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Invited review

Systematic review of surgery and outcomes in


patients with primary aldosteronism
A. Muth1 , O. Ragnarsson2 , G. Johannsson2 and B. Wngberg1
1

Section for Endocrine Surgery and Abdominal Sarcoma, Department of Surgery, Institute of Clinical Sciences, and 2 Section for Endocrinology,
Department of Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg,
Sweden
Correspondence to: Professor B. Wngberg, Department of Surgery, Bl Strket 5, 413 45 Gteborg, Sweden (e-mail: bo.wangberg@surgery.gu.se)
Background: Primary aldosteronism (PA) is the most common cause of secondary hypertension. The

main aims of this paper were to review outcome after surgical versus medical treatment of PA and partial
versus total adrenalectomy in patients with PA.
Methods: Relevant medical literature from PubMed, the Cochrane Library and Embase OvidSP from
1985 to June 2014 was reviewed.
Results: Of 2036 records, 43 articles were included in the final analysis. Twenty-one addressed surgical
versus medical treatment of PA, four considered partial versus total adrenalectomy for unilateral PA,
and 18 series reported on surgical outcomes. Owing to the heterogeneity of protocols and reported
outcomes, only a qualitative analysis was performed. In six studies, surgical and medical treatment had
comparable outcomes concerning blood pressure, whereas six showed better outcome after surgery. No
differences were seen in cardiovascular complications, but surgery was associated with the use of fewer
antihypertensive medications after surgery, improved quality of life, and (possibly) lower all-cause mortality compared with medical treatment. Randomized studies indicate a role for partial adrenalectomy in
PA, but the high rate of multiple adenomas or adenoma combined with hyperplasia in localized disease
is disconcerting. Surgery for unilateral dominant PA normalized BP in a mean of 42 (range 2072) per
cent and the biochemical profile in 96100 per cent of patients. The mean complication rate in 1056
patients was 47 per cent.
Conclusion: Recommendations for treatment of PA are hampered by the lack of randomized trials,
but support surgical resection of unilateral disease. Partial adrenalectomy may be an option in selected
patients.
Cutting edge articles are invited by the BJS Editorial Team, and focus on how current research and
innovation will affect future clinical practice.
Paper accepted 11 November 2014
Published online 20 January 2015 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9744

Introduction

Primary aldosteronism (PA), or Conns syndrome, is the


most common cause of secondary hypertension, with an
estimated prevalence of 513 per cent1 . PA is caused by
overproduction of aldosterone from one or both of the
adrenal glands. It typically presents with hypertension but
not always with hypokalaemia2 . Compared with patients
with essential hypertension and comparable BP levels,
patients with PA have an increased cardiovascular and
cerebrovascular risk, and more commonly impaired renal
function1,3 6 .
The most common (more than 90 per cent) diseases
underlying PA are idiopathic bilateral hyperplasia and
aldosterone-producing adenoma, although other rare
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causes exist7 . The recommended screening method for PA


is measurement of aldosterone and renin in plasma, and
subsequent calculation of the aldosterone to renin ratio
(ARR)8 10 . After confirmatory testing, identification of
the PA subtype is recommended for most patients because
unilateral dominant lesions are most commonly treated by
surgery. Adrenal venous sampling is the standard investigation for subtype evaluation and can be performed with low
morbidity. Patients with bilaterally increased aldosterone
production and patients with unilateral disease who are
not candidates for surgery are treated with mineralocorticoid (aldosterone) receptor antagonists (spironolactone or
eplerenone)11 . In unilateral dominant disease, laparoscopic
or retroperitoneoscopic surgical approaches have become
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308

A. Muth, O. Ragnarsson, G. Johannsson and B. Wngberg

Records identified through


database searching
n = 2033

Additional records identified through other sources


(hand-searching references from assessed
full-text articles) n = 3

Records after duplicates removed


n = 1351

Records screened
n = 1351
Records excluded
n = 1283
Full-text articles assessed
for eligibility
n = 68
Full-text articles excluded n = 25
No relevant data n = 16
Outcomes not uniformly reported with regard to
treatment modality n = 7
Overlapping publication n = 2
Studies included in qualitative synthesis n = 43
Surgical versus medical treatment of PA n = 21
Total versus partial adrenalectomy n = 4
Surgical outcomes n = 18

Studies included in
quantitative synthesis
(meta-analysis)
n=0
Fig. 1

PRISMA flow diagram showing selection of articles for review. PA, primary aldosteronism

the preferred methods owing to small tumour size and


low frequency of adrenocortical cancer in PA. The concept that unilateral disease is caused by a single adenoma
has made partial adrenalectomy a possible alternative
to total adrenalectomy12 . This has been challenged by
detailed histopathological studies showing hyperplasia,
combined adenoma and hyperplasia, or multiple adenomas
in many patients in whom adrenal venous sampling showed
unilateral disease13,14 .
Recent data from the German Conn Registry showed an
overall adrenal venous sampling rate in patients with PA
of 32 per cent (range 1984 per cent in the various centres). Adrenalectomy rates ranged from 15 to 44 per cent15 ,
suggesting large variation in practice. This implies that a
significant number of patients with unilateral PA are not
considered for surgery and therefore do not undergo subtype evaluation. To elucidate the outcome after surgical versus medical treatment of patients with PA, and after partial
versus total adrenalectomy in patients with PA, a systematic
review of the literature was performed. A secondary aim of
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the study was to assess overall complication and cure rates


after surgery for PA.

Methods

Standard Preferred Reporting Items for Systematic


Reviews and Meta-Analyses (PRISMA) guidelines16 were
followed. The two main study objectives were formulated
according to the PICO (Patient, Intervention, Comparison, Outcomes) model: surgical versus medical treatment in
PA (P, patients with PA; I, adrenalectomy; C, medical treatment; O, normalized potassium, normalized or improved
BP, cardiovascular events, quality of life, renal function,
complications and adverse effects); and partial versus total
adrenalectomy in PA (P, patients with lateralized PA; I,
partial adrenalectomy; C, total adrenalectomy; O, as in the
first objective, and normalized ARR). Outcome measures
were analysed from larger surgical series comprising 70 or
more patients.
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BJS 2015; 102: 307317

Surgery and outcomes in patients with primary aldosteronism

Table 1

309

Studies comparing medical and surgical treatment of primary aldosteronism

Reference

Location

Design

Miyake et al.18
(2014)

Japan
(multicentre)

Retrospective

Zacharieva
et al.19
(2006)

Sofia, Bulgaria

Prospective

Catena et al.3
(2008)

Udine, Italy

Prospective

Mulatero et al.4
(2013)

Torino, Italy

Reincke et al.20
(2012)

Study
period

Screening/
confirmatory
test/subtype
evaluation

ADX

Medical
treatment

Follow-up
(years)

Main
outcome
variables

Main findings

20032007

n.a.

733

626; type of
treatment n.a.

n.a.

BP and K

A somewhat better
effect on BP and
hypokalaemia for
ADX

n.a.

ARR/none/PT

30

34; all
spironolactone
( 100 mg)

30 ADX; 05
medical
treatment

BP and K

Similar effect on BP
and hypokalaemia
in the two groups

19942001 ARR/SIT/AVS
(26%), NP-59
(87%)

24

31; all
spironolactone
( 100 mg)

74

Cardiovascular
outcome

CHD, cerebrovascular
events and
arrhythmias no
different between
groups

Retrospective

19922009 ARR/SIT/AVS
(33%)

57

213; all
spironolactone
(dose n.a.)

12

Cardiovascular
outcome

CHD, cerebrovascular
events and
arrhythmias no
different between
groups

Germany
(multicentre)

Cross-sectional

19942010 ARR/SIT, FST or


CST/AVS
(selective)

157

180; all MRA


(type or dose
n.a.)

10

Cardiovascular
outcome

Increased
cardiovascular
mortality in PA;
all-cause mortality
increased in
medical treatment
group

Catena et al.21
(2007)

Udine, Italy

Prospective

24

30; all
spironolactone
( 100 mg)

64

Left ventricular
mass

Left ventricular mass


decreased in both
groups

Rossi et al.22
(2013)

Padua, Italy

Prospective

19922012 ARR/CST/AVS
(100%)

110

70; all MRA


(type or dose
n.a.)

30

Left ventricular
mass

Left ventricular mass


decreased in both
groups

Giacchetti et al.23
(2007)

Padua, Italy

Prospective

20032004 ARR/SIT/AVS
(selective)

25

36; 27 MRA
(type and dose
n.a.)

29 ADX; 46
medical
treatment

Left ventricular
mass/glucose
metabolism

Glucose metabolism
improved and left
ventricular mass
decreased in both
groups

Catena et al.24
(2006)

Udine, Italy

Prospective

20

27; all
spironolactone
(50300 mg/day)

57

Glucose
metabolism

Fasting glucose and


insulin sensitivity
improved similarly
in the two groups

Fourkiotis et al.25
(2013)

Germany
(multicentre)

Prospective

20082011 ARR/SIT, FST,


CST, OST/AVS
(5487%)

86

83; 65
spironolactone
(64 6 mg/day),
18 eplerenone
(88 11 mg/day)

55

Renal function

GFR and albumin


excretion
decreased to
comparable degree
in the two groups

Iwakura et al.26
(2014)

Sendai, Japan

Prospective

20072010 ARR/CST/AVS
(100%)

102

111; all MRA (type


or dose n.a.)

10 ADX; 07
medical
treatment

Renal function

Prevalence of chronic
kidney disease
increased, GFR and
albumin excretion
decreased to
comparable degree
in the two groups

Reincke et al.27
(2009)

Germany
(multicentre)

Casecontrol

19901999 ARR (88%)/SIT,


FST, CST or
OST (62%)/
AVS (34%)

51

63; all
spironolactone
(25150 mg/day)

n.a.

Renal function

GFR decreased and


serum creatinine
increased in both
groups

Sechi et al.28
(2006)

Udine, Italy

Prospective

19942001 ARR/SIT/AVS
(24%), NP-59
(88%)

22

28; all
spironolactone
(50300 mg/day)

64

Renal function

GFR and albumin


excretion
decreased to
comparable degree
in the two groups

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n.a.

n.a.

ARR/SIT/AVS
(26%), NP-59
(87%)

ARR/SIT/AVS
and/or NP-59
(100%)

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Table 1

A. Muth, O. Ragnarsson, G. Johannsson and B. Wngberg

Continued

Reference

Location

Design

Sechi et al.29
(2009)

Udine, Italy

Prospective

Wu et al.30
(2011)

Taiwan
(multicentre)

Wu et al.31
(2011)

Study
period
n.a.

Screening/
confirmatory
test/subtype
evaluation

ADX

Medical
treatment

Follow-up
(years)

Main
outcome
variables

Main
findings

ARR/SIT/AVS
(22%), NP-59
(87%)

24

30; all
spironolactone
(50300 mg/day)

10

Renal function

Intrarenal vascular
resistance
increased and
urinary protein
losses decreased
similarly in the two
groups

Prospective

20072009 ARR/CST + SIT/


AVS (54%),
NP-59 (42%)

63

61; all
spironolactone
(50 mg/day)

10

Renal function

GFR and albumin


decreased only
after ADX

Taiwan
(multicentre)

Prospective

20032007 ARR + CST/SIT/


AVS (52%),
NP-59 (69%)

185

101; all
spironolactone
(dose n.a.)

20 ADX; 10
medical
treatment

Renal function

GFR decreased and


serum creatinine
increased in both
groups

Ahmed et al.32
(2011)

Brisbane,
Australia

Prospective

20092010 ARR/FST/AVS
(100%)

22

21; 12
05
spironolactone
(12525 mg/day)

QoL

QoL improved more


slowly and to a
lesser degree in the
medical treatment
group

Kunzel et al.33
(2012)

Germany
(multicentre)

Prospective

20082009

49

56; 49
43 ADX; 54
spironolactone
medical
(15200 mg/day),
treatment
7 eplerenone
(25150 mg/day)

QoL

QoL worse in female


patients treated
with MRA than in
those having ADX

Apostolopoulou
et al.34
(2014)

Munich,
Germany

Cross-sectional

20082010 ARR/SIT or
FS/AVS (72%)

49

56; 49
43 ADX; 54
spironolactone
medical
(15200 mg/day),
treatment
7 eplerenone
(25150 mg/day)

Anxiety and
depression

Scores for depression


and anxiety worse
in female patients
treated medically
than in those having
ADX

Hanusch et al.35
(2014)

Germany
(multicentre)

Prospective and
cross-sectional

20082011 ARR/SIT, FST,


CST, OST/AVS
(5487%)

39

57; 39
53
spironolactone
(50240 mg/day),
13 eplerenone
(25200 mg/day)

Sleep

No difference in sleep
quality between the
groups

Kline et al.36
(2013)

Calgary, Canada

Retrospective

20052011 ARR/none/AVS
(96%)

38

39; 37 MRA (type


and dose n.a.)

Follow-up
time/visits

Follow-up time
shorter and clinical
visits fewer in ADX

n.a.

05 ADX; 11
medical
treatment

ADX, adrenalectomy; n.a., not available; K, potassium; ARR, aldosterone to renin ratio; PT, posture test; SIT, sodium infusion test; AVS, adrenal venous
sampling; NP-59, iodocholesterol scintigraphy; CHD, coronary heart disease; FST, fludrocortisone suppression test; CST, captopril suppression test;
MRA, mineralocorticoid receptor antagonist; PA, primary aldosteronism; OST, oral sodium loading test; GFR, glomerular filtration rate; QoL, quality of
life; FS, furosemide stimulation.

A detailed web-based search of the databases PubMed,


Cochrane Library and Embase OvidSP was last performed
on 25 June 2014. Search strategies combined the following terms: hyperaldosteronism, hyperaldosteronaemia,
aldosteronism, aldosteronaemia, adrenalectomy(-ies),
surgery, surgical, resection (Appendix S1, supporting information). The search was limited to articles published
after 1985 in English, German or the Scandinavian languages, to studies in humans, and to patients older than
18 years. Based on the title of the studies and abstracts,
reviews, letters, editorials and case reports were excluded
from analysis. Full articles of interest were retrieved and
analysed by at least two of the authors. Disagreement
was resolved by a third author. Small clinical series,
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publications without relevant outcome data, and duplicates


were excluded. For articles that reported data on the
same patient cohort and the same outcome, only the
latest publication with extractable data was included.
Main findings from relevant articles were extracted and
tabulated. Improved BP was defined as fewer medications
to maintain the same BP, or lower systolic or diastolic BP,
no higher than 140/90 mmHg, with unchanged or less
medication. Complications were classified according to
the ClavienDindo system17 .

Statistical analysis
Outcome data were categorized (normalized ARR (yes
or no), normalized potassium (yes or no), normalized or
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Surgery and outcomes in patients with primary aldosteronism

Table 2

311

Studies comparing total and partial adrenalectomy in localized primary aldosteronism

Reference

Location

Design

et al.37

Beijing,
China

212

RCT

Fu
(2011)

Nakada
et al.12
(1995)

Yamagata,
Japan

Walz et al.38
(2008)

Essen,
183
Germany

Ishidoya
et al.39
(2005)

Sendai,
Japan

48

92

RCT

Prospective

Screening/
confirmatory
test/subtype
evaluation
ARR/SIT/AVS
selectively

ARR/n.a./AVS
selectively,
NP-59 all

ARR/n.a./AVS
selectively

Retrospective n.a./n.a./AVS
selectively

Procedure
Total ADX
108
Partial ADX
104
Total ADX
22
Partial ADX
26

Hypertension
cured/
Normalized Follow-up
Normalized
K (%)
(years)
Comments
ARR (%) improved (%)
> 05

100

70/30

100

100

72/28

100

n.a.

n.a.

n.a.

n.a.

n.a.

n.a.

Total ADX
136

n.a.

22/63

n.a.

Partial ADX
47
Total ADX
63

n.a.

57/35

n.a.

100

n.a./100

n.a.

24

93

n.a./93

n.a.

52

Partial ADX
29

52

No blinding during
surgery or
follow-up
Details of
randomization not
provided. Similar
improvement with
regard to ARR, K
and hypertension.
Postop. response
to angiotensin II
infusion similar to
that in normal
subjects after
partial ADX,
blunted after total
ADX

49

Operations by 10
surgeons, 69%
multiple lesions in
partial
specimens, 27%
in total ADX

ARR, aldosterone to renin ratio; K, potassium; RCT, randomized clinical trial; SIT, sodium infusion test; AVS, adrenal venous sampling; ADX,
adrenalectomy; n.a., not available; NP-59, iodocholesterol scintigraphy.

improved BP (normalized, improved or not improved)),


and percentages calculated. Mean values for improvement
in BP after surgery were calculated, considering the sizes
of the different individual series.

of PA, heterogeneity in investigations and treatment


protocols, and lack of standardized reporting of outcomes,
data could not be extracted for a quantitative meta-analysis.

Results

Surgical versus medical treatment of primary


aldosteronism

Results of the web-based search are shown in Fig. 1.


After exclusion of duplicates, and screening of titles and
abstracts, 68 full-text articles were retrieved and further
analysed. Of these, 25 were excluded owing to lack of relevant data (16 articles), outcomes not reported uniformly
or not separated for treatment modality (7), or overlapping
publications (2). Forty-three publications were included
in the qualitative analysis; 213,4,18 36 addressed adrenalectomy versus medical treatment for PA, four12,37 39 total
versus partial adrenalectomy for lateralized PA, and
1813,38,40 55 reported outcomes after surgery for PA in
patient series comprising 70 or more patients. Owing to
wide variations in definitions of biochemical diagnosis

Data on surgical versus medical treatment of PA are summarized in Table 1. In six studies, five prospective3,19,22,29,35
and one retrospective36 , the effects on improvement
of BP and hypokalaemia were similar in surgically and
medically treated patients. In another six studies, four
prospective23,25,26,32 and two retrospective4,18 , the effects
on BP and hypokalaemia were better in surgically treated
patients, or they needed fewer antihypertensive drugs.
Reincke and colleagues20 reported reduced all-cause
mortality following adrenalectomy compared with medical
treatment. However, comparing medically and surgically treated patients with PA with regard to coronary
heart disease, cerebrovascular events and arrhythmias,

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Table 3

A. Muth, O. Ragnarsson, G. Johannsson and B. Wngberg

Summary of outcomes of surgery for primary aldosteronism

Reference

Screening/
confirmatory
test/subtype
evaluation

Normalized
ARR/K (%)

HT
cured/improved (%)

Mean
follow-up
(years)

n.a./n.a.

55/37

36

11

Duration of HT, plasma


aldosterone level
n.a.

Mean normal/100

58/42

37

n.a.

n.a./n.a.

n.a.

n.a.

n.a.

ARR/n.a./AVS
selectively
ARR/CST/AVS all

n.a./96

30/57

49

Age, sex, duration of HT, APA

99/n.a.

20/69

008

n.a.

ARR/sARR/AVS
selectively
ARR/SIT + CST/CT

100/n.a.

32/42

06

99/99

54/43

40

Urinary aldosterone excretion,


serum K level
n.a.

156

ARR/sARR/AVS
selectively

96/98

44/56

05

150

ARR/CST SIT/AVS
and NP-59
selectively
ARR/OST/AVS
selectively
ARR/SIT, CST,
FS/AVS and/or
NP-59 all
n.a.

n.a./n.a.

66/33

49

n.a./97

42/46

68

n.a.

100/n.a.

42/56

05

Age, duration of HT, number of


drugs, sex

n.a./n.a.

59/41

30

n.a.

Factors predictive
of cure

Zhang et al.40
(2013)
Quillo et al.13
(2011)*
Meria et al.47
(2003)
Lin et al.48
(2007)
Walz et al 38
(2008)
Ishidoya et al.52
(2011)
Letavernier et al.50
(2008)
Jiang et al.51
(2014)
van der Linden
et al.44
(2012)
Wu et al.42
(2009)

376

Lim et al.49
(2014)*
Utsumi et al.45
(2014)

133

Zhang et al.53
( 2009)
Wang et al.43
(2012)

127
124

ARR/SIT/AVS
selectively

n.a./n.a.

55/35

49

Zarnegar et al.41
(2007)
Proye et al.46
(1998)

102

ARR/n.a./AVS
selectively
ARR/n.a./AVS and
NP-59 selectively

n.a./n.a.

39/38

05

100/100

56/44

54

Lumachi et al.55
(2005)
Ip et al.54
(2013)

98

100/100

72/24

67

Duration of HT, number of drugs,


response to spironolactone,
genotype, APA
Normalized BP, BMI (men), age,
number of drugs
Response to spironolactone,
duration of HT, age, family
history of HT, unilateral disease
Age, duration of HT

n.a./n.a.

25/75

008

KCNJ5 mutation

ARR/SIT/AVS
selectively
ARR/OST/AVS
selectively
ARR/n.a./AVS
selectively
n.a.

215
212
195
183
174
168
164

132

100

83

ARR/OST/AVS and
NP-59 selectively
n.a.

Systolic BP, number of drugs,


duration of HT, urinary
aldosterone excretion
Duration of HT, BMI, age, diastolic
BP, renal function

*Overlapping series. Cure in 98 per cent defined as normalization of aldosterone and/or BP off all medications. Postoperative aldosterone to renin ratio
(ARR) available for 81 of 168 patients. Postoperative ARR available for 116 patients. Cure in 955 per cent defined as a combination of the
postoperative plasma aldosterone concentration, cure of hypokalaemia, and improvement or cure of hypertension; BP data based on 127 patients. K,
potassium; SIT, sodium infusion test; AVS, adrenal venous sampling; n.a., not available; HT, hypertension; OST, oral sodium loading test; APA,
aldosterone-producing adenoma; CST, captopril suppression test; sARR, supine aldosterone to renin ratio; NP-59, iodocholesterol scintigraphy; BMI,
body mass index; FS, furosemide stimulation.

outcomes were no different between the two groups


of patients3,4 (Table 1). Similar improvement in glucose
metabolism in surgically and medically treated PA was also
reported24 . Echocardiographic characteristics were evaluated in three studies21 23 in patients with PA; all showed
a reduction in left ventricular mass after adrenalectomy
and medical treatment (Table 1). The beneficial effect on

ventricular mass seemed to appear earlier after surgical


treatment21 .
The decrease in renal function, as measured by glomerular filtration rate (GFR), and the decrease in urinary
albumin excretion were similar in surgically and medically
treated patients25 28,31 (Table 1). Similarly, the low
intrarenal vascular resistance observed before treatment

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Surgery and outcomes in patients with primary aldosteronism

of PA (the plausible reason for increased GFR before


treatment) increased to similar levels after treatment in
both groups29 . In one study30 , GFR and albumin excretion
decreased only in patients treated with adrenalectomy,
probably explained by the low spironolactone dose used in
the medically treated group (50 mg/day).
General quality of life32,33 , and coexisting depression and
anxiety34 in patients with PA, evaluated in three studies,
showed better outcome after surgical compared with medical treatment.

Partial versus total adrenalectomy for localized


primary aldosteronism
Whether to perform partial or total adrenalectomy in
patients with PA was studied in two randomized clinical
trials (RCTs) and in prospective and retrospective series
(Table 2). In one RCT, where unilateral disease was confirmed with norcholesterol scintigraphy and CT, Nakada
and co-workers12 found no difference in BP improvement,
potassium values or plasma aldosterone between patients
randomized to open adrenalectomy or tumour enucleation
via a high lateral lumbar incision. Details of randomization
and blinding were not provided. More recently, Fu et al.37
published a large randomized trial on retroperitoneoscopic
partial or total adrenalectomy in PA. No differences in perioperative course or postoperative BP, ARR or potassium
levels were found between the groups of patients. Adrenal
venous sampling was performed only in selected patients,
and blinding of investigators for the treatment group was
not ascertained during follow-up.

Overall outcomes following adrenalectomy


for primary aldosteronism
A summary of overall outcomes after adrenalectomy for
PA is shown in Table 3 and detailed in Table S1 (supporting information). Various techniques were utilized,
but the lateral transperitoneal and posterior retroperitoneal approaches were most common. Open procedures
were reported only in the very early series. Based on
seven studies44 46,50 52,55 , including 992 patients, biochemical cure rates ranged from 96 to 100 per cent.
Based on 2482 patients from 16 studies38,40 47,49 55 , BP
was normalized in a mean of 42 (range 2072) per cent
of patients. The cure rate was higher in series with a
longer follow-up period. Positive predictive factors for cure
were short duration of hypertension, histologically verified
aldosterone-producing adenoma, female sex, young age,
preserved kidney function, low number of antihypertensive
drugs, and mutations in KCNJ5 (inwardly rectifying potassium channel, subfamily J, member 5 gene).
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313

Surgical complications were reported in six38,43,47,48,50,52


of 18 studies. The mean complication rate in 1056 patients
was 47 per cent with a range in the various studies of 210
per cent, the higher figure from an early series47 in the
investigated time interval. No deaths and only two grade III
complications17 were noted (Table S2, supporting information). No difference in outcome was seen for laparoscopic
or retroperitoneoscopic adrenalectomy, and hospital stay
was short for the endoscopic techniques.
Discussion

In this study, surgical treatment of PA has been reviewed


systematically, with special reference to outcomes after
surgical versus medical treatment, and after partial versus
total adrenalectomy. The literature search revealed only
two RCTs, both studying partial versus total adrenalectomy. There was wide variation in biochemical definitions of the diagnosis of PA, diagnostic procedures and
outcome measures. The outcome measures varied from
rate of normalization of serum potassium concentration,
mean change, normalization or improvement in BP, change
in the number of antihypertensive medications, and change
or normalization of the ARR. These outcome measures
of treatment are valid, but, as there was no consistency
in reported outcomes among trials, a formal meta-analysis
could not be performed. Instead, qualitative data from the
retrieved articles were summarized.
Comparisons of surgical and medical treatment of PA
were difficult in the absence of RCTs. Many studies came
from the same centres, included relatively small numbers of patients, and were designed primarily to compare
patients with PA with patients with essential hypertension.
In many studies, medical treatment was not predefined for
dose, type of medication or target BP. Some of the studies
that demonstrated superior effect of surgery over medically treated groups of patients received either no treatment with18 , or low doses of 25 , mineralocorticoid receptor
antagonists, or the medical treatment was not reported4 .
A further limitation was that the majority of surgically
treated patients supposedly had aldosterone-producing
adenomas and most medically treated patients had idiopathic bilateral hyperplasia; thus, a comparison was made
between two different subtypes of PA that may not be
entirely comparable. Comparisons between surgically and
medically treated patients with PA should, therefore, be
interpreted with caution.
Although several outcome variables, such as cardiovascular risk and albuminuria, appeared to improve to a
comparable level after medical and surgical treatment,
there are other important aspects that differ between the
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314

two types of treatment. Patients treated medically need


more antihypertensive drugs22,23,36 , and require a longer
follow-up and more clinical visits at specialized referral
centres than those treated surgically36 . Quality of life32,33 as
well as scores for anxiety and depression34 seem to be worse
in medically treated patients with PA. Side-effects are common in patients receiving treatment with mineralocorticoid receptor antagonists, especially spironolactone3,23,26 ,
contributing to worse quality of life, increased healthcare consumption, and increased risk of non-compliance.
Adrenalectomy for PA is also less expensive than long-term
medical treatment56,57 .
Two RCTs12,37 together with a large non-randomized
series38 reported comparable outcomes after partial and
total adrenalectomy for disease lateralized before surgery.
These studies are in contrast to other clinical findings39 and
studies of adrenal histology in patients with PA. By use of
conventional histopathology, immunohistochemistry and
in situ hybridization techniques, hyperplasia, multiple adenoma, or combined hyperplasia and adenoma has been
identified in 1627 per cent of patients with unilateral
dominant disease13,14,58,59 .
A number of large case series have confirmed that surgical
treatment of PA is a safe treatment with low morbidity and
short hospital stay (Table 3; Tables S1 and S2, supporting
information). No major differences in cure rate between
techniques were seen, but some authors38,40 44,46,50,54,55,60
have identified predictive characteristics for cure. Reported
complication rates ranged between 2 and 10 per cent, with
the highest rate in an early series47 , possibly reflecting a
laparoscopic learning curve. As complication rates were
reported in less than half of the studies, data are uncertain,
but major complications were rare.
Recommendations on treatment are hampered by the
lack of systematic reporting of clearly defined outcomes
and RCTs. The present data support surgical resection of
unilateral disease, which can be performed with low morbidity. Two RCTs12,37 showed no difference between partial or total adrenalectomy, but histological findings may
suggest an increased risk of treatment failure after partial resection. Surgical treatment improves quality of life,
is cost-effective and curative with normalization of aldosterone and renin levels. A suggested algorithm for diagnosis and treatment has been compiled based on consensus
documents and guidelines, together with the results of the
present study (Fig. S1, supporting information)1,7 10,61,62 .
Acknowledgements

A.M. and O.R. contributed equally to this paper. The


expert assistance of T. Svanberg at the Clinical Library
2015 BJS Society Ltd
Published by John Wiley & Sons Ltd

A. Muth, O. Ragnarsson, G. Johannsson and B. Wngberg

and Health Technology Assessment Centre at Sahlgrenska


University Hospital is greatly appreciated.
Disclosure: The authors declare no conflict of interest.
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Supporting information

Additional supporting information may be found in the online version of this article:
Appendix S1 Search strategies (Word document)
Table S1 Details of outcome of surgery for primary aldosteronism (Word document)
Table S2 Complications after surgery for primary aldosteronism as reported in major case series (Word document)
Fig. S1 Suggested algorithm for diagnosis and treatment of primary aldosteronism (JPEG file)

Snapshot quiz

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The answers to the above questions are found on p. 330 of this issue of BJS.
Karavokyros I, Moris D: First Department of Surgery, Laikon General Hospital, Athens 11527, Greece (dimmoris@yahoo.com)

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