Abstract
Objective
We aimed to investigate whether lifestyle and body fat mass have an impact on the occurence of nonfunctional adrenal incidentalomas (NFAI).
Methods
100 patients with NFAI were included . 50 people constituted the control group. Physical activities of these groups were evaluated (using the International Physical Activity Questionnaire), smoking status was determined, anthropometric measurements were made. Body fat mass, fat percentage, total body water and fat free mass were measured using bioelectrical impedance method.
Results
Body mass index (BMI), waist, hip, neck circumference, total body fat percentage and fat mass and smoking rate were found to be statistically higher in the patient group. Physical activities did not differ significantly. When a subgroup with similar age and BMI among was created, waist circumference and total fat mass were again significantly higher in the patient group. There was a significant positive correlation between the size of the adrenal mass and waist, neck circumference, BMI, and cortisol after 1 mg dexamethasone suppression test.
Conclusion
The increase in the fat mass may have an impact on the development of NFAI. Although the patients were regarded as nonfunctional, suppressibility of the cortisol decreases as the mass size of the incidentaloma increases.
Keywords: adrenal incidentaloma, body fat, physical activity, obesity
INTRODUCTION
Adrenal lesions detected incidentally during routine imaging performed on individuals without any complaints or physical examination findings associated with the adrenal gland are called adrenal incidentaloma (1). Adrenal masses detected during malignant disease staging or follow-up are not included in this definition (2).
While the prevalence is 1–8.7% in autopsy series, it reaches 10% when radiological examinations are evaluated and especially in the elderly population. Most of these masses are benign, nonfunctional adrenal adenomas (1). Nowadays, the number of patients with adrenal incidentalomas has increased gradually with the advancement of technology, the development of diagnostic imaging methods and their becoming more widely used (3, 4). The prevalence of incidentalomas also increases with age.
In the literature, 75% of patients with adrenal incidentalomas had a nonfunctional adrenal adenoma, 12% had autonomously cortisol-secreting, 7% had a pheochromocytoma, 2.5% a primary aldosteronism, and less than 8% had an adrenocortical carcinoma and 5% had a metastatic lesion (5).
Studies conducted among patients with adrenal incidentalomas have shown increased cardiovascular risk factors such as glucose intolerance, type 2 diabetes, obesity, insulin resistance, and dyslipidemia (6, 7). There are also studies which show that these patients have higher waist-hip circumference and higher total body fat (8).
In this study, we aimed to evaluate the relationship between body fat, lifestyle and adrenal incidentalomas by comparing the lifestyle and anthropometric measurements of patients with incidentalomas that were found to be nonfunctional and the lifestyle and anthropometric measurements of people without known chronic diseases.
MATERIALS AND METHODS
100 patients with a diagnosis of adrenal incidentalomas which have been proven to be nonfunctional were included in the study. The control group consisted of 50 people who were found to have no chronic disease by taking a detailed history. Height, body weight, waist, neck and hip circumference measurements and body composition measurements were made. Laboratory test results of the patient group were obtained from their files.
Patients between the ages of 35 and 85 were included in the study. All of the adrenal incidentalomas were detected during imaging studies performed for different reasons, and none of them had a history of malignancy. We made sure that none of the patients had clinical findings suggesting adrenal hyperfunction. Before enrollment, the presence of pheochromocytoma was excluded by running 24-hour urinary catecholamine tests for all patients with an adrenal incidentaloma. Serum aldosterone and renin levels were studied in hypertensive patients, and aldosterone/ renin ratios were calculated, and patients with aldosterone/ renin> 20 underwent further tests and patients without primary hyperaldosteronism were recruited. All patients underwent morning fasting cortisol level and midnight plasma cortisol level measurements and a 1mg overnight dexamethasone suppression test. A cortisol level of 1.8 mcg/dL was accepted as the cut-off for suppression. Only patients whose tumors were proven to be nonfunctional were included in the study. Adrenal mass size and characteristics of the adrenal mass were evaluated with adrenal tomography in all patients, and patients whose adrenal mass size was 1-4 cm and with an adrenal mass with benign features were evaluated.
An informed consent form containing study details was given to all participants in the study, and those who provided a written consent were included in the study. The study was approved by Eskisehir Osmangazi University Ethical Committee with the decision number 21 dated 11.09.2018.
Patients’ demographic information (age, gender) and smoking status were elicited, and the findings were recorded.Waist circumference was measured with the patient standing, at the end of expiration, between the iliac crest and the 12th rib, using a non-elastic measuring tape wrapped around the waist over the skin in a plane parallel to the floor from the midpoint; the hip circumference was measured from the symphysis pubis in front and the most protruding part of the gluteal region at the back; and the neck circumference was measured just below the larynx with a measuring tape and were all recorded in centimeters.
Body composition including body fat percentage, fat mass, lean body mass, total body water, ideal fat mass and fat ratio were measured with a Tanita bioimpedance analyzer (model: TBF-300, code: 06070151, software: Nutrisphere, producer: Tanita Corporation Tokyo-Japan) for both the patient and control groups. Bioelectrical impedance analysis measurement is an analysis method based on the difference in electrical permeability between lean tissue and fat.
For the physical activity evaluation, the patient and control group participating in the study were asked to fill in the “International Physical Activity Questionnaire Short Form (10)” (including the last 7 days). This form provides information about sitting, walking, moderately vigorous activities, and time spent on vigorous activities. Physical activity levels were determined as physically inactive (<600 MET-min/week), low physical activity level (600-3000 MET- min/week) and adequate physical activity (health benefits) (> 3000 MET-min/ week) (9, 10). The term MET, which is the abbreviation of Metabolic Equivalent, was used to express the amount of oxygen consumed during physical activity.
The localization and dimensions of the adrenal incidentalomas as determined by tomographic examinations were recorded. Then their fasting glucose, insulin, basal cortisol, ACTH, cortisol after 1 mg dexamethasone suppression test (DST), DHEA-S, HDL Cholesterol, Total Cholesterol, LDL Cholesterol, Triglyceride (TG), all measured within the last 6 months, were recorded.
Statistical analysis
Analysis of the data was carried out using the IBM SPSS 21 program. Summary values of qualitative variables were shown as frequency and percentage, and descriptive statistics for quantitative variables were expressed as mean ± standard deviation or median (Q1-Q3). The conformity of quantitative variables to normal distribution was investigated using the Shapiro-Wilk test. Comparison of two groups of variables conforming to normal distribution was carried out using the t-test, and the Mann-Whitney U test was used in cases that did not conform to a normal distribution. The relationship between qualitative variables was evaluated using chi-square analysis, and the relationship between quantitative variables was evaluated using Spearman correlation analysis. The cases where analysis results yielded a p <0.05 were considered significant.
RESULTS
A total of 100 patients, 76 female and 24 male, who were being followed for nonfunctional adrenal incidentalomas (NFAI), were included in our study; 50 people, 39 women and 11 men, were included in the control group. The mean age of the patients was 55.24 ± 7.54, and that of the control group was 52.74 ± 10.83. There was no statistically significant difference between the two groups in terms of gender and age. 44% of the incidentalomas were located on the left, 28% on the right, and 28% on both sides. The mean diameter of the adenomas was 21.46 ± 8.60 mm. Mean body mass index (BMI) was 31.5 ± 5.2 kg/m2 in the patient group and 29.9 ± 4.8 kg/ m2 in the control group. The BMI of patients with adrenal incidentaloma was higher than controls, and a statistically significant difference was found between the two groups (p = 0.037) (Table 1).
Table 1.
Comparison of the patient and control groups in terms of demographic and anthropometric characteristics
| NFAI(n=100) * | Control (n=50) * | p value | |
|---|---|---|---|
| Age | 55.24 ± 7.54 | 52.74 ± 10.83 | 0.147 |
| Male/Female | 76/24 | 39/11 | 0.786 |
| BMI (kg/ m2) | 31.51 ± 5.2 | 29.97 ± 4.8 | 0.037 |
| Waist circumference (cm) | 105.3 ± 10.96 | 99.9 ± 12.49 | <0.001 |
| Hip circumference (cm) | 112.1 ± 10.73 | 106.5 ± 7.11 | 0.002 |
| Neck circumference(cm) | 37.56 ± 3.56 | 35.77 ± 3.03 | 0.001 |
| Total fat percentage % | 36.7 ± 8.73 | 32.5 ± 8.04 | 0.002 |
| Total fat mass (kg) | 31.2 ± 11.07 | 24.29 ± 8.14 | <0.001 |
| Total fat free mass(kg) | 51.7 ± 7.79 | 50.2 ± 10.51 | 0.058 |
| Total body water(kg) | 31.23 ± 11.07 | 24.29 ± 8.14 | 0.041 |
Average ± standard deviation is given.
NFAI patients were found to have higher waist, hip and neck circumference than the control group. A statistically significant difference was found between the two groups in terms of waist circumference, hip circumference and neck circumference (p <0.001, p =0.002, p=0.001) (Table 1). There was a significant correlation between total fat mass and anthropometric measurements such BMI (r: 0.87, p <0.001), neck circumference (r: 0.336, p <0.187), waist circumference (r: 0.724, p <0.001), and hip circumference (r: 0.856, p <0.001). There was also a significant relationship between fat mass and DHEA-S (r: - 0.226, p <0.024), fasting blood glucose (r: 0.202, p <0.044), insulin (r: 0.498, p <0.001) and CRP (r: 0.319, p <0.001).
Smoking was found at a higher rate in the patients (35% in patients and 14% in the control group), and a statistically significant difference was found between the two groups (p = 0.012). There was no statistically significant difference between the groups in terms of physical activities (p = 0.38) (Table 2).
Table 2.
Evaluation of physical activity degrees of patient and control group
| Physical activity level* | Patient (n=100) | Patient (%) | Control (n=50) | Control (%) | Significance |
|---|---|---|---|---|---|
| Inactive | 28 | 28 | 15 | 30 | p=0.380 |
| Low physical activity | 58 | 58 | 21 | 42 | |
| Adequate physical activity | 14 | 14 | 14 | 28 |
Inactive: <600 MET-min/week, low activity: 600-3000 MET-min/week, adequately active: >3000 MET-min/week.
In our study, since the rate of overweight and obese patients was higher in the patient group than in the control group, we decided to create a subgroup by drawing subjects with similar ages and BMIs from both groups and then comparing them. For this purpose, a second group was formed by taking 28 people in the patient group with a BMI of 25.0-29.99 kg/m2 and 29 people in the control group. There was no significant difference in age between these two groups (p = 0.986). Waist circumference, total fat mass and smoking rate were found to be higher in the patient group even after correcting for BMI, and a statistically significant difference was found between them (p = 0.018, p = 0.213, p = 0.019).
In the patient group, the mean adrenal mass size was found to be 14.5 ± 5.12 mm in those with BMI <25 kg/m2, 22.26 ± 10.34 cm in those with a BMI of 25-29.99 kg/m2, and in those with a BMI> 30 kg/m2 it was 22.05 ± 7.80 cm. A significant difference was found between the groups in terms of size of the mass (p = 0.048). The adrenal mass size was higher in those with higher BMI. In addition, a positive correlation was found between mass size and neck circumference, waist circumference, BMI and cortisol after 1 mg DST in the patient group (Table 3). A significant negative correlation was found between mass size and ACTH (r: -0.314, p:0.002).
Table 3.
Correlation analysis of mass size and anthropometric measurements in the patient group
| Variable | Coefficient of correlation | p value |
|---|---|---|
| Waist circumference | 0.265 | 0.010 |
| Neck circumference | 0.226 | 0.029 |
| BMI | 0.238 | 0.022 |
| Fat percentage and mass level | 0.224 | 0.031 |
In our stepwise regression analysis, we found that waist circumference and cortisol after 1 mg DST made the most significant contribution to mass size (p: 0.007 and p: 0.004, respectively) (Table 4). In order to understand the extent to which the variables of waist circumference and cortisol levels post 1 mg DST affect mass size, we performed a multiple linear regression analysis and found R to be 0.409 and R2 to be 0.163. In other words, we saw that 16.3% of the total variance in mass size can be explained by waist circumference and cortisol level after 1mg DST.
Table 4.
B and β Correlation Coefficients and Significance Levels of the Variables
| B | Standardized β | p | |
|---|---|---|---|
| Waist circumference | 0.194 | 0.266 | 0.007 |
| Cortisol levels post 1 mg DST | 4.358 | 0.284 | 0.004 |
In addition, between the DHEA-S level and the percentage of total body fat (r: -0.261, p = 0.009) a very significant negative relationship; between the DHEA-S level and the total fat mass (r: -0.226 p = 0.024), a significant negative relationship and between the DHEA-S level and the BMI (r: -0.240, p = 0.016), a significant negative correlation was observed.
DISCUSSION
It has been suggested that adrenal incidentaloma may be one of the causes of metabolic syndrome (6,11). Past studies have shown an increased frequency of diabetes mellitus (DM), hypertension (HT), insulin resistance, abdominal obesity, hepatosteatosis, and hyperlipidemia in NFAI patients as well as in incidentaloma patients diagnosed with autonomously cortisol-secreting (12). The reason for this is thought to be due to slightly increased cortisol release from these masses (13, 14). However, this moderate cortisol elevation cannot be demonstrated with sufficient sensitivity and specificity. Whether these findings are a result of cortisol autonomy in patients with adrenal adenomas is a controversial issue.
It is unclear whether non-functional adrenal incidentalomas increase the risk of atherosclerosis and metabolic syndrome or are more common in people with cardiometabolic risk factors. Considering these, the following questions come to mind: Are obesity and fat accumulation more common in patients with incidentaloma? Could body fat have an effect on incidentaloma? We aim to investigate these in our study.
There was a significant difference between the groups in terms of BMI, and it was observed that patients with adrenal incidentaloma had higher BMI than the control group: 63% of the patient group was found to be obese and 29% to be overweight. Obesity causes many health problems especially type 2 diabetes and prediabetes, as well as cardiovascular diseases. In a study by Garrapa et al. (8), it was reported that the patient group with adrenal incidentaloma had higher BMI than the control group, and the patients were overweight compared to the healthy group. In another study, the mean BMI of non-functional adrenal incidentaloma patients was found to be high (30.17 ± 4.3 kg/m2) as we have found in our study (15).
In our study, it was observed that the waist circumference of the patient group was significantly higher than the control group. In the study of Arduç et al. (16), a significantly higher waist circumference was found in the patient group with adrenal incidentaloma compared to the control group. In our study, the number of overweight and obese BMI patients in the NFAI group was higher than the control group. In addition, when the patient and the control group with similar BMI (25.0-29.99 kg/m2) were compared, the mean waist circumference was found to be higher in the patient group.
In addition, higher hip circumference and neck circumference were found in patients with NFAI. There was a significant positive correlation between neck circumference and BMI, waist circumference, hip circumference, waist/hip ratio and fat percentage and mass. These findings suggest that the neck circumference can also be used effectively to indicate body fat.
Direct measurement methods are also used to determine body composition. One of them is Bioelectrical impedance analysis (BIA). With the bioimpedance method, we found significantly higher total body fat mass and fat percentage in the patient group compared to the control group. In addition, when the patient and the group with similar BMI were evaluated and the total fat mass was compared, we found that the average fat mass was higher in the patient group. In the study by Garrapa et al. (8), body composition was evaluated using DEXA (dual-energy x-ray absorptiometry), and it was reported that both patients with adrenal incidentaloma and patients with Cushing’s syndrome were overweight and had higher amounts of central adipose tissue compared to the control group.
The data we found suggest that body fat may be operative in the occurrence of incidentalomas. Though the cause and effect relationship is not clear, we should be more careful in terms of adrenal incidentaloma in people with obesity and body fatness, we should evaluate anthropometric measurements and examine fat values if possible. Obesity per se if not the causative factor may play a facilitative or permissive role in the ethiopathogenesis.
We also found a significant negative relationship between BMI, fat mass and fat percentage and DHEAS. The data we obtained suggest that as the DHEAS level decreases, fat accumulation increases or the opposite may be the case. There are studies reporting the antiglucocorticoid and antiatherosclerotic effects of DHEA-S (17). In our study, we did not find a relationship between fat mass and cortisol, ACTH, nor post DST cortisol.
Smoking rate was also higher in our patients. It may be possible that smoking plays a facilitating role in the emergence of adrenal incidentalomas. The insufficient understanding of the importance of physical activity for health and the gradual adoption of a sedentary lifestyle is increasing the prevalence of chronic diseases such as obesity, cardiovascular diseases, hypertension, diabetes, and osteoporosis. In terms of physical activities, we found no significant difference between the groups. Our inability to find a significant difference between the groups in terms of physical activity may be due to the subjective nature of the questionnaire we used to compare their levels of physical activity. We found no study in the literature evaluating smoking and physical activity in patients with nonfunctional adrenal incidentalomas. In clinical practice, it may be useful to question smoking and physical activity in patients with adrenal incidentaloma.
There are studies showing that there is a relationship between tumor size and parameters showing HPA axis dysfunction (18). Tsagarakis et al. (19) showed in their study that there is a significant correlation between tumor size and serum cortisol concentration post DST. We also found a highly significant positive correlation between mass size and serum cortisol concentration post DST. This finding indicates that as the size of the mass increases, cortisol suppression is less common after 1 mg DST. We also found a significantly negative correlation between ACTH and mass size. With increasing mass size, ACTH levels may decrease due to less easily suppressed cortisol. These findings suggest that cortisol hypersecretion may occur as the size of the mass increases. It may indicate that in incidentalomas with larger mass size the possibility of cortisol suppressibility decreases and this may be responsible from some of the adverse clinical outcomes.
In our study, we also evaluated whether there could be a relationship between mass size and anthropometric parameters. Statistically, we found a significant positive correlation between mass size and BMI, waist circumference, neck circumference and body fat percentage. In addition, we found that the size of the mass was larger in patients with higher waist circumference in the patient group. These data show that body fat has an effect on the size of the mass, and that mass size may be larger in people with high fat ratio. We found no study in the literature that evaluates body fat and mass size.
When we evaluated the parameters that we found correlated with mass size, we found that the most effective parameters in showing the mass size were waist circumference and post 1mg DST cortisol levels. In our study, 16% of the variance in the size of the mass can be explained by these variables. The low value of this ratio suggests that factors other than waist circumference and post 1mg DST cortisol levels also affect the size of the mass. More detailed studies are needed in order to elucidate these factors.
In conclusion, the data we have found suggest that body fat may be influential in the emergence of incidentalomas, however there is not enough data on whether this is a cause or an effect. A greater number of and more detailed studies are needed to clarify this issue and to find other factors that may lead to incidentalomas. Nevertheless, our findings may shed light in the pathogenesis of adrenal incidentalomas and may have some value in the development of prevention or treatment strategies.
Conflict of interest
The authors declare that they have no conflict of interest.
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