0021-972X/92/7501-0323$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright 0 1992 by The Endocrine Society

Vol. 75, No. 1 Printed in U.S.A.

Plasma Aldosterone Response to Upright Posture Angiotensin II Infusion in Aldosteyone-Producing Adenoma* KAORU NOMURA, MOTOHIKO AIBA,

SHOHZOH TORAYA, NOBUO HIROSHI DEMURA

HORIBA,

MAKOTO

and

UJIHARA,

AND

Department of Medicine, Institute of Clinical Endocrinology (K.N., S.T., N.H., M. U., H.D.) and Division Surgical Pathology (M.A.), Tokyo Women’s Medical College, Tokyo 162, Japan ABSTRACT

of

that APA is functionally insensitive to angiotensin II. A concomitant rise of ACTH, pretreatment with calcium channel blockade, and other modulating factors may be involved in this PAC rise. Whatever the reason, such a high frequency of patients with increased PAC in APA raises some question about the clinical value of the upright posture test. We believe, then, there is reason to check any interpretation concerning increased PAC in the case of the upright posture test in distinguishing between APA and idiopathic hyperaldosteronism. (J Clin Endocrinol Metab 75: 323-327, 1992)

Nineteen patients with primary aldosteronism due to surgically confirmed aldosterone-producing adenoma (APA) were examined to evaluate the response of aldosterone to upright posture and angiotensin II infusion. Upright posture reportedly decreases the plasma aldosterone concentration (PAC) in APA but raises it in idiopathic hyperaldosteronism. However, our findings showed the opposite result, in that the upright posture did not change or raised PAC in 15 of 19 cases (79%). Angiotensin II was infused iv at doses from 0.5-2 ng/min.kg body weight in six patients in whom the upright posture raised PAC, but did not raise PAC in all cases. This result supports the assumption

A

DIAGNOSIS differentiating aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) is important to therapy because, in principle, the former is surgically curable whereas the latter is not. Function tests attempting to differentiate between APA and IHA include the 4-h upright posture test after overnight recumbency. The upright posture has been found to decrease plasma aldosterone concentration (PAC) in APA but increase it in IHA (l-3). The reasoning behind such results holds that aldosterone secretion is ACTH-dependent in APA (3, 4) and angiotensin-II-dependent in IHA (5). Exceptions occur, however, in patients with APA whose PAC rose (l-lo). McLeod et al. (11) recently reported that a rise in PAC was observed in 8 (80%) of 10 patients with APA, although the increase was small. A recent study in 73 patients with APA showed a relatively small decrement (5%) in mean PAC values (12). Furthermore, some of the patients in whom upright posture raised PAC have been proposed for classification as a subgroup of APA (12-14). Thus, the upright posture appeared to provide complex information as a diagnostic clue. Another function test, angiotensin II infusion, reportedly raised PAC in IHA but not in APA (5, 15). However, Gordon et al. (14) reported a subgroup in which PAC was increased by angiotensin II infusion, posing problems in functionally diagnosing APA. Received March 12, 1991. Address editorial responses and reprint requests to: Kaoru Nomura, M.D., Department of Medicine, Institute of Clinical Endocrinoloav, Tokyo Women’s Medical College, 8-l Kawada-cho, Shinjuku-ku, Tokyo 162, Japan. * This study was supported in part by a grant for the treatment of intractable diseases from the Japanese Ministry of Health and Welfare.

The purpose of our study was to reevaluate the usefulness of the upright posture test in functionally diagnosing APA, and to examine the angiotensin II responsivenessin APA. Patients

and Methods

The 19 patients studied showed hypertension, high PAC, and suppressedPRA with normal urinary excretions of 17hydroxycorticoids and 17-ketosteroids. Urinary aldosterone levels were measured in 10 patients and found to be high (see Table 1). Adenoma was demonstrated by adrenal CT scanin all cases.Furthermore, at least one additional item of supporting evidence was demonstrated to diagnose APA in each case as follows: no responsein PAC on angiotensin II infusion as described later (patients l-5); significant laterality in adrenal venous PAC in patients 8, 9, and 11-13; and significant laterality in dexamethasone-suppressionadrenal scintigraphy in patients 1, 3-5, 7, 8, and 10-19. All cases were treated by adrenalectomy of the adenoma-bearing gland, which improved their hypertension, hypokalemia, and hyperaldosteronism with suppressedPRA (seeTable 1). The resected adrenal glands were histopathologically examined as described by Ferris et al. (16). Tests of upright posture and angiotensin II infusion were performed while patients were interned at our hospital. Patients took 7 g/day sodium chloride. Medication was stopped as described in Table 1 captions. Upright posture was started at 0800 h after overnight recumbency and stopped at 1200 h. Injectable angiotensin II (Hypertensin Chiba) provided by Chiba-Geigy Ltd., Basle, Switzerland was infused based on the method of Wisgerhof et al. (5). Infused doses(0.5 to 2 ng/min.kg body

323

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324

COMMENTS

weight) were reportedly enough to increase PAC in IHA but not in APA (5, 14, 15). Plasma levels of cortisol and PRA were measured by RIA as reported elsewhere (17). Normal values for cortisol ranged between 120 and 660 nmol/L, and those for PRA between 0.14 and 0.83 ng/(L.s). PAC was measured using a commercial RIA kit (Dainabot Co., Tokyo, Japan) (17). Twenty-four-hour urine specimens were collected in HCl to adjust pH 1 for 24 h, and urinary aldosterone was measured by RIA (17). The intraassay variations were 4.4%, 4.4%, and 3.2% at PAC of 233, 419, and 2572 pmol/ L. Interassay variations were 5.2%, 5.7%, and 4.4% in PAC as described above. The detection limit of PAC was 55.5 pmol/L. Antiserum cross-reacted 0.0021% with corticosterone; 0.0080% with 1 1-deoxycorticosterone; less than 0.0015% with testosterone, cortisone, and progesterone; less than 0.00015% with cortisol and dehydroepiandrosteronesulfate, and 0.00097% with 18hydroxycorticosterone (18 OH-B). Normal values for PAC ranged between 60 and 420 pmol/L.

Results Histopathological

findings

on resected adrenal

glands

Findings are shown in Table 1. Eighteen of 19 patients had a single adenoma. Patient 14 had two adenomas of equal size in one gland. All 19 patients had typical APA accompanying diffuse or focal hyperplasia of the zona glomerulosa with or without micronodules (less than 0.4 cm in diameter), a characteristic finding for APA (16, 18, 19). Rare forms of surgically correctable hyperplasia (20, 21) were not found. Upright

posture

test

Of the 19 patients studied, patients 1-15 (79%) showed increased PAC after standing (PAC-increase group), i.e. increases from 912 f 75 (SE) to I513 + I50 pmol/L (66%) (Table 1 and Fig. 1). The increase (66%) was less than that of normal controls (143%) and of aldosterone-producing renin-responsive adenoma (113 %) reported by others (12). Only patients 16-19 (21%) showed decreased PAC (PACdecrease group). The two groups showed no significant histological differences in adenoma and cortical tissues adjacent to the adenoma (Table 1). In the PAC-increase group, PRA also rose in 10 cases. Angiotensin

II infusion

test

Angiotensin II was infused in six patients (patients l-6) of a PAC-increase group (Table 1 and Fig. 2). PAC did not rise (patients 1-5) at all or rose only slightly, if any (patient 6). Discussion Our result showed that the upright posture increased PAC with a high frequency (79%). Ideally, the plasma cortisol concentration should be measured in monitoring ACTH release, but could be done only in four of our cases. A definite fall occurred for patients 1 and 6, but not patients 2 and 14.

JCE & M. 1992 Vol75.Nol

Plasma cortisol after standing have been reportedly decreased in APA, but some decreased only slightly or even rose (1, 2, 22, 23), resulting in relatively minor decreases in mean values (5 to 38%) (l-3). Therefore, our findings on plasma cortisol seemed to be essentially the same as that of others. However, the possibility that a high frequency of an increased PAC in our study could result from high frequency of concomitant ACTH rise cannot be excluded. Upright posture raised PRA both in our study and in others (2, 3, 10). Exogenously infused angiotensin II failed, however, to raise PAC in our study and in others (5, 15). Therefore, the rise in PAC was not attributable to the rise in endogeneous angiotensin II levels. Gordon et al. (14) reported, however, an angiotensin-responsive APA characterized by increased PAC both in the angiotensin II infusion test and in the upright posture test, by normal urinary excretions of 18-hydroxycortisol (18-OH-F) and 18-oxocortisol (18-0X0-F) and by histological characteristics showing lessened composition of the zona fasciculata type cell (large, lipid-laden clear cells) (24). Patients in our study differed from those in terms of their sensitivity to angiotensin II and histology. Biglieri et al. (12, 13) reported a subgroup of APA characterized both by increased PAC in the upright posture test and by normal 18-OH-B levels. This group was designated aldosterone-producing renin-responsive adenoma (AI’-RA) (12, 13), although the PAC response was not examined by direct angiotensin II infusion. Upright posture raised PAC more than 2-fold in AP-RA, more prominently than that in study. This difference may be attributable to the different sensitivity to angiotensin II. Because we did not measure 18-OH-F, 18-0X0-F, or 18-OH-B, and did not infuse angiotensin II into all patients, we could not completely exclude the possibility that some of our patients may have AP-RA. Vaughan et al. (7) reported that a high sodium diet and the administration of fluorocortisone reduced the frequency of PAC-increase patients from 22-O%. Ganguly et al. (1) found no difference, however, between patients treated with high and with low salt diets. Studies which used almost the same dose of salt intake as ours reported a relatively high frequency of PAC-decrease patients (6, 7, 10). Therefore, it seems unlikely that salt intake is significant in the PACresponse. In some patients, we hesitated to stop treatment with antihypertensive drugs, calcium (Ca”) channel blockade, for a long time for examinations. Ca2+ blockade was reported to decrease PAC in APA (25), but this was not supported by other studies (26, 27). The plasma half-life of the Ca2+ blockade is short, i.e. about 1 h both for nifedipine (28) and nicardipine hydrochloride (29). The percent increase of PAC was the same for patients who did not take Ca2+ blockade for a significant period and those who stopped taking the drug overnight, i.e. 63 + 12% (n = 4) us. 74 f 19% (n = 7) (because patients 3 and 8 had been taking spironolactone too, their data was excluded). This suggested that overnight interruption could exclude the possible effect of the drug. Furthermore, PAC rises were observed even in four patients in whom medication was stopped for a significant period,

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325

COMMENTS TABLE

1. Patient

profiles 4-h upright

Patient

Age (yr) and sex

PAC (pmol/L)

Ret

posture

before

PRA

Iw/(L

Hormonal data adrenalectomy

adrenalectomy

s)l

Plasma cortisol concentration (nmol/L)

Urinary aldosterone excretion (nmol/day)

Ret

Up

Ret

Up

1110 920

0.06 0.03

0.47 0.06

300 300

260 350

Up

30.5

710

50F 54M

1010

870

2050 1610

0.06 0.06

0.08 0.19

53M

920

1740

0.06

0.06

32F 42F

1120

1760

980

1910

0.03 0.06

0.17

7

8

51F

650

1050

0.11

0.14

9

37F

720

960

0.06

0.06

10

57F

770

830

0.03

0.03

11

55F

520

1000

0.06

0.19

12

47F

950

2420

0.03

0.06

13

38F

1000

1150

0.4

0.55

14

41M

1310

1470

0.08

0.19

15

61F

1610

2710

0.03

0.03

16

22F

1110

960

17

49M

1150

1030

0.11

0.08

85.4

18

43F

640 760

0.03 0.03

74.3

51M

920 1180

0.08

19

949

1373 +135 523

0.05 kO.01

0.12 kO.03

+91

fO.10

6

Mean

+ SE

Normal controls (n = 4)

540

f62 215 k52

77.9

43.3

240

200

0.11

42.4

35.0

58.0

470

460 44.4 33.0

0.31

0.03

1.81

kO.57

Histopathology: Adenoma (cm in diameter) adjacent tissue” Time

after

adT;;z;f)my

51F 52F

Clear cell (1.3) hyperplasia Clear and complex cell (2.0) hyperplasia Clear cell (1.6) hyperplasia Clear cell (1.9) hyperplasia with micronodules Clear and compact cell (1.5) hyperplasia with micronodules Clear cell (1.8) hyperplasia Clear and compact cell (2.1) hyperplasia with micronodules Clear and compact cell (1.2) hyperplasia with micronodules Clear cell (1.2) hyperplasia with micronodules Clear and compact cell (1.0) hyperplasia with micronodules Clear and compact cell (1.4) hyperplasia with micronodules Clear and compact cell (1.5) hyperplasia with micronodules Clear cell (1.2) hyperplasia with micronodules Clear and compact cell (1.4, 1.4) hyperplasia Clear and compact cell (2.0) hyperplasia Clear and compact cell (1.8) hyperplasia Clear cell (1.7) hyperplasia with micronodules Clear cell (1.0) hyperplasia Clear and compact cell (1.6) hyperplasia

PAC (pmol/L)

PRA [ng/(L s)]

6 4

103 125

0.61 0.33

12 12

419

1.81

105

0.14

14

142

0.17

7 7

286

0.69

94

0.28

13

128

0.42

24

244

0.61

36

219

1.08

1

136

0.25

12

106

0.95

12

255

0.58

4

272

0.33

7

136

0.53

48

391

0.53

10

252

0.78

12 13

89

122

0.36 0.25

189

k23 243 k21

after

0.55 kO.09

182 +70

Hormone data in recumbent (Ret) and unright (Up) positions are shown. In patients l-15, PAC rose whereas, in patients 16-19, PAC decreased (Fig. 1). Patients 1-6 were also examined by angiotensin II infusion (Fig. 2). Medication before the upright posture test was as follows: patient 1: 750 mg methyldopa plus 40 mg nifedipine stopped overnight; patient 2: 30 mg nifedipine stopped overnight; patient 3: 40 mg nifedipine plus 100 mg spironolactone stopped 2 weeks before the test; patient 4: 60 mg nicardipine hydrochloride stopped overnight; patient 5: 40 mg nifedipine stopped overnight; patient 6: no medication; patient 7: 40 mg nifedipine stopped overnight; patient 8: 75 mg spironolactone stopped for 2 weeks and 40 mg nifedipine stopped overnight; patient 9: no medication; patient 10: 20 mg nifedipine stopped 11 days; patient 11: no medication; patient 12: 40 mg nifedipine plus 150 mg hydralazine hydrochloride stopped overnight; patient 13: 40 mg nicardipine hydrochloride stopped overnight; patient 14: 30 mg nifedipine stopped overnight; patient 15: 60 mg nicardipine plus 1500 mg methyldopa stopped 4 days; patients 16 and 17: no medication; patient 18: 30 mg nifedipine stopped overnight; patient 19: no medication. At hormonal reevaluation done at the time shown after adrenalectomy, PAC and PRA were improved. Hypokalemia was cured in all cases (not shown). Some patients, however, still needed antihypertensive drugs; 2 mg trichlorothiazide in patient 1; 4 mg nilvadipine in patient 3; 40 mg nicardipine hydrochloride plus 50 mg atenolol in patient 5; 5 mg nitrendipine in patient 8; 1 mg prazosin hydrochloride in patient 13; 20 mg nicardipine hydrochloride in patient 14; 30 mg nifedipine in patient 15; 20 mg nifedipine in patient 18. ’ The histology of cortical tissues adjacent to the adenoma demonstrated the hyperplasia of glomerulosa type cells with or without micronodules.

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COMMENTS

326

t

3 2500 -

a s f L F s

2000 -

i

1500-

Vol75.Nol

role in the rise in PAC in the upright posture test, but it remains to be solved. In summary, angiotensin II infusion did not raise PAC, but upright posture did in most cases of APA, suggesting that the interpretation concerning the PAC-rise after upright posture should be cautious in distinguishing between APA and IHA.

3000

+j

JCE & M .1992

Acknowledgment

2

We thank

E 2 s

lOOO-

“E f a.

500

Ms. Jun Setoguchi

for editing

this manuscript.

References

Upright

Supine

Upright

Supine

FIG. 1. PAC in the upright posture test. Cases were separated into two subgroups, i.e. aldosterone-increase (15 cases) and aldosterone-decrease (4 cases). Data for each case is also presented in Table 1. 1500-

loo0

:e5

500

YE I

I 0 ”

0

.#l

0.1 Angiotensin

0.5

1

2

0

II (ng/kg/min)

FIG. 2. PAC in angiotensin II infusion test. Case 1 was treated with dexamethasone before the test as Wisgerhoff et al. (6) reported. Other cases were not pretreated. Data for each case is also presented in Table 1. The test was performed a few days after the upright posture test. In patients 1, 2, 4, and 5, calcium blockade was given until the day before the test, the same as for the upright posture test (dose and type of calcium blockade given in Table 1 captions). In patient 3, angiotensin II was infused 4 days after the upright posture test, and no medication was given during this interval. Patient 6 received no medication.

i.e. patient 15, who stopped taking nicardipine and methyl-

dopa for 4 days; and patients 6, 9, and 11, who had none at all. Thus, we concluded that pretreatment with Ca2+blockade did not present a major reason for the high frequency of PAC-increase patients or for the discrepancy in PAC responses between the upright posture and angiotensin II infusion. Aldosterone secretion from APA is modified by other factors, including potassium, dopamine (30), ANP (31), and the angiotensin receptor (32). These factors may play some

A, Melada GA, Luetscher JA, Dowdy AJ 1973 Control 1. Ganguly of plasma aldosterone in primary aldosteronism: distinction between adenoma and hyperplasia. J Clin Endocrinol Metab 37:765-75. 2. Biglieri EG, Schambelan M, Brust N, Chang 8, Hogan M 1974 Plasma aldosterone concentration: further characterization of aldosterone-producing adenomas. Circ Res 34, 35[Suppl 1]:183-9. M, Brust NL, Chang BCF, Slater KL, Biglieri EG 3. Schambelan 1976 Circadian rhythm and effect of posture on plasma aldosterone concentration in primary aldosteronism. J Clin Endocrinol Metab 43:115-31. 4. Kern DC, Weinberger MH, Gomez-Sanchez C, et al. 1973 Circadian rhythm of plasma aldosterone concentration in patients with primary aldosteronism. J Clin Invest 52:2272-7. 5. Wisgerhof M, Brown RD, Hogan MJ, Carpenter PC, Edis AJ 1981 The plasma aldosterone response to angiotensin II infusion in aldosterone-producing adenoma and idiopathic hyperaldosteronism. J Clin Endocrinol Metab 195:195-8. 6. Weinberger MH, Grim CE, Hollifield JW, et al. 1979 Primary aldosteronism: diagnosis, localization, and treatment. Ann Intern Med 90:386-95. 7. Vaughan NJA, Jowett TP, Slater JDH, et al. 1981 The diagnosis of primary hyperaldosteronism. Lancet 1:120-5. 8. Bravo EL, Tarazi RC, Dustan HP, et al. 1983 The changing clinical spectrum of primary aldosteronism. Am J Med. 74:641-51. 9. Grant CS, Carpenter P, van Heerden JA, Hamberger B 1984 Primary aldosteronism. Arch Surg. 119:585-90. 10. Lapworth R, Short F, James VH 1989 18-hydroxycorticosterone as a marker for primary aldosteronism. Ann Clin Biochem 26:227-32. 11. McLeod MK, Thompson NW, Gross MD, Grekin RJ 1989 Idiopathic aldosteronism masquerading as discrete aldosterone-secreting adrenal cortical neoplasms among patients with primary aldosteronism. Surgery 106:1161-8. 12. Biglieri EG, Irony I, Kater CE 1989 Identification and implications of new types of mineralocorticoid hypertension. J Steroid Biochem 32:199-204. 13. Irony I, Kater CE, Biglieri EC, Shackleton CHL 1990 Correctable subsets of primary aldosteronism. Primary adrenal hyperplasia and renin-responsive adenoma. Am J Hypertens 3:576-82. 14. Gordon RD, Gomez-Sanchez CE, Hamlet SM, Tunny TJ, Klemm SA 1987 Angiotensin-responsive aldosterone-producing adenoma masquerades as idiopathic hyperaldosteronism (IHA: adrenal hyperplasia) or low-renin essential hypertension. J Hypertens 5[Suppl 5]:5103-6. 15. Mantero F, Fallo F, Opocher G, Armanini D, Boscaro M, Scaroni C 1981 Effect of angiotensin II and converting enzyme inhibitor (captopril) on blood pressure, plasma renin activity, and aldosterone in primary aldosteronism. Clin Sci 61:289s-93s. 16 Ferris JB, Neville AM, Brown JJ, et al. 1970 Hypertension with aldosterone excess and low plasma renin: preoperative distinction between patients with and without adrenocortical tumour. Lancet 2:995-1000. 17 Nomura K, Demura H, Horiba N, Shizume K 1986 Long-term treatment of idiopathic hyperaldosteronism using trilostane. Acta Endocrinol (Copenh) 113:104-10. 18 Lack EE, Travis WD, Oertel JE 1990 Adrenal cortical neoplasms.

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COMMENTS In: Lack EE, ed. Pathology of the adrenal glands. New York: Churchhill Livingstone 115-71. 19. Aiba M, Suzuki H, Kageyama K, et al. 1981 Spironolactone bodies in aldosteronomas and in the attached adrenals. Enzyme histochemical study of 19 cases of primary aldosteronism and a case of aldosteronism due to bilateral diffuse hyperplasia of the zona glomerulosa. Am J Path01 103:404-10. 20 Ganguly A, Zager PG, Luetscher JA 1980 Primary aldosteronism due to unilateral adrenal hyperplasia. J Clin Endocrinol Metab 51:1190-4. 21 Banks WA, Kastin AJ, Biglieli EG, Ruiz AE 1984 Primary adrenal hyperplasia: a new subset of primary hyperaldosteronism. J Clin Endocrinol Metab 58:783-5. 22 Adamson U, EfendiC S, Granberg PO, Lindvall N, Lins PE, Low H 1980 Preparative localization of aldosterone-producing adenomas. Acta Med Stand 208:101-9. 23 Lardinois CK, Mazzaferri EL, McGregor DB 1984 Plasma cortisol and primary aldosteronism. Ann Intern Med 100:917-8. 24. Tunnv TL Gordon RD. Klemm SA. Cohn D 1991 Histoloeical and biochemical distinctiveness of atypical aldosterone-prod&g adenomas responsive to upright posture and angiotensin. Clin Endocrinol (Oxf) 34:363-9. 25. Nadler JL, Hsush W, Horton R 1985 Therapeutic effect of calcium

26.

27.

28. 29.

30.

31.

32.

channel blockade in primary aldosteronism. J Clin Endocrinol Metab 60:896-9. Bravo EL, Fouad MF, Tarazi RC 1986 Calcium channel blockade with nifedipine in primary aldosteronism. Hypertension [Suppl l] :191-4. Bursztyn M, Grossman E, Rosenthal T 1988 The absence of longterm therapeutic effect of calcium channel blockade in the primary aldosteronism of adrenal adenomas. Am J Hvpertens 1:88S-90s. Raemsch KD, Sommer J 1983 Pharmacokirtetics and metabolism of nifedipine. Hypertension 5[Suppl 2]:18-24. Higuchi S, Shiobara Y 1980 Comparative pharmacokinetics of nicardipine, a new vasodilator, in various species. Xenobiotica 10:447-54. Malchoff CD, Hughes JM, Carey RM 1987 Effect of upright posture on the aldosterone responses to dopamine, metoclopramide, angiotensin II, and adrenocorticotropin. J Clin Endocrinol Metab 65:203-7. Pedrinelli R, Bruschi G, Graziadei L, et al. 1988 Dietary sodium change in primary aldosteronism. Atria1 natriuretic factor, hormonal, and vascular responses. Hypertension 12:192-8. Brown G, Douglas J, Bravo E 1980 Angiotensin II receptor and in vitro aldosterone responses of aldosterone-producing adenomas, adjacent nontumorous tissue, and normal human adrenal glomerulosa. J Clin Endocrinol Metab 51:718-23.

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