The treatment of low-renin (“primary”) hyperaldosteronism

enin

“primar

J. B. Ferriss 3. @. Beevers K. Boddy CT.J. Rrown 3. E. Davies 3. Fraser D. Kremer A. F. Lever J. 1. S. Robertson Glasgow, ScofEand

In previous papers we reviewed the clinical, biocbemicai and pathological features’ and the differential diagnosis” of low-renin hyperaldosteronism (primary hyperaldosteronism). This paper describes the surgical and medical management of the condition. Primary hyperaldosteronism exists in a number of forms. Most commonly it is associated with a unilateral adrenocortical adenoma,“, 4 but in some cases an adrenal tumor is not. found, the adrenal glands th.en usually showing bilateral hyperplasia of the zona glomerulosa. +-I( Rarely all the abnormalities are reversed by glucocorticoids,15-18 while low-renin hyperaldosteronism has also been described associated with a malignant adrenocortica13, 1Q-21or ovarian tumor.““, 3y Several forms of treatment are available. These include adrenal surgery and drugs such as the mineralocorticoid antagonist spironolactone and the potassium-conserving diuretic amiloride, while rarely glucocorticoids such as dexamethasane are effective. This paper describes our results with trezltment and also reviews the experience of others. Previous reports have described the responses to spirono1actone,30-32 adrenal surgery,“” From the Medical Research Council Blood University Depar-tment of Medicine, Western the Scottish Uciversities Research Reactor Scotland. Received Reprint Western

for pubiication requests: infirmary,

May

Unit, and the Glasgow, and East Kilbride,

21,’ 1976.

Dr. J. I. S. Robertson, Giasgow Gil 6NT,

0002~8703178/0196-0097$01.20/O

Pressure Infirmary, Centre,

MRC Scotland.

0 1978

Blood

The

Pressure

C. V. Mosby

Unit,

Co.

and amiloride”+, present series.

,I2 in some of the pa,.ie&s

in the

AH patients had a mean outpatient diastolic blood pressure of 100 mm. Hg 0: more: an elevated plasma aldosterone concentration (nor-. ma1 up to 18 ng./IOO ml.) on at least one occasion and with a concurrent plasma renin roncentration below the mean of the normal range (less ml. of %nternational Stnnthan 44 microunits etails of these pstien%s are dard RenS6). Fulle given in a preceding pager.’ load pressure readings were obtained in the outpncient deparkment and hypotensive drugs other than those hod pressure and specified were not used. biochemical values obtained from the onset to tbe fourth week of treatment were exciuded from the analysis, as were all postoperative bjoehemical values in the four patients who underwent total adrenalec.tomy. Blood pressure readings within one standard deviat.ion of the means found in a. population ~tudy,“~ when m.atched Yor age and sex, were defined as “normal.” cry. Sixty-f&r patient2 (39 females) underwent adrenal surgery. A single ndrenocorticaf adenoma was found in 48 aal? unilateral adrenalectomy was usually performed. A tumor was not identified in 14; total ~~~~~~.~~~~~orn~ was undertaken in four of these, sub-tofa.! adrenalectomy (all of one gland and about. zhree-quarters

Ferriss

et al.

I& - ADENOMAaNON-ADENOMA

Systolic

GROUPS

Diastolic

ABP(mms Hg) SPIRONOLACTONE

n -37and

ADRENAL

14

SURGERY 0

-.

-.

-.;

-20 \

nw4a

and

13

- 60J 1, The mean fall in systolic and diastolic blood pressure (with S.E.M.) in patients with primary hyperaldosteronism during treatment with spironolactone and after adrenal surgery. Continuous lines represent patients with adenoma, broken lines those in the non-adenoma group. All changes were statistically significant, while the fall in diastolic pressure was significantly greater among adenoma patients with each treatment (see text). Fig.

of the other) was carried out in six, while in four one adrenal gland only was removed. In this group was one patient in whom a renal carcinoma was also found and nephrectomy was performed. Because renal carcinoma may itself contribute to hypertension,38 data from this patient were excluded from the following analysis. The adrenal lesion in two further patients proved difficult to classify; each lesion showed some histological features of an adenoma and some of a macronodu1e.l There was not a significant difference in the mean duration of follow-up between the groups with and without an adrenocortical adenoma (84 and 68 weeks respectively: t = 0.64; 0.6 > p > 0.5). Spironolactone. Ninety-five patients (56 females) were treated with spironolactone for a minimum period of four weeks (range 1 to 96 months, mean 9.7 months). These patients received 50 to 400 mg. daily (usually 300 to 400 mg. daily, smaller doses being used only when the

98

hypotensive response was satisfactory). A pathological diagnosis was subsequently available in 51 patients: a unilateral adrenocortical adenoma was found in 37, while in 14 a tumor was not identified, the adrenal glands usually showing bilateral hyperplasia of the zona glomerulosa. Amiloride. Eighteen patients (11 females) were treated with amiloride, increasing to 40 mg. daily in divided doses, for 6 to 8 weeks. Eight of these patients subsequently underwent adrenal surgery and a unilateral adenoma was found in each. A direct comparison between the effects of amiloride and spironolactone (400 mg. daily) was made in each case: patients were initially treated with amiloride (15 cases) or spironolactone (3 cases} and plasma levels of renin, angiotensin II and aldosterone, together with total exchangeable sodium and potassium, were measured on a fixed normal intake of sodium and potassium, before and during each treatment. Therapy was withdrawn for 6 to 8 weeks between each drug treatment. Fuller details of this protocol appear elsewhere.“5 Dexamethasone. Nineteen patients (9 females) in the present series received dexamethasone, 0.5 mg. four times daily for 14 days. Nine subsequently underwent adrenal surgery and a unilateral adenoma was found in six; a tumor was not identified in three, the adrenal glands showing hyperplasia of the zona glomerulosa in each. Blood pressure and plasma electrolytes were measured before and on the seventh and fourteenth days of treatment. Plasma renin concentration was measured before and during treatment in 14, while plasma aldosterone was measured before and during treatment in 13 cases. Other methods. Plasma (and serum) electrolytes, blood urea, plasma concentrations of renin, angiotensin II and aldosterone, total exchangeable sodium, tot,al exchangeable potassium, total body potassium and tot.al body water were measured as described previously,‘, 32,75 where sampling conditions are also outlined. Statistical calculations were made on a Hewlett-Packard 9810A calculator. Results Adrenal surgery. There was a significant fall in systolic and diastolic blood pressure after operation in both the adenoma and non-adenoma groups. The mean blood pressure fall after opera-

July, 1978, Vol. 96, No. 1

Table I. Comparison

Systolic

BP.

Diastoiic Plasma Plasma Flasma Blood

Plasma Plasma NaE’. NaE KEI KE Total

BP.

Hg)

(mm.

sodium

tC0,

Hg)

{mEq./L.)

potassium

urea

Plasma

(mm.

(mEq./L.)

(mg./lOO

ml.)

(I*units/ml.)

angioiensin

II (pg./ml.)

aldosterone

(ng./lOO

204

159

m!.)

(mEq./Kg.

IHW)

(mEq.)

water’

C test.). !~ie&n va~.~..?s

63

-13.01

<: 0.001

63

-11.29

< 0.001

(3.6)

102

(1.7)

(2.3)

142.8

139.0

56

(0.4)

(0.3) 4.4

56

(0.08) 30.1

(0.06) 24.5

53

(0.5) 32.3

(0.4) 46.6

53

8.32

.r, 0.001

(1.1) 23.2

(1.7) 63.5

40

7.91

c: 0.001

(0.3) 8.4

(0.9) 17.3

11

4.06

< 0.01

(1.2)

(2.7) 9.0

35

-6.69

<

0.031

19

-6.75

i

0.001

19

-6.98

< 0.001

43.0

(0.8) 2607.4

47.2

39.5

(1.0)

36.2

< 3.001

-9.35

14.01

,: 0.001

-8.68

< 0.001

(100.1)

(1.2)

34.6 (1.8)

(liters)

:paired

124

2320.2 (11.3)

BW)

;urgery

(4.1)

(4.9) 3073.6 (106.5)

(mEq.)

body

before and after adrenal

2.9

;mEq./L.!

renin

(mEq../Kg.

of variables

2606.4

18

2.53

38.4

18

2.08

(1.0) 35.2

15

< 0.05

(128.3)

-0.99

0.1

> p > 0.05

0.4 > p > 0.3

. NaE = exchangeable sodium, tKE = exchangeable potassium

tion in the adenoma group was 48/26 mm. Hg and among non-adenoma patients 40/Z mm. Hg (Fig. 1) (adenoma v, non-adenoma: systolic t = 0.95, N.S.; diastolic t = 2.66, p < 0.05). Blood pressure fell to the defined normal level after operation in 27 patients in the adenoma group (56 per cent) and in two patients in whom an adenoma was not found (15 per cent). After operation (Table I) there was a significant fall in plasma sodium, total exchangeable sodium, and in plasma tC0, and aldosterone concentrations. There was a significant rise in piasma and total exchangeable potassium, in blood urea, and in the plasma concentrations of renin and angiotensin II. A small fall in total body water was not statistically significant. There was a significant inverse correlation among individual patients between preoperative blood urea and the fall in blood pressure after operation (systolic r -0.35, p < 0.01; diastolic r -0.36, p < 0.01).

There was a highrv 3~gnificant fall in mean systolic and diastolic blood pressure during treatment with spironolactonr (Table Il). The mean blood pressure fall during treatment was 53/29 mm. Mg in the adenoma group and 45/ 19 mm. IIg among patients in whom a tumor was not found at operation (Fig. 1). The iall in systolic pressure did not differ significantly between the two pathological groups (t = 1.04; 0.4 > p > X3), but the fall in diastolic pressure was aigniflcantly greater in the adenoma group (t = 2.65; p < 0.02) (Fig. 1). Blood pressure fell to ~~~~~1 during treatment with spironolactone in 17 patients igl the adenoma group (46 per cent) and in seven patients in whom a tumor was not found (50 per cent). NQ evidence of escape of blood pressure from control was seen in any patient in up to eight years of therapy. Temporary withdra.wal of spironolactone in patients whose blood pressure had been well controlled resulted in a rise of blood

Ferriss et

al.

II. Comparison of variables before and during treatment with spironolactone (paired t test). Mean values ( +- S.E.M.) Table

Before treatment Systolic

B.P. (mm.

Diastolic

B.P.

(mm.

Plasma

sodium

Plasma

potassium

Plasma Blood Plasma

tCO? urea

Hg) Hg)

(mEq./L.) (mEq./L.)

renin

ml.)

@nits/ml.)

Plasma

angiotensin

II (pg./ml.)

Plasma

aldosterone

(ng./lOO

NaE* NaE KW

(mEq.) BW)

KE (mEq./Kg. Total Extra Plasma

body

148.1

95

-20.45

< 0.001

121.5 (1.12)

95

-17.96

< 0.001

142.4 (0.27)

138.2 (0.31)

83

-10.61

<

0.001

<

0.001

<

0.001

water’

cellular

(liters)

fluid’

volume’

(liters)

(liters)

28.6

74

-11.2

(0.33) 48.6

80

11

< 0.001

(1.2)

(2.1) 45

6.12

< 0.001

16

2.49

< 0.05

19

1.67

(16.9)

(5.0)

(5.0) 2464.9

57.4 (19.2) 41.7

36

0.2 > p > 0.1

< 0.001

-10.55

(72.7) 37.9 (0.9) 2551.2 (107.1)

36

< 0.001

-8.18

36

2.95

< 0.01

4.65

< 0.001

35.1

39.4

36

(1.4) 38.5

(1.3) 35.9

28

-4.73

<

(1.3)

(1.4) 16.6 (0.82)

13

-4.31

< 0.01

10

-2.27

< 0.05

19.3 (0.79) 3.07

2.80 (0.24)

0.001

sodium. potassium.

pressure towards pretreatment levels. There was an inverse correlation among individual patients between pretreatment blood urea and the fall in blood pressure during spironolactone (systolic r -0.25, p < 0.02; diastolic r -0.14, N.S.). Spironolactone corrected the plasma electrolyte abnormalities in every case, regardless of the hypotensive response. The changes which occurred during treatment are summarised in Table II. There was a significant decrease in plasma and total exchangeable sodium, in total body water, extracellular fluid and plasma volumes, and in plasma tC0, concentration. There was a significant increase in plasma and total exchangeable potassium, in blood urea, and in plasma concentrations of renin and angiotensin II. Plasma aldosterone was measured before and

100

129.5

(1.4) 10.2 (0.75) 31.2

(0.21) *NaE = exchangeable tKE = exchangeable

15.91

(0.40) 33.4

44.5

BW)

85 (0.:; 23.9

(1.0) 2347.0 (107.5)

(ml%.)

P

(2.82) 97.3 (1.50)

2969.4 (82.7)

(mEq./Kg.

t

198.6

26.8

ml.)

No. of pairs

(2.45)

3.2 (0.07)

(mEq./L.) (mg./lOO

During spironolactone

during treatment in 19 patients: levels rose in I3 but fell in six. Overall, the mean change was not significant. Aldosterone secretion rate was measured in two patients and values during treatment were unchanged. Changes in plasma concentrations of renin, angiotensin II, and aldosterone were similar in patients with and without an adrenocortical adenoma. These responses are reported in more detail elsewhere.’ The side effects included epigastric discomfort, gynecomastia, Raynaud’s phenomenon, menstrual irregularities, lassitude, cutaneous pigmentation, excessive sweating, and impotence. However, these unwanted effects were generally minor and in only three patients were they severe enough to lead to withdrawal of the drug.

July,

1978,

Vol.

96, No.

1

‘Table Ilk. Comparison values ( t S.E.M.)

3j?;stolic

BP.

3iastolic ?Iasma Ulasma Plasma

sodium

?iaema ‘?iasma

NaE* ‘C’aE

(mEq./Kg.

cc 0.001

18

-4.53

i

0.001

139.6

18

-7.07

i

0.001

(0.5) 4.5

18

,,mEq./L.)

(0.4) 3.2 (0.2) 30.1 (0.7)

25.7 (0.5)

18

30.1

36.7

18

4.10

T 0.001

(1.6)

(2.0) 72.0 (13.3)

17

3.16

<

33.8

,wnits/ml.) II

(3.3) 10.4

(pg./ml.)

(ng.1100

(mEy.)

KE

-5.18

(2.8)

aldoswrone

(m6q.j

18

(1.7) 142.6

angiotensin

33~

(paired ‘; :esz, i Mean

Hg)

(mEq./L.)

(mEy./Kg.

amiloride

151

(mEq./L.)

renm

with

(6.8)

Hg)

Shod urea (mg. Ii00 ml.) ?Issma

treatmen’:

184

potassium KU,

before and during

(4.4) 114

(mm.

(mm.

of variables

ml.)

(1.0) 25.0 (3.6) 2890 (127)

HW)

42.9 (1.1) 2540 (159)

BW)

Total body water’ (liters)

101

10.01 -6.43

< 0.001

O.Oi

22.5

16

3.09

< 0.01

(4.5) 38.5

16

2.49

-2 0.35

(6.4) 2529

17

-5.13

.c e.001

17

-5.21

< 5.001

(101) 37.0 (0.8)

3i.0

2840 (149) 40.9

(1.5) 38.2

(1.3) 37.3

(1.9)

(1.9)

17

3.43

< 0.01

17

2.55

c: c.05

16

-0.88 _____I

NaE = exchangeable i-KE = exchangeable

,: 0.001

(0.1)

0.:

:. p >

0.3 --

sodium. potassium.

Ami~~~~d~. Eighteen patients were treated with amiloride and blood pressure fell in all except one. ‘There was a highly significant fall in systolic and diastolic blood pressure for the group during treatment (Table III). The mean fall in patients with a proved adenoma was 40/22 mm. Hg. No Tatient in the non-adenoma group underwent adrenal surgery but quadric analysis” placed five patients in this diagnostic category: among these the mean fall was 18/12 mm. Hg. The fall in systolic pressure was significantly greater in the adenoma group (t = 2.46; p < 0.05), but the difference in diastolic response was not statistically significant (t = 1.71). Diastolic pressure fell 30normal levels during amiloride in four patients with a confirmed adenoma (50 per cent), but in only one of five in the predicted non-adenoma gDWp. Other significant changes (Fig. 3) included a [aallin plasma and exchangeabie sodium and a rise .an plasma and exchangeable potassium and in

blood urea, while mean values of plasma renin, angiotensin II, and aldosterone also 1olt.e. Three patients noticed excessive flatus in the first three weeks of treatment, but this symptom became less prominent as therap;y co~~~~~~~d~ Two complained of transient Sassi~de. No other side effects were encounter

priate adrenal surgery had been previously treated with spironolactone as described. There was a significant correlation a.mocg individuals between t,he blood pressure response to each treatment (systolic r = 0.66; p c 0.001, diastolic r = 0.60; p < 0.001). The correlation was particularly close for patients in the adex,oma group (systolic r 37, p < 0.001; &ast0!ic r -I 0.75, p < 0.001). owever, data from only BO rmnadenoma patients were suitable fcx- this cornparison and one patient behaved atyp‘icaliy i she failed to alter her blood pressure

Ferriss

et al.

200

180

p
sys.

160

130

BP mmHg

p
: 150

I pc

0.001

\ ’ \I

pco.05

i

t

t

Untreated

Spironolactone 400mg/d

Post-op Amiloride 40mg/d

Fig. 2. Mean systolic and diastolic blood pressure ( & S.E.M.) in eight patients with an aldosterone-producing adenoma untreated, while taking spironolactone, untreated, while taking amiloride and after adrenal surgery.

spironolactone, but had a considerable fall (mean 78/38 mm. Hg) following total adrenalectomy.“’ When this patient was excluded there was a significant correlation between the fall in diastolic pressure with the two forms of treatment (systolic r = 0.33, N.S.; diastolic r = 0.72, p < 0.05). The mean fall in blood pressure was again slightly greater during spironolactone treatment than after adrenal surgery, both in the adenoma group (mean fall 52/27 and 46/24 mm. Hg, respectively) and in the group in whom an adenoma was not found (mean fall 45/20 and 36/16 mm. Hg, respectively). However, these differences did not reach statistical significance. Both forms of treatment corrected the abnormalities of plasma electrolytes and renin concentration. However, the changes were slightly but consistently greater during spironolactone, possibly due to a greater shrinkage in extracellular and plasma volumes with this treatment.“2 surgery

and ami!oride.

Eight patients treated with amiloride subsequently underwent adrenal surgery and a single adenoma was found in each. The hypotensive effects of amiloride, spironolactone, and adrenal 102

140

$

\

9

of adrenal

f p
i

I

Untreated

Comparison

-I-

p
180

M can BP mmHg

-syst. B #f \ r \i

80 L

Untreated

Untreated

Spironolactone 400mg/d Fig. 3. Mean systolic and diastolic blood pressure in 18 patients with primary hyperaldosteronism and without adenoma) untreated, while taking tone, untreated and while taking amiloride.

Amiloride 40mg/d ( t S.E.M.) (both with spironolac-

surgery are compared in Fig. 2; all three treatments produced a highly significant fall in mean systolic and diastolic blood pressure, although values were slightly higher during amiloride than during spironolactone or after operation. There was a positive correlation between the blood pressure response to amiloride and that following adrenal surgery, although with the small numbers involved this did not reach significance (systolic r = 0.417; diastolic r = 0.673). The fall in plasma and exchangeable sodium and the rise in plasma and exchangeable potassium were not significantly different during each treatment Comparison

of spironolactone

and

amiloride.

Both treatments produced a significant fall in systolic and diastolic blood pressures, although the hypotensive effect of spironolactone was significantly greater with the doses used (Fig. 3). There was a significant positive correlation among individuals between the fall in blood pressure with each form of treatment (systolic r = 0.607, p < 0.01; diastolic r = 0.576, p < 0.02). Relationship between, total exchangeable and total body potassium, As shown in Fig. 4, there

was a close correlation

between

concurrent

July, 1978, Vol. 96, No. 1

Spironolactone Atniiorkdc

Therapy Therapy

c3 Post-operative

94.7

i 5.i SO

94.7iE.3SB 95.17i5.!1SD Mea1 Spiro3;olaclolic i?Acan Post-ogcratirc

2000 TOTAL

4. Relationship between concurrent (‘“K) in patients with primary o = taking amiloride; q = postoperative.

Fig.

potnssium

AU cases

r = 0.9716

n

Untreated

r = 0.5629

I, = 35

72

3000

4000

EXCHANGEABLE

POT.4SSIU.V

estimates of total hyperaldosteronism.

measurements of total exchangeable and total body potassium, whether the patient was untreated, taking amiloride or spironolactone, or bad been subjected to surgery, thus justifying the use of exchangeable potassium as a measure of potassium status. Total body potassium estimates were systematically slightly higher than exchangeable potassium estimates, Dexameahasone. Blood pressure and plasma electrolytes were unchanged in all of 19 patients during dexamethasone, 2 mg. daily for two weeks. No consistent changes in plasma renin or aldosterone concentrations were observed.

ery. Conn and associates3 have reviewed the literature and Conn has subsequently described his personal experienceSs of patients following the removal of an aldosteronesecreting adenoma. Blood pressure was reported as normal in 60 per cent to 70 per cent and hypertension was ameliorated in most of the remainder. Other reports have been in general agreement? :-‘-I~although we found that postoperative blood pressure fell to a normal level in only 50 per cent of case~.~::This expanded series is in general agreement with our earlier report. The effect of surgery on the blood pressure in non-adenoma casesis less satisfactory. Persistent

96.24 1 3.9 SD 94.1 ‘L 5.66 SD

cg3Ki

mEq.

exchangeable potassium (;,>K) 3 = untreated; @ = saking

and :;ota 50dy spironolactone;

hypertension has been reported,‘., -. ‘--I ). iii aithough some fall in blood preseui~e may occur.“. i2-11We have previously shown that blocd pressure may occasionally fall to noimal kilowing surgery, $-: but tbis expanded series again confirms that a smaller h~po~~Kx~~~eresponse occurs in the non-adenoma group. Debat,e continues on the choice 4” operative approach. This may be posteriorly through the eleventh rib (bilaterally if necessary) or anteriorly through a transverse upper abdominal incision.:‘:’Tbe amount of adrenal tissue which should be excised from patients without tumor is also uncertain. Total adrenalectomiy removes the site of aldosterone production, with zare exceptions,“‘. 41but the patient is thereafter dependent on corticosteroid replacement. By preserving a remnant of one gland it is hoped to avoid the need for replacement therapy while curiag the aldosterone excess fcorticosteroid rep!acenient was not necessary in any of the six patients so treated in the present series). However, recurrence of hyperaldosteronism after extensive adrenal surgery has been reportedi. 4?Less extensive adrenal surgery also leads to a smaller fall in blood pressu~e.~+..:J It is suggested that if surgery is tlo be worthwhile in such paGents removal of one adrenai and tat least three-quarters of the oth.er shouEd be undertaken. It is of interest that complete e.xcision of

Ferriss

et al.

both glands has largely replaced sub-total adrenalectomy in the surgical treatment of Cushing’s disease.43. 44 Spironolactone. Spirolactones are synthetic steroid compounds with an added lactone ring. These compounds block the renal affects of aldosterone and deoxycorticosterone by competitive inhibitiona5, 46In patients with primary hyperaldosteronism spirolactones cause urinary sodium excretion and potassium retention,47-4g and when treatment is prolonged, blood pressure falls.50-5’ There is also a good correlation between level of blood pressure during spironolactone treatment and after appropriate.adrenal surgery.40. 5:i.54 Spark and Melby’” reported a fall in blood pressure to normal in each of 20 patients with an aldosterone-producing adenoma, but in two further patients with low-renin hyperaldosteronism and histologically normal adrenal glands, blood pressure was unaltered during treatment with spironolactone. However, a satisfactory hypotensive response to spironolactone has been reported in some patients without an adrenocortical tumor.““, 32.55 This larger series confirms our previous reporF that spironolactone produced a significant fall in blood pressure in patients both with and without adenoma. However, blood pressure did not return to normal in all patients, even in the adenoma group. This observation was not unexpected as the removal of the cause of secondary hypertension does not always result in a fall of blood pressure to norma1.z6 Although the fall in systolic blood pressure did not differ significantly between the pathological groups, the fall in diastolic pressure was significantly greater in the adenoma group. Plasma electrolyte abnormalities were corrected in all cases, irrespective of the blood pressure response. Hyperkalemia was rare in the absence of renal impairment and resolved spontaneously when the dose of spironolactone was reduced or stopped.3’ However, potassium supplements were not needed and should be avoided during treatment with spironolactone. The increase in blood urea during treatment may result from a decrease in glomerular filtration rate, as a result of shrinkage in plasma and extracellular fluid volumes.“’ In the two patients in whom aldosterone secretion rate was measured before and during spiro-

104

nolactone treatment no appreciable change occurred. This failure of aldosterone secretion to increase despite several simultaneous potential stimuli (increases in plasma renin, angiotensin II, and potassium concentrations and in exchangeable and total body potassium, with a decrease in plasma and exchangeable sodium) suggests autonomy of the adrenal adenomata in these patients. Others describe a rise in aldosterone secretion40and excretion”” during spironolactone, suggesting a variable degree of autonomy of such tumors. Although changes in plasma aldosterone during treatment may not accurately reflect aldosterone secretion rate,3z contrasting changes in plasma aldosterone during spironolactone might suggest variable adrenal autonomy, with spontaneous fluctuations. However, the fall in plasma aldosterone levels observed in some patients might also result from a direct inhibition of aldosterone synthesis by spironolactone, an affect previously shown in the rat adrenal in vitro.57, 58 Spironolactone reduced the rise in aldosterone induced by other diuretic drugs in normals.5s Such an effect was suggested by Sundsfjord and colleagues,” who described a fall in plasma aldosterone and in aldosterone secretion in one patient with primary hyperaldosteronism treated with spironolactone. In the entire present series, spironolactone did not cause a significant rise in plasma aldosterone (Table II) while amiloride did (Table III): this could well reflect in part an inhibitory effect of spironolactone on aldosterone biosynthesis. By controlling hypertension and correcting electrolyte abnormalities, treatment with spironolactone or amiloride should increase the safety of subsequent adrenal surgery. It has also been suggested that by activating the renin-angiotensin system, spironolactone may reduce the risk of temporary hypoaldosteronism in the postoperative period.“’ However, Bravo and colleaguesF have been unable to confirm this and suggest that spironolactone may actually contribute to postoperative hypoaldosteronism, by direct inhibition of aldosterone synthesis. Side effects encountered were similar to those reported previously.31. 32Contrary to the experience of others40, 63the drug has been well tolerated in the great majority. Epigastric discomfort was usually overcome by taking the drug with or after meals. One patient experienced exacerba-

July, 1978, Vol. 96, No. 1

sion of a peptic ulcer necessitating withdrawal of the drug/ This woman subsequently did well on amiloride. Although there is little information on whether spironolactone can induce peptic ulceraxion, we have previously reported a patient with no history of dyspepsia who developed a gastric ulcer during spironolactone treatment; this healed rapidly following withdrawal of the drug and epigastric symptoms have not recurred.J1 Amiloride is a pyrazine-carbonylguanidine which appears to act on sodium reabsorption in the distal renat tubule, independently of aldosterone.6g, (ihWhen administered in five-day courses amiloride was reported to correct the electrolyte abnormalities but not the hypertension in a patient with an aldosterone-producing adenoma .lji We have shown that prolonged treatment in a patient unable to tolerate spironolactone also reduced blood pressure to norma1.61The present findings co&-m that amiloride can control the hypertension of primary hyperaldosteronism, with or wit.hout an adrenocortical adenoma, as well as correcting the electrolyte abnormalities and ~Qmpar~~o~ of sur cry, spironolactone, amilorida. This study again confirms the close correlation between blood pressure levels during spironolactone and after adrenal surgery ‘ii. 32.-,u.5:;.5i especially in the adenoma group. ThuH spironolactone is useful in predicting the blood pressure level after adrenal surgery. Although numbers are still small, a similar correlation seems to be emerging between the blood pressure responses to amiloride and surgery. The fall in both systolic and diastolic pressure during spironolactone was again slightly greater than the blood pressure fall after adrenal surgery.“? In the doses used, spironolactone was also more elective than amiloride and indeed the latter treatment was also slightly less effective than adrenal surgery. We do not know whether these differences reflect the dosage of amiloride used or whether the drug is inherently less effective. ~~a~~e~~a~o~~. Dexamethasone was ineffective in correcting the abnormalities in all I9 patients studied in this series. This confirms that glucocorticoid-remediable hyperaldosteronism is an uncommon variant. However, Giebink and associateslY have recently shown that treatment for longer than 14 days may sometimes be neces-

r”g~ a&&e:one suppressron, in ~c?ntxa~t “:o earlier cases.l”-‘7 Probably giucocor+coid treatment should be continued for at ?easi four weeks when screening for this condition. Newton and Laragh”” administered glucocorticoids for five day-s to patients with primary hyperaldosteronism. Aldosterone excretion fell in three, rose in one, and was unchanged in another, Slaton and colleaguesCjSJ reported that dexamethasane for three days suppressed aldosterone excretion significantly in six of fourteen patients with aldosterone-producing adenoma: althou& smaller increases occurred in four others. These findings are in general agreement with our own. The cause of g~~cocorticoid-r~med~a~~le hyperaldosteronism is as yet unkno:~n. .A specific adrenocortical biosynthetic block has not yet been identified 15.it, A dr~~~~~~~~~~~ ~~r~~~~~~. b7e have not encountered a single example of adrenocortical carcinoma producing aldostemne PX~SS in OUT series of I36 patients with low-renin hyperaldosteronism, despile prolonged follow- 11 casesand surgical exploration in 79. nized or suspected, prompt surgics required.‘! lit has been suggested that long-,term spironolactone treatment in patients with primary hyperaldosteronism is unsafe because an under.. lying adrenal carcinoma may be overlooked.“>- 7’. Crane and co-workers” reported a blood pressure fall to normal during spironolactone treatment in one of two such patients. Iioweve~, these rare cases should be recognisable preop~ratively~~: a large tumor may be palpable oi. displace the kidney on excretion pyelogram or renal arteriography; fever, severe muscle weakness and abdominal pain are common features and excessive secretion of adrenocorticosteroids other than aldosterone may be found.:% i%::::.::i. i.. 7.: sary

anagama~~ of the in tient. In nat,ients with primary hypera!dos?;ei,o3a:!fil-E? associated wit.h a.n adrenocortical adenoma, in whom preoperative spironolactone has reduced blood pressure to normal or near normal, re~moval of the tumor-bearing gland is usually the :.,reatment of choice. Wowever, when surgery is cor~trair~dicated or refused, long-term treatment with spironolactone is an acceptable alternative. Should the patient be unable to tolerate spironolactone, amiloride may be substituted, although it is

Ferriss et

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slightly less effective with the doses discussed, The evidence suggests that when there is an unsatisfactory hypotensive response to spironolactone in adequate dosage (300 to 400 mg. daily), a significantly greater fall in blood pressure after adrenal surgery is unlikely. Amiloride also seems unlikely to be effective and hypertension must be controlled with other conventional hypotensive drugs. However, irrespective of the effects on blood pressure, electrolyte abnormalities are invariably corrected by spironolactone, amiloride, or appropriate adrenal surgery. In those patients in whom an adrenocortical tumor is not found, effective adrenal surgery necessitates a total or a sub-total adrenalectomy. This exposes the patient to the risks of postoperative adrenal insufficiency, while with more conservative surgery there is a risk of recurrence of hyperaldosteronism. For these reasons the alternative of long-term spironolactone is probably the treatment of choice for most such patients. Should the patient be unable to tolerate spironolactone, amiloride may be substituted. Glucocorticoid-remediable hyperaldosteronism responds to dexamethasone, 1 to 2 mg. daily, usually within one week, although up to four weeks of treatment may be required. All patients with primary hyperaldosteronism should be screened for this condition, especially those in whom an adrenocortical adenoma is not identified preoperatively. Dexamethasone, 2 mg. daily, could theoretically lead to adrenal suppression when used for several weeks. Others”. l8 have administered dexamethasone, 2 mg. daily in divided dosage for two weeks, followed by dexamethasone 1 mg. daily thereafter. In responsive cases, blood pressure will fall and. electrolyte abnormalities are corrected: aldosterone values also fall, while plasma concentrations of renin and angiotensin should rise. Even with this regime it would seem prudent to test the adrenal responses to synthetic ACTH at the end of this period. When an adrenocortical carcinoma is diagnosed or suspected, prompt surgical excision is required. Summary

Sixty-four patients with low-renin (“primary”) hyperaldosteronism underwent adrenal surgery. A unilateral adrenocortical adenoma was found in 48; no tumor was identified in 14, the adrenal

106

glands then usually showing hyperplasia of the zona glomerulosa. The adrenal lesion in two further patients was difficult to classify. There was a significant fall in systolic and diastolic blood pressure after operation in both the adenoma and hyperplasia groups, although the fall in diastolic pressure was significantly greater in the adenoma group. Blood pressure fell to an arbitrary normal level in 56 per cent of patients with adenoma and in 15 per cent of patients in the hyperplasia group. Ninety-five patients with primary hyperaldosteronism received spironolactone for a minimum period of four weeks. There was a significant fall in mean systolic and diastolic pressure during treatment in both the adenoma and hyperplasia groups. However, the fall in diastolic pressure was again significantly greater in the adenoma group. There was a significant positive correlation between the fall in blood pressure during spironolactone, and following adrenal surgery. Eighteen patients also received amiloride preoperatively and again there was a significant fall in systolic and diastolic blood pressure, although levels were slightly higher than during spironolactone or after subsequent adrenal surgery. Nineteen patients received a two week course of dexamethasone, without effect on blood pressure or the electrolyte abnormalities. It is suggested that removal of the tumorbearing gland is usually the treatment of choice for patients with an aldosterone producing adenoma, provided preoperative spironolactone has reduced blood pressure to normal or near normal. However, long-term spironolactone is an acceptable alternative. For patients in the hyperplasia group, long-term spironolactone is usually the treatment of choice. If this drug is not tolerated, amiloride may be substituted. If preoperative spironolactone does not produce a satisfactory hypotensive response, adrenal surgery is unlikely to do so and hypertension should be controlled with other conventional hypotensive drugs. All patients with primary hyperaldosteronism in whom an adrenocortical adenoma is not identified preoperatively should be screened for the rare glucocorticoid-remediable variant. Dexamethasone 1 to 2 mg. daily for two to four weeks will reverse the biochemical abnormalities and reduce blood pressure. When an adrenocortical carcinoma is suspected, prompt surgical excision is required.

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We are grateju: to 6. 3. Searle England, a,nd to Merck, Sharp &gland. for financial support.

& Co., High Wycombe, & Dohme, Hoddesdon, 16.

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Ferriss, J. B., Beevers, D. G.. Brown, J. J., Davies, D. L., Fraser, R., Lever, A. I?., Mason, P., Neville, A. M., and Robertson, J. I. S.: Clinical, biochemical and pathological features of low-renin (“primary”) hyperaldosteronism, AM. HEART J. 95:375, 1978. Fe&s, J. B., Beevers, D. G., Brown, J. J., Fraser, R., Lever, A. F., Padfield, P. L., and Robertson, J. I. S.: Lowrenin (“primary”) hyperaldosteronism: differential diagnosis and distinction of sub-groups within the syndrome, AM. HEART J. 95:641, 1978. Conn, J. W., Knopf, R. F., and Nesbit, R. M.: Clinical characteristics of primary aldosteronism from an analysis of 145 cases, Am. J. Surg. 107:159, 1964. Brown, J. J., Chinn, R. H., Davies, D. L., Dusterdieck, G., Fraser, R., Lever, A. F., Robertson, J. I. S., Tree, M., and Wiseman, .4.: Plasma electrolytes, renin and aldosterone in the diagnosis of primary hyperaldosteronism, with a note on plasma corticosterone concentration, Lancet, 2, .55, 1968. !>a&, W. W., Newsome, H. H., Wright, L. D., Hammond, W. G., Easton, J., and Bartter, F. C.: Bilateral adrenal hyperplasia as a cause of primary aldosteronism with bypertersion, hypokalaemia and suppressed renin activity, Am. J. Med. 42642, 1967. Katz, F. IF.: Primary aldosteronism with suppressed plasma renin activity due to bilateral nodular adrenocortical hyperplasia, Ann. Intern. Med. 67:1035, 1967. Laragh, J. H., Ledingham, J. G. G., and Sommers, S. C.: Secondary aldosteronism and reduced plasma renin in 1lypertensive disease. Trans. Assoc. Am. Physicians aal68, 1967. Grim, C. E., McBryde, A. C., Glenn, J. F., and Gunnells, .1. C.: Childhood primary aldosteronism with bilateral adrenocortical hyperplasia: plasma renin activity as an aid to diagnosis, J. Pediatr. 7 I :377, 1967. Rhamy, R. K., McCoy, R. M., Scott, H. W., Fishman, L. M.. Mikelakis, A. M.. and Liddle. G. W.: Primarv aidosteranism: experience with current diagnostic criteria and surgica! treatment in fourteen patients, Ann. Surg. 167:718, 1968. Distler, A., Barth, C., Roscher, S., Vecsei, P., Dhom, G., and Wolff, H. P.: Hochdruck und aldosteronismus bei solitaren adenomen und bei nodularer hyperplasie der nebennierenrinde, Klin. Wochenschr. 47:688, 1969. Ferriss, J. B., Brown, J. J., Fraser, R., Kay, A. W., Lever, .A. F.,Neville. A. M.. O’Muircheartaieh. I. G.. Robertson. J. I. s., and &m&ton, T.: Hype&&ion with aldoster: one excess and low plasma renin: pre-operative distinction between patients with and without adrenocortical rumour; Lancet 2:995, 1970. George, J. M., Wright, L., Bell., N. H., and Bartter, F. C.: The syndrome of primary aldosteronism, Am. J. Med. Baer, I,., Sommers, S. C., Krakoff, L. R., Newton, M. A., and Laragh, J. TX: Pseudo-primary aldosteronism: an entity distinct from true primary aldosteronism, Circ. and 27(Suppl. 1):203, 19?0. Bielieri, E. G., Schambeian. M.. Slaton. P. E.. and S&kig~, J. R.: The intercurrent hypert,ension of primary aldosteronism, Circ. Res. 26 and 27(Suppl. 1):195, 1970. Sutherland, D. J. A., Ruse, J. L., and Laidlaw, J. C.: Hypertension, increased aldosterone secretion and low

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plasma renm aceivlty relieved ‘ny :jexa:n~~:t&one, :‘a%. Med. Assoc. J. $5:1109, 1966. New, M. I., and Petersor., R. E.: A nerv ‘arm oi’coggenital adrenal hyperplasia, J. Clin. Endocrine!. Metab. 27, 300, 1967. Miura, K., Yoshinaga, K., Goto, K., Katsushima, I., YMaebashi, M., Demura, i-l., Iino, M., Demxs, R., and Torikai, T.: A case of glucocorticoid-respcmsive hyperaidosteronism, J. Clin. Endocrinol. Metab. Z&1807, 1968, Giebink, G. S., Gotlin, R. W., Biglieri, E. G., and K.atz, F. H.: A kindred with familial glucocortici,id-suppressible aldosteronism, J. Clin. Endoctinol. Metab. 36:715, “973. Foye, L. V., Feicbtmeir, T. V.: Adrenal corticai carcinoma producing solely mineralocortjcoid efiect. Am. J. Nled. 19:966, 1955. Brooks, R. V., McSwiney; R. R., Prun~q, F. T. G., azd Wood, F. J. U.: Potassium deficiency of renal and adyenal origin, Am. J. Med. 23:391, 1957. Zimmermann, B., Moran, W. H., Rosenberg, 6. C., Kennedy, B. J., and Frey, R. J.: Phyaioiogic and sur$cai oroblems in the management of primary aldosteronism, Ann. Surg. 150:653, 1959. Crane, M. G., Harris, J. J., and Herber, R.: Primary aldosteronism due to an adrenal carcinoma. Ann. Intern. Med.

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71. Brown, J. :., Fraser,

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‘73.

Srooks,

R. V., Felix-Davies,

D., Lee, M. R., and Robert-

75.

son, P. W.: Xyperaidosteronism ‘rum 3~:” d. .drcm~lmd, Br. Med. J. t :220. 1972. Brown, J. J., Ferriss, 3. B., Fraser, R., ker? A. F., a;~! Robertson, J. I. S.: Aldosterone excess and adrenal carcinoma, Br. Med. 6. 1:686, 1972, Boddy, K., King, P. C., Tathill, P., and Strong, J. A.: Measurement of total body potassium witi- a high sensitivity shadow-shield whole-body connter: calibration and sources of error, Phys. Med. Biol. ‘I E::275, 1971.