ELSEVIER SAUNDERS
Diseases of the adrenal gland
E. Darracott Vaughan Jr, MD
Department of Urology, Weill Medical College of Cornell University, New York-Presbyterian Hospital, 525 East 68th Street, New York, NY 10021, USA
Currently, the diagnosis of adrenal disorders is extremely accurate using the combination of precise analytical methods for the measurement of the abnormal secretion of adrenal hormones and sophisticated radiographic techniques for the localization and characterization of specific adrenal lesions [1,2]. In addition, before the use of these sophisticated techniques usually a careful history and physical examination reveal clues of under- lying adrenal disease. Unfortunately, the diseases to be discussed (primary hyperaldosteronism, Cushing’s syndrome, adrenal carcinoma, and pheo- chromocytoma) are all rare and often not initially considered. The busy practicing physician may not associate polyuria and muscle weakness with primary aldosteronism, hypertension and headaches with pheochromocy- toma, or obesity with Cushing’s syndrome. Obviously, if not considered, the diagnosis is missed.
The diagnosis and management of patients with adrenal tumors requires a clear understanding of the normal physiology of the adrenal, medulla, and cortex; a three-dimensional concept of the adrenal anatomy and adjacent structures; and the knowledge of the various pathologic entities that may involve the adrenal. The internist must recognize the critical symptoms and signs coupled with a clear knowledge of the appropriate screening tests, which identify the various entities. The operating surgeon must be well aware of the nuances involved in the diagnosis of the different adrenal entities, be aware of potential intraoperative phenomena that are unique to these patients, and be alert to specific postoperative complications [3] that may occur.
This article emphasizes the diagnostic aspects of these diseases with emphasis on pitfalls that may occur during this process (Box 1). The reader is referred to more thorough surgically oriented texts for technical details [1,4].
Box 1. Pitfalls in the diagnosis of surgical adrenal disorders
Primary aldosteronism
Challenge with sodium loading (10 g/d) before measuring plasma potassium (K+)
Repletion of K+ to normalize plasma K+ before measuring plasma or urinary aldosterone
Complete reliance on a postural aldosterone stimulation test (70% accuracy)
Failure to measure cortisol during adrenal vein sampling of aldosterone to validate correct positioning
Failure to recognize bilateral adrenal hyperplasia Adrenal hemorrhage during adrenal vein sampling
Cushing’s syndrome resulting from adrenal adenoma or carcinoma
Failure to identify the use of exogenous steroids causing Cushing’s syndrome
Inadequate physical examination essential for the diagnosis Knowledge that alcoholism and depression can mildly elevate plasma cortisol (pseudo Cushing’s syndrome)
Inability to diagnose pituitary Cushing’s syndrome by finding elevated plasma adrenocorticotropic hormone
Adrenal carcinoma Evaluation for metastatic disease
Incidentaloma
Metabolic evaluation to identify functional lesions
MRI to determine tissue composition Pheochromocytoma
Careful evaluation to reveal multiple lesions
Measurement of urinary catecholes and metabolites even if plasma catecholes are normal
Evaluation for other components when multiple endocrine abnormality syndromes are suspected
History and physical examination
There are few entities where a careful history and physical are more revealing than in patients with adrenal disorders. These signs and symptoms require a clear understanding of the physiologic actions of the specific hormones involved. For example, the underlying abnormality in Conn’s syndrome is oversecretion of the mineralocorticoid aldosterone. The retention of sodium leads to mild, volume-dependent hypertension without
edema or eyeground changes and the hypokalemia leads to muscle weakness and polyuria. A subtler historical hint is that the patient notes a diminution of symptoms on self-induced sodium restriction. The physical examination does not usually differentiate the patient from one with essential hyper- tension unless the patient is severely hypokalemic.
The most common clinical findings in patients with Cushing’s syndrome are shown in Table 1. Patients with adrenal carcinoma more often show evidence of androgen excess with hirsutism, male pattern baldness, or clitoral hypertrophy, although these changes are often absent. Old photo- graphs are useful in showing the progression of changes especially the development of moon facies, truncal obesity, and hirsutism.
The findings in patients with pheochromocytoma are multiple (Table 2). Obviously the family history is also important especially in children and those with other tumors suggesting the multiple endocrine adenopathy syndromes.
Screening tests
Fortunately, accurate screening tests are readily available for office and outpatient use that identify these entities with a high degree of sensitivity and specificity (Box 2). These plasma and urine tests if positive lead to further evaluation, which is discussed by specific entity [4].
| Manifestation | All (%) | Disease (%) | Adenoma/ carcinoma (%) |
|---|---|---|---|
| Obesity | 90 | 91 | 93 |
| Hypertension | 80 | 63 | 93 |
| Diabetes | 80 | 32 | 79 |
| Centripetal obesity | 80 | — | — |
| Weakness | 80 | 25 | 82 |
| Muscle atrophy | 70 | 34 | — |
| Hirsutism | 70 | 59 | 79 |
| Menstrual abnormalities/ sexual dysfunction | 70 | 46 | 75 |
| Purple striae | 70 | 46 | 36 |
| Moon facies | 60 | — | — |
| Osteoporosis | 50 | 29 | 54 |
| Early bruising | 50 | 54 | 57 |
| Acne or pigmentation | 50 | 32 | — |
| Mental changes | 50 | 47 | 57 |
| Edema | 50 | 15 | — |
| Headache | 40 | 21 | 46 |
| Poor healing | 40 | — | — |
From Scott HW Jr, editor. Surgery of the adrenal glands. Philadelphia: JB Lippincott; 1990; with permission.
| Symptoms | Percent paroxysmal (%) (37 Patients) | Percent persistent (%) (39 patients) |
|---|---|---|
| Symptoms presumably owing to excessive catecholamines or hypertension | ||
| Headache (severe) | 92 | 72 |
| Excessive sweating (generalized) | 65 | 69 |
| Palpitations ± tachycardia | 73 | 51 |
| Anxiety or nervousness (± fear of impending death, panic) | 60 | 28 |
| Tremulousness | 51 | 26 |
| Pain in chest, abdomen (usually epigastric), | 48 | 28 |
| lumbar regions, lower abdomen, or groin | ||
| Nausea ± vomiting | 43 | 26 |
| Weakness, fatigue, prostration | 38 | 15 |
| Weight loss (severe) | 14 | 15 |
| Dyspnea | 11 | 18 |
| Warmth ± heat intolerance | 13 | 15 |
| Visual disturbances | 3 | 21 |
| Dizziness or faintness | 11 | 3 |
| Constipation | 0 | 13 |
| Paresthesia or pain in arms | 11 | 0 |
| Bradycardia (noted by patient) | 8 | 3 |
| Grand mal | 5 | 3 |
Manifestations caused by complications
Congestive heart failure ± cardiomyopathy
Myocardial infarction
Cerebrovascular accident
Ischemic enterocolitis ± megacolon
Azotemia
Dissecting aneurysm
Encephalopathy Shock
Hemorrhagic necrosis in a pheochromocytoma Manifestations caused by coexisting diseases
or syndromes
Cholelithiasis
Medullary thyroid carcinoma ± effects of secretions of serotonin, calcitonin, prostaglandin, or corticotrophin-like substance
Hyperparathyroidism
Mucocutaneous neuromas with characteristic facies
Thickened corneal nerves (seen only with slit lamp) Marfanoid habitus
Alimentary tract ganglioneuromatosis
Neurofibromatosis and its complications
Cushing’s syndrome (rare)
| Symptoms | Percent paroxysmal (%) | Percent persistent (%) |
|---|---|---|
| (37 Patients) | (39 patients) |
Hippel-Lindau disease (rare) Virilism, Addison’s disease, acromegaly (extremely rare)
Symptoms caused by encroachment on adjacent structures or by invasion and pressure effects of metastases
From Manger WM, Gifford RW Jr. Pheochromocytoma. In: Laragh JH, Brenner BM editors. Hypertension: pathophysiology, diagnosis, and management. New York: Raven Press; 1995. p. 2229; with permission.
Anatomy
The adrenal glands are paired retroperitoneal organs that lie within the perinephric fat, at the anterior, superior, and medial aspects of the kidneys. Their location in juxtaposition with other organs and the periadrenal fat renders them ideal for sectional imaging by CT. Thin-cut CT scanning allows precise identification of lesions as small as 0.5 cm. The CT scan remains the best imaging device for the identification of small adrenal lesions, whereas MRI gives information concerning cell type and aids in the differentiation of adenomas from medullary tumors or metastatic carcinoma [5,6]. Other advantages of MRI scanning are discussed later. The right adrenal lies above the kidney posterior and lateral to the inferior vena cava and its solitary venous drainage is by a short study vein that enters the inferior vena cava in a posterior fashion. The right adrenal gland is best removed through a posterior or modified posterior approach. The left adrenal is in more intimate contact with the kidney, overlying the upper pole of the kidney with its
Box 2. Screening tests of the adrenal gland
Primary hyperaldosteronism
Plasma K+
Plasma aldosterone
Plasma renin activity
Cushing’s syndrome
24-Hour urinary cortisol three times
Dehydroepiandrosterone or androstenedione
Pheochromocytoma
Plasma norepinephrine-epinephrine (during a hypertensive attack)
24-Hour urine norepinephrine, epinephrine, metanephrine, and vanillylmandelic acid
anterior surface and medial surface behind the pancreas and splenic artery. It is best exposed through either an abdominal or flank approach; an open thoracoabdominal approach is used if the lesion is large.
The adrenals have a delicate, rich blood supply estimated to be 6 to 7 mL/ g/min without a dominant adrenal artery. The inferior phrenic artery is the main blood supply with additional branches from the aorta and renal arteries. The small arteries penetrate the gland in a circumferential stellate fashion leaving both the anterior and posterior surfaces avascular. During adrenalectomy, an important technical goal is to divide the superior and lateral blood supply to the adrenal first, allowing the adrenal to remain attached to the kidney, which can be used to draw the adrenal gland in- feriorly and anteriorly during the resection. On the left side, the adrenal vein drains into the left renal vein; however, there is also a medially located phrenic drainage branch, which if not appropriately ligated can cause troublesome bleeding. The left adrenal vein is also a guide to the left renal artery, which often lies dorsal to the vein. One potential complication of left adrenalectomy is the 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.
Cushing’s syndrome
Cushing’s syndrome is the term used to describe the symptom complex caused by excessive circulating glucocorticoids. It must be remembered that the term is all-encompassing and includes patients with pituitary hyperse- cretion of adrenocorticotropic hormone (corticotrophin [ACTH]); Cush- ing’s disease, which accounts for 75% to 80% of patients with endogenous Cushing’s; patients with adrenal adenomas or carcinomas; and patients with ectopic secretion of ACTH or corticotrophin-releasing hormone syndrome [7].
Before assuming a patient has one of these pathologic entities there should be a thorough questioning of the patient about the use of steroid- containing preparations. At times patients are unaware that a substance they use, particularly creams or lotions, contains steroids, and if the patient is on any type of medication at all, it should be carefully reviewed for steroid content. There are few diseases in which the clinical appearance of the patient can be as useful in suspecting the diagnosis. As stated previously, old photographs are helpful in documenting recent changes in appearance that occurred. Patients with ectopic ACTH may present with manifestations of the primary tumor. It is also important to remember that some non- endocrine disorders mimic the clinical and even the biochemical manifes- tations of Cushing’s syndrome. These patients have been termed to have “pseudo” Cushing’s syndrome; this may exist in patients with major depression or in patients with chronic alcoholism [7].
There are a myriad of tests to diagnose the presence of Cushing’s syndrome and then to identify which subentity is present. Fortunately, because of the recent development of extremely accurate assays for urinary and plasma cortisol and plasma corticotrophin this task has become much easier. The approach that has been reported by Orth [7] is shown in Fig 1.
The clinical diagnosis of Cushing’s syndrome is confirmed by the demonstration of cortisol hypersecretion. At the present time the de- termination of 24-hour urinary excretion of cortisol in the urine is the most direct and reliable index of cortical secretion. Orth [7] recommends that urinary cortisol should be measure in two and preferably three consecutive 24-hour urine specimens, collected on an outpatient basis.
Once the diagnosis has been established, the next chore is to determine whether there is Cushing’s disease caused by hypersecretion of plasma
Clinical diagnosis of Cushing’s syndrome
2 or 3 24-hr urine collections for measure- ment of cortisol and creatinine
No Cushing’s syndrome
Cushing’s syndrome
Equivocal, possible pseudo- Cushing’s syndrome
Low-dose dexamethasone suppression test
Cushing’s syndrome
Possible pseudo- Cushing’s syndrome
No Cushing’s syndrome
Midnight plasma cortisol, CRH-dexamethasone, or naloxone test
Cushing’s syndrome
Major depressive disorder
2 or 3 Late-afternoon or midnight plasma corticotropin and cortisol measurements
No Cushing’s syndrome
Corticotropin-dependent Cushing’s syndrome
Corticotropin-independent Cushing’s syndrome
High-dose dexamethasone suppression test
Adrenal CT or MRI Surgery
Cushing’s disease
Cushing’s disease or ectopic corticotropin syndrome
Radionuclide imaging, CT, or MRI Metyrapone or CRH test
Cushing’s disease
Cushing’s disease or ectopic corticotropin syndrome
Operable tumor Surgery
Inferior-petrosal-sinus sampling
Cushing’s disease
Ectopic corticotropin syndrome
Pituitary CT or MRI Surgery
Abdominal CT or MRI
Surgery
ACTH from the pituitary or primary adrenal disease. Herein lays the major change in the approach to patients with Cushing’s disease. In the past, high- and low-dose dexamethasone suppression tests have been used to accom- plish this task. At present, the low-dose dexamethasone is generally used to rule out pseudo Cushing’s syndrome. The differentiation of corticotrophin- dependent Cushing’s versus corticotrophin-independent Cushing’s syn- drome is determined by the concurrent late afternoon or midnight measurement of collection of blood for the simultaneous measurement of plasma corticotrophin and cortisol. If the patient’s cortisol concentration is above 50 µg/dL and the corticotrophin concentration is below 5 pg/mL, then the cortisol secretion is ACTH independent and the patient has a primary adrenal problem. In contrast, if the plasma ACTH concentration is greater than 50 pg/mL, then the cortisol secretion is ACTH dependent and the patient has Cushing’s syndrome or ectopic ACTH or corticotrophin- releasing hormone syndrome. In situations where the two-site immunor- adiometric assay test is not available, the high-dose dexamethasone suppression test has always been used as the standard test to differentiate between pituitary and adrenal Cushing’s syndrome. Patients are given high- dose dexamethasone (2 mg every 6 hours for 2 days) and plasma cortisol and urinary free cortisol levels are measured. In patients with pituitary disease, there should be a 50% or greater suppression in cortisol. Patients with adrenal adenomas or carcinomas fail to suppress cortisol secretion. The high-dose dexamethasone suppression test may also be useful to identify ectopic ACTH syndrome, where there is usually complete resistance to high- dose dexamethasone suppression.
Treatment is obviously dependent on the underlying lesion. Patients with adrenal adenomas or carcinomas are generally treated with surgical extirpation of the lesions. Patients with Cushing’s disease have confirmation with pituitary CT or MRI and usually are treated with transsphenoidal pituitary tumor removal, and patients with ectopic ACTH have treatment directed toward the primary tumor. The surgical approach and preparation of patients with adrenal Cushing’s disease is discussed later.
If the patient is identified as having adrenal Cushing’s, the next step is radiographic localization with CT scanning [6]. Adrenal adenomas are usually larger than 2 cm, solitary, and associated with atrophy of the op- posite gland. The density is low because of the high concentration of lipid. Adrenal carcinomas are often indistinguishable from adenomas except for the larger size, carcinomas usually being greater than 6 cm [8]. Necrosis and calcification are also more common in association with adrenal carcinomas but are not specific. Clearly, large irregular adrenal lesions with invasion represent carcinoma; however, metastatic carcinoma to the adrenal has the same appearance.
MRI is not usually necessary in patients with Cushing’s syndrome unless the lesion is large; the rationale for MRI is to obtain anatomic information concerning surrounding structures or invasion of the inferior vena cava, a rare
but well-recognized entity [9]. Adrenal cortical scanning with iodinated cholesterol agents is no longer routinely used but can be helpful in differ- entiating functional adrenal tissue from other retroperitoneal lesions [6].
Incidentally discovered adrenal masses
The increased use of abdominal ultrasound and CT scanning has led to a new classification of adrenal lesions termed the “incidentally identified unsuspected adrenal mass” or “incidentaloma” [10]. The author’s approach to the incidentally identified adrenal mass is shown in Fig. 2. Several points do not warrant controversy. First, there is agreement that all patients with solid adrenal masses should undergo biochemical assessment. If biochemical abnormalities are identified, the lesions should be treated appropriately as described elsewhere in this article, usually by removal of the offending lesion. The extent of biochemical abnormalities has been reviewed and a selective approach has been outlined that markedly limits cost without sacrificing diagnostic accuracy [11]. A very limited evaluation is recom- mended including tests only to rule out pheochromocytoma, K+ levels in
Functional adrenal mass
Yes
Full evaluation
No
Remove
Determine size on CT
<5 cm
>5 cm
Solid
Cystic
Solid
MRI
? Cyst puncture
Remove
High signal T2
Low signal T2
Follow
Remove
Every 6 months: CT
Stable
Larger
Follow
Repeat functional tests
Remove
hypertensive cases, and glucocorticoid evaluation only in the presence of clinical stigmata of Cushing’s syndrome or virilization.
The second point that is noncontroversial is that nonfunctioning solid lesions larger than 5 cm should be removed. This is based on the finding that adrenal malignancies are almost always larger than 6 cm. The author believes, however, that CT scanning may underestimate the size of an adrenal and he suggests that exploration be performed when lesions are more than 5 cm on CT or MRI [12]. Furthermore, if lesions are purely cystic by CT or MRI, cyst puncture is often not necessary and these lesions can be followed. The controversy arises in the management strategy for the solid adrenal lesions smaller than 5 cm in size. The current approach has been to use MRI imaging in this situation. Most adenomas appear slightly hypointense or isointense relative to the liver or spleen on T1-weighted images and slightly hyperintense or isointense relative to hepatic or splenic parenchyma on T2-weighted images. There is little change in the intensity from T1- to T2-weighted studies. In contrast, the general notion is that adrenal cortical carcinoma is hypointense relative to liver or spleen on T1- weighted images and hyperintense to the liver or spleen on T2-weighted images. If the mean signal intensity ratio between the lesion and the spleen is over 0.8, it is unlikely that the lesion is a benign adenoma. It should be remembered, however, that there are a number of entities other than adrenal carcinoma that can cause high intensity including neural tumors, metastatic tumors to the adrenal, adrenal hemorrhage, and other retroperitoneal lesions [13]. An additional study that has shown accuracy is the fine-needle adrenal biopsy guided by ultrasound or CT. In a large series from Finland, significant cytologic material was obtained in 96.4% and the accuracy to differentiate benign from malignant disease was 85.7% [14]. The use of aspiration cytology requires an extremely experienced cytologist, however, and in fact there is often inability to distinguish an adrenal adenoma from a carcinoma even on pathologic review of the entire specimen.
It is the author’s general approach that if there is either any radiographic evidence that argues against a characteristic benign adenoma or any change in size of an adrenal lesion with repeated studies then an adrenalectomy is indicated. This fairly aggressive approach is justified in view of the extremely poor prognosis of patients when adrenal carcinoma is diagnosed even when the lesion is localized.
Adrenal carcinoma
Adrenal carcinoma is a rare disease with a poor prognosis. The incidence is estimated as 1 case per 1.7 million, accounting for only 0.02% of cancers. A practical subclassification for adrenal carcinomas is according to their ability to produce adrenal hormones. In a series by Luton et al [15], 79% of adrenal tumors were functional, a higher percentage than previously reported because of more sensitive assays. The varieties of functioning
tumors are shown in Box 3. This classification is somewhat contrived, however, because many of these tumors produce multiple adrenal hormones and also because of the clear evidence that a tumor may secrete one hormone at one point in its natural history and additional hormones at a later phase when there is increased tumor mass. The most commonly identified functional tumor is one causing Cushing’s syndrome. The most common characteristic to delineate Cushing’s syndrome caused by carci- noma rather than adenoma has been the presence of virilization with elevated 17-ketosteroid levels. More recently the measurement of dehydroepiandros- terone has been useful in identifying these patients.
Other rare functional tumors include both testosterone- and estrogen- secreting adrenal cortical tumors. Rarely, virilization can occur in the absence of elevated urinary 17-ketosteroids and raises the possibility of pure testosterone-secreting ovarian or adrenal lesions [16]. Of the two sites of origin, adrenal cortical tumors secreting testosterone are exceedingly rare. In contrast to other tumors described in this section, these tumors are usually small, less than 6 cm in size, and many behave in a benign fashion. In contrast, most feminizing tumors occur in men 25 to 50 years of age, and they are usually larger, often palpable, and highly malignant [17]. Characteristically, the patients present with gynecomastia; in addition, they may exhibit testicular atrophy, impotence, or decreased libido. The author has also seen a presentation with infertility and oligospermia. These tumors secrete androstenedione, which is converted peripherally to estrogen. Other steroids may also be secreted and the clinical picture may be mixed with associated cushingoid features.
The management of adrenal cortical carcinoma is surgical removal of the primary tumor. The most common sites of metastasis include lung, liver, and lymph nodes [18]. Often these tumors extend directly into adjacent structures, especially the kidney, and surgical removal may require removal of the primary tumor and adjacent organs including the kidney, spleen, and
Box 3. Classification of adrenal carcinoma
Functional Cushing’s syndrome Virilization in females Increased dehydroepiandrosterone, 17-ketosteroids Increased testosterone Feminizing syndrome in males Hyperaldosteronism Mixed combination of above Nonfunctional
local lymph nodes. Unfortunately, despite en bloc resection even in patients without evidence of metastatic disease, the 5-year survival rate is only approximately 50% with complete resection and 25% overall [19]. Because of the poor prognosis there has been an intense search for effective adjunctive chemotherapy, but this search has been frustrating, and it is generally believed that conventional chemotherapy is not effective, probably because of P-glycoprotein expression [20]. The most success has been reported with the adrenolytic 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chloro- phenyl)-ethane(o,p’-DDD) or mitotane. This dichlorodiphenyltrichloro- ethane derivative has been shown to induce tumor response in 35% in a review of 551 cases reported in the literature. Despite these response rates, however, survival time has not been prolonged and there is intense toxicity. Recently, it has been suggested that patients even without the presence of metastatic disease be given adjunctive o,p’-DDD, and trials are currently in progress to determine if this approach is efficacious.
In general, there is an extremely poor prognosis in patients with adrenal cortical carcinoma and there is obvious need for the development of new treatment strategies.
Hyperaldosteronism
The term “hyperaldosteronism” originally was coined by Conn [21] to describe the clinical syndrome characterized by hypertension, hypokalemia, hypernatremia, alkalosis, and periodic paralysis caused by an aldosterone- secreting adenoma. It is now realized that this metabolic syndrome can be caused by either a solitary adrenal adenoma or by bilateral adrenal zona glomerulosa hyperplasia. One of the clinical chores is to delineate pa- tients with hyperplasia from those with adenoma [22]. The syndrome of primary hyperaldosteronism is now identified by the combined findings of hypokalemia, suppressed plasma renin activity despite sodium restriction, and a high urinary and plasma aldosterone level after sodium repletion in hypertensive patients. The current evaluation of patients suspected of having hyperaldosteronism is shown in Fig. 3. The primary physiologic control of aldosterone secretion is angiotensin II. Other control mechanisms are ACTH and K+ [23]. A clear knowledge of the physiology of the renin- angiotensin-aldosterone system is mandatory to understand the pathophys- iology and evaluate patients with primary hyperaldosteronism. The critical sensor in the renin-angiotensin-aldosterone system resides in the juxtaglo- merular apparatus within the kidney. In response to a variety of stimuli, but primarily decreased renal perfusion, or a decreased intake of sodium, there is an increased renin release, formation of angiotensin II, and subsequent aldosterone secretion. The term “secondary hyperaldosteronism” is used when there is increased renin secretion and secondary aldosterone pro- duction. The most common examples of secondary hyperaldosteronism are
Hypertension
>3.6
Serum K
≤3.6
≤1.0
PRA
>1.0
replete K and Na
1’ aldosteronism is unlikely
24-hr urine: K > 40 mEq and aldosterone > 15 µg
1’ aldosteronism is unlikely
GRA present
No
Check urine:
· Cortisol . DOC
Adrenal CT scan
Hyperplasia or normal
Equivocal
Unilateral adenoma
Postural stimulation test (+) -or- Plasma 18-OHB > 100 ng% -or- Elevated urinary 18-OHF, 18-oxo-F
No
Yes
Adrenal sampling
Not lateralized
Lateralized
Medication
Adrenalectomy
renovascular hypertension and malignant hypertension. In contrast, with an adrenal adenoma or adrenal hyperplasia there is primary secretion of aldosterone and subsequently the sodium retention that occurs leads to a suppression of plasma renin activity.
The hallmark of the entity is hypokalemia (Fig. 4). Some patients realize, however, that weakness occurs with increased sodium intake and restrict their sodium, and may have more normal K+ than that first observed. The entity should not be ruled out until the patient has sodium loading with 10 g of sodium a day for several weeks and repeat K+ measurements. A small subset of patients exhibit normokalemic hyperaldosteronism, and if there is a high index of suspicion for the disease, these patients should be studied further. If there is hypokalemia, a 24-hour urine should be collected demonstrating that there is urinary loss of K+. The critical test is the measurement plasma renin activity at a time when the patient is either on a low-sodium diet or is challenged with a diuretic. If the patient has hyperaldosteronism, the plasma renin activity remains inappropriately low
HISTORY PHYSICAL EXAM BP X3 > 140/90 BASIC LAB TESTS
SUSPECT PHEOCHROMOCYTOMA
Plasma Norepinephrine
Diagnosis Pheochromocytoma
Elevated
Epinephrine Dopamine Urinary Catechols
Normal
LOCALIZE
Evaluate for
CTT MIBG MRI
Venous Sampling
Other Causes
Ox -blockade, then Remove
despite sodium depletion. Because K+ is also a stimulus of aldosterone, the patient should be K+ repleted before measuring 24-hour urine and plasma aldosterone levels. Both of these values should be elevated in hyper- aldosteronism.
At this point the question is whether the patient has a unilateral adenoma or bilateral adrenal hyperplasia, and the imaging study of choice is an adrenal gland CT with 3- to 5-mm cuts through both adrenal glands. The next step that is traditionally performed is adrenal vein sampling. The difficulty with adrenal vein sampling is obtaining adequate collections from the short, stubby, right adrenal vein, and when samples are collected, cortisol levels should always also be collected to ensure proper catheter placement. An appropriate way of analyzing aldosterone levels is with comparative aldosterone-cortisol ratios from each side. It is the author’s general policy to have positive lateralizing information and a positive CT scan before recommending exploration and unilateral adrenalectomy. More recently, however, in patients who have elevated plasma 18-hydroxy-B levels and elevated urinary 18-hydroxy-F levels at times the author has not required sampling when a clear adenoma was demonstrated on CT scan. In contrast, the author has demonstrated a subset of patients with radiographic bilateral hyperplasia who lateralize adrenal vein sampling for aldosterone. In this setting the author has performed unilateral adrenalectomy and a significant number of those patients have favorable biochemical and blood pressure responses, although most have required the continuation of some antihypertensive medication [22].
Finally, in patients who have normal CT scans yet lateralize on sampling, if they show elevated 18-hydroxy products the author operates; if not, he
follows those patients. Most patients with bilateral hyperplasia do not lateralize with adrenal vein sampling for aldosterone. Those patients are treated with spironolactone at an appropriate dose to control blood pressure. Often they need other medications, such as calcium channel blockers.
Pheochromocytoma
Pheochromocytoma is an uncommon entity but one that has potentially lethal sequelae for the patient if not diagnosed. It is generally believed that all patients with sustained hypertension should have the appropriate studies performed to rule out pheochromocytoma (see Fig. 4) [11].
The clinical manifestations exhibited by patients with pheochromocyto- ma are caused by the physiologic effects of the catecholamines, dopamine, epinephrine, and norepinephrine. Other signs and symptom complexes exhibited may be extremely variable, however, including the asymptomatic patient in whom a lesion is picked up simply on CT scan. In all reported series hypertension is by far the most common sign [24]. As far as the type of hypertension, the patients may have either sustained hypertension, parox- ysmal or dramatic attacks of hypertension, or sustained hypertension with superimposed paroxysms. Most series have shown this latter constellation of findings to be the most common in patients with pheochromocytoma. In addition, the frequency of attacks among patients is quite variable, ranging from a few times a year to multiple daily episodes. In addition, the duration may be minutes or hours and the nature of the attacks can vary dramatically. Most patients exhibit a paroxysm or an episode once a week and most of the attacks last less than an hour. Usually the attacks occur in the absence of recognizable stimuli, but a number of factors (particularly exercise, posture, trauma, or a variety of other situations) may precipitate an attack.
One specific entity is noteworthy: catecholamine-induced myocardio- pathy [25]. These patients present with decreased cardiac function and congestive heart failure, and it is mandatory that their cardiac status be stabilized with the use of appropriate a- and ß-adrenergic blocking agents and a-methylparatyrosine (a tyrosine hydroxylase inhibitor) to cut down on catecholamine production before surgery is contemplated. Generally the cardiomyopathy is reversible, and the patients can be operated on within weeks or months after the initial diagnosis and treatment is instituted.
An appreciable number of pheochromocytomas have been found in association with other disease entities and hereditary syndromes. These entities include the association of tumors of the glomus jugulary region, neurofibromatosis, Sturge-Weber syndrome, Hippel-Lindau disease, and the familial multiendocrine adenopathy syndromes. Pheochromocytomas occur in multiendocrine adenopathy-2, a triad including pheochromocytoma, medullary carcinoma of the thyroid, and parathyroid adenomas (Sipple’s syndrome). Pheochromocytomas may also be a part of multiendocrine
adenopathy-3, which also includes medullary carcinoma of the thyroid, mucosal neuromas, thickened corneal nerves, ganglioneuromatosis, and frequently marfanoid habitus. It is now believed that the relatives of patients with all of these syndromes should be evaluated for the presence of occult pheochromocytoma. In addition, there is a well-known entity of familial pheochromocytoma whereby multiple members of the kindred are found to have multiple lesions and all members of such families should be screened and then followed for the appearance of these tumors. The mechanism of the increased incidence of pheochromocytomas in association with neu- roendocrine dysplasias and medullary carcinoma of the thyroid may be explained by the amine precursor uptake and decarboxylation cell system of Pierce. The amine precursor uptake and decarboxylation cells derive from the neural crest of the embryo, sharing common ultrastructural and cytochemical features and elaborating amines by precursor uptake and decarboxylation [24,26].
The laboratory diagnosis of pheochromocytoma is now extremely accurate, using the urinary plasma measurements of catecholamines and their by-products. Extremely accurate assays exist for these amines [4]. It is believed that urinary catecholamines remain the measurement of choice with the measurement of total urinary catecholamines and metanephrines. Approximately 95% of patients have elevated levels of these substances. In the patient with a severe paroxysmal hypertension who presents in the midst of hypertensive crisis, the plasma catecholamines are almost always elevated and can be used.
Stimulation or suppression tests are generally not used. The one situation where they may be useful is in the patient who seems to have essential hypertension but borderline elevated catecholamines, and in this setting a clonidine suppression test may be useful. Following a single 0.3-mg oral dose of clonidine the patients with neurogenic hypertension at rest show a fall in norepinephrine, whereas patients with pheochromocytomas do not [4].
The radiographic test that is most useful in both identifying and characterizing neuroendocrine adrenal tumors, and in identifying surround- ing structures, is the MRI scan. The author is impressed with the multiple uses of MRI scans in patients with pheochromocytoma. The test is as accurate as a CT scan in identifying lesions and also has a characteristic bright lightbulb appearance on the T2-weighted study [5,6]. In addition, sagittal and coronal imaging can provide excellent anatomic information concerning the relationship between the tumor and the surrounding vasculature. The author believes that the MRI should be the initial scanning procedure in patients with the biochemical findings of pheochromocytoma.
An alternative approach that also is useful at times, particularly for residual or multiple pheochromocytomas, is the metaiodobenzylguanidine scan that images medullary tissue [27]. This test may be more sensitive than CT or MRI picking up small extra-adrenal lesions and has major use in patients where multiple lesions are suspected.
Treatment
Adrenalectomy is the treatment of choice in most patients who have undergone appropriate metabolic evaluation and have been found to have a surgical lesion [28]. Although most adrenal tumors are removed with a laparoscopic approach the principles of open adrenal surgery apply and warrant review. The surgeon must be aware, however, that there are unique aspects to the care of these patients including specific preoperative management as outline in Box 4 [3]. Accordingly, patients with hyper- aldosteronism who are generally healthy require spironolactone, 100 to 400 mg/d, to restore their K+ supply. Patients with Cushing’s syndrome have severe systemic effects from the hyperglucocorticoidism. They are often obese, have diabetic tendencies, are poor wound healers, easily sustain bony fractures, and are susceptible to infection. They are at high risk for complications. In selected patients with markedly elevated cortisol levels the preoperative use of metabolic blockers, such as metyrapone, is required to reverse some of the clinical findings before adrenalectomy. Certainly, glucocorticoid replacement is required throughout the surgical procedure and postoperatively until the function of the contralateral adrenal gland occurs. Finally, in patients with a pheochromocytoma, adrenergic blockade generally with phenoxybenzamine is required, and at times the blockade of
Box 4. Errors in patient preparation for adrenal surgery
Primary aldosteronism K+ repletion
Blood pressure control
Cushing’s syndrome
Inhibition of glucocorticoid production when there are severe manifestations using metyrapone
Control of diabetes Preoperative antibiotics
Operative steroid administration
Incidentalomas
Anesthetic preparation for pheochromocytoma; 5% have negative diagnostic studies
Adrenal carcinoma
Consent for adjacent organ removal
Failure to identify inferior vena cava involvement Pheochromocytoma Preoperative catecholamine blockade
Volume expansion Anesthesia consultation
catecholamine production with metyrosine is also useful. The additional preoperative evaluation that is mandatory in patients with pheochromocy- toma is consultation with the anesthesiologist, who can be well aware of the patient and can plan strategy for management [29].
The management of patients with an adrenal disorder is approached on a team basis including experienced endocrinologists, radiologists, anesthesi- ologists, and urologists or general surgeons.
Numerous approaches can be made to the adrenal gland (Table 3). At the present time, however, except for large adrenal tumors, adrenal carci- noma or pheochromocytoma are approached laparoscopically. A variety of laparoscopic approaches to the adrenal exist [30,31]. The lateral trans- peritoneal, anterior transperitoneal, lateral retroperitoneal, and posterior retroperitoneal techniques have been described similar to the rationale for an open approach. The laparoscopic approach depends on the patient’s habitus, the underlying pathology, and the skill and experience of the operating surgeon [1]. The results of these approaches mirror the results of open adrenalectomy with less morbidity and hospitalization time for the patient [32].
The lateral transperitoneal approach is the technique most often reported in the literature. Most laparoscopic surgeons have extensive experience identifying, dissecting, and mobilizing the adjacent organs required to obtain adrenal exposure and removal. For this approach the patient is
| Adrenal disorder | Approach |
|---|---|
| Primary hyperaldosteronism | Posterior (left or right) |
| Modified posterior (right) | |
| Eleventh rib (left > right) | |
| Posterior transthoracic | |
| Cushing's adenoma | Eleventh rib (left > right) |
| Thoracoabdominal (large) | |
| Posterior (small) | |
| Cushing's disease | Bilateral posterior |
| Bilateral hyperplasia Adrenal carcinoma | Bilateral eleventh rib (alternating) |
| Thoracoabdominal | |
| Eleventh rib | |
| Transabdominal | |
| Bilateral adrenal ablation | Bilateral posterior |
| Pheochromocytoma | Transabdominal (chevron) |
| Thoracoabdominal (large, usually right) | |
| Eleventh rib | |
| Neuroblastoma | Transabdominal |
| Eleventh rib |
From Vaughan ED Jr. Adrenal surgery. In: Marshall FF, editor. Textbook of operative urology. Philadelphia: WB Saunders; 1996.
placed in a full lateral position (Fig. 5). Bilateral adrenalectomy requires repositioning and redraping.
In contrast, the retroperitoneal approaches avoid dissection and mobilization of intra-abdominal viscera (Fig. 6). The major limitation is the small working space that compromises instrument placement and crossing of instruments can occur. The approach is best for patients with small adrenal tumors. Balloon inflation is used to dissect the retroperitoneal space. During this procedure close blood pressure monitoring is necessary in patients with pheochromocytoma because the expanding balloon may compress the tumor with catechol release.
Partial adrenalectomy
The standard treatment for patients with the adrenal lesions described has been total adrenalectomy. There recently has been reported, however, an excellent paper showing the use of partial adrenalectomy in patients with primary hyperaldosteronism [33]. The author has not used partial adrenalectomy in a patient for normal contralateral adrenal, but certainly has used the technique in patients with bilateral disease. In one patient with a pheochromocytoma on one side and a nonfunctioning adenoma on the other, the adenoma was simply enucleated from the adrenal. In a second patient with bilateral pheochromocytomas, the larger lesion was totally excised, with partial adrenalectomy used to remove the contralateral tumor. Care has to be made to obtain thorough hemostasis when performing a partial adrenalectomy because of the vascular nature of the adrenal. Partial adrenalectomy, adrenal-sparing surgery, is most useful in patients at risk for multiple adrenal tumors, such as Hippel-Lindau kindreds [34,35].
Cryosurgery
Cryoablation is currently used as a surgical alternative for the treatment of prostatic, lung, brain, pharyngeal, and liver tumors. It has been demonstrated in a canine model [36] that adrenal cryoablation is effective in destroying adrenal tissue and is safe. The author has successfully used the technique in one patient with primary hyperaldosteronism. Adrenal laparoscopic cryoablation may shorten operative time and be as effective as total adrenalectomy in patients with small lesions.
Ablation
Successful adrenal ablation using transcatheter arterial infusion of ethanol has been described in 33 cases of primary hyperaldosteronism; the approach was successful in 27 cases (82%). Five patients required surgical
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A Bouman
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2
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adrenalectomy. This technique may be useful in the patient who is at high risk with use of general anesthesia [37]. More recently direct percutaneous tumor injection with ethanol has given excellent results in 41 patients with pheochromocytoma with reversal of hormonal abnormalities [38].
Summary
It is fortunate that the ability to diagnose the specific adrenal entities that mandate a surgical approach is extremely accurate. The combination of analytic methodology to measure the appropriate adrenocortical and medullary hormonal production and the radiologic techniques for locali- zation are superb. The management of these adrenal disorders usually using a laparoscopic approach following localization is highly successful, resulting in a reversal of both metabolic abnormalities and the hypertension that often accompanies these diseases. Indeed, this is a true success story with the evolution of these different techniques over the past 50 years.
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