Clinical Science and Molecular Medicine (1975) 49, 187-192.

Location of aldosterone-producing adenomas by the determination of plasma aldosterone in adrenal vein or renal vein blood S. F U K U C H I , * T. TAKENOUCHI,* K . NAKAJIMA,* H. WATANABEt A N D A. S U G I T A t *Department of Internal Medicine and tDepartment of Urology, Tohoku University School of Medicine, Sendai, Japan

(Received 29 November 1974)

SummarY

Introduction

1. Aldosterone-producing adenomas were located before operation in eighteen patients by comparison of aldosterone concentrations in blood obtained by percutaneous catheterization of the adrenal vein or renal vein. The concentration of aldosterone in the venous effluent from the adrenal glands containing adenomas was significantlygreater than in the venous effluent from contralateral glands. 2. Catheterization of the adrenal vein is, however, technicallydifficult.Thelocationof adrenaladenomas was also possible by analysis of blood from the renal vein. 3. If the concentrations of aldosterone in blood from the left renal vein were higher than those from the right, the existence of a left adrenal adenoma was suggested. A high value in plasma, obtained from the inferior vena cava above the entry of the right adrenal vein, showed a right adrenal adenoma. This procedure identified very small functional adenomas which could not be demonstrated radiographically, or seen or palpated at surgery. 4. It was concluded that differential aldosterone measurement after percutaneous bilateral adrenal vein or renal vein catheterization can be used as a definitive test for the location of an aldosteroneproducing adenoma, where this is uncertain.

Even when the diagnosis of primary aldosteronism is obvious before operation, it is very difficult to locate the adenoma in the correct adrenal gland. Pre-operative radiological demonstration of the tumour, including presacral air insufflation and adrenal phlebography, is rarely successful because of the relative avascularity and small size of the tumour. For such reasons it may also escape notice during surgical exploration. Horton & Fink (1972) reported that a comparison of aldosterone concentrations in blood from the right and left adrenal veins could confirm the presence and location of a unilateral aldosteroneproducing adenoma. However, it is very difficult to insert a catheter into the adrenal veins, especially on thq right. It is also difficult sometimes to obtain a sufficient volume of blood to determine the aldosterone. Blood from the renal vein can be much more easily obtained through a catheter than adrenal vein blood. In this study a direct comparison was made between concentrations of aldosterone in blood samples obtained from both adrenal vein and renal vein by percutaneous trans-femoral vein catheterization during adrenal venography.

Key words: adenoma, aldosterone, primary aldosteronism.

Eighteen patients diagnosed as having primary aldosteronism had persistent and sustained hypertension, increased aldosterone production, suppressed plasma renin activity and no suppression of aldosterone secretion by deoxycorticosterone

Methods

vein blood,

Correspondence: Dr s. Fukuchi, Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.

187

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S. Fukuchi et al.

acetate. Hypokalaemia was found in fourteen of the patients. Adrenal exploration revealed an adrenocortical adenoma in seventeen patients and two adenomas in one patient. In all these cases unilateral adrenalectomy was carried out. A further seven patients who were undergoing tests for surgically correctable hypertension were taken as control subjects for the experiment. Of these seven, three patients had essential hypertension with blood pressure greater than 140/90 mmHg. In these patients serum electrolytes were within the normal range. Measurement of the serum creatinine concentration and creatinine clearance showed that in all three cases there was normal renal function and no evidence of any renovascular or endocrine abnormality. Two patients had chronic glomerulonephritis with slight albuminuria. They had normal serum electrolytes, and no oedema. A further two patients had renovascular hypertension with arteriographic evidence of either fibromuscular dysplasia or arteriosclerosis in the main renal arteries. On admission to hospital the patients were given a normal diet containing 250 mmol of sodium and 50 mmol of potassium per day. The relatively high intake of sodium is usual in the northern part of Japan. Bilateral catheterization was carried out during the course of a radiological examination of the adrenal glands using retroperitoneal pneumography and, in some cases, selective adrenal venography. Adrenal vein or renal vein catheterization was performed through the right femoral vein under local anaesthesia, with the patient supine. The position of the right adrenal vein was then checked by the injection of 0.5 ml of methylglucamine iothalamate (Conray). Reflux into the adrenal gland was seen on the fluoroscopic screen, and the patient usually experienced slight discomfort in the right flank. It was also possible to see the mouth of the left adrenal vein after a small test injection into the left proximal renal vein. After injection of 25 mg of heparin via the catheter and 50 mg of heparin into a peripheral vein, bilateral adrenal vein blood was collected from the catheter for the determination of aldosterone. The blood was allowed to flow spontaneously from the catheter for periods of from 2 to 5 min. After blood samples had been taken, venography was performed by the retrograde injection of 2-5 ml of contrast agent, and four to six serial films were obtained at 0.5 s intervals. During the introduction of the catheter, blood samples for the estimation of aldosterone were also

taken from both renal veins and from the inferior vena cava above and below the entrance of the renal veins. Even when adrenal vein blood samples could not be obtained, bilateral renal vein blood was easily collected for the estimation of plasma aldosterone in heparinized tubes, preferably by free drip from the catheter. The aldosterone in plasma was determined by radioimmunoassay after column and paper chromatography of methylene chloride extracts, according to a slight modification of the method of Mayes, Furuyama, Kem & Nugent (1970), namely the omission of the silica gel column stage after paper chromatography. The mean recovery of [1,2-3H]aldosterone in the analysis of thirty samples was 73 k8.6 (SD) %. The sensitivity of the method was 5.5 fmol. The mean measured amount of aldosterone in five 3 ml aliquots of pre-extracted plasma was 0 k 0.94 (SD)fmol. The aldosterone concentrations in plasma drawn in the morning for twenty-one normal subjects, aged 18-67 years, taking a diet containing 150-250 mmol of sodium and 50-75 mmol of potassium per day, ranged from 116 to 377 pmol/l (average 238 pmol/l, SDk77.7). Results Plasma aldosterone

In peripheral veins. Plasma aldosterone values in the supine position, which were elevated in ten of thirteen patients studied, are illustrated in Table 1. In three patients having normal values for plasma aldosterone in peripheral vein blood, plasma renin activity was consistently suppressed and hypokalaemia was present. Adrenal exploration was therefore performed in the three patients diagnosed as having primary aldosteronism. In adrenal veins. The concentration of aldosterone in the venous blood from the uninvolved adrenal glands averaged 1380 pmol/l of plasma. This was usually similar to the value in peripheral vein plasma. The concentration in the blood from the tumourbearing adrenal gland was over 18 800 pmol/l of plasma (mean value in nine patients). The concentration of aldosterone in the adrenal vein samples from the affected glands was significantly greater than the concentration in the blood from the inferior vena cava above the entry of the right adrenal vein. The concentrations of aldosterone in blood from the affected glands were found to be

Aldosterone in adrenal or renal veins

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TABLE 1. Chemical localization of aldosrerone-producingadenomas Values in parentheses under plasma aldosterone are concentrations for renal vein blood. Plasma aldosterone (pmol/l) Patient Age Adrenal (or renal) vein Id.vena cava Peripheral no. and vein sex Right Left High Low 1

54

1250

233

572

247

294

Surgical Chemical findings and diagnosis size (mm) of adenoma Right

2

39

1370

(266)

993

283

Right

F 3

58

35

314

366

Left

20

(952)

(2940)

1590

Left

1000

38

(549)

(388)

1050

499

438

Right

(283)

(280)

830

Right

327

1270 (1430)

3770

1400 (1350)

25000 (3220)

2860

1560

1350

Left

13800 (2480)

2370 (2310)

3610

2340

2400

Right

24800 (2090)

2120 (2040)

5240

2060

2030

Right

1210 (1120)

74900 (6940)

1730

6740 (2670)

2400 (2520)

4550

(940)

10800 (5160)

2620

M 45

12400 (641)

721 (569)

2060

616

544

Right

1050

1050

Right

(1020)

866 (1180)

7100

F 39

(438)

(766)

519

F 8

12

F 9

57

F 10

41

M 11

34

M 12

36

F 13 14

38

F 15

16

36

1370

1300

Right

35

M 18

46

Right (25x20~15)

Left (lox 11x 9) Right (14x 20)

Right (10 x 8 x 7)

Left

1030

Left (8x 7 x 8)

2470

2560

Right

Right (15x l o x 10)

824

866

Left

Left (15x 13x 13)

Right (lox 16x 12) Right (18x 13x 14) (8 x 13 x 6)

311

530

Left

Left (20 x 20 x 20)

F 17

Right (15x 17x 13)

4130 (1460)

38

Right (17x 19x 13)

M 7

Left (22x 18x 10)

F 6

Left (13x 12x 8)

M 5

Right (15x 12x 13)

F 4

Right (6x 7 x 9)

F

696 (682) (1420)

3500 (1730) (1260)

744

610

Left

Left (22x 18x 10)

2280

F

unrelated to the size of the adenomas (Table 1). In patient no. 3 (left adrenal adenoma), only the blood from the right adrenal and the peripheral veins was collected for aldosterone estimation. The aldosterone concentration in blood from the peri-

1540

Right

Right (29x 24x 10)

pheral vein was within normal range, and was almost the same as that from the right adrenal vein. This suggested there was no right adrenal adenoma. However, aldosterone in peripheral vein blood drawn at times other than the catheterization was

S. Fukuchi et al.

190

always over 416 pmol/l. Adrenal exploration was therefore performed and the operation confirmed the presence of a left adrenal adenoma. In renal veins. In several cases it was impossible to obtain blood samples from the adrenal veins although the injection of contrast medium proved the catheter to be properly placed. This was presumably due to collapse of the vein caused by the suction effect of the syringe. Blood from the renal vein could be more easily withdrawn than from the adrenal vein. Plasma aldosterone in the renal vein was measured in fifteen patients with primary aldosteronism, of which nine had a right adrenal adenoma and six had a left adrenal adenoma. The concentration ratio of aldosterone of blood from the left renal vein to that of the right renal vein blood was between 1.75 :1 and 6*19:1 in the six patients with a left adrenal adenoma. In the six patients with right adrenal adenoma no marked difference in aldosterone concentration was found between the left and right renal veins. On the other hand, the concentration ratio of aldosterone in blood obtained from the inferior vena cava above the entry of the right adrenal vein to that of blood from the left renal vein was 1.56 :1 to 6.00 :1 in nine patients with a right adrenal adenoma, and was below 1.0:l in the six patients with a left adrenal adenoma (Fig. 1). In

eight patients, thealdosterone content of blood taken from both adrenal and renal veins was compared. In the five patients with a right adrenal adenoma the concentration of aldosterone in the blood from the adrenal vein was found to be twice that in the blood from the right renal vein. But no marked difference in aldosterone concentrations between left renal vein and adrenal vein blood was found in these cases. In the three patients with a left adenoma, on the other hand, the concentration of aldosterone in left adrenal vein blood was definitely higher than that in left renal vein blood. Aldosterone concentrations of renal vein blood from seven patients without adrenal adenoma varied from 21 1 to 1660 pmol/l of plasma, without marked difference between the left and right renal veins. The mean aldosterone concentrations averaged 755 pmol/l of plasma in the right and 782 pmol/l of plasma in the left renal vein (Table 2). TABLE 2. Plasma aldosterone concentrations in venous blood from hypertensive patients

Aldosterone (pmol/l) Patient no.

*ge and sex

Clinical diagnosis Renal vein

Inf. vena cava

Right Left High Low 0 6.0

0

1

2 0

3

8

4 5 8

6

0

7

08 0

08

0

0

48, M Renovascular 580 491 533 hypertension 26, F Renovascular 1260 1660 1340 hypertension 45, M Essential 225 211 172 hypertension 400 455 319 36, M Essential hypertension 56, M Chronic 580 497 533 glomerulonephritis 1290 1310 1090 4 8 , F Chronic glomerulonephritis 46, F Essential 943 843 899 hypertension

535 1220 255 300 535

I150 810

0

0

Adrenal exploration and post-operative course

0

-

0

R. adrenal adenoma

L.adrenal adenoma

Other hypertension

Pr irnary aldosteronism

FIG. 1. Ratio of aldosterone concentration in inferior vena caval plasma to that in left renal venous plasma.

At operation, adrenal glands diagnosed as having adenomas were exposed through the posterior approach and completely mobilized from the surrounding retroperitoneal tissue. Adrenal glands which appeared normal at first inspection were

Aldosterone in adrenal or renal veins often found to be enlarged or to contain a tumour after mobilization. If a tumour was found, the gland containing the tumour was excised. There were no misdiagnoses for the location of adrenal tumours. After removal of the tumour, the electrolyte abnormalities and high plasma aldosterone disappeared in all cases. Blood pressure decreased in all patients. In four patients hypotension developed in the 48 h immediately after operation. If this hypotension did not respond to cortisol or blood and fluid replacement therapy, it was found to respond to small doses of deoxywrticosterone acetate. Six months after the operation, blood pressure was normal (below 90 mmHg diastolic pressure) in thirteen patients and was improved (more than 20 mmHg below pre-operative values) in the remaining five patients.

Discussion In this study unilateral aldosterone-producing adenomas were located before operation, without exception, in patients with primary aldosteronism studied by comparison of aldosterone concentrations in blood specimens from adrenal and renal veins. This was possible even when the adenomas were as small as 6 mm in diameter. It should be emphasized that most of these tumours had escaped detection by

191

radiological examination, and by palpation and inspection of the adrenal gland in situ. The adrenal adenomas of patients nos. 9, 10, 11 and 13 were undetectable even by adrenal scan with 19-[1311]iodocholesterol. Only after careful dissection of the glands were some of the tumours apparent. A significant finding was the invariably high concentration of aldosterone in the venous effluent from the adrenal glands containing adenomas. Also important was the apparent lack of correlation between the size of the adenomas and the concentration of aldosterone in the corresponding adrenal vein blood. This study demonstrated clearly that functional activity and tumour mass are not proportionate. Melby, Spark, Dale, Egdahl & Kahn (1967) reported that differential aldosterone measurement was useful for the location of the adrenal adenoma. However, since an insensitive method of photofluorimetry by means of Tetrazolium Blue was used, only aldosterone concentrations in blood from adrenal glands with adenomas were detectable by this method. It has always been difficult to obtain sufficient blood from the adrenal vein to estimate aldosterone, and also to be certain that the blood drained through the catheter is wholly of adrenal origin. The anatomy of the renal and adrenal veins is fortunately comparaL/R

= 1.0

U/R 4 U / L /*

FIG.2. Diagrammatic outline of the logic of the lateral localization techniques. Left: Primary aldosteronism with left-sided adenoma; both left renal vein and vena caval plasma aldosterone concentrations are raised. Right: primary aldosteronism with right-sided adenoma; vena caval plasma concentration of aldosterone (ALD) is raised, but left renal vein plasma concentration is suppressed. U=plasma aldosterone from inferior vena cava above the entry of the right adrenal vein. L= plasma aldosterone from left renal vein. R= plasma aldosterone from right renal vein. L/R= ratio of aldosterone in blood from left renal vein to that in right renal vein. U/R= ratio of aldosterone in blood from inferior vena cava above entry of right adrenal vein to that in blood from right renal vein. U/L=ratio of aldosterone in blood from inferior vena cava above entry of right adrenal vein to that in blood from left renal vein.

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tively simple. Both adrenal glands are usually drained by single veins. The right adrenal vein flows into the inferior vena cava and the left adrenal vein flows into the left renal vein (Fig. 2). Catheterization of the renal veins for blood sampling was found to be much easier than that of the adrenal veins. In this investigation, the insertion of the catheter into each renal vein was successful in every patient. Enough blood to estimate aldosterone was easily withdrawn from the renal veins. Scoggins, Oddie, Hare & Coghlan (1972) found that the concentration ratio of aldosterone in left adrenal venous plasma to inferior vena caval plasma was distinctly different in patients with a left-sided adenoma from that in patients with a right-sided adenoma. Our results showed that, when the aldosterone concentrations in the left renal vein plasma were high in primary aldosteronism, the presence of a left adrenal adenoma was certain. When there was no difference in aldosterone between left and right renal vein blood, the existence of a right adrenal adenoma was suggested. The concentration ratio of aldosterone in blood from the inferior vena cava above the entry of the right adrenal vein to that in left adrenal vein blood was also valuable for the location of adrenal adenoma. A high value in the ratio showed a right adrenal adenoma, whereas a value lower than 1 .O suggested a left adrenal adenoma. Although techniques based on steroid analysis with or without simultaneous radiological procedures may enable pre-operative diagnosis of lateral localization of an aldosterone-producing adenoma, they do not differentiate patients with bilateral hyperplasia. The latter group, described as having either idiopathic (Biglieri, Schambelan, Slaton & Stockigt, 1970) or pseudoprimary aldo-

steronism (Baer, Sommers, Krakoff, Newton & Laragh, 1970), may account for 20-30% of all patients diagnosed as having primary aldosteronism. Procedures for the pre-operative delineation of this group will have to be used in conjunction with existing lateral localization techniques to prevent unnecessary adrenalectomies being performed, since the hypertension in these patients does not respond to surgical treatment (Biglieri et al., 1970). In our study no cases of adrenal hyperplasia were detected at surgery. The value of pre-operative chemical localization of the tumour as described is most evident in the operating room. The anterior abdominal approach with transperitoneal exploration of both adrenal glands is no longer required with prior knowledge of the differential aldosterone concentrations in adrenal vein or renal vein blood.

References BAER,L., SOMMERS, S.C., KRAKOFF, L.R., NEWTON, M.A. & LARAGH,J.H. (1970) Pseudo-primary aldosteronisman entity distinct from true primary aldosteronism. Circulation Research, 26-27 (Suppl. l), 203-206. BIGLIERI, E.G., SCHAMBELAN, M., SLATON, P.E. & STOCKIGT, J.R. (1970) The intercurrent hypertension of primary aldosteronism. Circulation Research, 26-27 (Suppl. l), 195-202. HORTON, R. & FINK,E. (1972) Diagnosis and localization in primary aldosteronism. Annals of Internal Medicine, 76, 885-890. MAYES,D., FURUYAMA, S., KEM, D.C. & NUGENT,C.A. (1970) A radioimmunoassay for plasma aldosterone. Journal of Clinical Endocrinology, 30, 682-685. MELBY,J.C., SPARK,R.F., DALE,S.L., EGDAHL, R.H. & KAHN,P.C. (1967) Diagnosis and localization of aldosterone-producing adenomas by adrenal-vein catheterization. New England Journal of Medicine, 277, 1050-1056. SCOGGINS, B.A., ODDIE,C.J., HARE,W.S.C. & COGHLAN, J.P. (1972) Preoperative lateralization of aldosterone producing tumors in primary aldosteronism. Annals of Internal Medicine. 76, 891-897.

Location of aldosterone-producing adenomas by the determination of plasma aldosterone in adrenal vein or renal vein blood.

1. Aldosterone-producing adenomas were located before operation in eighteen patients by comparison of aldosterone concentrations in blood obtained by ...
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