism at computed tomography possesses excellent spatial resolution for the Mayo Clinic.4 In this study, adrenal vein sampling identified a unilateral source of increased aldosterone production in 87 of 176 patients with the following CT findings: a normal CT scan (24/58), a unilateral micronodule (24/47), a unilateral macronod- ule (21/32), bilateral macronodules (16/33), and bilateral macro- nodules (2/6). If the treating physicians had relied on CT scan findings alone, 42 patients (21.7%) would have been inappropri- ately excluded from consideration for adrenalectomy, and an addi- tional 48 patients (24.7%) who showed no lateralization on adren- al vein sampling might have been subjected to an unnecessary operation. These results argue for liberal use of adrenal vein sam- pling in deciding which patients with primary hyperaldosteronism should undergo adrenalectomy. Management For patients with an aldosteronoma, the treatment of choice is laparoscopic adrenalectomy [see 5:26 Adrenalectomy]. Before the operation, hypertension should be brought under control and hypokalemia corrected. The aldosterone antagonist spironolac- tone may be useful for preoperative control of blood pressure. Figure 2 CT scan shows a right adrenal aldosteronoma (arrow). Adrenalectomy cures hypertension in as many as 30% to 80% of
  3. 3. © 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 38 Disorders of the Adrenal Glands — 3 patients and improves blood pressure control in the remainder.5-8 The reasons for failure to cure hypertension in some patients may Cushing syndrome is suspected be related to the effects of longstanding hypertension from the Measure 24-hr urinary free cortisol level, hyperaldosteronism, more advanced age, or coexisting essential and perform overnight dexamethasone hypertension. In one follow-up study, a positive family history of suppression test. hypertension and the use of more than two antihypertensive med- ications preoperatively were independent predictors of residual hypertension after adrenalectomy.5 Hypokalemia should be cor- rected in virtually 100% of patients. Initial test results are normal Initial test results are abnormal For patients with idiopathic hyperaldosteronism, treatment is medical, consisting of dietary sodium restriction and potassium Patient does not have Measure plasma ACTH level. supplementation. As in patients with aldosteronomas, spironolac- Cushing syndrome. tone is effective in controlling hypertension and hypokalemia. However, it also blocks testosterone synthesis and peripheral androgen action and thus may have undesirable side effects— namely, impotence, decreased libido, and gynecomastia. Plasma ACTH level is Plasma ACTH level is elevated suppressed (< 5 pg/ml) or in upper normal range Eplerenone is a newer aldosterone-receptor antagonist that exhibits little binding to androgen receptors and therefore may not Obtain abdominal CT scan Evaluate patient for pituitary have the same side effects as spironolactone.9 to localize adrenal lesion. Cushing syndrome or ectopic ACTH-secreting tumor. SECONDARY HYPERALDOSTERONISM Figure 3 Algorithm illustrates diagnostic evaluation of the Secondary hyperaldosteronism is an elevation of plasma aldo- patient with suspected Cushing syndrome. sterone occurring in response to increased renin production by the kidney. It may be caused by a variety of conditions, including reno- vascular hypertension [see 6:26 Renovascular Hypertension and Clinical Evaluation Stenosis], reduced intravascular volume (from congestive heart fail- ure, nephrosis, or cirrhosis), Bartter syndrome, and normal preg- A number of characteristic clinical symptoms and signs are asso- nancy. Adrenal function is normal in such cases, and treatment ciated with Cushing syndrome [see Table 3]. Obesity is the most should be directed at the underlying disorder. consistent feature and is typically distributed in a central pattern around the face, the trunk, the neck, and the abdomen. Patients CUSHING SYNDROME may have especially prominent supraclavicular fat pads and fat Cushing syndrome is an uncommon condition, with an annual over the upper back (so-called buffalo hump). Skin changes are incidence of 1 to 10 cases per million.10 It may be caused by common and include easy bruising, increased fragility, and skin ACTH-secreting pituitary tumors, by ectopic ACTH-secreting striae (sometimes pigmented). Facial plethora is also frequently tumors, or by cortisol-producing adrenal tumors. Of these condi- present. Generalized skin hyperpigmentation is seen more often in tions, ACTH-secreting tumors of the pituitary are the most com- patients with ectopic ACTH production. Hirsutism from increased mon cause of Cushing syndrome, accounting for approximately secretion of adrenal androgens may be present in women, but vir- 65% to 70% of cases. Ectopic production of ACTH accounts for ilizing features are more often associated with ACCA. Increased between 10% and 15% of cases; small cell lung carcinomas are the production of adrenal androgens also causes gonadal dysfunction, most common ectopic ACTH-secreting tumors (50% of ectopic manifested by amenorrhea and infertility. In men, increased corti- cases), but thymic tumors, carcinoid tumors, and medullary thy- sol secretion may result in reduced libido, decreased body hair, and roid carcinomas may also give rise to this syndrome. Adrenal testicular atrophy. tumors account for about 20% of cases of Cushing syndrome. The initial goal in the evaluation of a person who may have Cortisol-producing adenomas are the most common cause of Cushing syndrome is to determine whether a state of increased adrenal Cushing syndrome, followed by adrenocortical carcino- cortisol production exists. If it does, subsequent testing should be mas (ACCAs). Primary nodular adrenal hyperplasia is a rare cause undertaken (1) to determine whether the cause is ACTH depen- of adrenal Cushing syndrome. dent (a pituitary or ectopic ACTH-producing tumor) or ACTH independent (a primary adrenal lesion) and (2) to locate the source [see Figure 3]. Table 3 Symptoms and Signs of Cushing Syndrome Investigative Studies Detection of Cushing syndrome When Cushing syndrome Symptoms Signs is suspected on clinical grounds, the initial diagnostic tests should be measurement of urinary free cortisol and an overnight dexam- Weight gain Obesity (central distribution) ethasone suppression test. Urinary free cortisol levels are elevated Florid complexion Facial fullness (moon facies) in more than 90% of patients with Cushing syndrome.11 False pos- Oligomenorrhea or amenorrhea Buffalo hump itive elevations can, however, occur as a result of use of medications Decreased libido Prominent supraclavicular fat pads (e.g., barbiturates or phenytoin), obesity, serious illnesses, or psy- Spontaneous bruising Telangiectasias chiatric disorders. Furthermore, mild degrees of hypercortisolism Muscle weakness and fatigue Skin striae (violaceous) Mood swings, depression Osteopenia and osteoporosis may be missed in a single 24-hour collection because of variation Insomnia Hirsutism* in cortisol secretion rates. Dexamethasone is a potent glucocorticoid that suppresses adren- *May be associated with adrenocortical carcinoma. al production of corticosteroids in normal persons but not in per-
  4. 4. © 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 38 Disorders of the Adrenal Glands — 4 sons with Cushing syndrome.To screen for this syndrome, the low- cross-sectional imaging with CT is recommended. If a pituitary dose dexamethasone suppression test is usually employed. A single source is suspected, MRI of the pituitary should be the initial 1 to 3 mg dose of dexamethasone is administered orally at 11:00 imaging test. Pituitary MRI with gadolinium enhancement will P.M., and the plasma cortisol level is measured at 8:00 A.M. In nor- identify an adenoma in more than 60% of patients with pituitary mal persons, the 8:00 A.M. plasma cortisol levels are typically lower Cushing syndrome. However, as much as 10% of the general pop- than 1.8 µg/dl, whereas in patients with Cushing syndrome, the cor- ulation may have a pituitary incidentaloma, though these lesions tisol levels are usually higher than 10 µg/dl. If both the dexametha- are typically small (< 5 mm in diameter). If MRI is not conclusive, sone test and the urinary free cortisol measurement yield normal measurement of inferior petrosal sinus ACTH levels is recom- results, the patient does not have Cushing syndrome. A notable fea- mended as the most direct method of differentiating pituitary from ture of Cushing syndrome is the loss of the normal diurnal variation nonpituitary causes of ACTH-dependent Cushing syndrome. In in cortisol; however, because of variation in levels, random cortisol this test, ACTH levels are simultaneously measured peripherally determinations cannot be relied on in making the diagnosis. Late- and in the two inferior petrosal sinuses both before and after I.V. night (11:00 P.M.) salivary cortisol levels have now been found to administration of CRH (100 μg). An inferior petrosal sinus– be highly sensitive and specific in screening for Cushing syndrome to–periphery ACTH ratio that is higher than 3.0 is diagnostic of and, as a result, may see increasing use in the future.12,13 pituitary Cushing syndrome; a ratio that is lower than 1.8 is indica- Levels of 17-hydroxycorticosteroid and 17-ketosteroid (urinary tive of an ectopic ACTH-secreting tumor.15 In experienced hands, metabolites of cortisol) may be measured, but these levels are less this procedure has a sensitivity and specificity of 80% to 90%.11,15 useful in the diagnosis of Cushing syndrome than urinary free cor- Ectopic ACTH-producing tumors are most often detected by tisol levels are. If the patient exhibits virilizing features, a plasma means of CT scanning or radionuclide imaging with indium- testosterone level should be obtained. 111–labeled octreotide analogues, which detect tumors that express somatostatin receptors. Differentiation of ACTH-dependent causes from inde- DISORDERS OF EXCESS ADRENAL ANDROGEN PRODUCTION pendent causes Once the diagnosis of Cushing syndrome is established, a plasma ACTH level should be obtained to differen- Excess androgen production may be either acquired (as in tiate ACTH-dependent causes of the syndrome (i.e., pituitary and Cushing syndrome or adrenocortical carcinoma [ACCA]) or con- ectopic ACTH-secreting tumors) from ACTH-independent caus- genital (as in congenital adrenal hyperplasia). Congenital adrenal es (i.e., adrenal lesions). In patients with pituitary Cushing syn- hyperplasia comprises a group of autosomal recessive disorders drome, ACTH levels are typically normal or only moderately ele- characterized by defective synthesis of cortisol. This defect in cor- vated (> 20 pg/ml). In patients with ectopic ACTH-secreting tisol synthesis results in increased ACTH production, which, in tumors, ACTH levels are usually higher, though there is some turn, leads to adrenal hyperplasia and increased production of overlap with the levels measured in patients with Cushing disease. adrenal androgens and androgen precursors. The most common In patients with Cushing syndrome caused by an adrenocortical variant of congenital adrenal hyperplasia is 21α-hydroxylase defi- tumor, plasma ACTH levels are suppressed (< 5 pg/ml). ciency, which accounts for about 95% of cases. 21α-hydroxylase If it appears that the syndrome has an ACTH-dependent cause, deficiency may be divided into three main subtypes: classic salt- the next step is to determine whether the cause is of pituitary or wasting, classic non–salt-wasting, and nonclassic. The two classic ectopic origin. Historically, the high-dose dexamethasone suppres- subtypes generally are more severe and typically present early in sion test has generally been employed for this purpose. The ratio- life (i.e., in infancy or early childhood) with virilizing features and nale for this test is that high doses of glucocorticoids will suppress adrenal insufficiency. The nonclassic subtype tends to be milder: ACTH secretion from most ACTH-secreting pituitary adenomas the androgen excess is less pronounced, and there is no cortisol but not from ectopic ACTH-secreting tumors. Dexamethasone is deficiency. As many as 80% of patients with the classic salt-wast- administered either in eight doses over 2 days (2 mg every 6 hours) ing subtype experience severe electrolyte and fluid losses as a result or in a single oral 8 mg dose. Cortisol levels (in plasma for the sin- of an associated defect in aldosterone production. gle-dose version, in urine for the 2-day version) are measured Excess adrenal androgen production from an androgen-secret- before, during, and after administration of dexamethasone. With ing tumor can lead to testicular atrophy (in men) or to hirsutism, either version of the test, if the patient has pituitary Cushing syn- acne, and irregular or absent menses (in women).Women may also drome, the plasma or urinary cortisol levels should be markedly experience other virilizing features, such as male pattern baldness, suppressed (< 50% of the basal level), whereas if the patient has an clitoral enlargement, increased facial hair, and deepening of the ectopic ACTH-producing tumor, the cortisol levels should gener- voice. Biochemically, the diagnosis is established by measuring ally be unchanged. However, between 20% and 30% of patients plasma levels of androgens, including dehydroepiandrostenedione with mildly increased ACTH secretion and pituitary Cushing syn- (DHEA), DHEA sulfate, testosterone, and dihydrotestosterone. drome do not show suppression of steroid production to a level Other causes of hirsutism and virilism that must be considered in below 50% of baseline, and some patients with ACTH-secreting women include the polycystic ovary syndrome and androgen- tumors do show this degree of suppression of plasma or urinary secreting ovarian tumors. steroids. Therefore, the overall diagnostic accuracy of high-dose ADRENOCORTICAL CARCINOMA dexamethasone suppression testing is only 70% to 80%.14 Other tests, such as the corticotropin-releasing hormone (CRH) stimula- ACCA is a rare tumor: the estimated annual incidence ranges tion test, are available for differentiating among the possible caus- from 0.5 to 2 per one million adults. The age distribution is es of ACTH-dependent Cushing syndrome, but at present, they bimodal, with peak occurrences noted in the first 5 years of life and are less commonly employed. in the fourth and fifth decades of life.16 Localization Once biochemical evaluation is complete, the Clinical Evaluation and Investigative Studies next step is radiographic localization of the source of the Cushing ACCAs are typically large (> 6 to 8 cm) at presentation, and syndrome. If adrenal Cushing syndrome is suspected, abdominal most patients present with advanced (i.e., stage III or IV) disease
  5. 5. © 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 38 Disorders of the Adrenal Glands — 5 [see Table 4]. In two large series, the mean tumor size at diagnosis adrenal insufficiency is autoimmune adrenal disease; in the devel- was 12 cm and 15 cm.17,18 The clinical presentation may be relat- oping world, it is tuberculosis.21 Other causes of primary adrenal ed to the large size of the tumor (e.g., abdominal or back pain or insufficiency include bilateral adrenal hemorrhage, adrenal metas- other mass effects) or to increased secretion of one or more steroid tases, adrenal leukodystrophy, and certain viral or fungal infec- hormones. Approximately 60% of ACCAs are hyperfunctioning19; tions.The primary cause of secondary adrenal insufficiency is sup- about 30% secrete cortisol and give rise to Cushing syndrome, and pression of ACTH secretion and normal adrenal cortical function 20% secrete androgen and have virilizing effects. A mixed hor- as a result of long-term steroid administration. Several weeks of mone secretion pattern is frequently present. Adrenal cancers that exogenous administration of glucocorticoids are required before secrete estrogen or aldosterone exist but are much less common. adrenal insufficiency develops upon steroid withdrawal.21 Biochemical evaluation of ACCA patients should consist of testing for hypercortisolism [see Cushing Syndrome, above] and Clinical Evaluation measurement of adrenal androgens (i.e., DHEA sulfate and Chronic AI (Addison disease) is characterized by weakness, testosterone). chronic fatigue, anorexia, loss of appetite, abdominal pain, nausea, and diarrhea. Hyperpigmentation of the skin from chronic hyper- Management secretion of melatonin (a product of the ACTH precursor pro-opi- ACCA is an aggressive tumor that may spread locally to region- omelanocortin) may be apparent as well. Many patients with pri- al lymph nodes, adjacent organs, and distant sites (including the mary AI also have an associated mineralocorticoid deficiency, the liver, the lungs, and bones). Complete surgical resection [see 5:26 symptoms and signs of which include salt craving, postural Adrenalectomy] offers the only chance for a cure and is the best pre- hypotension, and electrolyte abnormalities. Because many of the dictor of clinical outcome.16 Overall 5-year actuarial survival rates symptoms of AI are nonspecific, patients may go undiagnosed for after complete resection range from 32% to 48%.16 Patients whose a long time. The symptoms of primary AI are usually more severe tumors are incompletely resected (i.e., who have residual local or than those of secondary AI. distant gross disease) have a median survival of less than 1 year. In patients with inadequate adrenal reserve, an acute adrenal The presence of tumor thrombus in the renal vein or inferior vena crisis may be precipitated by the stress imposed by surgery, trau- cava is not a contraindication for surgical resection, provided that ma, infection, or dehydration and may result in vascular collapse the tumor can be completely excised.16,19 with hypotension, shock and, if untreated, death. Consequently, Treatment options for patients with unresectable or recurrent patients with unexplained cardiovascular collapse in whom this ACCA are limited. Locally recurrent tumors may be resected sur- diagnosis is suspected should be treated empirically with replace- gically. Radiation therapy is generally ineffective, though a few ment corticosteroids. investigators have reported tumor response rates as high as 42%.19 Mitotane is toxic for adrenocortical cells and is the most specific Investigative Studies chemotherapeutic agent available for the treatment of ACCA. Laboratory abnormalities associated with adrenal insufficiency Objective tumor response rates as high as 25% have been report- include hyponatremia, hyperkalemia (in primary AI), hypo- ed, but complete responses to mitotane are rare,19 and treatment is glycemia, and azotemia, with increased blood urea nitrogen and often limited by gastrointestinal and central nervous system side creatinine concentrations.The diagnosis is confirmed by measure- effects. In addition, because of mitotane’s toxic effects on normal ment of plasma cortisol and ACTH levels. In primary adrenal adrenal cortical function, patients being treated for ACCA with insufficiency, 8 A.M. plasma cortisol levels are typically low (< 3 this agent require glucocorticoid replacement. Mitotane has occa- µg/dl),22 and plasma ACTH levels are high (> 100 pg/ml). Plasma sionally been used as adjuvant therapy after resection of ACCA, ACTH levels are usually low or inappropriately normal if pituitary but the data are inconclusive.The results of conventional cytotox- failure or hypothalamus pathology is the cause.21 The ACTH stim- ic chemotherapy in ACCA patients have been disappointing. The ulation test may be necessary to establish the diagnosis in patients poor response rates to chemotherapy may be related to high with partial adrenal insufficiency or to assess recovery of the pitu- expression of the multiple drug resistance gene MDR1; this results itary-adrenal function after treatment of Cushing’s syndrome. For in high levels of P-glycoprotein, which acts as a drug efflux this test, 250 µg of synthetic ACTH is administered intravenously, pump.19,20 and plasma cortisol levels are measured at 0, 30, and 60 minutes. A serum cortisol level higher than 18 µg/dl at either 30 or 60 min- ADRENAL INSUFFICIENCY utes is considered a normal response. Adrenal insufficiency (AI) may be either primary or secondary. In industrialized countries, the primary cause of spontaneous Management AI is treated with exogenously administered glucocorticoids [see Table 5]. If the patient is in an acute adrenal crisis, hydrocortisone Table 4 Staging of Adrenocortical Carcinoma* should be given in a dosage of 100 mg I.V. every 8 hours. If the patient requires oral replacement therapy for chronic AI, hydrocor- Stage Description tisone should be given in a dosage of 10 to 12.5 mg/m2/day.21 Hydrocortisone (20 to 30 mg/day) is often preferred to other Stage I T1 (≤ 5 cm) N0 M0 steroids because its short half-life (8 to 12 hours) more closely mim- Stage II T2 (> 5 cm) N0 M0 ics the normal circadian rhythm of cortisol secretion; however, it must be administered twice or three times daily, whereas pred- Stage III T3 (locally invasive), or T1–2 N1 M0 nisone (equivalent dose, 5 mg/day) may be administered once or T4 (invasion of adjacent organs), or any T with distant metastases twice daily. For patients who are on long-term steroid therapy, out- Stage IV (M1) comes after surgery appear to be essentially the same whether they received their normal replacement doses orally or whether they *Based on the staging system of the Union Internationale contre le Cancer (UICC).51 received stress doses intravenously.23 Patients who have primary AI
  6. 6. © 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 38 Disorders of the Adrenal Glands — 6 Table 5 Equivalent Dosages for Commonly Used Pheochromocytoma should be suspected in any patient with Glucocorticoids21,22 severe hypertension, any patient with hypertension that is episodic or associated with spells, any hypertensive pediatric patient, any patient with a family history of pheochromocytoma or multiple Glucocorticoid Relative Dose Equivalent t (hr) Potency (mg/day) 1/2 endocrine neoplasia type 2A (MEN 2A) or 2B (MEN 2B), and any hypertensive patient with medullary thyroid carcinoma. Hydrocortisone 1 20 8–12 Investigative Studies Prednisone 4 5 18–36 Laboratory tests The diagnosis of pheochromocytoma is Methylprednisolone 5 4 18–36 established by demonstrating elevated levels either of cate- Dexamethasone 25–50 0.5 36–54 cholamines and metabolites (metanephrines) in urine or of frac- tionated metanephrines in plasma.31-33 The urinary vanillylman- delic acid (VMA) concentration is the least specific test because or have undergone bilateral adrenalectomy should also receive min- of the frequency of false positive results caused by ingestion of eralocorticoid therapy (fludrocortisone, 0.05 to 0.2 mg/day). related foods (e.g., coffee, tea, and raw fruits) or drugs (e.g., alpha-methyldopa). Because the plasma fractionated metaneph- rine concentration is both sensitive for pheochromocytoma and Disorders of the Adrenal Medulla considerably simpler than a 24-hour urine collection, it is the pre- ferred initial screening test in many institutions; however, some PHEOCHROMOCYTOMA investigators have found that measurement of 24-hour urinary Pheochromocytomas (often referred to as pheos) are cate- catecholamine and metanephrine levels yields fewer false positive cholamine-producing tumors that arise from chromaffin tissue.24 results.32 In most cases, abnormal plasma metanephrine and nor- The majority (85% to 90%) develop in the adrenal gland, but some epinephrine levels should be confirmed by measurement of uri- occur at extra-adrenal sites.These tumors have their peak incidence nary catecholamine and metanephrine concentrations. In cases during the fourth and fifth decades of life, and they affect males and where diagnosis is particularly difficult, direct measurement of females with equal frequency. The prevalence of pheo- plasma catecholamine levels during a hypertensive episode may chromocytoma in hypertensive patients is approximately 0.1% to be useful. 0.5%. Clinically silent pheochromocytomas may be present in as Certain agents may interfere with biochemical testing for many as 10% of patients who present with an adrenal incidentalo- pheochromocytoma, including iodine-containing contrast media, ma.25 Several features of pheochromocytomas have been charac- labetalol, tricyclic antidepressants, and levodopa.34 Major stress terized by a 10% frequency of distribution: 10% are extra-adrenal, (e.g., from a recent stroke, a major operation, obstructive sleep 10% are bilateral, 10% occur in children, 10% are familial, and apnea, or renal failure) may also affect catecholamine and metabo- 10% are malignant. Some more recent series, however, have lite levels. Because of the sensitivity of current tests and the risk of reported lower percentages of malignant pheochromocytomas.26,27 blood pressure alterations, provocative testing with agents such as Because extra-adrenal pheochromocytomas (also referred to as glucagon or histamine and suppression testing with clonidine are paragangliomas) lack the enzyme phenylethanolamine-N-methyl- no longer commonly used for diagnosis of pheochromocytoma. transferase (PNMT), they can secrete norepinephrine but not epinephrine. Imaging Given that only 2% to 3% of pheochromocytomas are found outside the abdomen, localization of suspected tumors Clinical Evaluation The clinical features of pheochromocytoma are related to the effects of increased secretion of norepinephrine and epineph- rine.24,28 Hypertension is the most consistent feature and may be either paroxysmal or sustained. Paroxysmal hypertension can be severe and may be associated with “spells” consisting of pounding in the chest, tachycardia, headache, anxiety and pallor; these spells are related to catecholamine surges. Other symptoms that may be noted include temperature elevation, flushing, and sweating, and some patients experience a feeling of marked anxiety and an impending sense of doom. Most attacks are short and last less than 15 minutes.The paroxysms may occur spontaneously, or they may be precipitated by postural changes, vigorous exercise, sexual inter- course, alcohol, and the use of certain drugs (e.g., histamine, tri- cyclic antidepressants, and metoclopramide) or anesthetic agents. Some patients with pheochromocytoma present with an extreme hypertensive crisis that may result in severe headaches, diaphoresis, visual changes, acute myocardial infarction, cardiac dysrhythmias, congestive heart failure, pulmonary edema, or even stroke. Sudden death has been reported in patients with unsus- pected pheochromocytomas who have undergone percutaneous biopsy of the tumor29,30 or surgical procedures for other indica- Figure 4 MRI shows a left adrenal pheochromocytoma. tions. Hypertensive emergencies are treated with I.V. esmolol, Pheochromocytomas typically appear bright on T2-weighted phentolamine (or sodium nitroprusside), or both. images.
  7. 7. © 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 38 Disorders of the Adrenal Glands — 7 should begin with abdominal CT or MRI.33 The uniquely bright Table 6 Inherited Pheochromocytoma Syndromes appearance pheochromocytomas typically exhibit on T2-weighted MRI sequences [see Figure 4] makes MRI the preferred imaging Syndrome Mutation Chromosome Frequency* modality in many institutions. Another option is scintigraphy with iodine-labeled metaiodobenzylguanidine (I-MIBG). MIBG ret MEN 2A and 2B 10q11 30%–50% labeled with iodine-131 (131I-MIBG) selectively accumulates in (proto-oncogene) chromaffin tissues but does so more rapidly in pheochromocy- Von Hippel–Lindau VHL tomas than in normal adrenal medullary tissue. Multi-institution- (tumor suppressor 3p25 15%–20% syndrome al experience with 131I-MIBG imaging for pheochromocytomas gene) has found this modality to have an overall sensitivity of 77% to Neurofibromatosis NF1 17q11 1%–5% 87% and a specificity of 96% to 100%.35 A second iodine isotope (iodine-123) is now available for use in this setting, and there are Familial paragan- SDHD† 11q23 - glioma and some suggestions that 123I-MIBG scintigraphy may have more extra-adrenal SDHB† 1p35-36 - favorable imaging characteristics than 131I-MIBG scintigraphy pheochromocytoma does. I-MIBG scintigraphy is most useful for localizing extra- SDHC† 1q21 - adrenal tumors that are not visualized by conventional imaging *Clinical incidence of tumors within persons affected by the mutation. modalities and for following patients with malignant pheochromo- †SDHD, SDHB, and SDHC designate specific mutations within the succinate dehydroge- cytomas. Its main disadvantages are its greater complexity and cost nase gene (SDH). Patients with SDHD mutations are more likely to have head and neck (in comparison with other imaging techniques), the need to block paragangliomas, whereas SDHB mutations are more likely to be associated with extra- thyroid uptake with oral iodine, and the fact that some medica- adrenal pheos and malignant tumors. tions interfere with pharmacologic uptake of the tracer. suggest the need for careful screening for a familial disorder in this Pharmacologic Preparation for Operation setting. Once the diagnosis of pheochromocytoma has been established biochemically and radiographically, the next step is to prepare the Management patient for adrenalectomy pharmacologically so as to prevent an Patients undergoing adrenalectomy for pheochromocytoma intraoperative hypertensive crisis. Preoperative alpha blockade should be monitored intraoperatively via an arterial line. Although with phenoxybenzamine is initiated, usually starting at a dosage of pheochromocytomas are highly vascular, and the larger ones can 10 mg twice daily, which is then gradually increased to a total of be quite challenging to remove, a laparoscopic approach is feasible 60 to 90 mg/day in divided doses until hypertension is controlled in most cases. Any intraoperative exacerbation of hypertension and the patient is mildly orthostatic. As alpha blockade progress- may be managed with esmolol or nitroprusside. es, fluids should be administered liberally to fill the expanded After resection, patients who have significant cardiac disease or intravascular space. If the patient has marked tachycardia or dys- who exhibited significant hemodynamic changes during the oper- rhythmia, beta blockade with atenolol or metoprolol may also be ation should be observed in the intensive care unit overnight. required. Beta blockade should never be initiated until alpha Glucose levels should be monitored; catecholamine-induced sup- blockade has first been achieved, because unopposed alpha-recep- pression of insulin secretion often leads to rebound hyperinsuline- tor stimulation can induce a hypertensive crisis. mia and thence to hypoglycemia. Most patients can be discharged within 24 to 28 hours after adrenalectomy. Periodic follow-up bio- Associated Inherited Syndromes chemical testing is indicated because of the potential for recur- Pheochromocytomas may occur in the setting of a number of rence after resection of even benign-appearing tumors. different inherited endocrine tumor syndromes [see Table 6]. Of these, the ones most commonly associated with pheochromocy- toma are von Hippel–Lindau (VHL) syndrome and the MEN Adrenal Incidentaloma type 2 syndromes. In addition to pheochromocytoma, VHL syn- Today, the incidentally discovered adrenal mass is by far the drome is characterized by bilateral renal tumors and cysts, cere- most commonly encountered adrenal lesion, primarily because of bellar and spinal hemangioblastomas, retinal angiomas, pancreat- the frequency with which patients currently undergo cross-sec- ic cysts and tumors, epididymal cystadenomas, and inner ear canal tional imaging.41 Various series have reported finding adrenal inci- tumors.36 MEN 2A and 2B are associated with medullary thyroid dentalomas in 1% to 5% of patients who undergo CT scanning for carcinoma in 100% of cases. The incidence of pheochromocy- other reasons.42 tomas in MEN 2A and 2B patients ranges from 30% to 50%. CLINICAL EVALUATION MEN type 2 arises from mutations in the ret proto-oncogene on chromosome 10. Specific ret mutations associated with pheochro- Most adrenal incidentalomas are clinically silent, do not secrete mocytoma occur predominantly on codons 618 and 634. In addi- excess adrenal hormones, and do not cause pain. The differential tion, familial paragangliomas of the neck are now known to be diagnosis of an adrenal incidentaloma includes all of the function- associated with mutations in the succinate dehydrogenase subunit ing adrenal tumors, primary or metastatic adrenal malignancy, and B (SDHB) and succinate dehydrogenase subunit D (SDHD) various nonfunctioning lesions. Nonfunctioning cortical adenoma genes,37,38 which encode mitochondrial enzymes involved in oxida- is the most common adrenal incidentaloma, accounting for tive phosphorylation.39 approximately 60% of cases.43 Other miscellaneous adrenal lesions Familial pheochromocytoma may be more common than was that are sometimes seen in this setting are myelolipomas and cysts. previously thought. A 2002 study found mutations in 24% of Of the hyperfunctioning tumors, cortisol-producing adenomas patients who presented without a known familial pheochromocy- (most of which are subclinical in behavior) and pheochromocy- toma association: 30 had mutations of the VHL gene, 13 of ret, 11 tomas are the most frequently identified. Some adrenal inciden- of the SDHD gene, and 12 of the SDHB gene.40 These findings talomas are bilateral; in such cases, the differential diagnosis
  8. 8. © 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 38 Disorders of the Adrenal Glands — 8 includes adrenal cortical hyperplasia, bilateral pheochromocy- tomas, metastases, lymphoma, myelolipomas, and infection Adrenal mass is incidentally discovered on diagnostic imaging (tuberculosis). Carry out biochemical evaluation: INVESTIGATIVE STUDIES • Measure plasma concentrations of Evaluation of the patient with an adrenal incidentaloma should fractionated metanephrines or urinary levels be directed toward determining whether the lesion is hypersecre- of catecholamines and metanephrines. tory and assessing the likelihood of malignancy [see Figure 5]. • Perform dexamethasone suppression test. • If the patient is hypotensive or hypokalemic, Laboratory Tests measure plasma concentrations of aldosterone and renin. For all patients with adrenal incidentalomas, biochemical screening should include, at a minimum, an overnight dexa- methasone test to exclude hypercortisolism and measurement of the concentrations of either plasma metanephrines or urinary Carry out radiographic assessment, reviewing catecholamines and metabolites to test for pheochromocytoma. images for lesion size, attenuation, and homogeneity. If CT cannot determine the nature and characteristics Although aldosteronomas, being relatively small, do not often of the lesion, perform MRI. present as incidentalomas, measurement of plasma aldosterone and renin levels is nonetheless indicated for hypertensive or hypokalemic patients with an incidentally discovered adrenal mass. Approximately 8% of patients with adrenal incidentalomas have subclinical Cushing syndrome.44 In these patients, there is Lesion is nonfunctioning, Lesion is Lesion is > 4–5 cm biochemical evidence of some degree of nonsuppressibility of < 4 cm, and benign functioning or has atypical cortisol secretion (e.g., failure to suppres cortisol secretion with appearing appearance dexamethasone, a low plasma ACTH level, or both), but the clas- sic features of Cushing syndrome are absent.44 Adrenalectomy is Observe patient. appropriate if the operative risk is acceptable. In view of the pos- Repeat imaging at 4 and 12 mo. Repeat biochemical sibility that the function of the contralateral gland may be sup- evaluation at 12 mo. Perform adrenalectomy. pressed, supplemental corticosteroids should be given after oper- ation to prevent postoperative adrenal insufficiency. Figure 5 Algorithm illustrates diagnostic evaluation of the Imaging patient with an incidentally discovered adrenal mass. The second component of the evaluation of an adrenal inci- dentaloma is assessment of the imaging features. Size is the vari- adrenal lesion with a high lipid content (e.g., an adrenal adenoma) able that should be addressed first; a lesion smaller than 4 cm in a is imaged with MR chemical-shift imaging, the mass will be visi- patient without a known malignancy is very unlikely to be malig- ble on in-phase images but will lose signal intensity on opposed- nant. The shape and visual texture of the lesion should then be phase images (because the water signal and the fat signal will tend considered. Benign lesions tend to be smooth and homogeneous, to cancel each other out). In contrast, if an adrenal lesion with a whereas malignant lesions often have irregular contours and areas low lipid content (e.g., an adrenal malignancy or a pheochromo- of inhomogeneity. Cortical adenomas are further characterized by the presence of intracellular lipid, which on noncontrast CT scan- ning gives the mass an appearance that is homogeneous and low in attenuation (< 10 Hounsfield units, which is less than the liver or the kidney but higher than retroperitoneal fat) [see Figure 6]. ACCAs and metastases are higher in water content and therefore have higher attenuation values (usually > 18 Hounsfield units). There may, however, be some overlap in attenuation values between adenomas and malignancies, and in any case, many patients with incidentalomas initially underwent CT scanning with I.V. contrast which makes subsequent assessment of attenu- ation values problematic. Pheochromocytomas, because of their vascularity, show prominent enhancement on I.V. contrast studies and may have areas of cystic degeneration. On unenhanced scans, their density is similar to that of the liver. In cases where the nature of the lesion cannot be determined on the basis of CT scanning, MRI can provide additional characteri- zation of the lesion that may help direct management. For exam- ple, on T2-weighted sequences, adenomas typically exhibit low sig- nal activity, whereas pheochromocytomas and metastases appear bright. Magnetic resonance (MR) chemical-shift imaging may also have significant diagnostic value. This modality is based on the different resonance frequencies of the protons in water and those in fat. Depending on the imaging parameters, the water and Figure 6 CT scan shows a nonfunctioning cortical adenoma lipid magnetic dipoles will be either in phase or out of phase. If an (arrow).
  9. 9. © 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 38 Disorders of the Adrenal Glands — 9 a b Figure 7 Shown are (a) CT and (b) PET images of a metastasis to the left adrenal gland. cytoma) is imaged with this technique, the mass will not show a also involve the adrenal. Occasionally, the adrenal gland is the site significant loss of signal intensity on opposed-phase images of an apparent solitary metastasis for which resection is indicated. (because there will not be sufficient fat protons to cancel out the Imaging characteristics associated with adrenal metastases include water signal). Some reports have found the loss of signal on MR larger size (> 3 cm), higher attenuation on CT, and no signal loss chemical-shift imaging to be highly predictive of an adenoma.45 on MR chemical-shift imaging. PET is often indicated to exclude Although positron emission tomography (PET) is increasingly extra-adrenal metastatic disease that would preclude resection [see employed for evaluation of adrenal incidentalomas, its role in this Figure 7]. Biopsy of a suspected adrenal metastasis should be car- setting remains to be determined. The main value of PET with ried out only if a tissue diagnosis is needed to direct therapy—that respect to adrenal disease is to identify extra-adrenal tumor sites in is, if the patient is not a surgical candidate either for medical rea- patients with a known cancer. sons or because of metastases at other sites. Biopsy is not indicat- ed before resection of a solitary resectable lesion, because it could Biopsy lead to tumor seeding or other complications. Reported 5-year Needle biopsy of adrenal masses is rarely indicated. It does not actuarial survival rates after resection of an isolated adrenal metas- often yield diagnostic information, it cannot differentiate benign tasis range from 24% to 29%.47 from malignant adrenal cortical tumors, and it is associated with a not insignificant risk of complications. Moreover, if the lesion is an Miscellaneous Adrenal Lesions undiagnosed pheochromocytoma, needle biopsy may lead to hyper- tensive crisis and sudden death. Despite these known drawbacks, in The adrenal disorders previously described (see above) are the three series from the past few years, a number of patients with undi- ones most frequently seen and managed by surgeons; however, agnosed pheochromocytomas presenting as incidentalomas under- went adrenal biopsy before any biochemical testing.26,27,46 MANAGEMENT Most adrenal surgeons recommend removing nonfunctioning adrenal masses larger than 5 cm and observing masses smaller than 3 cm unless they are obvious myelolipomas or cysts [see Miscellaneous Adrenal Lesions, below]. Management of masses 4 to 5 cm in size should be individualized, with adrenalectomy favored if the patient is young or if the imaging features are at all atypical for an adenoma. Patients for whom resection is not appro- priate should be followed with repeat imaging at 4 months and with both repeat imaging and biochemical testing at 1 year. If the lesion is nonfunctioning and stable in size throughout the follow- up period, no further monitoring is required. Adrenal Metastases Adrenal metastases occur most commonly in the setting of more widespread metastatic disease. Renal cell cancer, lung can- cer, and melanoma are the malignancies that most frequently metastasize to the adrenal gland, but various other tumors (e.g., Figure 8 Shown is a myelolipoma of the right adrenal gland. The breast cancers, colon and other GI cancers, and lymphomas) may areas of macroscopic fat (arrows) are typical for this lesion.
  10. 10. © 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 38 Disorders of the Adrenal Glands — 10 Indications for Adrenalectomy there are a number of other adrenal lesions that surgeons may also encounter, such as myelolipomas, ganglioneuromas, cysts, and Any adrenal lesion that is hyperfunctioning or that is suspected hemorrhage. of being malignant or possibly malignant on the basis of size or Myelolipomas are benign lesions that are composed of fat and other imaging criteria should be removed. Adrenal metastases bone marrow elements and are usually identified as incidentalo- should be resected only if they are solitary and appear in the mas. In most instances, they can be diagnosed radiographically absence of extra-adrenal metastatic disease. Most of the adrenal on the basis of macroscopic fat that is present within the mass disorders discussed in this chapter are amenable to laparoscopic [see Figure 8]. Myelolipomas may become quite large (> 6 cm), resection. At present, the only absolute contraindication to laparo- but regardless of their size, they should not be removed unless scopic adrenalectomy is a tumor with local or regional extension. they are causing symptoms. Ganglioneuromas are benign There remains some controversy surrounding laparoscopic tumors that may arise either within the adrenal medulla or at an removal of large (> 6 to 8 cm) or potentially malignant primary extra-adrenal site. Most adrenal cysts are lymphangiomatous adrenal lesions; this issue is beyond the scope of the present dis- cysts, but pseudocysts from previous hemorrhage may also cussion but has been reviewed in greater detail elsewhere [see 5:26 develop.48 Adrenalectomy].49 Surgeons who attempt laparoscopic adrenalecto- Hemorrhage in the adrenal gland is most often the consequence my in this setting should be highly experienced with the procedure. either of trauma or of an underlying adrenal tumor. Accordingly, Preparation for adrenalectomy consists of control of hypertension, follow-up imaging should be performed to search for an adrenal correction of underlying electrolyte abnormalities, and manage- mass that may be obscured by the bleeding. ment of comorbid conditions (to the extent possible). Discussion Adrenal Physiology ferent conditions may result in increased adrenal androgen pro- The anatomy of the adrenal is described in greater detail else- duction, including Cushing syndrome, adrenal carcinoma, and where [see 5:26 Adrenalectomy]. Accordingly, the ensuing discussion congenital adrenal hyperplasia. In normal males, adrenal andro- focuses on adrenal physiology—specifically, on the secretion of gens account for less than 5% of total testosterone production, but steroid hormones and catecholamines. in normal females, they are the major source of androgens. The adrenal cortex is the site where cortisol, aldosterone, and The principal action of aldosterone is regulation of extracellu- androgens are synthesized.These steroid hormones are all derived lar fluid volume and sodium and potassium balance. Aldosterone from cholesterol, which is converted to pregnenelone under the is secreted in response to increased renin production via the influence of ACTH. There are three histologic zones within the renin-angiotensin-aldosterone pathway. Decreased pressure in adrenal cortex: the zona glomerulosa, the zona fasciculata, and the the renal afferent arterioles (as a consequence of hypotension or zona reticularis. The zona glomerulosa lacks the enzyme 17α- other conditions causing reduced intravascular volume) and hydroxylase, which is necessary for synthesis of cortisol and andro- decreased plasma sodium levels stimulate increased renin secre- gens; consequently, it is the exclusive site for the synthesis of aldos- tion from the juxtaglomerular cells. Renin then stimulates con- terone. Cortisol secretion is regulated by the hypothalamus, which version of angiotensinogen into angiotensin I, which is in turn secretes CRH, and the pituitary, which secretes ACTH. ACTH cleaved by angiotensin-converting enzyme (ACE) in the lung to stimulates cortisol synthesis and secretion from the adrenal gland, form angiotensin II. Angiotensin II, in addition to its direct vaso- and high circulating cortisol levels inhibit pituitary and hypothala- constrictive effects, acts on the zona glomerulosa to stimulate mic secretion of ACTH and CRH. Cortisol exerts its effects on aldosterone secretion. Aldosterone then stimulates renal tubular intermediary metabolism via a wide range of cells and tissues. retention of sodium, which is reabsorbed in exchange for potas- These effects include stimulation of hepatic gluconeogenesis and sium and hydrogen ion. The ultimate effect of these actions is to glycogen synthesis, inhibition of protein synthesis, increased pro- expand intravascular volume. In pathologic states such as prima- tein catabolism, and lipolysis of fat. Cortisol also inhibits peripher- ry hyperaldosteronism, the cumulative effect is chronic volume al uptake of glucose in most tissues (except in the liver, the brain, expansion and sodium retention, leading to hypertension and and red blood cells), and this inhibitory effect may cause hyper- hypokalemia. glycemia and increased insulin secretion, especially in states of The adrenal medulla is derived embryologically from the neur- chronic cortisol excess.50 Other effects of glucocorticoids include al crest and is the principal site for synthesis of the catecholamines promotion of collagen loss and impairment of wound healing by epinephrine and norepinephrine. Only the adrenal medulla has the inhibition of fibroblast activity, inhibition of bone formation and enzyme phenylethanolamine-N-methyltransferase, which is neces- acceleration of the development of osteoporosis, and numerous sary for conversion of norepinephrine to epinephrine; however, anti-inflammatory actions. Glucocorticoids are also critical for car- norepinephrine itself may be synthesized in other chromaffin tis- diovascular stability, which helps explain why some patients with sues. Catecholamines are secreted in response to a variety of stim- acute adrenal insufficiency experience cardiovascular collapse. uli, including bleeding, trauma, exercise, hypoglycemia, angina, Adrenal androgens are synthesized predominately in the zona myocardial infarction, hypoxia, and fright.The effects of increased reticularis. The primary androgen produced by the adrenal is catecholamine secretion include vasoconstriction (alpha receptor) DHEA, though DHEA sulfate and androstenedione also play and increased heart rate and myocardial contractility (beta1 recep- important roles. Peripherally, the adrenal androgens undergo con- tor). The effects of epinephrine include vasodilatation and version to testosterone and dihydrotestosterone. A number of dif- bronchial dilatation, which are mediated via beta2 receptors.
  11. 11. © 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 GASTROINTESTINAL TRACT AND ABDOMEN 38 Disorders of the Adrenal Glands — 11 References 1. Young WF Jr: Primary aldosteronism: a common Endocrine Surgeons study group. World J Surg Kebebew E, Eds. Elsevier Saunders, Philadelphia, and curable form of hypertension. Cardiol Rev 25:891, 2001 2005, p 621 7:207, 1999 19. Allolio B, Fassnacht M: Adrenocortical carcino- 35. Velchik MG, Alavi A, Kressel HY: Localization of 2. Mulatero P, Stowasser M, Loh K-C, et al: ma: clinical update. J Clin Endocrinol Metab pheochromocytoma: MIBG, CT and MRI corre- Increased diagnosis of primary aldosteronism, 91:2027, 2006 lation. J Nucl Med 30:328, 1989 including surgically correctable forms, in centers 20. Abraham J, Bakke S, Rutt A, et al: A phase II trial 36. Linehan WM, Lerman MI, Zbar B: Identification from five continents. J Clin Endocrinol Metab of combination chemotherapy and surgical resec- of the von Hippel-Lindau (VHL) gene: its role in 89:1045, 2004 tion for the treatment of metastatic adrenocortical renal cancer. JAMA 273:564, 1995 3. Obara T, Ito Y, Iihara M: Hyperaldosteronism. carcinoma: continuous infusion doxorubicin, vin- 37. Neumann HP, Pawlu C, Peczowska M, et al: Textbook of Endocrine Surgery. Clark OH, Duh cristine, and etoposide with daily mitotane as a P- Distinct clinical features of paraganglioma syn- Q-Y, Kebebew E, Eds. Elsevier Saunders, glycoprotein antagonist. Cancer 94:2333, 2002 dromes associated with SDHB and SDHD gene Philadelphia, 2005, p 595 mutations. JAMA 292:943, 2004 21. Salvatori R: Adrenal insufficiency. JAMA 294: 4. Young WF, Stanson AW,Thompson GB, et al: Role 2481, 2005 38. Benn DE, Gimenez-Roqueplo A-P, Reilly JR, et al: for adrenal venous sampling in primary aldosteron- Clincial presentation and penetrance of pheochro- 22. Krasner AS: Glucocorticoid-induced adrenal ism. Surgery 136:1227, 2004 mocytoma/paraganglioma syndromes. J Clin insufficiency. JAMA 282:671, 1999 5. Sawka AM, Young WF, Thompson GB, et al: Endocrinol Metab 91:827, 2006 23. Glowniak JV, Loriaux DL: A double-blind study of Primary aldosteronism: factors associated with 39. Baysal BE, Ferrell RE, Willett-Brozick JE, et al: perioperative steroid requirements in secondary normalization of blood pressure after surgery. Ann Mutations in SDHD, a mitochondrial complex II adrenal insufficiency. Surgery 121:123, 1997 Intern Med 135:258, 2001 gene, in hereditary paraganglioma. Science 287: 24. Bravo EL, Tagle R: Pheochromocytoma: state-of- 6. Lo CY, Tam PC, Kung AW, et al: Primary aldo- 848, 2000 the-art and future prospects. Endocr Rev 24:539, steronism: results of surgical treatment. Ann Surg 40. Neumann HP, Bausch B, McWhinney SR, et al: 2003 224:125, 1996 Germ-line mutations in nonsyndromic pheochro- 25. Kudva YC, Young WF Jr, Thompson GB, et al: 7. Proye CAG, Mulliez, EA, Carnaille, BM, et al: mocytoma. N Engl J Med 346:1459, 2002 Adrenal incidentaloma: an important component Essential hypertension: first reason for persistent 41. Young WF Jr: The incidentally discovered adrenal of the clinical presentation spectrum of benign hypertension after unilateral adrenalectomy for mass. N Engl J Med 356:601, 2007 sporadic adrenal pheochromocytoma. Endocrino- primary aldosteronism? Surgery 124:1128, 1998 logist 9:77, 1999 42. Brunt LM, Moley JF: Adrenal incidentaloma. 8. Blumenfeld JD, Sealey JE, Schlussel Y, et al: World J Surg 25:905, 2001 26. Cheah WK, Clark OH, Horn JK, et al: Laparo- Diagnosis and treatment of primary hyperaldo- scopic adrenalectomy for pheochromocytoma. 43. Brunt LM, Moley JF: The pituitary and adrenal steronism. Ann Intern Med 121:877, 1994 World J Surg 26:1048, 2002 glands. Sabiston Textbook of Surgery: The 9. Auchus RJ: Aldo is back: recent advances and Biologic Basis of Modern Surgical Practice, 17th 27. Kercher KW, Novitsky YW, Park A, et al: unresolved controversies in hyperaldosteronism. ed.Townsend CM, Beauchamp RD, Evers BM, et Laparoscopic curative resection of pheochromocy- Curr Opin Nephrol Hyperten 12:153, 2003 al, Eds. Elsevier Saunders, Philadelphia, 2004, p tomas. Ann Surg 241:919, 2005 10. Orth DN: Cushing’s syndrome. N Engl J Med 1023 332:791, 1995 28. Pacak K, Linehan WM, Eisenhofer G, et al: Recent advances in genetics, diagnosis, localization, and 44. Reincke M: Subclinical Cushing’s syndrome. 11. Findling JW, Raff H: Diagnosis and differential treatment of pheochromocytoma. Ann Intern Endocrinol Metab Clin N Am 29:43, 2000 diagnosis of Cushing’s syndrome. Endocrinol Med 134:315, 2001 45. Mitchell DG, Crovello M, Matteuci T, et al: Metab Clin N Am 30:729, 2001 Benign adrenocortical masses: diagnosis with 29. McCorkell SJ, Niles NL: Fine-needle aspiration of 12. Arnaldi G, Angeli A, Atkinson AB, et al: Diagnosis catecholamine-producing adrenal masses: a possi- chemical shift MR imaging. Radiology 185:345, and complications of Cushing’s syndrome: a con- bly fatal mistake. AJR Am J Roentgenol 145:113, 1992 sensus statement. J Clin Endocrinol Metab 1985 46. Quayle FJ, Spitler JA, Pierce RA, et al: Needle 88:5593, 2003 biopsy of incidentally discovered adrenal masses is 30. Casola G, Nicolet V, van Sonnenberg E, et al: 13. Papanicolaou DA, Mullen N, Kyrou I, et al: Unsuspected pheochromocytoma: risk of blood- rarely informative and potentially hazardous. Nightime salivary cortisol: a useful test for the pressure alterations during percutaneous adrenal Surgery 2007 diagnosis of Cushing’s syndrome. J Clin biopsy. Radiology 159:733, 1986 47. Sarela A, Murphy I, Coit DG, et al: Metastasis to Endocrinol Metab 87:4515, 2002 the adrenal gland: the emerging role of laparo- 31. Eisenhofer G, Lenders JW, Linehan WM, et al: 14. Findling JW, Doppman JL: Biochemical and radio- Plasma normetanephrine and metanephrine for scopic surgery. Ann Surg Oncol 10:1191, 2003 logic diagnosis of Cushing’s syndrome. Endocrinol detecting pheochromocytoma in von Hippel- 48. Schultz CL, Martino CR, Kaufman B: Radiologic Metab Clin North Am 23:511, 1994 Lindau disease and multiple endocrine neoplasia techniques in evaluating endocrine disorders: the 15. Invitti C, Giraldi FP, Cavagnini F: Inferior petros- type 2. N Engl J Med 340:1872, 1999 pituitary and adrenal glands. Diagnosis and al sinus sampling in patients with Cushing’s syn- 32. Sawka AM, Jaeschke R, Singh RJ, et al: A compar- Pathology of Endocrine Diseases. Mendelsohn G, drome and contradicting response to dynamic ison of biochemical tests for pheochromocytoma: Ed. JB Lippincott, Inc, Philadelphia, 1988, p 547 testing. Clin Endocrinol 51:255, 1999 Measurement of fractionated plasma metaneph- 49. Brunt LM: Minimal access adrenal surgery. Surg 16. Dackiw AP, Lee JE, Gagel RF, et al: Adrenal corti- rines compared with the combination of 24-hour Endosc 20:351, 2006 cal carcinoma. World J Surg 25:914, 2001 urinary metanephrines and catecholamines. J Clin 50. Brunt LM, Halverson JD: The endocrine system. 17. Harrison LE, Gaudin PB, Brennan MF: Endocrinol Metab 88:553, 2003 The Physiologic Basis of Surgery. O’Leary JP, Ed. Pathologic features of prognostic significance for 33. Ilias I, Pacak K: Current approaches and recom- Lippincott Williams & Wilkins, Philadelphia, 2002, adrenocortical carcinoma after curative resection. mended algorithm for the diagnostic localization p 351 Arch Surg 134:181, 1999 of pheochromocytoma. J Clin Endocrinol Metab 51. World Health Organization Classification of 18. Icard P, Goudet P, Charpenay C, et al: Adrenocor- 89:479, 2004 Tumours: Pathology and Genetics of Tumours of tical carcinomas: surgical trends and results of a 34. Grant CS: Pheochromocytoma. Textbook of Endocrine Organs. DeLellis RA, Lloyd RV, Heitz 253-patient series from the French Association of Endocrine Surgery. Clark OH, Duh Q-Y, PU, et al, Eds. IARC Press, Lyon, 2004, p 139