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WORLD Journal of SURGERY @ 1998 by the Société Internationale de Chirurgie
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XEIPOUPTIKHI
Adrenalectomy for Primary Aldosteronism: Long-term Follow-up Study in 29 Patients
Jukka Sirén, M.D.,1 Matti Valimäki, M.D.,2 Kauko Huikuri, M.D.,1 Arto Sivula, M.D.,1 Petri Voutilainen, M.D.,1 Reijo Haapiainen, M.D.1
1Department of Surgery, Helsinki University Central Hospital, Haartmaninkatu 4, SF-00290 Helsinki, Finland
2Department of Medicine, Helsinki University Central Hospital, Haartmaninkatu 4, SF-00290 Helsinki, Finland
Abstract. Primary aldosteronism consists of a mixture of subgroups. The operative treatment is successful only in cases of aldosterone-producing neoplasia (and in rare cases of primary unilateral hyperplasia); all other cases should be treated medically. The aim of this study was to determine if aldosterone-producing neoplasia had been successfully differentiated from the other subgroups and the outcome of operative treatment. Altogether 29 patients with primary aldosteronism were operated on between January 1, 1979 and December 31, 1993. Patient charts were reviewed retrospectively. The follow-up data were collected from the patients’ charts, and all patients were contacted to obtain recent blood pressure and serum potassium values. The patients were asked about symptoms related to hyperaldosteronism. If any suspicion of recidive aldosteronism was present, patients were carefully reexamined by hor- monal tests and computed tomography (CT). A total of 27 patients had unilateral adenoma, 1 patient had hyperplasia, and 1 patient had an aldosterone-producing cortical carcinoma. There was no operative mor- tality or morbidity. The serum potassium level had normalized in all patients. Mean follow-up time was 76 months. One patient died during the follow-up from cholangiocarcinoma; 11 patients (41%) were cured by the operation, 10 patients (37%) have a mild but medicated hypertension, and in the remaining 22% the hypertension persisted but was well controlled by the medication. Of the 29 patients, 28 were correctly diagnosed as having an aldosterone-producing neoplasm. Basic hormonal studies and CT can be used effectively to differentiate aldosterone- producing neoplasia from hyperplasia in most cases.
Primary aldosteronism is a syndrome characterized by hyperten- sion, hypokalemia, suppressed plasma renin activity, and elevated serum aldosterone levels. Conn first described it 1955 [1] in association with adrenal cortical adenoma (Conn syndrome). Now we know that primary aldosteronism can be divided into at least six distinctive subgroups: aldosterone-producing adenoma (60- 80%), aldosterone-producing adrenocortical carcinoma (1%), bi- lateral adrenocortical hyperplasia (idiopathic hyperaldosteron- ism) (20%), glucocorticoid-remediable hyperaldosteronism (<1%), renin-responsive adrenocortical adenoma ( << 1%), and primary adrenocortical hyperplasia ( << 1%) [2]. Some authors also add a seventh group, “indeterminate aldosteronism,” for those rare patients for whom the diagnosis remains uncertain. Primary aldosteronism accounts for around 1% of all hypertensive patients [3, 4]. Operative treatment is the treatment of choice for primary
hyperaldosteronism caused by an aldosterone-producing neopla- sia (adenoma or carcinoma). Medical treatment with aldosterone antagonists (spironolactone) seems better in most cases of hyper- plasia [3, 5]. The aim of the present study was to determine if preoperative diagnosis of surgically correctable aldosteronism was accurate and to analyze the effect of operation on hyperaldoste- ronism-related symptoms and signs in patients suspected to have primary aldosteronism caused by an aldosterone-producing neo- plasia.
Materials and Methods
At Helsinki University Central Hospital, from January 1979 through December 1993, a total of 29 patients with primary aldosteronism were operated on. Primary aldosteronism was suspected in hypertensive patients with hypokalemia, inappropri- ately high urinary excretion of potassium (>30 mmol/24 hr), and suppressed plasma renin activity together with a normal or high serum aldosterone level. When appropriate hyperaldosteronism was ascertained by showing high urinary excretion of aldosterone (>13 nmol/24 hr) during volume load [6]. The indication for operative treatment was a suspicion of aldosterone-producing neoplasia (adenoma) in all cases. The distinction between unilat- eral neoplasia and bilateral hyperplasia was made using computed tomography (CT) (n = 29), 1311-6-ß-iodomethyl norcholesterol scan (n = 13) with dexamethasone suppression, and a postural test during volume load (n = 18) [6]. Venography or adrenal venous sampling were not used.
Patients’ charts were reviewed retrospectively and the relevant data collected. The follow-up data were obtained from the patients’ charts and by a letter (and if necessary by a telephone call) to the patient and to the patient’s primary physician. One patient had died, and the cause of death was verified from the national register of death causes. If recent blood pressure and serum potassium measurements were not available, the patient was instructed to obtain them, and the values were recorded. The patient was reexamined if any indication of persistent hyperaldo- steronism was present (CT and postural test during volume load).
Because no systematic analysis of symptoms had been per-
formed preoperatively, all patients were asked to report their preoperative symptoms and the symptoms they had after the operation. The symptoms asked about were headache, weakness, fatigue, nocturia, polydipsia, chest pain, numbness, and muscle cramps.
The results were analyzed statistically. The paired t-test was used to compare pre- and postoperative blood pressures and serum potassium levels. McNemars test was used to compare preoperative with postoperative symptoms. Conventional regres- sion analysis was used to determine if the duration of hyperten- sion was associated with the postoperative blood pressure.
Results
Altogether 29 patients with primary aldosteronism were operated on; 18 were women (62%), and 11 were men. The mean age was 48 years (range 29-71 years). All patients were hypertensive, and all but one had a low serum potassium level (mean 2.9 mmol/L, range 2.2-3.6 mmol/L). The hypertension was generally not in good control. The mean duration of hypertension was 105 months (range 1-360 months). The finding that primarily had led to the suspicion of primary aldosteronism was poorly controlled hyper- tension with low serum potassium in most cases. Clinical symp- toms, such as headache, weakness, and fatigue, were cited as the leading indication for hormonal analysis in only two cases, al- though these patients also had hypertension and hypokalemia. There was a statistically significant difference between the re- ported symptoms preoperatively and postoperatively only for headache (p = 0.003).
The postural test during volume load could be reliably inter- preted in 18 cases. There was a clear decline in plasma aldoste- rone level (a finding suggestive of adenoma) from 8 a.m./recum- bent to 12 p.m./supine in 16 cases (15 adenomas, 1 adenoma with micronodular hyperplasia). The result was inconclusive in one case (adenoma), and the plasma aldosterone level increased (a finding suggestive of hyperplasia) in 1 case (adenoma).
The CT scan was done and localized the tumor in every case. 131I-6-B-Iodomethyl-norcholesterol scan with dexamethasone suppression was used in 13 cases (all solitary adenomas), and the localization was accurate in 12 cases (92%). In one case there was a bilateral take-up. A tumor was seen by CT on the left side and at operation the left adrenal was removed; the right gland was biopsied even though macroscopically normal. The left adrenal contained an adenoma; the biopsy of the right adrenal was microscopically normal. This patient was cured by the operation.
Twenty-five patients were operated on via anterior laparotomy, three patients via lumbotomy, and one patient via dorsal incision. Twenty-five patients had a unilateral solitary adenoma with otherwise normal adrenal histology. The mean size of the adeno- mas was 15 mm (range 8-32 mm). Fourteen adenomas were on the left side and eleven on the right. One patient had an aldosterone-producing cortical carcinoma, 11 cm in diameter, with no lymph node involvement or distant metastases. One patient had macronodular hyperplasia. The largest nodule (10 mm) was seen on CT; the contralateral gland appeared normal on CT and at laparotomy. Two patients had an encapsulated ade- noma (15 and 25 mm in diameter) but also micronodular hyper- plasia. In one of these cases a hormonal analysis of cultured adrenal cells had been carried out, and only the adenoma cells
produced aldosterone. The cells of micronodular hyperplasia were inactive.
There were no operative or postoperative complications or mortality. The serum potassium level was normalized in all patients during the first postoperative week. The blood pressure levels at the time of discharge (mean 140/90 mmHg) were significantly lower than preoperatively (mean 183/113 mmHg) (p < 0.001). Only three patients had a diastolic blood pressure >100 mmHg, although the effect could be partly due to periop- erative antihypertensive treatment.
The mean follow-up time was 76 months (range 9-154 months). One patient died during the follow-up period, 21 months postop- eratively, owing to cholangiocarcinoma with distant metastases. The patient operated for the adrenocortical carcinoma has mild medicated hypertension and has no signs of recurrent disease 36 months postoperatively. The effect of the operation on hyperten- sion in 27 living patients with benign disease was estimated by the patient and her or his doctor at the end of the follow-up. The hypertension was totally cured, and no antihypertensive medica- tion was needed in 11 cases (41%). In 10 cases (37%) the hypertension after the operation was mild and responded well to medication. In the remaining 6 cases (22%) the blood pressure values did not respond to the operation, although the hyperten- sion is better controlled by the medication. The duration of preoperative hypertension did predict the outcome of surgery (Fig. 1), although the difference between groups 2 and 3 is not clear.
In two patients (solitary adenomas) the serum potassium level dropped below normal during the follow-up (3.4 and 3.5 mmol/L). One of them was reexamined 8 years after the operation, but all test results were normal (urine aldosterone 52 nmol/24 hr, plasma renin 0.8 µg/L/hr), and no signs of recidive hyperaldosteronism could be found. The remaining adrenal gland appeared normal on CT examination. The other patient was reexamined 116 months postoperatively. CT examination of the remaining gland was normal, and hormonal studies were all normal (in postural tests during volume loading: urine aldosterone 4 nmol/24 hr; plasma renin at 08:00 a.m. 0.3 µg/L/hr and at 12:00 p.m. 0.6 µg/L/hr; serum aldosterone at 8:00 a.m. and 12:00 a.m. 132 pmol/L and 159 pmol/L, respectively). There were no signs of persistent hyperal- dosteronism.
Discussion
Having first described primary aldosteronism in 1955 [1] Conn et al. published a series of 145 cases in 1964 [7] and suspected the prevalence of primary aldosteronism in the hypertensive popula- tion to be as high as 20% [8]. Today the generally accepted prevalence among hypertensive patients is less than 1% [3, 4], although a prevalence as high as 2.2% has been reported [9]. The most recent studies in Australia among hypertensive normokale- mic population suggest that the incidence of primary aldosteron- ism could be as high as 10% [10].
The main issues in the evaluation of primary aldosteronism are to differentiate adenomas from hyperplasia and to localize ade- nomas. Glucocorticoid suppressible hyperaldosteronism is rare and typically diagnosed in young adults with a family history of hypokalemia-associated hypertension [11]. It is identified by a dexamethasone suppression test and, if found, treated by glu- cocorticoids. Renin-responsive adrenocortical adenoma has been
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considered to be a rare disease; but this might not be the case, and renin-responsive adenoma could be a common finding among the hypertensive normokalemic population [10]. Primary adrenocor- tical hyperplasia is a rare condition [2].
Operative treatment is curative for aldosterone-producing ad- enomas (and for renin-responsive adenomas), but patients with bilateral adrenal hyperplasia are generally best treated with spironolactone. Hypokalemia, alkalosis, plasma aldosterone, and suppression of plasma renin seem to be greater in patients with adenomas, and this feature has been used successfully in math- ematic analysis to distinguish between adenoma and hyperplasia [12]. We have not used this method.
The aldosterone secretion of adenomas is sensitive to adreno- corticotrophic hormone (ACTH), unlike aldosterone secretion from hyperplastic adrenocortical tissue, which is regulated by the renin-angiotensin axis. ACTH excretion follows a circadian rhythm, where the ACTH level (and in case of an adenoma the aldosterone level as well) is decreased during the forenoon [13]. This fall in plasma aldosterone level can be shown by measuring its concentration at 8 a.m. after overnight recumbency and at noon after 4 hours of ambulation. The accuracy of this postural test is about 75% in collected literature [14], and in our series it was accurate in 89%. The postural test is negative not only in patients with hyperplasia but also in patients with renin-sensitive
cortical adenomas, which can be a diagnostic problem if the incidence of these adenomas is as high as recently suggested [10].
In skillful hands the most accurate test differentiating adeno- mas from hyperplasia is selective adrenal venous sampling for aldosterone measurement [15]. It is invasive, the technique is difficult, and the failure rate for catheterization of the right adrenal vein is 26% [5]. Hence it is not used widely. Venous sampling is also the best test for localizing aldosterone-producing adenomas. CT seems also to be accurate, with a sensitivity of 88%, specificity of 83%, and accuracy of 86% [16].
Doppman et al. compared the efficacy of CT and adrenal venous sampling in a series of 24 patients [17] and reported that venous sampling was significantly more sensitive (100% vs. 71%) and specific (67% vs. 33%) than CT. The most common error was diagnosis of hyperplasia based on the presence of bilateral nodules on CT scans.
In our series all adenomas were correctly localized with CT, although a hyperplastic nodule gave a false-positive result in one case. This patient with macronodular hyperplasia may represent the rare unilateral hyperplasia. However, we do not know if some adenomas were missed owing to the limitations of CT. Iodocho- lesterol scintigraphy during dexamethasone inhibition can also be used, but it does not seem to have advantages over CT scans, and the accuracy is 72% to 92% [5]. Magnetic resonance imaging (MRI) has also been used as a localization method but has not been better than CT [5]. Despite of the limitations of the sensitivity and specificity of CT, we continue to use it as a primary localization method and consider a unilateral adrenal mass to be an indication for operative treatment.
The treatment of choice for patients with aldosterone-produc- ing adenoma is laparoscopic unilateral adrenalectomy [18, 19]. Adrenalectomy through the posterior approach was the method of choice before laparoscopic surgery came into wide use and can still be used by surgeons not familiar with laparoscopic methods. The anterior approach (laparotomy) should be avoided because it seems to increase the duration of the hospital stay, morbidity, and mortality [20].
In the collected literature, calculated from 694 cases [5], the long-term cure rate of operatively treated aldosterone-producing adenomas was 69%. Most patients have improved blood pressure control after operation. In our series 41% were without antihy- pertensive medication, and 37% had a mild hypertension well controlled by mild medication. The blood pressure level in the remaining 22% did not decrease but is better controlled by medication. The long duration of the hypertension preoperatively is believed to cause adaptive and irreversible vascular changes that maintain hypertension [21]. The present study shows that the duration of hypertension can predict the outcome of surgery to some extent, but there is considerable overlap between the groups. Obara et al. estimated the risk factors for postoperative persistent hypertension by univariate analysis in 100 patients [22]. They showed that only age and sex, and not the duration of hypertension, were independent risk factors. The serum potas- sium level normalizes in almost all cases.
Conclusions
The diagnosis of primary aldosteronism is usually suspected when the patient presents with poorly controlled hypertension with hypokalemia. Symptoms related to hyperaldosteronism are non-
specific and seldom suggest the diagnosis. When the diagnosis of primary aldosteronism is established, aldosterone-producing ade- nomas and idiopathic hyperplasia must be distinguished. CT can be used as the primary examination; and if a clear unilateral mass (≥1 cm) is found, no further evaluation is indicated. Laparoscopic unilateral adrenalectomy is then performed. If both adrenals have nodules, venous sampling may be used to rule out unilateral adenoma. If no lateralization is found, the patient is considered to have idiopathic hyperplasia and is treated medically, usually with spironolactone. Hypertension is cured or better controlled by the operative treatment in most cases. The duration of hypertension predicts the outcome in some extent. The serum potassium level normalizes in almost all cases.
References
1. Conn, J.W .: Presidential address. Part I. Painting the background. Part II. Primary aldosteronism, a new clinical syndrome. J. Lab. Clin. Med. 43:3, 1955
2. Irony, I., Kater, C.E., Biglieri, D.G., Shackleton, C.H.L .: Correctable subsets of primary aldosteronism: primary adrenal hyperplasia and renin responsive adenoma. Am. J. Hypertens. 3:576, 1990
3. Scoggins, B.A., Coghlan, J.P .: Primary hyperaldosteronism. Pharma- col. Ther. 9:367, 1980
4. Berglund, G., Andersson, O., Wilhelmsen, L .: Prevalence of primary and secondary hypertension: studies in a random population sample. B.M.J. 2:554, 1976
5. Young, W.F., Hogan, M.J., Klee, G.G., Grant, C.S., van Heerden, J.A .: Primary aldosteronism: diagnosis and treatment. Mayo Clin. Proc. 65:96, 1990
6. Vaughan, N.J.A., Jowett, T.P., Slater, J.D.H., Wiggins, R.C., Light- man, S.L., Ma, J.T.C., Payne, N.N .: The diagnosis of primary hyper- aldosteronism. Lancet 1:120, 1981
7. Conn, J.W., Knopf, R.F., Nesbit, R.M .: Clinical characteristics of primary aldosteronism from an analysis of 145 cases. Am. J. Surg. 107:159, 1964
8. Conn, J.W .: Plasma renin activity in primary aldosteronism. J.A.M.A. 190:222, 1964
9. Streeten, D.H.P., Tomycz, N., Andersson, G.H .: Reliability of screen-
Invited Commentary
William F. Young, Jr., M.D.
Division of Endocrinology, Metabolism, and Internal Medicine, School of Medicine, Mayo Clinic, Rochester, Minnesota, USA
Siren and colleagues focus on two major issues: (1) the efficacy of adrenal computed tomography (CT) for subtype evaluation of primary aldosteronism, and (2) the long-term cure rate of hyper- tension following surgery for aldosterone-producing adenomas (APAs) detected by CT. For the last 40 years much debate and controversy have surrounded the optimal diagnostic approach to the subtype evaluation in primary aldosteronism [1-3]. During the last decade of this century it has become clear that, beyond historical interest, there are limited or nonexistent roles for many of tests that have been default standards for subtype evaluation (e.g., [68-131I]iodomethyl-19-norcholesterol scintigraphy, posture stimula- tion test, and serum 18-hydroxycorticosterone concentration) [4].
ing methods for the diagnosis of primary aldosteronism. Am. J. Med. 67:403, 1979
10. Gordon, R.D., Stowasser, M., Tunny, T.J., Klemm, S.A., Rutherford, J.C .: High incidence of primary aldosteronism in 199 patients referred with hypertension. Clin. Exp. Pharmacol. Physiol. 21:315, 1994
11. Giebink, E.S., Gotlin, R.W., Biglieri, E.G., Katz, F.H .: A kindred with familial glucocorticoid suppressible aldosteronism. J. Clin. Endocri- nol. Metab. 36:715, 1973
12. Aitchison, J., Brown, J.J., Frazer, R., Kay, A.W., Lever, A.F., Neville, A.M., Symington, T., Robertson, J.I.S .: Quadric analysis in the preoperative distinction between patients with and without adreno- cortical tumors in hypertension with aldosterone excess and low plasma renin. Am. Heart J. 82:660, 1971
13. Schambelan, M., Brust, N.L., Chang, B.C.F., Slater, K.L., Biglieri, E.G .: Circadian rhythm and effect of posture on plasma aldosterone concentration in primary aldosteronism. J. Clin. Endocrinol. Metab. 43:115, 1976
14. Granberg, P.O., Adamson, U., Cohn, K.H., Hamberger, B., Lins, P.E .: The management of patients with primary aldosteronism. World J. Surg. 6:757, 1982
15. Doppman, J.L., Gill, J.R., Jr .: Hyperaldosteronism: sampling the adrenal veins. Radiology 198:309, 1996
16. Ikeda, D.M., Francis, I.R., Glazer, G.M., Amendola, M.A., Gross, M.D., Aisen, A.M .: The detection of adrenal tumors and hyperpla- sia in patients with primary aldosteronism: comparison of scintig- raphy, CT, and MR imaging. A.J.R. Am. J. Roentgenol. 153:301, 1989
17. Doppman, J.L., Gill, J.R., Jr., Miller, D.L., Chang, R., Gupta, R., Friedman, T.C., Choyke, P.L., Feuerstein, I.M., Dwyer, A.J., Jicha, D.L., Walther, M.M., Norton, J.A., Linehan, W.M .: Distinction between hyperaldosteronism due to bilateral hyperplasia and unilat- eral aldosteronoma: reliability of CT. Radiology 184:677, 1992
18. Prinz, R.A .: A comparison of laparoscopic and open adrenalectomies. Arch. Surg. 130:489, 1995
19. Horgan, S., Sinanan, M., Helton, S., Pellegrini, C.A .: Use of laparo- scopic techniques improves outcome from adrenalectomy. Am. J. Surg. 173:371, 1997
20. Russell, C.F., Hamberger, B., van Heerden, J.A., Edis, A.J., Ilstrup, D.M .: Adrenalectomy: anterior or posterior approach? Am. J. Surg. 144:322, 1982
21. Folkow, B .: Physiological aspects of primary hypertension. Physiol. Rev. 62:347, 1982
22. Obara, T., Ito, Y., Fujimoto, Y .: Textbook of Endocrine Surgery. Philadelphia, Saunders, 1997
Today, subtype evaluation of primary aldosteronism may re- quire one or more tests, the first of which is imaging the adrenal with CT. The report from Siren and colleagues supports the approach that when a solitary unilateral macroadenoma (> 1 cm) and normal contralateral adrenal morphology are found on CT in a patient with primary aldosteronism, unilateral adrenalectomy is a reasonable therapeutic option. Adrenal CT can accurately diagnose APAs that are macroadenomas.
However, Siren and colleagues did not address the large group of patients with primary aldosteronism with ambiguous findings on adrenal CT. CT imaging may reveal normal-appearing adre- nals, minimal unilateral adrenal limb thickening, unilateral mi- croadenomas (≤1 cm), or bilateral macroadenomas. In these cases additional testing is required to determine the source of excess aldosterone secretion. Small APAs may be labeled incor- rectly as idiopathic hyperaldosteronism (IHA) on the basis of CT findings of bilateral nodularity or normal-appearing adrenals [5]. Also, apparent adrenal microadenomas may represent areas of hyperplasia, and unilateral adrenalectomy would be inappropriate [6]. Patients with APAs have more severe hypertension, more
profound hypokalemia (< 3.0 mEq/L), higher plasma (> 25 ng/ dl) and urinary (> 30 µg/24 hr) levels of aldosterone, and younger age (< 50 years) than those with IHA [2]. Patients fitting these descriptors are considered to have a “high probability of APA.” Improved methods and advances in catheter technology have greatly enhanced the overall success rate of adrenal venous sampling [7]; we have found a unilateral APA in 36% of those with clinically “high probability” APA who had normal findings or unilateral adrenal limb thickening on CT [8].
The treatment goal in patients with primary aldosteronism is to prevent morbidity and mortality associated with hypertension and hypokalemia. The cause of the primary aldosteronism determines the appropriate treatment. Siren and colleagues found a hyper- tension cure rate of 41% and a major improvement in blood pressure control in 37% of patients. The persistent hypertension following unilateral adrenalectomy for APA was correlated in part with the duration of hypertension. Age has also been shown to be a predictor of cure of hypertension following unilateral adrenal- ectomy [9]. This type of information is useful when deciding which patients are the best candidates for surgery.
In conclusion, Siren and colleagues confirm the concept that adrenal CT is a reasonable initial test for subtype evaluation of primary aldosteronism. When a unilateral adrenal macroadenoma is found with CT, ipsilateral adrenalectomy can cure or markedly improve the hypertension in approximately 78% of patients. Patients who have a high probability of APA based on clinical predictors and lack a macroadenoma on adrenal CT should be considered for adrenal venous sampling.
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6. Radin, D.R., Manoogian, C., Nadler, J.L .: Diagnosis of primary hyperaldosteronism: importance of correlating CT findings with endo- crinologic studies. Am. J. Radiol. 158:553, 1992
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