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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 23  |  Issue : 3  |  Page : 332-346

Nonfunctioning and subclinical cortisol secreting adrenal incidentalomas and their association with metabolic syndrome: A systematic review


Department of Diabetes and Endocrinology, University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Rd, Coventry, West Midlands, U.K. Post Code- CV2 2DX, UK

Date of Web Publication30-Jul-2019

Correspondence Address:
Uzma Khan
120 Blandford Drive, Coventry, West Midlands, U.K. Post Code - CV2 2NE
UK
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijem.IJEM_52_19

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   Abstract 


Background: A growing body of evidence suggests that nonfunctioning and subclinical cortisol secreting adrenal incidentalomas (AIs) are associated with several components of metabolic syndrome resulting in increased cardiometabolic risk. The long-term metabolic outcome of these AIs is largely unknown and their most appropriate management remains controversial. Objectives: To undertake a systematic review of the prevalence of cardiometabolic abnormalities in nonfunctioning and subclinical cortisol secreting AIs and long-term outcome of conservative treatment and adrenalectomy. Methods: MEDLINE, Cochrane Controlled Trials Register, and EMBASE were searched for relevant studies and systematic review was performed. National Institutes of Health (NIH) quality assessment tool for observational cohort and cross-sectional studies was used to assess the risk of bias in the studies. Results: Of the 65 studies screened, 18 (10 retrospective, 5 prospective, 2 cross-sectional studies, and 1 randomized controlled trial) were included in the systematic review. Prevalence of hypertension (HTN), impaired glucose metabolism, dyslipidaemia, and raised body mass index (BMI) was higher in subclinical cortisol secreting AIs as compared with nonfunctioning AIs. Surgical intervention had a beneficial effect on blood pressure, glucometabolic control, and obesity in patients with subclinical Cushing's syndrome. The results for lipid metabolism were equivocal. There was no significant improvement in cardiometabolic risk factors after adrenalectomy in nonfunctioning AIs. The quality of evidence was found to be low to moderate. Conclusions: The systematic review demonstrated increased prevalence of components of metabolic syndrome in patients with subclinical cortisol secreting and nonfunctioning AIs. A beneficial role of adrenalectomy on HTN, glucometabolic control, and BMI was observed in patients with subclinical cortisol secreting AIs.

Keywords: Adrenal incidentalomas, metabolic syndrome, subclinical Cushing's syndrome, systematic review


How to cite this article:
Khan U. Nonfunctioning and subclinical cortisol secreting adrenal incidentalomas and their association with metabolic syndrome: A systematic review. Indian J Endocr Metab 2019;23:332-46

How to cite this URL:
Khan U. Nonfunctioning and subclinical cortisol secreting adrenal incidentalomas and their association with metabolic syndrome: A systematic review. Indian J Endocr Metab [serial online] 2019 [cited 2019 Aug 21];23:332-46. Available from: http://www.ijem.in/text.asp?2019/23/3/332/263741




   Introduction Top


Adrenal incidentalomas (AIs) are defined as adrenal mass lesions >1 cm in diameter, discovered incidentally during investigation for conditions unrelated to adrenal disease. These incidentally discovered adrenal masses may be hormonally active or nonfunctioning and malignant or benign; the need for any treatment depends on the nature of the mass.

A growing body of evidence, both clinical and experimental, indicates that hormone-secreting AIs are associated with several components of metabolic syndrome, such as hypertension (HTN), atherogenic dyslipidemia, increased thrombogenicity, impaired glucose tolerance, insulin resistance, fatty liver disease, and abdominal obesity, through the effects of excessive adrenal hormones on various metabolic pathways.[1],[2],[3] A similar association has been found in subclinical autonomous cortisol-secreting AIs and, paradoxically, nonfunctioning AIs, adding a new dimension to the clinical management and follow-up of these patients.[4]

It has been suggested that patients with AI meet the criteria for the metabolic syndrome and that hyperinsulinemia is a major factor promoting tumor growth.[5] According to the modified National Cholesterol Education Program criteria,[6] the presence of any three of the five factors is required for a diagnosis of metabolic syndrome: abdominal obesity, hypertriglyceridemia (triglycerides ≥1.7 mmol/L); low high-density lipoprotein (HDL) (cholesterol ≤1.03 mmol/L for men and ≤1.29 mmol/L for women); elevated blood pressure (systolic blood pressure ≥130 mmHg and/or diastolic blood pressure ≥85 mmHg or current use of antihypertensive drugs); impaired fasting glucose (fasting plasma glucose ≥ 5.6 mmol/L).

Subclinical Cushing's syndrome (SCS) is the most frequent hormonal abnormality detected in patients with AI with wide variation in prevalence (5–47%) and the issue of subtle cortisol secretion by AIs is among the most controversial issues in endocrine practice. It has been hypothesized that subtle cortisol overproduction in subjects with AI may impact on carbohydrate metabolism.[7] Comparison of groups of patients has generally revealed modest increases in body mass index (BMI), HTN, reduced insulin sensitivity, glucose intolerance or frank diabetes, adverse cardiovascular risk profile, and osteopenia/osteoporosis in patients with SCS compared to controls; however, most of the studies suffer to a degree from referral bias.[8],[9]

Nonfunctioning AIs paradoxically have been recently implicated to predispose to metabolic syndrome and increasing evidence supports an association between nonfunctioning AIs and obesity, HTN, hyperglycemia, dyslipidemia, and insulin resistance.[1],[7],[10],[11],[12],[13] This relationship appears to be theoretically inexplicable, as nonfunctioning AIs usually remain inactive; the cause–effect relationship and the underlying mechanisms have not been conclusively delineated and remain to be further elucidated.

Improvement in certain metabolic parameters has also been observed after unilateral adrenalectomy in patients with AIs. The aim of this systematic review is to advance the understanding of the association between nonfunctioning and subclinical autonomous cortisol secreting AIs and components of metabolic syndrome and the long-term clinical implications including surgical outcome, in order to appropriately address the management issues and to formulate suggestions for future research.


   Methods Top


Search strategy

A systematic search was performed for English language articles using MEDLINE, Cochrane Controlled Trials Register (1960–2005), and EMBASE (1991–2005). The literature was searched for the period from each database's earliest inception up to June 2018. In addition, the reference lists of the retrieved articles were examined to identify additional eligible studies. Combinations of keywords were used including “adrenal incidentalomas” or “adrenal mass,” “subclinical Cushing's syndrome” or “preclinical Cushing's syndrome” or “autonomous cortisol secretion”, “nonfunctioning adrenal incidentalomas” in combination with “metabolic syndrome”, or “cardiometabolic” or “cardiovascular risk”, or “insulin resistance” in the title or the abstract. The review was conducted in line with the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement.[14]

Inclusion and exclusion criteria

Original retrospective, prospective, or cross-sectional studies which analyzed patients with nonfunctioning and/or subclinical cortisol secreting AIs based on their biochemical profile reporting at least two components of metabolic syndrome (diabetes, impaired glucose tolerance, fasting hyperinsulinemia, dyslipidemia, HTN, and obesity/central adiposity) and the results of adrenalectomy and/or conservative management on these outcomes were included.

Studies without biochemically confirmed subclinical hypercortisolism and studies reporting only preoperative data or insufficient postoperative data were excluded from the systematic review, as were case reports and series including fewer than ten operated patients. Data quoted as unpublished or derived from abstracts were not used in the systematic review. The patients in the studies were classified into two groups: nonfunctioning AIs and subclinical cortisol secreting AIs. Nonfunctioning AI was defined as a subgroup of AI where the possibility of profound or even subclinical adrenal hormone excess was ruled out based on a comprehensive endocrine evaluation. Subclinical cortisol secreting AI was defined as a subgroup of AI with an abnormal response to standard tests of hypothalamic–pituitary–adrenal (HPA) axis function.

A predesigned data extraction form was used to collect data from the eligible studies. All variables were listed for which data were sought and information was extracted from each study including: 1) first author's last name, country, study design, number of participants; 2) age range and gender of study participants; 3) endocrine tests performed for autonomous cortisol secretion; 4) AI category: subclinical autonomous cortisol secreting or non-functioning; 5) outcome measures including, a) prevalence of components of metabolic syndrome in subclinical cortisol secreting AIs and nonfunctioning AIs, b) cardiometabolic outcomes of conservative management and adrenalectomy.

Methodological quality and risk of bias assessment

NIH quality assessment tool for observational cohort and cross-sectional studies was used to assess the risk of bias. It is based on the key concepts for evaluating the internal validity of a study; the critical assessments are made separately and are divided into 14 set of questions.[15]


   Results Top


The literature search yielded 65 publications in total. After screening abstracts for relevance, 36 full-text articles were assessed for eligibility and after applying the inclusion/exclusion criteria, 18 studies were included in the systematic review. Quantitative meta-analysis was not performed owing to significant clinical heterogeneity among the studies. A flow chart of this process is presented in [Figure 1].
Figure 1: PRISMA flowchart of study selection process

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A total of 15 cohort studies (5 prospective and 10 retrospective), 1 randomized controlled trial (RCT), and 2 cross-sectional studies were included in the systematic review. Studies were mostly from European centers; 9 of the studies originated from Italy,[2],[16],[17],[18],[19],[20],[21],[22],[23] 4 from Japan,[24],[25],[26],[27] 2 from Greece,[28],[29] and 1 each from Turkey,[30] Hungary,[31] and Korea.[32] The studies were published between 2002 and 2017. They involved in total 1772 patients with AI. Of these, 1028 (58%) had nonfunctioning AI, while 500 (28.2%) had SCS. The main characteristics and demographics of the studies and outcome definitions are presented in [Table 1] and [Table 2], respectively.
Table 1: Study characteristics and baseline demographics

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Table 2: Definitions of clinical outcomes

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Diagnostic criteria or definition of SCS were heterogeneous in the studies, as presented in [Table 3]. They were mostly based on high morning cortisol concentrations after dexamethasone suppression test (DST) combined with at least one other test of HPA axis function.
Table 3: Definitions of subclinical Cushing's syndrome

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All the studies included in the systematic review had patients with subclinical cortisol secreting AIs and half of the studies had patients with nonfunctioning AIs. The clinical characteristics at baseline and outcome on follow-up in patients with SCS are presented in [Table 4].
Table 4: SCS and cardiometabolic outcomes

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Out of 18 studies included in the review, 9 had patients with nonfunctioning AIs, 3 of the studies had no follow-up data, so they were only used for comparison between SCS and nonfunctioning AIs at baseline.[2],[17],[32] The clinical characteristics at baseline and outcome on follow-up in patients with nonfunctioning AIs are presented in [Table 5].
Table 5: Nonfunctioning AIs and cardiometabolic outcomes

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Six studies compared the prevalence of cardiometabolic risk factors in patients with nonfunctioning AIs and subclinical cortisol secreting AIs.[2],[16],[17],[18],[29],[32] The comparison is presented in [Table 6].
Table 6: Comparison of prevalence of cardiometabolic risk factors between SCS and NFAI

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The systematic review demonstrated higher prevalence of HTN, impaired glucose metabolism, dyslipidemia, and raised BMI in patients with subclinical cortisol secreting AIs as compared to patients with nonfunctioning AI. In patients with SCS surgical intervention had a beneficial effect on blood pressure, glucometabolic control, and obesity when compared with conservative management. The results for lipid metabolism were equivocal. There was no significant improvement in cardiometabolic risk factors after adrenalectomy in patients with nonfunctioning AIs. Summary of the results is presented in [Table 7].
Table 7: Summary of results

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Quality assessment and risk of bias

Most of the studies included in the systematic review were observational cohort studies, two were cross-sectional studies, and there was a single Randomized controlled trial (RCT). The methodological quality of the studies was therefore assessed using the NIH quality assessment tool for observational cohort and cross-sectional studies.[15]

In view of inclusion of only a single RCT which was available on the review subject, it was suspected that the quality of evidence would be very low or poor. However, the assessment using the tool specifically designed for observational cohort and cross-sectional studies revealed that the quality of evidence was low to moderate or “fair” as per the NIH tool.

The risk of bias was mainly due to lack of confirmed presence of exposure prior to the outcomes; lack of sample size justification; heterogeneity between studies for diagnostic protocols, definitions of outcome and duration of follow-up; lack of blinded outcome assessments; and absence of adjustment for confounders. The results of quality assessment of individual studies as per NIH quality assessment tool are presented in [Table 8].
Table 8: Results of NIH quality assessment for observational cohort and cross-sectional studies

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   Discussion Top


Systematic review of studies with heterogeneous and limited published data suggest increased prevalence of components of metabolic syndrome in subclinical cortisol secreting and nonfunctioning AIs; a beneficial role of adrenalectomy on HTN, glucometabolic control, and BMI was observed in patients with subclinical cortisol secreting AIs.

For SCS, baseline prevalence of abnormal glucose metabolism ranged from 16.6% to 90%, HTN from 33 to 85%, high BMI from 25 to 80%, and dyslipidemia from 9 to 90% in the included studies. There were lesser number of studies on nonfunctioning AIs in the present review and the baseline prevalence of abnormal glucose metabolism ranged from 9% to 27%, HTN from 24% to 86%, high BMI from 27% to 63%, and dyslipidaemia from 5% to 60%. One study also looked into the prevalence of cardiovascular events and showed increased prevalence in patients with SCS [20] and another study reported increased prevalence of coronary heart disease and stroke in SCS.[17]

Studies assessing surgical outcome in SCS patients showed significant improvement in blood pressure from baseline in most of the studies, improvement in glucose metabolism in more than half, and improved BMI in more than a third of the studies. In the study by Petramala et al.,[21] where outcome on metabolic syndrome (as per ATP III criteria)[35] was studied, there was significant improvement in metabolic syndrome following adrenalectomy in SCS patients. For the conservatively managed SCS group, only a single study showed a significant worsening of HTN.

There was no significant improvement in any of the cardiometabolic parameters in patients with nonfunctioning AIs who underwent adrenalectomy. One study [31] showed significant worsening in diabetes and dyslipidemia. For the conservatively managed patients with nonfunctioning AIs, follow-up data showed significant worsening of diabetes in a quarter of the included studies and worsening of dyslipidemia in half of them. There was no significant worsening of the other metabolic parameters in any of the studies.

The summary of results is presented in [Table 7].

When the prevalence of cardiometabolic risk factors was compared between patients with nonfunctioning and subclinical cortisol secreting AIs, parameters of glucose metabolism and dyslipidemia were significantly worse for patients with SCS in most of the studies. However, there was no significant difference between the two groups for HTN and BMI. When the operated groups of nonfunctioning AI and SCS were compared in the study by Chiodini et al., there was significant improvement in diabetes, HTN, and obesity in surgically treated SCS patients.[16] Comparison of prevalence of cardiometabolic risk factors between SCS and nonfunctioning AI is presented in [Table 6].

The reason for a higher prevalence of cardiometabolic risk factors in patients with subclinical cortisol secreting AIs may be subtle or intermittent autonomous cortisol hypersecretion and the outcomes might have been related not only to the degree but also on the duration of hypersecretion, as well as the sensitivity of each individual to cortisol excess. As most patients with AIs are of an age when HTN, diabetes, and obesity are highly prevalent, establishing whether these metabolic complications are truly related to excess cortisol in a patient with an AI is not clear-cut.

Results from studies on outcomes of adrenalectomy have been conflicting but in general, the data indicated an improvement in metabolic complications, especially in blood pressure and diabetes, in patients with subclinical cortisol secreting AI after unilateral adrenalectomy, and deterioration or no improvement in patients treated conservatively. Five studies in the review directly compared the difference between surgical and medical outcomes and assessed changes in cardiovascular risk factors in the long term [19],[21],[23],[24],[27] including one prospective randomized study.[23] Petramala et al. also investigated metabolic syndrome (as per ATP III criteria)[35] and the ambulatory BP (nondipper profile) and found a significant improvement in metabolic syndrome and nondipper profile in SCS group managed by adrenalectomy.[21]

There is no consensus on management of SCS associated with AIs and one major issue is that there is no formal agreement as to its definition. The overnight low-dose DST is favored as the most sensitive screening test in patients with AI based on pathophysiological reasoning, simplicity, and the fact that the test was incorporated in the diagnostic algorithms of most studies.[36] As patients lack the classical clinical features of Cushing's syndrome, it is difficult to determine the true value of the test. Diagnosing SCS by arbitrary cut-offs of cortisol secretion leads to unavoidable misclassifications in some patients. Therefore, additional tests in combination with the dexamethasone test are usually required to validate the biochemical diagnosis of hypercortisolism, although each has some limitations.

Increased prevalence of cardiometabolic risk factors was also observed in nonfunctioning AIs, although less than subclinical cortisol secreting AIs. It is speculated that the nonfunctioning AIs may not be entirely nonsecretory and may constitute an almost continuous spectrum of heterogeneous endocrine abnormalities. They may not produce adrenocortical hormones in sufficient amounts to cause clinically apparent disease or be detected biochemically, but they may have subtle qualitative alterations of steroidogenesis, which might adversely affect various metabolic pathways.[37],[38]

The studies included in the current review did not reveal any significant impact of surgery on cardiometabolic morbidities in nonfunctioning AIs and there was significant worsening in diabetes and dyslipidemia in one study.[31] Some studies on nonfunctioning AIs suggest improvement in parameters of metabolic syndrome after surgical treatment;[11],[12],[39] however, they were not included in the review due to small number of operated patients. One of the likely explanations for this observation could be a potential misclassification of patients; for example, one study described that a significant proportion of patients with nonfunctioning AIs developed adrenal insufficiency after surgery, clearly suggesting that autonomous glucocorticoid production was not recognized preoperatively.[39] Overall, glucocorticoid production has been linked to HTN, abnormal glucose tolerance, and increased BMI.[40] Therefore, it is also possible that a temporary reduction of the glucocorticoid load caused by unilateral adrenalectomy could have contributed to a short-term improvement in blood pressure described in patients with nonfunctioning AIs.

Strengths and limitations

This systematic review has important strengths including an in-depth and comprehensive literature search, focused review questions, predefined inclusion and exclusion criteria, and use of standard quality assessment tool.

Limitations were heterogeneity in definitions of SCS in the studies with variable definitions of endpoints and outcomes and wide variations in length of follow-up. The length of time these metabolic risk factors were present was unknown. Groups also varied in the medical treatment for cardiovascular risk factors and it was unclear in the studies how aggressive the conservative management was in nonoperated patients. Subgroup analysis of age, gender, and size of the AI which might influence cardiovascular outcomes, was not possible, as individual variables were not consistently reported.

Future research directions

There is a clear need for prospective and appropriately powered studies to evaluate disease-specific and all-cause mortality and other hard clinical endpoints (i.e., myocardial infarction or stroke) to assess the potential cardiovascular morbidity associated with subclinical cortisol secreting AIs and nonfunctioning AIs and to substantiate whether surgical excision is beneficial in these patients. Such studies on subclinical cortisol secreting AI should also provide evidence for a suitable biochemical definition of autonomous cortisol secretion and help define the optimal investigation algorithm that balances the false-positive and negative endocrine test rates. Establishment of an international collaborative study group to develop a database of patients with clinically silent adrenal adenomas might be a useful step in this regard.


   Conclusions Top


Available low-to-moderate-quality evidence obtained from heterogeneous studies in this systematic review with at least 12 months of follow-up suggests increased prevalence of components of metabolic syndrome in patients with subclinical cortisol secreting and nonfunctioning AIs. Screening for independent cardiometabolic risk factors in patients with subclinical cortisol secreting AI is recommended and careful evaluation and long-term follow-up are required. Adrenalectomy might be considered for patients with mild hypercortisolism when medical treatment fails and there is progression of cardiovascular risks. Patients with subclinical cortisol secreting AI who are not candidates for surgery should be followed up clinically to detect, treat, and control cardiovascular risk factors. Until more data are available, a flexible approach guided by clinical judgment is recommended. Detailed endocrine workup of nonfunctioning AIs should include the evaluation of components of metabolic syndrome to identify patients at high cardiometabolic risk and appropriate lifestyle changes and medical treatment should be advised. Surgical intervention in the absence of hormonal excess is not recommended at present and is an area requiring further research.

Given the increasing prevalence of subclinical cortisol secreting and nonfunctioning AIs, their associated cardiometabolic morbidities and the controversies surrounding their management, there is a clear need for further studies and randomized controlled trials to guide future recommendations for therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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