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The Biochemical Basis of Adrenal Surgery
r The Biochemical Basis of Adrenal Surgery VIRGINIA V. WELDON, M.D.':' CLARENCE S. WELDON, M.D.'::::'
Neoplasia and hyperplasia of endocrine tissue frequently result in excessive hormone production with concomitant derangement of metabolism. Surgical ablation of abnormal endocrine tissue can restore the patient to a normal metabolic state but must be performed before irreversible organ changes occur. Until recently, excessive hormone production was identified by recognition of syndromes of organ and system malfunction. Diagnostic errors resulted from confusion of endocrine disorders with other diseases producing similar organ and system malfunctions. Operations were frequently performed on patients with marked. metabolic derangement, which greatly increased the risk of anes thesia or surgical procedure. Surgeons searching for abnormal tissue were guided by a simple statistical analysis of pathologic morphology. A series of recent biochemical and pharmacologic investigations has made it possible to measure directly the concentration of hormones in body fluids. Wherever the biologically active hormone can be identified, isolated, and synthesized and can be isotopically labeled, it is possible to measure actual secretion rates. More recently, competitive protein binding analysis has made possible the micro and ultramicro measurement of steroid hormones. Pharmacologic agents that stimulate or suppress From the Departments of Pediatrics and Surgery, The Washington University School of Medicine, St. Louis, Missouri, and the Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland "'Instructor in Pediatrics, Washington University School of Medicine; Assistant Pediatrician, St. Louis Children's Hospital, St. Louis Maternity Hospital, and McMillan Hospital **Associate Professor of Surgery, Washington University School of Medicine; Cardiothoracic Surgeon-in-Chief, Barnes and Allied Hospitals and St. Louis Children's Hospital "'**Professor and Head of the Department of Surgery, The Johns Hopkins University School of Medicine; Surgeon-in-Chief, The Johns Hopkins Hospital Surgical Clinics of North America- Vol. 49, No.3, June, 1969
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hormone production have been identified. The response to such agents not only aids in the detection of abnormal secretion but frequently permits differentiation of neoplasms, which secrete autonomously, from a hyperplastic gland, which secretes under the influence of tropic hormones. Clarification of pathologic physiology resulting from excessive hormone secretion has not only permitted more accurate diagnosis by analysis of organ function but also has resulted in the development of pharmacologic control of pathologic physiology, allowing patients to be operated upon without excessive risk. The development of a variety of radiologic, isotopic, and catheterization techniques has led to methods that permit precise localization of abnormal endocrine tissue. The modern endocrine surgeon is thus frequently able to operate upon a patient with endocrine neoplasia or hyperplasia in whom metabolism is controlled and regulated, diagnosis is relatively certain, and abnormal tissue is localized. Ideally a surgeon should accept nothing less. It is likely that additional advances in the field of endocrinology will achieve this ideal. It is the purpose of this paper to outline the current status of biochemical information which forms the basis for modern adrenal surgery.
CUSHING'S SYNDROME The symptoms of Cushing's syndrome, which may include truncal obesity, hypertension, acne, hirsutism, muscular weakness, amenorrhea, increased capillary fragility, growth failure, and osteoporosis, are all due to cortisone excess. This excess cortisone production may be due to an adrenocorticotropic hormone (ACTH) producing tumor of the pituitary, to an ectopic ACTH-producing tumor, to unexplained adrenal hyperplasia, or to an independently functioning adrenal gland adenoma or carcinoma. In most patients with Cushing's syndrome, the symptoms do not indicate the underlying pathology, and the surgeon must therefore rely on biochemical and radiologic methods to arrive at a proper diagnosis and to localize the tumor if one exists. Early in the course of the disease, many of the symptoms of florid Cushing's syndrome may be absent. We have recently seen an adolescent boy who was asymptomatic except for marked growth failure of 5 years' duration and a similar degree of bone age delay in whom the only biochemical abnormalities were a mildly elevated cortisol production rate, elevated baseline urinary 17-hydroxycorticosteroids (17-0HCS), and a slight hyperresponse to intravenous ACTH. This patient has responded to bilateral adrenalectomy by growing 3.4 inches in the first 9 postoperative months. Within the past decade, more refined laboratory methods have made diagnosis in such patients easier. The measurement of the cortisol production rate (CPR) with 14C_ or 3H -labeled cortisol is the most direct means of assessing adrenal activity. Although this test has previously been performed only in a few large medical centers, it is becoming increasingly available throughout the
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country. Kenny et aU reported CPR in 48 normal subjects from 4 months to 48 years of age and found the mean to be 11.8 ± 2.5 mg. per square meter per 24 hours. Because simple exogenous obesity can mimic most of the clinical symptoms of Cushing's syndrome, it is essential to separate these patients. Migeon and co-workers 12 reported a mean CPR of 15.0 ± 5.6 mg. per square meter per 24 hours in 31 obese subjects, which is significantly higher than the normal average. The use of baseline urinary 17-0HCS in simple obesity may also result in a mistaken diagnosis of Cushing's syndrome. Migeon et al}2 found the mean urinary 17-0HCS excretion to be 3.1 ± 1.1 mg. per square meter per 24 hours in 180 normal subjects. The mean urinary 17-0HCS corrected for surface area in a group of 160 obese subjects was 4.3 ± 1.9 mg. per square meter per 24 hours, again significantly higher than that obtained in normal subjects. On the basis of these studies these workers propose a scheme for the diagnosis of Cushing's syndrome (Figs. 1 and 2, reproduced with permission of the authors). If the urinary 17-0HCS level is less than 5.5 mg. per square meter per 24 hours (3.1 mg. + 2 standard deviation [S.D.]), one is dealing with obesity, whereas a value greater than 10 mg. per square meter per 24 hours is indicative of Cushing's syndrome. Suppression of the adrenal gland with dexamethasone (Decadron), a potent synthetic cortisone analogue excreted in the urine in minute amounts, is useful in distinguishing the patient with simple obesity in whom the baseline urinary corticoids are in the 5.5 to 10.0 mg. per square meter per 24 hour
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CUSHING'S
Figure 1. Scheme for diagnosis of Cushing's syndrome by measurement of urinary 17-hydroxycorticosteroids (l7-0HCS).
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ACTH TEST
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ADRENAL CARC I NOMA PITLITARY TLMOR?
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Figure 2. Scheme for diagnosis of adrenal disorders by stimulation and suppression of adrenal function.
range. The Decadron test can be further extended by giving a triple dose to differentiate adrenal hyperplasia from adrenal carcinoma and ectopic ACTH-producing tumors. The use of a human growth hormone suppression test to distinguish adrenocortical hyperfunction due to hypersecretion of ACTH has recently been proposed by Schteingart and Conn. 15 In addition, the intravenous ACTH stimulation test is useful in distinguishing hyperplasia from carcinoma. These biochemical tests, however, are not always foolproof. Braverman and co-workers 2 reported a patient with Cushing's syndrome in whom the response to single Decadron suppression was normal. There have been similar reports suggesting the occasional unreliability of both the Decadron suppression test and the ACTH stimulation test. Additional information to localize the source of hormonal overproduction can be gained from plasma ACTH levels. Liddle8 has reported slightly elevated levels in patients with pituitary tumor or bilateral adrenal hyperplasia, markedly elevated levels in the ectopic ACTH syndrome, and decreased levels in cases of adrenal tumor. Because reliance on hormone secretion rate, stimulation, and suppression tests can occasionally be misleading, several workers are using catheterization studies and more refined radiographic techniques to localize ectopic tumors or tumors of the adrenal glands. N ey et al. 13 reported studies of inferior vena caval catheterization in which an abrupt increase in the concentration of plasma 17-0HCS at the Lllevellocalized an ectopic adrenocortical tumor. In additon Bucht et al.,3 Sutton,16 and Melby et al. l l have utilized adrenal vein catheterization to localize aldosterone-
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producing tumors. Such techniques can also be applied to the localization of glucocorticoid-producing tumors. At the present time there are several pharmacologic agents available for the suppression of adrenal steroid production. The use of o,p'-DDD (2, 2-bis(2-chlorophenyl-4-chlorophenyl)-1 ,1-dichloroethane) has been reported in adrenal hyperplasia in a lO-year-old child with good results during 15 months of therapy. 1 This drug has also been used in the management of adrenocortical carcinoma but has a formidable toxicity.9. 10 The use of aminoglutethiInide as a suppressor of adrenal steroid production has been reported in normals 4 • 5 and in patients with adrenal carcinoma,14 adrenal adenoma, and bilateral adrenal hyperplasia, as well as in a patient with ectopic ACTH syndrome. 6 It is possible that these agents may be useful in the preoperative preparation of the patient with Cushing's syndrome, much as iodides and propylthiouracil or methimazole (Tapazole) are used in the patient with hyperthyroidism.
PRIMARY HYPERALDOSTERONISM In 1955 Conn3 first described a syndrome characterized by hypertension and severe potassium depletion resulting in hypokaleInic alkalosis. Other symptoms associated with this syndrome are due to the potassium depletion and include paresthesias, muscular weakness, cramps, tetany, polydipsia, and nocturia. Although sodium is retained and the extracellular volume is expanded, edema is not a clinical feature. During the years since Conn first established this syndrome as a clinical entity due to overproduction of aldosterone, the methods for measuring this hormone in urine and plasma have become increasingly refined. Aldosterone was first isolated in 195216 and its chemical structure identified in 1953. 14 Subsequently various bioassays were used which measured the hormone in a seIniquantitative way until 1960, when Kliman and Peterson9applied the method of double isotope dilution to the quantitation of aldosterone. The suggestion that renin, a hormone secreted by the kidney which leads to the production of angiotensin, was responsible for control of aldosterone production was made by Laragh and others 10 and Genest.7 In 1963, Conn5 proposed the use of renin and/or angiotensin to distinguish primary aldosteronism from renal secondary aldosteronism. The method of Boucher, Veyrat, and deChamplain 1 has made possible an accurate bioassay of renin and angiotensin when performed in a reliable laboratory. Only patients with hypertension who have an elevated aldosterone secretory rate (ASR) which remains elevated after sodium loading and a low plasma renin level measured while on a low sodium diet can be considered to fulfill the diagnostic criteria for Conn's syndrome. 12 It should be pointed out that accurate determinations for ASR and plasma renin and/or angiotensin levels are as yet available only in large medical centers. Although the measurement of these three hormones is most useful in the diagnosis of primary hyperaldosteronism, numerous causes of secondary elevations of aldosterone and the inherent difficulties in measuring minute quantities of renin and angiotensin have
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necessitated reliance on certain ancillary tests. When renovascular hypertension is suspected, renal arteriography is mandatory. The use of saline infusion has recently been proposed by Espiner and co-workers.6 These workers found that normal subjects on low sodium diets decreased their aldosterone secretion significantly, whereas patients with primary aldosteronism showed only small changes in secretion with sodium loading. Other workers are currently investigating the response of ASR to high sodium diets in an effort to differentiate primary aldosteronism from benign and malignant hypertension and renovascular hypertension. In addition, response to an infusion of angiotensin was proposed by Kaplan 8 as another means of evaluating these patients. He suggested that patients with renovascular hypertension show less rise than normal patients, whereas patients with primary hyperaldosteronism are unusually sensitive to the pressor action of angiotensin. Several pharmacologic agents are available which antagonize the action of aldosterone. Although these agents have been generally used in the long-term medical management of patients who are unsuitable for surgery or in whom tumor cannot be found, their use in the preoperative preparation of patients should be considered. Spironolactone, one of the steroid 17-spirolactones, has been found to block sodium reabsorption at the distal nephron where aldosterone is known to act. This decreases potassium loss and results in return of plasma potassium and bicarbonate to normal. Triamterene (2,4,7-triamino-6-phenylpteridine) has been found to cause sodium excretion and potassium conservation in patients with Conn's syndrome,t3 and unlike spironolactone, it is not an aldosterone antagonist, but instead has an effect on the distal tubule opposite to the effect of sodium-retaining steroidsY Since Conn has emphasized the frequency of small adrenocortical adenomas causing hypertension and aldosteronism,'4 there has been an increased effort to localize these small tumors. Bucht and co-workers2 in 1964 reported percutaneous catheterization of the left adrenal vein with sampling of blood for determination of aldosterone that resulted in localization of the tumor. Using a similar technique, Sutton '5 successfully catheterized the left adrenal vein in 22 of 27 cases and identified seven tumors, all of which were confirmed at surgery. Melby and others" have reported successful percutaneous transfemoral bilateral adrenal vein catheterization. With such a procedure, they were able to detect small (0.3 to 2.3 cm.) adenomas by comparing aldosterone levels of adrenal venous blood. This group has pointed out the 10 per cent frequency of bilateral adenomas, thereby emphasizing the diagnostic importance of bilateral catheterization.
PHEOCHROMOCYTOMA Pheochromocytomas are tumors arising from chromaffin tissue which secrete excessive amounts of the catecholamines epinephrine and norepinephrine. These hormones in excess produce systemic hypertension. Because the disorder can be completely cured by the removal of the tumors, it is essential that all hypertensive patients be viewed as pos-
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sibly harboring a pheochromocytoma. Certain clinical features aid in the diagnosis of pheochromocytomas. These include excessive sweating, orthostatic decrease in blood pressure without treatment, and the presence of other neuroepidermal disorders, such as von Recklinghausen's neurofibromatosis or Lindau-von Hippel disease. Pheochromocytoma has also been noted with medullary carcinoma of the thyroid and as a part of a syndrome including hyperparathyroidism. The tumor is known to be a familial disease. In these instances the adrenal tumors are ordinarily bilateral. Fluorometric procedures have now been developed for determination of the concentration of catecholamines in plasma and urine. 17, 18, 22 At the present time, however, these techniques are available only in specific laboratories and are subject to considerable error and variability. Armstrong and McMillan! discovered in 1957 the presence of the catecholamine metabolite 3-methoxy-4-hydroxymandelic acid (VMA) in human urine. Subsequently Axelrod and other investigators demonstrated that epinephrine (E) and norepinephrine (NE) were metabolized principally to metanephrine (M) and normetanephrine (NM) respectively by O-methylation. 2, 11, 16 It was demonstrated later that NM and M may be metabolized to 3-methoxy-4-hydroxymandelic aldehyde (L), which may either be reduced to 3-methoxy-4-hydroxyphenylglycol (G)3, 6 or oxidized to VMA. Further studies have demonstrated the quantity of combined NM and M excreted and that smaller quantities of G also may be detected. lO Techniques for urinary assays of the metanephrines have been described from several laboratories. The methods have employed chromatography,l2 ion exchange procedures,9 fiuorometry,4 paper electrophoresis,19 and chromatoelectrophoresis,13,23 Sheps et al. l4 have recently reported a comparative study of the measurement of catecholamine in serum and blood with the techniques for measuring urinary metanephrines and VMA. They concluded that the measurement of metabolites was much less subject to false positive results than the determination of catecholamines. The first appropriate tests for the confirmation of pheochromocytoma to become available were pharmacologic tests employing agents that stimulated release of catecholamines or blocked the action of catecholamines circulating in the blood. The histamine vasopressor test and the phentolamine test gained general wide acceptance as diagnostic tools; unfortunately, both of these tests were associated with severe side reactions and occasional death. Most important, the incidence of positive results in proved cases of pheochromocytoma was only about 75 per cent,7 and there was an appreciable prevalence of false positive reactions. Tyramine, an agent that releases catecholamine from nerve endings, was later introduced. With this agent, false positive reactions have been quite rare, but the incidence of false negatives remains about the same as with the phentolamine and histamine tests. At the present time, it appears that because of the frequent false negative and occasional false positive reactions associated with pharmacologic tests and the difficulty of performing catecholamine estimations, as well as the number of agents
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which interfere with catecholamine assays and metanephrine assays, the reliable diagnosis of pheochromocytoma still must be based on multiple studies in an appropriate clinical setting. Much of the mortality associated with pheochromocytomas has occurred at the time of surgical removal of these tumors. Severe hypertension resulting from manipulation of the hormone-containing tumor, hypotension following the removal of the tumor, and cardiac arrhythmia induced by a high level of circulating catecholamines are the chief causes of mortality. Considerable attention has been directed toward the cause of hypotension, which follows almost universally the removal of pheochromocytomas. It has been suggested that patients with pheochromocytoma frequently have a reduced total blood volume and that hypovolemia is the major factor in the hypotension seen after surgical removal of the tumor. 7 Waldman20 studied the total circulating red cell and plasma volumes in 15 patients with pheochromocytoma. True polycythemia was noted on rare instances in patients with pheochromocytoma. It was thought that the erythrocytosis associated with pheochromocytoma is secondary to the production of erythropoiesis stimulating factor by these tumors. In this series of patients, only four of 18 patients studied with radioactive iodinated albumin were found to have reduced circulating blood volume, and only three of 15 patients studied with chromium-tagged red cells were found to have abnormally low total blood volumes. It thus appears that the majority of patients with pheochromocytomas have a normal or near normal blood volume. Nonetheless, it has been noted empirically8 that replacement or even overreplacement of blood lost at operation is of major importance in the control of the hypotension seen after resection of the tumor. It has been further noted that pressure agents are frequently ineffective in the management of intraoperative hypotension. 21 It is therefore important that the surgical team be prepared to provide blood volume replacement even in the absence of major intraoperative blood loss so that a drop in blood pressure can be empirically but adequately combated. With the recent development of pharmacologic agents that block the action of circulating catecholamines, it has been possible to pharmacologically control adverse physiologic effects of the tumor. The commonly available alpha-adrenergic blocking agent is phenoxybenzamine, and the common beta-adrenergic agent is propranolol. In addition, agents which prevent the synthesis of catecholamine in man have been developed. These agents prevent the hydroxylation of tyrosine to dihydroxyphenylalanine. Such an inhibiting agent is alpha-methylparatyrosine, which has received some clinical trials. 15 With appropriately designed regimens employing these pharmacologic agents, it is now possible to reduce catecholamine levels to normal or near normal in patients with functioning pheochromocytomas. In addition, these regimens are especially valuable for treating patients who are judged to be unacceptable surgical risks and those with malignant pheochromocytomas that cannot be surgically extirpated. Several objections to the use of these agents for the preparation of surgical patients can, however, be raised. The patient who is autonomically unrespon-
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sive loses the sometimes valuable sign of a hypertensive response with massage of the tissue at the time of the operation. This response is frequently helpful in the location of pheochromo'cytomas in aberrant sites. Such autonomically unresponsive patients are also incapable of responding normally to massive hemorrhage when this surgery is done in areas where there are large blood vessels. In many cases such patients can be handled without pharmacologic control but with precise attention to the choice of anesthetic agents (avoiding those which produce catecholamine release, such as ether and cyclopropane), with rapid infusion of blood to combat hypotension, and with the intraoperative use of pressor amines. In addition, lidocaine, a valuable antiarrhythmic agent, has proved extremely valuable in controlling catecholamine-induced arrhythmias. Many tests have been advocated for localizing the tumor site prior to operation. These include retroperitoneal gas insufflation, arteriography, and caval catheterization to determine the site in which a tumor is releasing the catecholamine into the circulation. It must, however, be remembered that these patients do not tolerate manipulative diagnostic procedures well and that 99 per cent of pheochromocytomas are located within the abdominal cavity. Rare exceptions to the abdominal location include functioning tumors of the carotid body and intrathoracic turri.ors which present posterior mediastinal paravertebral masses. In addition, since approximately 20 per cent of pheochromocytomas are multiple, the preoperative localization of a tumor in no way excuses the surgeon from carrying out an extensive abdominal exploration. It is probably correct that such techniques as caval catheterization, angiography, and retroperitoneal air insufflation should be reserved for special cases. Useful preoperative procedures are intravenous pyelograms and laminography of the renal areas. These tests can be done without hazard to the patient and frequently provide some localization of the tumor. It is also essential in these patients because of the coexistence of thyroid and parathyroid disease to evaluate these organs and also because of the frequent coexistence of cholelithiasis to evaluate the patients for the presence of gallstones.
REFERENCES CUSHING'S SYNDROME 1. Bar-Hay, J., Benderiy, A., and Rumney, G.: Treatment of a case of non-tumorous Cushing's syndrome with o,p'DDD. Pediatrics, 33:239,1964. 2. Braverman, L. E., Woeber, K. A., and Ingbar, S. H.: An unusual case of Cushing's syndrome. New Eng.']. Med., 273:1018,1965. 3. Bucht, H., Bergstrom, J., Lindholmer, B., Wijnbladh, H. J., and Hokfelt, K.: Catheterization of the left adrenal vein for contrast injection and steroid analysis in a case of Conn's syndrome. Acta Med. Scand., 176:233, 1964. 4. Cash, R., Brough, A. J., Cohen, M. N. P., and Satoh, P. S.: Amino-glutethimide (EliptEinCiba) as an inhibitor of adrenal steroidogensis: Mechanism of action and therapeutic trial. J. Clin. Endocrin., 27:1239,1967. 5. Fishman, L., Liddle, G. W., Island, D. P., Fleischer, N., and Kuchel, 0.: Effects of aminoglutethimide on adrenal function in man. J. Clin. Endocrin., 27:481,1967. 6. Gorden, P., Becker, C. E., Levey, G. S., and Roth, J.: Efficacy of amino-glutethimide in the ectopic ACTH syndrome. J. Clin. Endocrin., 28:921,1968.
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7. Kenny, F. M., Preeyasombat, C., and Migeon, C. J.: Cortisol production rate: II. Normal infants, children and adults. Pediatrics, 37:34, 1966. 8. Liddle, G. W., Givens, J. R., Nicholson, W. E., and Island, D. P.: The ectopic ACTH syndrome. Cancer Res., 25:1056,1965. 9. Lipsett, M. B., Hertz, R., and Ross, G. T.: Clinical and pathophysiologic aspects of adrenocortical carcinoma. Amer. J. Med., 35:374,1963. 10. May, R. H.: Studies of the pharmacology of o,p'DDD in man. J. Lab. Clin. Med., 58:296, 1961. 11. Melby, J. C., Spark, R. F., Dale, S. L., Egdahl, R. H., and Kahn, P. C.: Diagnosis and localization of aldosterone-producing adenomas by adrenal-vein catheterization. New Eng. J. Med., 277:1050,1967. 12. Migeon, C. J., Green, O. C., and Eckert, J. P.: Study of adrenocortical function in obesity. Metabolism, 12:718, 1963. 13. Ney, R. L., Hammond, W., Wright, L., Davis, W. L., Acker, J., and Bartter, F. C.: Studies in a patient with an ectopic adrenocortical tumor. J. Clin. Endocrin., 26:299,1966. 14. Schteingart, D. E., Cash, E. R., and Conn, J. W.: Amino-glutethimide and metastatic adrenal cancer. J.A.M.A., 198:1007, 1966. 15. Schteingart, D. E., and Conn, J. W.: Suppression of adrenal cortical function by human growth hormone (HGH) in Cushing's syndrome (abstract). Third International Congress of Endocrinology, 1968. 16. Sutton, D.: Diagnosis of Conn's and other adrenal tumours by left adrenal phlebography. Lancet, 1 :453, 1968.
PRIMARY HYPERALDOSTERONISM
1. Boucher, R., Veyrat, R., deChamplain, J.: New procedures for measurement of human plasma angiotensin and renin activity levels. Canad. Med. Ass. J., 90: 194, 1964. 2. Bucht, H., Bergstrom, J., Lindholmer, B., Winjbladh, H. J., and Hokfelt, K.: Catheterization of the left adrenal vein for contrast injection and steroid analysis in a case of Conn's syndrome. Acta Med. Scand., 176:233, 1964. 3. Conn, J. W.: Primary aldosteronism: A new Clinical syndrome. J. Lab. Clin. Med., 45:6, 1955. 4. Conn, J. W., Cohen, E. L., Rovner, D. R., and Nesbit, R. M.: Normokalemic primary aldosteronism: Detectable cause of curable 'essential' hypertension. J.A.M.A., 193:200, 1965. 5. Conn, J. W., Knopf, R. F., and Nesbit, R. M.: Primary aldosteronism. Present evaluation of its clinical characteristics and of the results of surgery. In International Conference on Aldosteronism for International Organization of Medical Science. Prague, 1963, p. 339. 6. Espiner, E. A., Tucci, J. R., Jagger, P. I., and Lauler, D. P.: Effect of saline infusions on aldosterone secretion and electrolyte excretion in normal subjects and in patients with primary aldosteronism. New Eng. J. Med., 277:1,1967. 7. Genest, J.: Angiotensin, aldosterone and human arterial hypertension. Canad. Med. Ass. J., 84:403, 1961. 8. Kaplan, N. M.: Primary aldosteronism with malignant hypertension. New Eng. J. Med., 269:1282,1963. 9. Kliman, B., and Peterson, R. E.: Double isotope derivative assay of aldosterone in biological extracts. J. BioI. Chern., 235: 1639, 1960. 10. Laragh, J. H., Angers, M., Kelly, W. G., and Lieberman, S.: Hypotensive agents and pressor substances. Effect of epinephrine, norepinephrine, angiotensin II and others on the secretory rate of aldosterone in man. J.A.M.A., 174:234, 1960. 11. Melby, J. C., Spark, R. F., Dale, S. L., Egdahl, R. H., and Kahn, P. C.: Diagnosis and localization of aldosterone-producing adenomas by adrenal-vein catheterization. New Eng. J. Med., 277:1050,1967. 12. Rhamy, R. K., McCoy, R. M., Scott, H. W., Jr., Fishman, L. M., Michelakis, A. M., and Liddle, G. W.: Primary aldosteronism experience with current diagnostic criteria and surgical treatment in 14 patients. Ann. Surg., 167:7l8, 1968. 13. Ross, E. J.: Aldosterone and its antagonists. Clin. Pharm. Therap., 6:65,1965. 14. Simpson, S. A., Tait, J. F., Wettstein, A., Nehrer, R., Von Euw, J., and Reichstein, T.: Isolierung eines neuen kristallisierten Hormone aus Nebennieren mit besonders hohen Wirksamkeit auf den mineral StoffwechseI. Experientia, 9:333,1953. 15. Sutton, D.: Diagnosis of Conn's and other adrenal tumours by left adrenal phlebography. Lancet, 1 :453, 1968. 16. Tait, J. F., Simpson, S. A., and Grundy, H. M.: The effect of adrenal extract on mineral metabolism. Lancet, 1 :122,1952.
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PHEOCHROMOCYTOMA 1. Armstrong, M. D., and McMillan, A.: Identification of major urinary metabolites of norepi-
nephrine. Fed. Proc., 16:146, 1957. 2. Axelrod, J.: O-methylation of epinephrine and other catechols in vitro and in vivo. Science, 126:40,1957. 3. Axelrod, J., Kopin, I. J., and Mann, J. D.: 3-methoxy-4-hydroxy-phenylglycol sulfate; new . metabolite of epinephrine and norepinephrine. Biochem. Biophys. Acta, 36:576,1959. 4. Bertler, A., Karlsson, A., and Oresengren, E.: Fluorometric method for differential estimation of 3-0-methylated derivatives of adrenalin and noradrenalin (metanephrine and normetanephrine). Clin. Chim. Acta, 4:456, 1959. 5. Brunjes, S., Johns, V. J., Jr., and Crane, M. G.: Pheochromocytoma: Post-operative shock in blood volume. New Eng. J. Med., 262:393,1960. 6. Clinical staff conference on metabolism of catecholamines, clinical implications; combined clinical staff conference of National Institutes of Health. Ann. Int. Med., 56:960, 1962. 7. Gifford, R. W., Jr., Kvale, W. F., Maher, F. T., Roth, G. M., and Priestly, J. T.: Clinical features, diagnosis and treatment of pheochromocytoma. A review of 76 cases. Mayo Clin. Proc., 39:281, 1964. 8. Goldfein, A.: Pheochromocytoma diagnosis and anesthetic and surgical management. Anesthesiology, 24:462,1963. 9. Goodall, M., Kirshaner, N., and Rosen, L.: Metabolism of noradrenalin in humans. J. Clin. Invest., 38:707,1959. 10. Kopin, I. J.: Technique for study of alternate metabolic pathways; epinephrine metabolism in man. Science, 131: 1372, 1960. 11. LaBrosse, E. H., Axelrod, J., and Kety, S. S.: O-methylation principal route of metabolism of epinephrine in man. Science, 128: 593, 1958. 12. LaBrosse, E. H., Axelrod, J., and Sjoerdsma, A.: Urinary excretion of normetanephrine by man. Fed. Proc., 17:386, 1958. 13. Pisano, J. J.: Simple analysis for normetanephrine and metanephrine in urine. Clin. Chim. Acta, 5:406,1960. 14. Sheps, S. G., Tyce, G. M., Flock, E. V., and Maher, F. T.: Current experience in the diagnosis of pheochromocytoma. Circulation, 34:473, 1966. 15. Sjoerdsma, A., Engleman, K., Spector, S., and Undenfriend, S.: Inhibition of catecholamine synthesis in man with alpha-methyl-tyrosine, an inhibitor of tyrosine hydroxylase. Lancet, 2:1092,1965. 16. Sjoerdsma, A., Leeper, L. C., Terry, L. L., and Udenfriend, S.: Studies on biogenesis and metabolism of norepinephrine in patients with pheochromocytoma. J. Clin. Invest., 38:31, 1959. 17. Sobel, C., and Henry, R. J.: Determination of catecholamine (adrenaline and noradrenalin) in urine and tissues. Amer. J. Clin. Path., 27:240,1957. 18. von Euler, U. S., and Floding, I.: Fluorometric micro method for differential estimation of adrenalin in noradrenalin. Acta Physiol. Scan., 33(Suppl. 118):45, 1955. 19. von Studnitz, W.: Separation and determination of noradrenalin and metanoradrenalin by high voltage paper electrophoresis. Clin. Chim. Acta, 4:456,1959. 20. Waldman, T. A.: Discussants: Engleman, K., Waldman, T. A., Cooperman, L. A., and Hammond, W. G.: Clinical staff conference-Pheochromocytoma. Current concepts of diagnosis and treatment. Combined clinical staff conferences. The National Institutes of Health, Albert Sjoerdsma, Moderator. Ann. Intern. Med., 65:1302,1966. 21. Watkins, D. B.: Pheochromocytoma. J.Chron. Dis., 6:510,1957. 22. Weil-Malherbe, H., and Bone, A. D.: Chemical estimation of adrenalin-like substance in the blood. Biochem. J., 51 :311, 1952. 23. Wolf, R. L.: New catecholamine metabolite (CM) test for pheochromocytoma. Heart Bulletin, 13:96, 1964. Washington University School of Medicine St. Louis, Missouri 63110
Neoplasia and hyperplasia of endocrine tissue frequently result in excessive hormone production with concomitant derangement of metabolism. Surgical ablation of abnormal endocrine tissue can restore the patient to a normal metabolic state but must be performed before irreversible organ changes occur. Until recently, excessive hormone production was identified by recognition of syndromes of organ and system malfunction. Diagnostic errors resulted from confusion of endocrine disorders with other diseases producing similar organ and system malfunctions. Operations were frequently performed on patients with marked. metabolic derangement, which greatly increased the risk of anes thesia or surgical procedure. Surgeons searching for abnormal tissue were guided by a simple statistical analysis of pathologic morphology. A series of recent biochemical and pharmacologic investigations has made it possible to measure directly the concentration of hormones in body fluids. Wherever the biologically active hormone can be identified, isolated, and synthesized and can be isotopically labeled, it is possible to measure actual secretion rates. More recently, competitive protein binding analysis has made possible the micro and ultramicro measurement of steroid hormones. Pharmacologic agents that stimulate or suppress From the Departments of Pediatrics and Surgery, The Washington University School of Medicine, St. Louis, Missouri, and the Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland "'Instructor in Pediatrics, Washington University School of Medicine; Assistant Pediatrician, St. Louis Children's Hospital, St. Louis Maternity Hospital, and McMillan Hospital **Associate Professor of Surgery, Washington University School of Medicine; Cardiothoracic Surgeon-in-Chief, Barnes and Allied Hospitals and St. Louis Children's Hospital "'**Professor and Head of the Department of Surgery, The Johns Hopkins University School of Medicine; Surgeon-in-Chief, The Johns Hopkins Hospital Surgical Clinics of North America- Vol. 49, No.3, June, 1969
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hormone production have been identified. The response to such agents not only aids in the detection of abnormal secretion but frequently permits differentiation of neoplasms, which secrete autonomously, from a hyperplastic gland, which secretes under the influence of tropic hormones. Clarification of pathologic physiology resulting from excessive hormone secretion has not only permitted more accurate diagnosis by analysis of organ function but also has resulted in the development of pharmacologic control of pathologic physiology, allowing patients to be operated upon without excessive risk. The development of a variety of radiologic, isotopic, and catheterization techniques has led to methods that permit precise localization of abnormal endocrine tissue. The modern endocrine surgeon is thus frequently able to operate upon a patient with endocrine neoplasia or hyperplasia in whom metabolism is controlled and regulated, diagnosis is relatively certain, and abnormal tissue is localized. Ideally a surgeon should accept nothing less. It is likely that additional advances in the field of endocrinology will achieve this ideal. It is the purpose of this paper to outline the current status of biochemical information which forms the basis for modern adrenal surgery.
CUSHING'S SYNDROME The symptoms of Cushing's syndrome, which may include truncal obesity, hypertension, acne, hirsutism, muscular weakness, amenorrhea, increased capillary fragility, growth failure, and osteoporosis, are all due to cortisone excess. This excess cortisone production may be due to an adrenocorticotropic hormone (ACTH) producing tumor of the pituitary, to an ectopic ACTH-producing tumor, to unexplained adrenal hyperplasia, or to an independently functioning adrenal gland adenoma or carcinoma. In most patients with Cushing's syndrome, the symptoms do not indicate the underlying pathology, and the surgeon must therefore rely on biochemical and radiologic methods to arrive at a proper diagnosis and to localize the tumor if one exists. Early in the course of the disease, many of the symptoms of florid Cushing's syndrome may be absent. We have recently seen an adolescent boy who was asymptomatic except for marked growth failure of 5 years' duration and a similar degree of bone age delay in whom the only biochemical abnormalities were a mildly elevated cortisol production rate, elevated baseline urinary 17-hydroxycorticosteroids (17-0HCS), and a slight hyperresponse to intravenous ACTH. This patient has responded to bilateral adrenalectomy by growing 3.4 inches in the first 9 postoperative months. Within the past decade, more refined laboratory methods have made diagnosis in such patients easier. The measurement of the cortisol production rate (CPR) with 14C_ or 3H -labeled cortisol is the most direct means of assessing adrenal activity. Although this test has previously been performed only in a few large medical centers, it is becoming increasingly available throughout the
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country. Kenny et aU reported CPR in 48 normal subjects from 4 months to 48 years of age and found the mean to be 11.8 ± 2.5 mg. per square meter per 24 hours. Because simple exogenous obesity can mimic most of the clinical symptoms of Cushing's syndrome, it is essential to separate these patients. Migeon and co-workers 12 reported a mean CPR of 15.0 ± 5.6 mg. per square meter per 24 hours in 31 obese subjects, which is significantly higher than the normal average. The use of baseline urinary 17-0HCS in simple obesity may also result in a mistaken diagnosis of Cushing's syndrome. Migeon et al}2 found the mean urinary 17-0HCS excretion to be 3.1 ± 1.1 mg. per square meter per 24 hours in 180 normal subjects. The mean urinary 17-0HCS corrected for surface area in a group of 160 obese subjects was 4.3 ± 1.9 mg. per square meter per 24 hours, again significantly higher than that obtained in normal subjects. On the basis of these studies these workers propose a scheme for the diagnosis of Cushing's syndrome (Figs. 1 and 2, reproduced with permission of the authors). If the urinary 17-0HCS level is less than 5.5 mg. per square meter per 24 hours (3.1 mg. + 2 standard deviation [S.D.]), one is dealing with obesity, whereas a value greater than 10 mg. per square meter per 24 hours is indicative of Cushing's syndrome. Suppression of the adrenal gland with dexamethasone (Decadron), a potent synthetic cortisone analogue excreted in the urine in minute amounts, is useful in distinguishing the patient with simple obesity in whom the baseline urinary corticoids are in the 5.5 to 10.0 mg. per square meter per 24 hour
I
URINARY 17-0HCS
I
~1~ > >
<5.5 MGjM2jOAY
I <2 MGjOAY
/ OBESITY
1 SINGLE
/1 >
2 MGjOAY
1 I
20 MGjM 2jOAY
5.5 AND <20
POSSI BLE CUSHING'S I NVESTI GATE FURTHER
1 SUPPRESS I ON
TEST
>
1 1
2 MGj DAY
CUSHING'S
Figure 1. Scheme for diagnosis of Cushing's syndrome by measurement of urinary 17-hydroxycorticosteroids (l7-0HCS).
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VIRGINIA WELDON, CLARENCE
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ACTH TEST
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~!~ NO RESPONSE
!
!
ADRENAL CARC I NOMA PITLITARY TLMOR?
>2
i
HYPER-RESPONSE
B I LATERAL HYPERPLAS I A
NORMAL
! DOES NOT EXCLUDE: ADREN. TLMOR - BILAT. HYPER. OBES I TV
i
MG/DAY
<2 MG/DAY
~i TR I PLE SUPPRESS I ON TEST
Figure 2. Scheme for diagnosis of adrenal disorders by stimulation and suppression of adrenal function.
range. The Decadron test can be further extended by giving a triple dose to differentiate adrenal hyperplasia from adrenal carcinoma and ectopic ACTH-producing tumors. The use of a human growth hormone suppression test to distinguish adrenocortical hyperfunction due to hypersecretion of ACTH has recently been proposed by Schteingart and Conn. 15 In addition, the intravenous ACTH stimulation test is useful in distinguishing hyperplasia from carcinoma. These biochemical tests, however, are not always foolproof. Braverman and co-workers 2 reported a patient with Cushing's syndrome in whom the response to single Decadron suppression was normal. There have been similar reports suggesting the occasional unreliability of both the Decadron suppression test and the ACTH stimulation test. Additional information to localize the source of hormonal overproduction can be gained from plasma ACTH levels. Liddle8 has reported slightly elevated levels in patients with pituitary tumor or bilateral adrenal hyperplasia, markedly elevated levels in the ectopic ACTH syndrome, and decreased levels in cases of adrenal tumor. Because reliance on hormone secretion rate, stimulation, and suppression tests can occasionally be misleading, several workers are using catheterization studies and more refined radiographic techniques to localize ectopic tumors or tumors of the adrenal glands. N ey et al. 13 reported studies of inferior vena caval catheterization in which an abrupt increase in the concentration of plasma 17-0HCS at the Lllevellocalized an ectopic adrenocortical tumor. In additon Bucht et al.,3 Sutton,16 and Melby et al. l l have utilized adrenal vein catheterization to localize aldosterone-
THE BIOCHEMICAL BASIS OF ADRENAL SURGERY
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producing tumors. Such techniques can also be applied to the localization of glucocorticoid-producing tumors. At the present time there are several pharmacologic agents available for the suppression of adrenal steroid production. The use of o,p'-DDD (2, 2-bis(2-chlorophenyl-4-chlorophenyl)-1 ,1-dichloroethane) has been reported in adrenal hyperplasia in a lO-year-old child with good results during 15 months of therapy. 1 This drug has also been used in the management of adrenocortical carcinoma but has a formidable toxicity.9. 10 The use of aminoglutethiInide as a suppressor of adrenal steroid production has been reported in normals 4 • 5 and in patients with adrenal carcinoma,14 adrenal adenoma, and bilateral adrenal hyperplasia, as well as in a patient with ectopic ACTH syndrome. 6 It is possible that these agents may be useful in the preoperative preparation of the patient with Cushing's syndrome, much as iodides and propylthiouracil or methimazole (Tapazole) are used in the patient with hyperthyroidism.
PRIMARY HYPERALDOSTERONISM In 1955 Conn3 first described a syndrome characterized by hypertension and severe potassium depletion resulting in hypokaleInic alkalosis. Other symptoms associated with this syndrome are due to the potassium depletion and include paresthesias, muscular weakness, cramps, tetany, polydipsia, and nocturia. Although sodium is retained and the extracellular volume is expanded, edema is not a clinical feature. During the years since Conn first established this syndrome as a clinical entity due to overproduction of aldosterone, the methods for measuring this hormone in urine and plasma have become increasingly refined. Aldosterone was first isolated in 195216 and its chemical structure identified in 1953. 14 Subsequently various bioassays were used which measured the hormone in a seIniquantitative way until 1960, when Kliman and Peterson9applied the method of double isotope dilution to the quantitation of aldosterone. The suggestion that renin, a hormone secreted by the kidney which leads to the production of angiotensin, was responsible for control of aldosterone production was made by Laragh and others 10 and Genest.7 In 1963, Conn5 proposed the use of renin and/or angiotensin to distinguish primary aldosteronism from renal secondary aldosteronism. The method of Boucher, Veyrat, and deChamplain 1 has made possible an accurate bioassay of renin and angiotensin when performed in a reliable laboratory. Only patients with hypertension who have an elevated aldosterone secretory rate (ASR) which remains elevated after sodium loading and a low plasma renin level measured while on a low sodium diet can be considered to fulfill the diagnostic criteria for Conn's syndrome. 12 It should be pointed out that accurate determinations for ASR and plasma renin and/or angiotensin levels are as yet available only in large medical centers. Although the measurement of these three hormones is most useful in the diagnosis of primary hyperaldosteronism, numerous causes of secondary elevations of aldosterone and the inherent difficulties in measuring minute quantities of renin and angiotensin have
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necessitated reliance on certain ancillary tests. When renovascular hypertension is suspected, renal arteriography is mandatory. The use of saline infusion has recently been proposed by Espiner and co-workers.6 These workers found that normal subjects on low sodium diets decreased their aldosterone secretion significantly, whereas patients with primary aldosteronism showed only small changes in secretion with sodium loading. Other workers are currently investigating the response of ASR to high sodium diets in an effort to differentiate primary aldosteronism from benign and malignant hypertension and renovascular hypertension. In addition, response to an infusion of angiotensin was proposed by Kaplan 8 as another means of evaluating these patients. He suggested that patients with renovascular hypertension show less rise than normal patients, whereas patients with primary hyperaldosteronism are unusually sensitive to the pressor action of angiotensin. Several pharmacologic agents are available which antagonize the action of aldosterone. Although these agents have been generally used in the long-term medical management of patients who are unsuitable for surgery or in whom tumor cannot be found, their use in the preoperative preparation of patients should be considered. Spironolactone, one of the steroid 17-spirolactones, has been found to block sodium reabsorption at the distal nephron where aldosterone is known to act. This decreases potassium loss and results in return of plasma potassium and bicarbonate to normal. Triamterene (2,4,7-triamino-6-phenylpteridine) has been found to cause sodium excretion and potassium conservation in patients with Conn's syndrome,t3 and unlike spironolactone, it is not an aldosterone antagonist, but instead has an effect on the distal tubule opposite to the effect of sodium-retaining steroidsY Since Conn has emphasized the frequency of small adrenocortical adenomas causing hypertension and aldosteronism,'4 there has been an increased effort to localize these small tumors. Bucht and co-workers2 in 1964 reported percutaneous catheterization of the left adrenal vein with sampling of blood for determination of aldosterone that resulted in localization of the tumor. Using a similar technique, Sutton '5 successfully catheterized the left adrenal vein in 22 of 27 cases and identified seven tumors, all of which were confirmed at surgery. Melby and others" have reported successful percutaneous transfemoral bilateral adrenal vein catheterization. With such a procedure, they were able to detect small (0.3 to 2.3 cm.) adenomas by comparing aldosterone levels of adrenal venous blood. This group has pointed out the 10 per cent frequency of bilateral adenomas, thereby emphasizing the diagnostic importance of bilateral catheterization.
PHEOCHROMOCYTOMA Pheochromocytomas are tumors arising from chromaffin tissue which secrete excessive amounts of the catecholamines epinephrine and norepinephrine. These hormones in excess produce systemic hypertension. Because the disorder can be completely cured by the removal of the tumors, it is essential that all hypertensive patients be viewed as pos-
THE BIOCHEMICAL BASIS OF ADRENAL SURGERY
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sibly harboring a pheochromocytoma. Certain clinical features aid in the diagnosis of pheochromocytomas. These include excessive sweating, orthostatic decrease in blood pressure without treatment, and the presence of other neuroepidermal disorders, such as von Recklinghausen's neurofibromatosis or Lindau-von Hippel disease. Pheochromocytoma has also been noted with medullary carcinoma of the thyroid and as a part of a syndrome including hyperparathyroidism. The tumor is known to be a familial disease. In these instances the adrenal tumors are ordinarily bilateral. Fluorometric procedures have now been developed for determination of the concentration of catecholamines in plasma and urine. 17, 18, 22 At the present time, however, these techniques are available only in specific laboratories and are subject to considerable error and variability. Armstrong and McMillan! discovered in 1957 the presence of the catecholamine metabolite 3-methoxy-4-hydroxymandelic acid (VMA) in human urine. Subsequently Axelrod and other investigators demonstrated that epinephrine (E) and norepinephrine (NE) were metabolized principally to metanephrine (M) and normetanephrine (NM) respectively by O-methylation. 2, 11, 16 It was demonstrated later that NM and M may be metabolized to 3-methoxy-4-hydroxymandelic aldehyde (L), which may either be reduced to 3-methoxy-4-hydroxyphenylglycol (G)3, 6 or oxidized to VMA. Further studies have demonstrated the quantity of combined NM and M excreted and that smaller quantities of G also may be detected. lO Techniques for urinary assays of the metanephrines have been described from several laboratories. The methods have employed chromatography,l2 ion exchange procedures,9 fiuorometry,4 paper electrophoresis,19 and chromatoelectrophoresis,13,23 Sheps et al. l4 have recently reported a comparative study of the measurement of catecholamine in serum and blood with the techniques for measuring urinary metanephrines and VMA. They concluded that the measurement of metabolites was much less subject to false positive results than the determination of catecholamines. The first appropriate tests for the confirmation of pheochromocytoma to become available were pharmacologic tests employing agents that stimulated release of catecholamines or blocked the action of catecholamines circulating in the blood. The histamine vasopressor test and the phentolamine test gained general wide acceptance as diagnostic tools; unfortunately, both of these tests were associated with severe side reactions and occasional death. Most important, the incidence of positive results in proved cases of pheochromocytoma was only about 75 per cent,7 and there was an appreciable prevalence of false positive reactions. Tyramine, an agent that releases catecholamine from nerve endings, was later introduced. With this agent, false positive reactions have been quite rare, but the incidence of false negatives remains about the same as with the phentolamine and histamine tests. At the present time, it appears that because of the frequent false negative and occasional false positive reactions associated with pharmacologic tests and the difficulty of performing catecholamine estimations, as well as the number of agents
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which interfere with catecholamine assays and metanephrine assays, the reliable diagnosis of pheochromocytoma still must be based on multiple studies in an appropriate clinical setting. Much of the mortality associated with pheochromocytomas has occurred at the time of surgical removal of these tumors. Severe hypertension resulting from manipulation of the hormone-containing tumor, hypotension following the removal of the tumor, and cardiac arrhythmia induced by a high level of circulating catecholamines are the chief causes of mortality. Considerable attention has been directed toward the cause of hypotension, which follows almost universally the removal of pheochromocytomas. It has been suggested that patients with pheochromocytoma frequently have a reduced total blood volume and that hypovolemia is the major factor in the hypotension seen after surgical removal of the tumor. 7 Waldman20 studied the total circulating red cell and plasma volumes in 15 patients with pheochromocytoma. True polycythemia was noted on rare instances in patients with pheochromocytoma. It was thought that the erythrocytosis associated with pheochromocytoma is secondary to the production of erythropoiesis stimulating factor by these tumors. In this series of patients, only four of 18 patients studied with radioactive iodinated albumin were found to have reduced circulating blood volume, and only three of 15 patients studied with chromium-tagged red cells were found to have abnormally low total blood volumes. It thus appears that the majority of patients with pheochromocytomas have a normal or near normal blood volume. Nonetheless, it has been noted empirically8 that replacement or even overreplacement of blood lost at operation is of major importance in the control of the hypotension seen after resection of the tumor. It has been further noted that pressure agents are frequently ineffective in the management of intraoperative hypotension. 21 It is therefore important that the surgical team be prepared to provide blood volume replacement even in the absence of major intraoperative blood loss so that a drop in blood pressure can be empirically but adequately combated. With the recent development of pharmacologic agents that block the action of circulating catecholamines, it has been possible to pharmacologically control adverse physiologic effects of the tumor. The commonly available alpha-adrenergic blocking agent is phenoxybenzamine, and the common beta-adrenergic agent is propranolol. In addition, agents which prevent the synthesis of catecholamine in man have been developed. These agents prevent the hydroxylation of tyrosine to dihydroxyphenylalanine. Such an inhibiting agent is alpha-methylparatyrosine, which has received some clinical trials. 15 With appropriately designed regimens employing these pharmacologic agents, it is now possible to reduce catecholamine levels to normal or near normal in patients with functioning pheochromocytomas. In addition, these regimens are especially valuable for treating patients who are judged to be unacceptable surgical risks and those with malignant pheochromocytomas that cannot be surgically extirpated. Several objections to the use of these agents for the preparation of surgical patients can, however, be raised. The patient who is autonomically unrespon-
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sive loses the sometimes valuable sign of a hypertensive response with massage of the tissue at the time of the operation. This response is frequently helpful in the location of pheochromo'cytomas in aberrant sites. Such autonomically unresponsive patients are also incapable of responding normally to massive hemorrhage when this surgery is done in areas where there are large blood vessels. In many cases such patients can be handled without pharmacologic control but with precise attention to the choice of anesthetic agents (avoiding those which produce catecholamine release, such as ether and cyclopropane), with rapid infusion of blood to combat hypotension, and with the intraoperative use of pressor amines. In addition, lidocaine, a valuable antiarrhythmic agent, has proved extremely valuable in controlling catecholamine-induced arrhythmias. Many tests have been advocated for localizing the tumor site prior to operation. These include retroperitoneal gas insufflation, arteriography, and caval catheterization to determine the site in which a tumor is releasing the catecholamine into the circulation. It must, however, be remembered that these patients do not tolerate manipulative diagnostic procedures well and that 99 per cent of pheochromocytomas are located within the abdominal cavity. Rare exceptions to the abdominal location include functioning tumors of the carotid body and intrathoracic turri.ors which present posterior mediastinal paravertebral masses. In addition, since approximately 20 per cent of pheochromocytomas are multiple, the preoperative localization of a tumor in no way excuses the surgeon from carrying out an extensive abdominal exploration. It is probably correct that such techniques as caval catheterization, angiography, and retroperitoneal air insufflation should be reserved for special cases. Useful preoperative procedures are intravenous pyelograms and laminography of the renal areas. These tests can be done without hazard to the patient and frequently provide some localization of the tumor. It is also essential in these patients because of the coexistence of thyroid and parathyroid disease to evaluate these organs and also because of the frequent coexistence of cholelithiasis to evaluate the patients for the presence of gallstones.
REFERENCES CUSHING'S SYNDROME 1. Bar-Hay, J., Benderiy, A., and Rumney, G.: Treatment of a case of non-tumorous Cushing's syndrome with o,p'DDD. Pediatrics, 33:239,1964. 2. Braverman, L. E., Woeber, K. A., and Ingbar, S. H.: An unusual case of Cushing's syndrome. New Eng.']. Med., 273:1018,1965. 3. Bucht, H., Bergstrom, J., Lindholmer, B., Wijnbladh, H. J., and Hokfelt, K.: Catheterization of the left adrenal vein for contrast injection and steroid analysis in a case of Conn's syndrome. Acta Med. Scand., 176:233, 1964. 4. Cash, R., Brough, A. J., Cohen, M. N. P., and Satoh, P. S.: Amino-glutethimide (EliptEinCiba) as an inhibitor of adrenal steroidogensis: Mechanism of action and therapeutic trial. J. Clin. Endocrin., 27:1239,1967. 5. Fishman, L., Liddle, G. W., Island, D. P., Fleischer, N., and Kuchel, 0.: Effects of aminoglutethimide on adrenal function in man. J. Clin. Endocrin., 27:481,1967. 6. Gorden, P., Becker, C. E., Levey, G. S., and Roth, J.: Efficacy of amino-glutethimide in the ectopic ACTH syndrome. J. Clin. Endocrin., 28:921,1968.
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7. Kenny, F. M., Preeyasombat, C., and Migeon, C. J.: Cortisol production rate: II. Normal infants, children and adults. Pediatrics, 37:34, 1966. 8. Liddle, G. W., Givens, J. R., Nicholson, W. E., and Island, D. P.: The ectopic ACTH syndrome. Cancer Res., 25:1056,1965. 9. Lipsett, M. B., Hertz, R., and Ross, G. T.: Clinical and pathophysiologic aspects of adrenocortical carcinoma. Amer. J. Med., 35:374,1963. 10. May, R. H.: Studies of the pharmacology of o,p'DDD in man. J. Lab. Clin. Med., 58:296, 1961. 11. Melby, J. C., Spark, R. F., Dale, S. L., Egdahl, R. H., and Kahn, P. C.: Diagnosis and localization of aldosterone-producing adenomas by adrenal-vein catheterization. New Eng. J. Med., 277:1050,1967. 12. Migeon, C. J., Green, O. C., and Eckert, J. P.: Study of adrenocortical function in obesity. Metabolism, 12:718, 1963. 13. Ney, R. L., Hammond, W., Wright, L., Davis, W. L., Acker, J., and Bartter, F. C.: Studies in a patient with an ectopic adrenocortical tumor. J. Clin. Endocrin., 26:299,1966. 14. Schteingart, D. E., Cash, E. R., and Conn, J. W.: Amino-glutethimide and metastatic adrenal cancer. J.A.M.A., 198:1007, 1966. 15. Schteingart, D. E., and Conn, J. W.: Suppression of adrenal cortical function by human growth hormone (HGH) in Cushing's syndrome (abstract). Third International Congress of Endocrinology, 1968. 16. Sutton, D.: Diagnosis of Conn's and other adrenal tumours by left adrenal phlebography. Lancet, 1 :453, 1968.
PRIMARY HYPERALDOSTERONISM
1. Boucher, R., Veyrat, R., deChamplain, J.: New procedures for measurement of human plasma angiotensin and renin activity levels. Canad. Med. Ass. J., 90: 194, 1964. 2. Bucht, H., Bergstrom, J., Lindholmer, B., Winjbladh, H. J., and Hokfelt, K.: Catheterization of the left adrenal vein for contrast injection and steroid analysis in a case of Conn's syndrome. Acta Med. Scand., 176:233, 1964. 3. Conn, J. W.: Primary aldosteronism: A new Clinical syndrome. J. Lab. Clin. Med., 45:6, 1955. 4. Conn, J. W., Cohen, E. L., Rovner, D. R., and Nesbit, R. M.: Normokalemic primary aldosteronism: Detectable cause of curable 'essential' hypertension. J.A.M.A., 193:200, 1965. 5. Conn, J. W., Knopf, R. F., and Nesbit, R. M.: Primary aldosteronism. Present evaluation of its clinical characteristics and of the results of surgery. In International Conference on Aldosteronism for International Organization of Medical Science. Prague, 1963, p. 339. 6. Espiner, E. A., Tucci, J. R., Jagger, P. I., and Lauler, D. P.: Effect of saline infusions on aldosterone secretion and electrolyte excretion in normal subjects and in patients with primary aldosteronism. New Eng. J. Med., 277:1,1967. 7. Genest, J.: Angiotensin, aldosterone and human arterial hypertension. Canad. Med. Ass. J., 84:403, 1961. 8. Kaplan, N. M.: Primary aldosteronism with malignant hypertension. New Eng. J. Med., 269:1282,1963. 9. Kliman, B., and Peterson, R. E.: Double isotope derivative assay of aldosterone in biological extracts. J. BioI. Chern., 235: 1639, 1960. 10. Laragh, J. H., Angers, M., Kelly, W. G., and Lieberman, S.: Hypotensive agents and pressor substances. Effect of epinephrine, norepinephrine, angiotensin II and others on the secretory rate of aldosterone in man. J.A.M.A., 174:234, 1960. 11. Melby, J. C., Spark, R. F., Dale, S. L., Egdahl, R. H., and Kahn, P. C.: Diagnosis and localization of aldosterone-producing adenomas by adrenal-vein catheterization. New Eng. J. Med., 277:1050,1967. 12. Rhamy, R. K., McCoy, R. M., Scott, H. W., Jr., Fishman, L. M., Michelakis, A. M., and Liddle, G. W.: Primary aldosteronism experience with current diagnostic criteria and surgical treatment in 14 patients. Ann. Surg., 167:7l8, 1968. 13. Ross, E. J.: Aldosterone and its antagonists. Clin. Pharm. Therap., 6:65,1965. 14. Simpson, S. A., Tait, J. F., Wettstein, A., Nehrer, R., Von Euw, J., and Reichstein, T.: Isolierung eines neuen kristallisierten Hormone aus Nebennieren mit besonders hohen Wirksamkeit auf den mineral StoffwechseI. Experientia, 9:333,1953. 15. Sutton, D.: Diagnosis of Conn's and other adrenal tumours by left adrenal phlebography. Lancet, 1 :453, 1968. 16. Tait, J. F., Simpson, S. A., and Grundy, H. M.: The effect of adrenal extract on mineral metabolism. Lancet, 1 :122,1952.
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PHEOCHROMOCYTOMA 1. Armstrong, M. D., and McMillan, A.: Identification of major urinary metabolites of norepi-
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