iacobone et al-2015-british journal of surgery

Invited review

Systematic review of surgical treatment ofsubclinical Cushing’s syndrome

M. Iacobone1, M. Citton1, M. Scarpa3, G. Viel1, M. Boscaro2 and D. Nitti11Minimally Invasive Endocrine Surgery Unit, Department of Surgery, Oncology and Gastroenterology, and 2Endocrinology Unit, Department ofMedicine, University of Padua, and 3Surgical Oncology Unit, Veneto Institute of Oncology, Padua, ItalyCorrespondence to: Dr M. Iacobone, Minimally Invasive Endocrine Surgery Unit, Department of Surgery, Oncology and Gastroenterology, University ofPadua, Via Giustiniani 2, 35128 Padova, Italy (e-mail: [email protected])

Background: Subclinical Cushing’s syndrome (SCS) is a condition of biochemical cortisol excess withoutthe classical clinical features of overt hypercortisolism; it may be associated with some consequences ofmetabolic syndrome. The most appropriate treatment remains controversial. This study aimed to assessthe outcomes of adrenalectomy for SCS.Methods: A systematic review was performed. MEDLINE, Embase and Cochrane Databases(1980–2013) were searched for studies reporting the outcomes of unilateral adrenalectomy with respectto hypertension, diabetes, dyslipidaemia, obesity and osteoporosis in patients with SCS. Studies with aquestionable diagnosis of SCS, bilateral adrenal involvement and insufficient data were excluded.Results: Of the 105 papers screened, seven were selected; there were six retrospective studies andone randomized clinical trial, including 230 patients. Data analysis was limited by heterogeneity indefinition of SCS and endpoints. Hypercortisolism was cured in all operated patients. Laparoscopy wasthe preferred approach, with a morbidity rate of 0⋅8 per cent. A beneficial effect of surgery on bloodpressure, glucometabolic control and obesity was evident in all studies, with cure or improvement in72, 46 and 39 per cent of patients respectively, compared with conservative management. The resultsfor lipid metabolism were equivocal, because of a decrease in triglyceridaemia but discordant effects oncholesterol metabolism among the different studies. No beneficial effects on osteoporosis were found.Conclusion: Laparoscopic adrenalectomy seems to be beneficial in reversing several metabolic effects ofhypercortisolism, with a low morbidity rate. However, the heterogeneity and low quality of the availablestudies preclude definitive recommendations.

Cutting edge articles are invited by the BJS Editorial Team, and focus on how current research andinnovation will affect future clinical practice.

Paper accepted 11 November 2014Published online 2 February 2015 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9742

Introduction

Subclinical Cushing’s syndrome (SCS) is an ill definedcondition of altered hypothalamic–pituitary–adrenal axissecretion in patients who do not have the classical signs andsymptoms of clinically apparent Cushing’s syndrome1–3.In recent years it has become a topic of increasinginterest and controversy4–6. Clinically overt Cushing’ssyndrome is rare, with an incidence of two diagnosedpatients in 100 000 per year, whereas SCS is consideredan ‘epidemic’ disease with a prevalence of 0⋅2–2 per centin the general adult population7. SCS is associated withadrenal incidentalomas8 that, following the widespreaduse of diagnostic imaging tools1,9, are being diagnosed inabout 4–7 per cent of subjects undergoing radiological

studies6. Adrenal incidentalomas have autonomousadrenocorticotropic hormone (ACTH)-independentcortisol hypersecretion in 5–48 per cent of patients2,5,9–12.SCS is usually associated with unilateral adrenal inci-dentalomas, but it may also occur bilaterally and requirebilateral adrenalectomy13. The benefits of surgery in theseasymptomatic patients are highly controversial becauseof permanent hypocorticoadrenalism, and the need forlifelong substitutive corticosteroid treatment, with the riskof life-threatening addisonian crises13.

SCS was first described in the 1970s and 1980s14,15,and was initially defined as ‘preclinical Cushing’s syn-drome’. However, the term ‘subclinical’ is preferredbecause it does not imply the progression toward classicalCushing’s syndrome, which occurs in less than 1 per cent of

© 2015 BJS Society Ltd BJS 2015; 102: 318–330Published by John Wiley & Sons Ltd

Surgical treatment of subclinical Cushing’s syndrome 319

patients6,10,16–18. Although the US National Institutes ofHealth (NIH) state-of-the-science conference8 concludedthat a more precise definition should be ‘subclinicalautonomous glucocorticoid hypersecretion’ or ‘subclinicalhypercortisolism’, these terms never gained widespreadacceptance. SCS is currently the most commonly usedterm to describe autonomous ACTH-independent cortisolhypersecretion from an adrenal mass detected serendipi-tously in patients without a clear cushingoid phenotype4,8.

Several controversies exist concerning the criteria usedto define an individual patient affected by SCS. Cortisolsecretion may range from normal to clearly increased, withsubclinical and mild cortisol excess lying between theseextremes. Thresholds associated with various outcomesare often arbitrary and unrelated to solid evidence19. Bydefinition SCS should not present clinical features that arespecific for overt Cushing’s syndrome3, but identificationof the typical phenotype depends mainly on the experienceand clinical judgement of the physician and may be a sourceof bias. The phenotype may vary not only according to thedegree and duration of hypercortisolism but also owing toglucocorticoid sensitivity. Glucocorticoid sensitivity maybe different among individuals and tissues in the sameindividual, because of polymorphisms of both glucocorti-coid receptor20–23 and 11β-hydroxysteroid dehydrogenasetype 1 genes24,25.

Although subtle cortisol hypersecretion is by definitionnot associated with the classical features of Cushing’ssyndrome, there is clear evidence that SCS may leadto long-term consequences of cortisol excess, includingarterial hypertension, diabetes, dyslipidaemia, obesity,osteoporosis and impairment of quality of life5,26–31. Anincreased mortality rate has also been demonstrated amongpatients with SCS32.

Adrenalectomy represents the definitive treatment forclinically evident Cushing’s syndrome, whereas the mostappropriate treatment for SCS associated with benignadrenal incidentalomas remains controversial; eithersurgery or follow-up is recommended1,5,8,26,27,30,31,33–35.

The aim of the present systematic review was to assessthe diagnostic criteria and outcomes of adrenalectomy inpatients with SCS and unilateral adrenocortical inciden-talomas in terms of morbidity, mortality, postoperativeadrenal insufficiency, and the effects of surgery on hyper-tension, diabetes, dyslipidaemia, obesity, osteoporosis andquality of life.

Methods

The present review was conducted according to thePreferred Reporting Items for Systematic Reviews andMeta-Analyses (PRISMA) guidelines36.

Search strategy

A systematic literature search was conducted usingMEDLINE, Cochrane Database of Systematic Reviews,Cochrane Central Register of Controlled Trials (CEN-TRAL) and Embase. Keywords and medical subjectheadings (MeSH) used and combined by Boolean opera-tors were: (‘Cushing syndrome’ or ‘Cushing’s Syndrome’or ‘Cushing’s’ or ‘Cushing’ or ‘hypercortisolism’ or‘adrenocortical hyperfunction’ or ‘hypercorticism’ or‘hyperadrenocorticism’ or ‘adrenal gland hyperfunction’or ‘hyperadrenalism’) and (‘preclinical’ or ‘subclinical’) and(‘adrenalectomy’ or ‘adrenalectomies’). A manual searchof references in the eligible papers was also performedto identify additional pertinent articles. The search waslimited to original papers based on human studies, writ-ten in English and published between January 1980 andDecember 2013.

Inclusion and exclusion criteria

Studies were eligible for inclusion if they reported theresults of adrenalectomy in patients with SCS and uni-lateral adrenocortical incidentaloma, and addressed atleast one of the following postoperative outcomes: arterialhypertension, diabetes, dyslipidaemia, obesity, osteoporo-sis and quality of life.

Studies reporting only preoperative data or insufficientpostoperative data were excluded, as were case reports andseries including fewer than ten operated patients. Reviews,letters and studies including patients with clinically mani-fest Cushing’s syndrome or absence of biochemically con-firmed hypercortisolism were excluded. Studies of patientswith other adrenal disease in addition to hypercortisolism,such as primary hyperaldosteronism or phaeochromo-cytoma, and studies that did not differentiate between clin-ically overt hypercortisolism and SCS, were also excluded,as were those including bilateral adrenalectomy or bilateraladrenal involvement.

In the event of duplicate publications that reported onparts of, or similar, patient data, only the most recentand complete data set was considered. Data quoted asunpublished or derived from abstracts were not used.Any discordance among the researchers was resolved bydiscussion.

The corresponding authors of papers with incompletedata were contacted and asked for additional information;when obtained, the requested data were used for analysis.

From the initial search results, two researchers inde-pendently selected studies that matched the inclusion andexclusion criteria according to the title, abstract and fulltext of the article.

© 2015 BJS Society Ltd www.bjs.co.uk BJS 2015; 102: 318–330Published by John Wiley & Sons Ltd

320 M. Iacobone, M. Citton, M. Scarpa, G. Viel, M. Boscaro and D. Nitti

Quality assessment of retrieved articles

The methodological quality of the articles was assessedindependently for possible inclusion in a meta-analysis.The Cochrane quality assessment list37 was used to con-struct the list of items against which the quality of selectedpapers was judged. These comprised the number of oper-ated patients (more than 20), whether the study was aprospective randomized trial or not, whether there was acontrol group and whether the control group comprisedpatients who had conservative treatment of SCS, complete-ness of reported data and whether a clear definition of theoutcomes was used. A quality score was determined foreach study, with a maximum of 6 points indicating the high-est quality.

Data extraction

Data were extracted from original articles using a pro formawith a set of predefined parameters: demographic data,diagnostic criteria for SCS, surgical approaches, pathology,adrenal mass size, postoperative morbidity and mortality,length of follow-up, postoperative adrenal insufficiency,

preoperative and postoperative arterial BP, glycometabolicparameters, lipid profile, body mass index (BMI), bonemass density and quality of life.

Statistical analysis

A clinical statistician assessed the accuracy of the analysis.Review Manager 5.1 software (The Cochrane Collabora-tion, Nordic Cochrane Centre, Copenhagen, Denmark)was used for data analysis. To analyse potential benefitsof surgery for SCS, odds ratios and mean differences with95 per cent c.i. were calculated for each study. Overallodds ratios or weighted mean differences were not calcu-lated because of the clinical heterogeneity of the availablestudies.

Results

Study selection

The process of selection of articles for review is summa-rized in Fig. 1. The initial literature search yielded 105citations, of which 77 studies were excluded after initial

Excluded based on titlen = 25

Excluded based onabstract n = 52

Additional full-text articles(screened following cross-

referencing) n = 9

Excluded n = 30 Letters or case series including < 10 operated patients n = 11 Duplications n = 2 Absence of required data n = 13 Controversial SCS diagnosis n = 2 Inclusion of bilateral adrenalectomy n = 2

Publications identified through databasesearching (human studies published

in English, before 2014) n = 105

Records screened by title n = 80

Records screened by abstract n = 28

Full-text articles assessedfor eligibility

n = 37

Studies included inqualitative synthesis

n = 7

Fig. 1 Flow chart illustrating the screening and selection of papers for analysis. SCS, subclinical Cushing’s syndrome



Table 1 Studies on the effects of adrenalectomy for subclinical Cushing’s syndrome included in the present review

Operated patients with SCS Control

Reference Time span Study type

n

(M : F)

Age

(years)

Tumour

size (mm)

Follow-up

(months)

n

(M : F)

Age

(years)

Tumour

size (mm)

Follow-up

(months)

Perysinakiset al.67

(2013)

1997–2011

Retrospective 29(8 : 21)

54 (31–68)* 37 (19–67)* 77 – – – –

Iacoboneet al.66

(2012)

2000–2009


56⋅8(11⋅9) 39⋅1(6⋅5) 54(34) 15 SCS-ct(8 : 7)

57⋅4(11) 38⋅5(7⋅4) 56(37)

Maehanaet al.38

(2012)

1995–2008


56 (31–72)* 36⋅4 11⋅7* 21 ONFAI(n.a.)

n.a. n.a. n.a.

Guerrieriet al.65

(2010)

1997–2009


54⋅8(2⋅7) n.a. 46⋅6(3⋅9) 28 SCS-ct(10 : 18)

57⋅8(2⋅2) n.a. 50⋅1(29⋅2)

Chiodini et al.1

(2010)2002–

2007Retrospective 25

(5 : 20)54⋅8(11⋅6) 32(1) 29⋅4(13⋅8) 16 SCS-ct

(3 : 13)64⋅4(10⋅1) 24(8) 36⋅4(11⋅7)

Toniato et al.35

(2009)1991–

2005Prospective

randomized23

(12 : 11)63(4⋅1) 29⋅8(29) 92⋅4

(24–204)*22 SCS-ct

(10 : 12)64(1⋅8) 26⋅5(4⋅2) 92⋅4 (24–204)*

Tsuiki et al.64

(2008)1995–

2006Retrospective 10

(2 : 8)58⋅4(9⋅8) 34⋅5(9⋅7) 13⋅8(3⋅8) 10 SCS-ct

(4 : 6)60⋅9(11⋅3) 28(5⋅8) 27⋅3(15⋅2)

Values are mean(s.d.) unless indicated otherwise; *values are median (range). SCS, subclinical Cushing’s syndrome; –, not assessed; SCS-ct, conservativelytreated SCS; ONFAI, operated non-functioning adrenal incidentaloma; n.a., not available.

screening of titles (25 publications) and abstracts (52). Thefull text of 28 articles plus nine additional articles followingcross-referencing1,9,26,27,30,34,35,38–67 was assessed for eligi-bility. Thirty studies9,26,27,30,34,39–63 were excluded becausethey did not fulfil the inclusion criteria. Finally, sevenstudies1,35,38,64–67 contained sufficient details and met thecriteria to merit inclusion in the present review (Table 1).All had been published within the past 6 years; six studieswere retrospective and one was a randomized clinical trial.

Quality assessment

Four studies1,35,66,67 had an adequate sample size of atleast 20 patients, and six1,35,38,64–66 included a control

group, which was composed of patients with SCS infive studies1,35,64–66 (Table 2). The outcome data wereincomplete, imprecise or sparse in four studies35,38,65,67.A precise definition of the outcomes was not availablefor one study38. The median quality score was 4, rangingbetween 1 (1 publication) and 5 (3 publications).

General characteristics

The total number of patients undergoing surgery becauseof SCS was 139, median 20 (range 10–29) patients, andthe pooled female-to-male ratio was 91 to 48. The meanage ranged from 54 to 63 years and the mean follow-upfrom 13⋅8 to 92⋅4 months. The control groups included

Table 2 Quality assessment of included papers

Reference

No. of

operated

patients (≥ 20)

Study

design (RCT)

Presence

of control

group

Control

group with

conservatively

treated SCS

Completeness

of reported

data

Clear

definition of

inclusion criteria

and outcomes

Quality

assessment

score

Perysinakis et al.67 + – – – – + 2

Iacobone et al.66 + – + + + + 5

Maehana et al.38 – – + – – – 1

Guerrieri et al.65 – – + + – + 3

Chiodini et al.1 + – + + + + 5

Toniato et al.35 + + + + – + 5

Tsuiki et al.64 – – + + + + 4

RCT, randomized clinical trial; SCS, subclinical Cushing’s syndrome.



Table 3 Postoperative adrenal insufficiency and glucocorticoid treatment in patients undergoing adrenalectomy for subclinicalCushing’s syndrome.

Reference

No. of patients with

adrenal insufficiency

Hydrocortisone

supplementation

Hydrocortisone

daily dose (mg) Duration

Perysinakis et al.67 0 All patients 20 Mean 1⋅3 (range 1–6⋅6) months

Iacobone et al.66 0 All patients Range 25–37⋅5 3–6 weeks

Maehana et al.38 0 All patients n.a. Mean 14 (range 1–144) months

Guerrieri et al.65 n.a. n.a. n.a. n.a.

Chiodini et al.1 0 All patients Range 25–37⋅5 Mean(s.d.) 12⋅3(14⋅1) months

Toniato et al.35 0 All patients Range 25–37⋅5 3–5 weeks

Tsuiki et al.64 n.a. n.a. n.a. n.a.

n.a., Not available.

a total of 91 patients with SCS who received conser-vative treatment and 21 with operated non-functioningadrenal incidentalomas; mean age ranged from 57⋅4 to64⋅4 years and mean follow-up from 27⋅3 to 92⋅4 months.The enrolment period ranged from 4 to 15 years. Thesurgical approach was specified in six publications: infive studies35,38,65–67 laparoscopic adrenalectomy was per-formed in all patients, and no conversions to open surgerywere reported; in one study1, open surgery was carried outthrough a laparotomy depending on the size of the massand the clinical characteristics in an unspecified number ofpatients.

The mean size of the adrenal mass ranged from 29⋅8 to39⋅1 mm for operated patients with SCS and from 24 to38⋅5 mm in conservatively treated patients. Histopathologyrevealed a benign adrenal tumour in all patients.

Postoperative biochemical cure was detailed infive1,35,38,66,67 of seven studies, and reported normalpostoperative hormone tests in all patients.

Data on postoperative morbidity and mortality wereavailable in six studies1,35,38,65–67 and included 129patients; a low-output pancreatic fistula was reportedin one patient67, with no morbidity in the remainingpatients. No postoperative deaths were reported.

Data on postoperative adrenal insufficiency were avail-able in five studies1,35,38,66,67 which included 110 patients(Table 3). Perioperative corticosteroid treatment wasadministered in all patients at an equivalent dose ofhydrocortisone ranging between 20 and 37⋅5 mg/day.Substitution was started during surgery, with a meanduration of 5⋅2 months (range 3 weeks to 144 months). Noaddisonian crises were reported.

Diagnosis of subclinical Cushing’s syndrome

Diagnostic criteria for SCS were highly heterogeneousand varied among the studies (Table 4). Absence of clinicalsigns specific for overt Cushing’s syndrome was assessed

in all papers, as this was a mandatory inclusion criterionin the present review. However, detailed criteria for overtCushing’s syndrome were available in only two studies1,66,and consisted of proximal muscle weakness, facial plethora,striae rubrae and skin atrophy/easy bruising. The dexa-methasone suppression test (DST) was listed in all studiesamong the biochemical diagnostic criteria. Overnightadministration of 1 mg dexamethasone was used in sixstudies1,35,38,64–66, and in two studies 4 mg67 and 8 mg64

were administered. Failure to suppress cortisol secretion inresponse to dexamethasone was considered mandatory infive studies35,38,64,66,67. The required cut-off for a patholog-ical DST ranged between 50 and 138 nmol/l. Additionalcriteria were considered necessary for the diagnosis of SCSin all studies1,35,38,64–67, including low ACTH and de-hydroepiandrosterone sulphate (DHEAS) levels, highurinary free cortisol (UFC) levels, loss of cortisol rhythmand an attenuated corticotropin-releasing hormone test.Unilateral adrenal scintigraphy uptake was listed in twostudies38,64.

Clinical outcomes

Outcomes are reported in Figs 2 and 3, Figs S1–S3 (sup-porting information) and Table 5. Seven studies1,35,38,64–67

investigated the outcomes of surgery on hypertension andglucose metabolism, six1,35,38,64–66 on lipid metabolism,six1,35,64–67 on obesity and two35,66 on osteoporosis. Defi-nitions of hypertension, obesity, impaired glucose and lipidmetabolism, and bone mass impairment, as well as defini-tions of cure, improvement and worsening of the outcomesstudied, were sometimes not given or were heterogeneous(Tables S1 and S2, supporting information). Quantitativemeta-analysis was not performed owing to clinical hetero-geneity among the studies.

A trend toward a beneficial effect of surgery on bloodpressure was described in all studies analysed35,64–66. Cureor improvement of hypertension after adrenalectomy was



Table 4 Diagnostic criteria for subclinical Cushing’s syndrome

Reference Diagnostic criteria Dexamethasone dose (mg) DST cut-off (nmol/l)

Perysinakis et al.67 Absence of symptoms+DST+one of: blunted diurnal cortisol circadian rhythm (ratio of plasmacortisol at 24.00 hours to 08.00 hours > 50%), ACTH<2⋅2 pmol/l, 24-hUFC>276 nmol/l

4 > 50

Iacobone et al.66 Absence of symptoms (facial plethora, striae rubrae, easy bruising andproximal muscle weakness)+DST+ACTH<2⋅2 pmol/l+high 24-h UFC

1 > 138

Maehana et al.38 Absence of symptoms+DST+at least one of: low ACTH, loss of cortisol circadian rhythm, lowDHEAS, unilateral uptake at adrenal scintigraphy

1 > 83

Guerrieri et al.65 Absence of symptoms+at least two of: DST, high 24-h UFC, ACTH<2⋅2 pmol/l

1 > 50

Chiodini et al.1 Absence of symptoms (moon facies, striae rubrae, skin atrophy, proximalmuscle weakness)+at least two of: DST, high 24-h UFC, ACTH<2⋅2 pmol/l

1 > 83

Toniato et al.35 Absence of symptoms+DST+at least two of: low ACTH, loss of cortisol circadian rhythm, high 24-hUFC, low DHEAS

1 > 69

Tsuiki et al.64 Absence of symptoms+DST (low- and high-dose)+at least one of: ACTH<2⋅2 pmol/l, blunted ACTH after CRH (< 150%increase with respect to baseline), loss of cortisol diurnal rhythm(>138 nmol/l at midnight), low DHEAS, unilateral uptake at adrenalscintigraphy

18

> 83> 28

DST, dexamethasone suppression test; ACTH, adrenocorticotropic hormone; UFC, urinary free cortisol; DHEAS, dehydroepiandrosterone sulphate;CRH, corticotropin-releasing hormone.

observed in 54 (72 per cent) of 75 patients (range 53–100per cent), and in none of the 60 conservatively treatedpatients with SCS (Table 5). This trend was confirmedby three studies1,65,66 that reported a significant decreasein systolic and diastolic BP in operated compared withnon-operated patients (Fig. 2).

Adrenalectomy seemed to have a beneficial effect onglucose metabolism. After surgery, impaired glucosemetabolism normalized or improved in 19 of 41 patients,but in none of the 21 patients who had conservative treat-ment (Table 5). Odds ratios for studies with comparativedata are shown in Fig. 3.

Normalization or improvement of dyslipidaemia wasobtained in 13 of 43 affected patients after surgery,

and in none of the 18 conservatively treated patients(Table 5). This trend was confirmed by two studies65,66

that described a decrease in triglyceride levels in operatedpatients. However, the effects of surgery on total choles-terol, high-density lipoprotein and low-density lipoproteincholesterol levels were not concordant among the studies(Figs S1 and S2, supporting information).

Normalization or improvement of an abnormal BMIwas reported in 15 of 38 patients after adrenalectomy,but in none of the 15 patients who received conservativetreatment (Table 5). Data on BMI were available in only twostudies65,66, which both reported a postoperative decreasein patients who had adrenalectomy (Fig. S3, supportinginformation).



Improvement in hypertension

Reference

Chiodini et al.1 n.a.

12 of 12

8 of 15

12 of 18

5 of 6

0 of 10

0 of 20

0 of 12

0 of 15

0 of 3

Not estimable

1025·00 (19·10, 54 993·88)

28·33 (1·42, 564·77)

59·62 (3·05, 1163·62)

25·67 (0·80, 824·72)

Guerrieri et al.65

Iacobone et al.66

Toniato et al.35

Tsuiki et al.64

a Hypertension

b Systolic blood pressure

c Diastolic blood pressure

Adrenalectomy Observation Odds ratio

0·001 0·1 1 10

Favours adrenalectomyFavours observation

1000

Odds ratio

Reference

Chiodini et al.1 123·9(11·5)

126·9(1·9)

136(20)

n.a.

n.a.

139·4(14·2)

136·1(3·2)

152(20)

n.a.

n.a.

16

28

15

25

19

20

–15·50 (–25·39, –5·61)

–9·20 (–10·66, –7·74)

–16·00 (–29·39, –2·91)

Not estimable

Not estimable

Guerrieri et al.65

Iacobone et al.66

Toniato et al.35

Tsuiki et al.64

Adrenalectomy

n n

Observation

BP (mmHg)* BP (mmHg)*

Adrenalectomy

n n

Observation

BP (mmHg)* BP (mmHg)*

Mean difference

–20 –10 0 10 20

Favours observation Favours adrenalectomy

Mean difference

Reference

Chiodini et al.1 75·5(7·3)

74·7(2·0)

83(8)

n.a.

n.a.

83·1(10·0)

80·6(2·7)

92(7)

n.a.

n.a.

16

28

15

25

19

20

–7·60 (–13·27, –1·93)

–5·90 (–7·24, –4·56)

–9·00 (–13·98, –4·02)

Not estimable

Not estimable

Guerrieri et al.65

Iacobone et al.66

Toniato et al.35

Tsuiki et al.64

Mean difference

–5–10 0 5 10

Favours observationFavours adrenalectomy

Mean difference

Fig. 2 Effect of adrenalectomy on a hypertension, and b systolic and c diastolic BP. Mantel–Haenszel (a) and inverse-variance (b,c)random-effects methods were used for analysis. *Values are mean(s.d.). Odds ratios and mean differences are shown with 95 per cent c.i.n.a., Not available

No beneficial effects on bone mass density wereobserved; it worsened in one of 11 operated patients andin one of nine patients who had conservative treatmentof SCS.

Only one study66 reported results concerning quality oflife. Quality of life was compared by means of the ShortForm 36 (SF-36®; QualityMetric, Lincoln, Rhode Island,USA) questionnaire in patients who had surgery versusthose who had conservative treatment for SCS. Signif-icant improvements in mental components of SF-36®(mean(s.d.) score 43⋅8(11⋅8) and 54⋅1(10⋅1) before andafter surgery respectively; P = 0⋅003) and physical com-ponents (50⋅9(7⋅3) and 56⋅7(7⋅3); P = 0⋅002) were foundin operated patients with SCS, with mean score increasesof 23 and 11 per cent respectively. No significant changes

were observed with conservative treatment during theobservation period in either mental score (from 44⋅5(10⋅8)to 44⋅9(12⋅4); P = 0⋅78) or physical score (from 51⋅7(9⋅7)to 50⋅7(9⋅4); P = 0⋅45). At the end of the study the mentaland physical components of SF-36® were significantlybetter in operated patients than in controls (P = 0⋅016 andP = 0⋅039 respectively).

Discussion

SCS has become one of the most discussed topics inendocrine surgery in recent years, because of its increasingprevalence. An increased risk of cardiovascular mor-bidity and mortality has been confirmed even in mildand subclinical hypercortisolism32, possibly caused



Improvement in glucose metabolism

Reference

Chiodini et al.1 n.a.

n.a.

5 of 10

5 of 8

2 of 9

n.a.

0 of 4

0 of 6

0 of 6

0 of 5

Not estimable

Not estimable

13·00 (0·58, 291·41)

20·43 (0·86, 487·97)

3·67 (0·15, 92·65)

Guerrieri et al.65

Iacobone et al.66

Toniato et al.35

Tsuiki et al.64

Adrenalectomy Observation Odds ratio

0·002 0·1 1 10

Favours adrenalectomyFavours observation

500

Odds ratio

Fig. 3 Effect of adrenalectomy on diabetes mellitus. Mantel–Haenszel random-effects methods were used for analysis. Odds ratios areshown with 95 per cent c.i. n.a., Not available

Table 5 Clinical outcomes after adrenalectomy and conservative treatment in patients with subclinical Cushing’s syndrome

Proportion of patients with improvement or cured

Arterialhypertension

Impaired glucosemetabolism

Impaired lipidmetabolism

Increased bodymass index

Impaired bonemass density

Reference Surgery Control Surgery Control Surgery Control Surgery Control Surgery Control

Perysinakis et al.67 12 of 17 – 5 of 12 – – – 6 of 14 – – –Iacobone et al.66 8 of 15 0 of 12 5 of 10 0 of 6 2 of 10 0 of 7 6 of 15 0 of 12 0 of 6 0 of 4Maehana et al.38 5 of 7 – 2 of 2 – 2 of 3 – – – – –Guerrieri et al.65 12 of 12 0 of 20 n.a. n.a. 0 of 13 n.a. n.a. n.a. – –Chiodini et al.1 n.a. 0 of 10 n.a. 0 of 4 n.a. n.a. n.a. n.a. – –Toniato et al.35 12 of 18 0 of 15 5 of 8 0 of 6 3 of 8 0 of 7 3 of 6 n.a. 0 of 5 0 of 5Tsuiki et al.64 5 of 6 0 of 3 2 of 9 0 of 5 6 of 9 0 of 4 0 of 3 0 of 3 – –

–, Not assessed; n.a., not available.

by glucocorticoid vascular alterations resulting fromcortisol-mediated activation of the mineralocorticoidreceptor32 and insulin resistance syndrome10, as alsooccurs in overt Cushing’s syndrome.

However, the optimal treatment of benign adrenal inci-dentaloma with SCS is still debated. Published studieshave reported conflicting results concerning the impact ofsurgery on metabolic syndrome features and osteoporosis,with both improvements and no changes1,26,27,30,31.

This systematic review aimed to assess the effects ofadrenalectomy in patients with SCS. Only a qualitativecomparison of the outcomes after surgery was possible.A proper meta-analysis was not attempted because of theconsiderable clinical heterogeneity of the published stud-ies, although the data seem to confirm a beneficial effect ofsurgery on several outcomes.

The review showed that the number of patients havingsurgery for SCS in each study remained limited, rangingbetween 10 and 29. To date, only two larger studies62,63

of SCS have been published, including 71 and 55 patients.These studies were not incorporated in the present analysisbecause they included patients who had bilateral adrenalec-tomy or patients without confirmation of postoperativenormalization of hormone levels.

Only five studies1,35,64–66 analysed here compared theeffects of surgery with a control group of patients who had

conservative treatment for SCS. The remaining studiesincluded patients with adrenal incidentaloma withouthormonal hypersecretion who underwent adrenalec-tomy as control group38, or simply described the effectof surgery without any controls67. Other publishedstudies26,39,44,49,62,63 included patients with overt Cushing’ssyndrome as controls. No study compared the results ofsurgery with that of best medical management of associateddiseases following specific treatment guidelines.

The main limitations in data analysis were heterogeneityin definitions of SCS, variable and often inadequate defi-nitions of endpoints and outcomes, and wide variations inlength of follow-up and age at study entry.

Although absence of the clinical phenotype of overtCushing’s syndrome is mandatory for the diagnosis of SCS,only two studies1,66 clearly described in detail these featuresaccording to specific guidelines3. To limit this possible bias,some frequently cited series of patients with clinically evi-dent overt Cushing’s syndrome26,27,39,61 were not includedin the present review.

The biochemical definition of SCS may be a sourceof bias in data analysis, because of the lack of clear andaccepted standards for the diagnosis of SCS. All selectedstudies included use of a DST. A low dose of dexametha-sone (1 mg) was administered overnight in most patients,and the diagnostic cut-off varied widely between 50 and



138 nmol/l. Additional tests were considered necessary inall studies, but varied significantly.

Previous studies have confirmed that the overnightlow-dose DST is the most sensitive screening test foran abnormal hypothalamic–pituitary–adrenal axis6. TheNIH12, and the American Association of Clinical Endocri-nologists and the American Association of EndocrineSurgeons33 have recommended the use of a thresholdhigher than 138 nmol/l because of its high specificity. Todecrease the false-negative rate of this cut-off value, theFrench Society of Endocrinology70 has proposed a lowercut-off (50 nmol/l). Some authors1,5 have suggested anintermediate cut-off (83 nmol/l), which was validated ona clinical basis, and this may represent the best compro-mise between sensitivity and specificity71. However, thefalse-positive rate may be a problem with this threshold.For these reasons, additional tests in combination withthe DST are usually required to validate the biochemicaldiagnosis of hypercortisolism, although each has somelimitations. Low morning ACTH levels and high UFClevels are the most frequently used tests; however, they maybe flawed by technical laboratory problems, or by patientfactors such as fluid intake, depression and obesity4,28.A low level of DHEAS has been considered as an indexof autonomous cortisol secretion10,35,38,64, but its value islimited because of the physiological decline with age6.

Suppression of the hypothalamic–pituitary–adrenal axismay occur in patients with SCS, with the risk of postoper-ative adrenal insufficiency, as in overt Cushing’s syndrome.The present analysis failed to assess the prevalence ofpostsurgical adrenal insufficiency, as no addisonian crisesoccurred because prophylactic corticosteroid treatmentwas administered systematically in all studies. Symp-tomatic adrenal insufficiency was reported previously in52 per cent of patients after surgery for SCS when peri-operative corticosteroid substitution was not administeredroutinely62. The frequency of adrenal insufficiency hasbeen related to the severity of hypercortisolism; it occurredmore frequently when more restrictive criteria were usedto define SCS32,50.

The present analysis revealed that substitutive corticos-teroid treatment was withdrawn after a mean of 5⋅2 months,with surprisingly wide variation ranging from 3 weeks to12 years. This could be explained by the different diagnos-tic criteria for SCS, or may have been due to reluctance ofsome physicians to wean patients off corticosteroid treat-ment owing to the possibility of an acute adrenal crisis72.In the absence of evidence-based guidelines, publisheddata may suggest prophylactic perioperative and postoper-ative glucocorticoid supplementation to avoid the risk of alife-threatening addisonian crisis43,73.

The effects of adrenalectomy on the metabolic con-sequences of SCS seem to be beneficial comparedwith conservative treatment, but the heterogeneity ofavailable studies strongly limited the analysis. The def-initions of hypertension, diabetes, dyslipidaemia andobesity, and the criteria used to define cure, ameliora-tion and worsening, were not given consistently or wereheterogeneous1,26,27,30,34,45,52,64,74. It has been reportedpreviously26,52 that the positive effects of surgery maybe less impressive or absent when only the presence orabsence of hypertension or diabetes before and aftersurgery are considered as endpoints, whereas they may bemore evident1,30,34,45,52,64 when defined following specificguidelines68,69.

Bearing in mind these limitations, the present analysisseems to confirm a beneficial role of adrenalectomy onhypertension, glucometabolic control and BMI comparedwith conservative treatment, in agreement with the find-ings of previous small series1,5,26,27,29,30,34,35. Analysis ofstudies with available data on systolic and diastolic arterialBP and on BMI demonstrated a significant positive effect,with a reduction in all series. No data regarding lifestyleor dietary changes were available. The beneficial effectsof adrenalectomy on lipid metabolism seem less evident.A decrease in triglyceridaemia was reported in all studies,but the results for cholesterol metabolism were discordant,and no data on lipid-lowering medical treatments wereavailable. Surgery did not show a beneficial effect onosteoporosis.

Only one study66 focused on the impact of surgery onquality of life in patients with SCS66. This study showedthat adrenalectomy led to a significant improvement ofquality of life compared with conservative management, asevaluated using the generic instrument SF-36®.

During conservative treatment of SCS some worseningof the metabolic risk profile may occur, even in patients fol-lowed up adequately with appropriate medical therapy. It islikely that adrenalectomy is advantageous in patients withSCS, particularly in those with metabolic complications,although this conclusion is based on a pragmatic interpre-tation of the available evidence.

Acknowledgements

The authors are grateful to M. Apostolico, clinical librar-ian at Veneto Institute of Oncology, Padua, for his helpin retrieving papers; F. Cavallin, statistician at VenetoInstitute of Oncology, for statistical advice; and C. Draceat Veneto Institute of Oncology, for help with Englishrevision.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:

Fig. S1 Effect of adrenalectomy on A dyslipidaemia, and B triglyceride and C total cholesterol levels (Worddocument)

Fig. S2 Effect of adrenalectomy on A high-density lipoprotein and B low-density lipoprotein cholesterol levels(Word document)

Fig. S3 Effect of adrenalectomy on body mass index (Word document)

Table S1 Definition of clinical outcomes in patients with subclinical Cushing’s syndrome included in the presentreview (Word document)

Table S2 Definition of improvement or worsening of clinical outcomes in patients with subclinical Cushing’ssyndrome included in the present review (Word document)

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