Dig Dis Sci (2011) 56:2354–2360 DOI 10.1007/s10620-011-1681-3
ORIGINAL ARTICLE
Lower Serum Level of Adiponectin Is Associated with Increased Risk of Endoscopic Erosive Gastritis Shunsuke Yamamoto • Kenji Watabe • Shusaku Tsutsui • Shinichi Kiso • Toshimitsu Hamasaki • Motohiko Kato • Yoshihiro Kamada • Yuichi Yoshida • Shinji Kihara • Miyuki Umeda • Aiko Furubayashi • Kazuo Kinoshita • Osamu Kishida • Takashi Fujimoto • Akira Yamada • Yoshifumi Tsukamoto • Norio Hayashi • Yuji Matsuzawa
Received: 10 December 2010 / Accepted: 11 March 2011 / Published online: 30 March 2011 Ó Springer Science+Business Media, LLC 2011
Abstract Background Obesity is recently known as a risk factor for endoscopic gastritis. Adiponectin is an anti-inflammatory cytokine secreted from fat tissue, and its serum concentrations are reduced in obesity. The relation between adiponectin and gastritis remains unclear. Aims The aim of this study was to determine whether lower serum adiponectin level is associated with the risk of endoscopic gastritis. Methods We analyzed medical records of participants of a routine health check-up examination. Association among endoscopic findings, serum adiponectin level, and other clinical factors including age, sex, alcohol habit, smoking
S. Yamamoto K. Watabe (&) S. Tsutsui S. Kiso M. Kato Y. Kamada Y. Yoshida Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan e-mail:
[email protected] T. Hamasaki Department of Biomedical Statistics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan S. Kihara Department of Biomedical Informatics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan M. Umeda A. Furubayashi K. Kinoshita O. Kishida T. Fujimoto A. Yamada Y. Tsukamoto Y. Matsuzawa Sumitomo Hospital, 5-3-20 Nakanoshima, Kita-ku, Osaka 530-0005, Japan N. Hayashi Kansai Rosai Hospital, 3-1-69 Inabashou, Amagasaki, Hyogo 660-8511, Japan
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habit, body mass index (BMI), blood pressure, cholesterol, triglyceride, glucose, and insulin were investigated. Endoscopic erosive gastritis was defined as a flat or minimally depressed white spot surrounded by a reddish area or small elevation with central umbilications mimicking octopus’ suckers. Results A total of 2,400 participants were enrolled. BMI was significantly higher in gastritis-positive participants than in gastritis-negative participants. Serum adiponectin levels were significantly lower in gastritis-positive participants than in gastritis-negative participants. Multivariate logistic regression analysis revealed that lower serum adiponectin level (OR 0.96; 95% CI 0.93–0.99), smoking (OR 0.50; 95% CI 0.30–0.80), higher blood pressure (OR 1.02; 95% CI 1.01–1.03), and duodenitis (OR 1.8; 95% CI 1.00–3.09) were significantly associated with endoscopic erosive gastritis. Conclusions Lower serum level of adiponectin may increase the risk of endoscopic erosive gastritis, independently of BMI. Our findings facilitate further study to clarify the role of hypoadiponectinemia in erosive gastritis. Keywords Erosive gastritis Adiponectin Obesity Health check-up examination
Introduction The incidence of obesity continues to increase, especially in industrialized countries, and is a serious concern because it increases the risk of cardiovascular disease, diabetes, and cancer [1]. Obesity is associated with common gastrointestinal disorders, including gastro-esophageal reflux disease (GERD), gallstone disease, and neoplasia of the esophagus, colon, and pancreas [2]. Recent studies indicate that obesity
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is also associated with gastritis and gastric ulcers. Morbidly obese subjects have a higher frequency of endoscopic gastritis than non-obese subjects [3, 4]. Moreover, in the general population, increasing body mass index (BMI) is significantly associated with gastritis and gastric ulcers [5, 6]. In obese subjects, the accumulation of abdominal visceral fat is accompanied by metabolic disorders such as diabetes mellitus, dyslipidemia, and hypertension, and results in atherosclerotic vascular diseases [7]. Dysregulation of bioactive molecules secreted from excess visceral fat is proposed to contribute to the progression of metabolic disorders. Adiponectin is one of these molecules, which we isolated from the human adipose tissue cDNA library [8]. Adiponectin exists abundantly in the circulation and has anti-diabetic, anti-atherogenic, and anti-inflammatory properties [9]. Serum adiponectin levels are lower in obese subjects compared with normal subjects, and this impaired secretion leads to metabolic disorders [8, 10]. We previously demonstrated that the anti-inflammatory properties of adiponectin have a protective role in several gastrointestinal diseases, such as liver fibrosis, colitis, pancreatitis, and gallstone disease [11–15]. Because the incidence of gastritis is increased in obese subjects, we hypothesized that lower serum adiponectin level in obese subjects is a risk factor for gastritis. The aim of the present study was to elucidate the relationship between adiponectin and gastritis and to determine whether a decreased serum adiponectin level (hypoadiponectinemia) is independently associated with the prevalence of endoscopic gastritis. Diabetes mellitus, dyslipidemia, and hypertension were included in our study, because these are frequently comorbid metabolic disorders in obese patients and could be competing factors for gastritis.
Methods Subjects We retrospectively analyzed the medical records and laboratory results of individuals who had undergone esophagogastroduodenoscopy (EGD) as part of a health check-up examination, not as a clinical reference, at Sumitomo Hospital, Osaka, Japan, between April 2007 and March 2009. All participants underwent a variety of examinations, including physical examinations, blood chemistry tests, ultrasonography, and EGD, as part of a routine health checkup. Participants also completed a questionnaire regarding smoking and alcohol habits. Participants with a history of esophagogastric surgery or whose serum creatinine level was higher than 130 lmol/l were excluded. The study complied with the ethical rules for human experimentation stated in the Declaration of Helsinki, and was
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approved by the ethics committee of both Osaka University and Sumitomo Hospital. Clinical and Laboratory Evaluations Height, weight, and blood pressure were measured using a standardized protocol. Waist circumference was measured at the umbilical level in the late exhalation phase while standing [16]. Venous samples were drawn after an overnight 12-h fast to determine cell counts, serum adiponectin, total cholesterol, high-density lipoprotein (HDL) cholesterol, lowdensity lipoprotein (LDL) cholesterol, triglyceride (TG), fasting plasma glucose (FPG), and immunoreactive insulin (IRI) levels. These biochemical variables were measured using a conventional automated analyzer. Serum concentrations of adiponectin were measured by two methods. We used a sandwich enzyme-linked immunosorbent assay system (adiponectin ELISA kit, Otsuka Pharmaceutical Corporation, Tokushima, Japan) from April 2007 to May 2008, and a latex particle-enhanced turbidimetric assay (Otsuka Pharmaceutical Corporation, Tokushima, Japan) from June 2008 to March 2009. The values obtained with these two methods were very strongly correlated (R value = 0.99074). Smoking habit was classified as current, past, and nonsmoker and alcohol habit was defined as drinking more than 22 g of alcohol per day, which was calculated from data acquired by the questionnaire. Endoscopic Findings and Definitions Standardized non-sedated EGD was performed by one of six experienced endoscopists at Sumitomo Hospital, each of whom had at least 3 years of endoscopic experience with over 2,000 cases. Endoscopic reports were prospectively documented by each endoscopist on a computer-based endoscopic reporting form by selecting prepared findings: ‘‘reflux esophagitis,’’ ‘‘esophageal cancer,’’ ‘‘hiatus hernia,’’ ‘‘esophageal varices,’’ ‘‘acute gastritis,’’ ‘‘chronic gastritis,’’ ‘‘erosive gastritis,’’ ‘‘gastric cancer,’’ ‘‘gastroduodenal ulcer,’’ ‘‘ulcer scar,’’ ‘‘duodenitis,’’ ‘‘polyp,’’ ‘‘diverticula,’’ and ‘‘submucosal tumor.’’ Differential definitions of three type of gastritis were as follows. 1.
We diagnosed ‘‘erosive gastritis’’ when we identified any type of gastritis which accompanied erosions. Erosion was defined as a flat or minimally depressed white spot surrounded by a reddish area that was sometimes accompanied by small superficial bleeding. Erosive gastritis also included small nodules typically with central umbilication mimicking octopus’ suckers that were often observed in the antrum and generally called verrucous gastritis or gastritis varioliformis.
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Fig. 1 Representative images of endoscopic erosive gastritis. a Erosions were identified as flat or minimally depressed white spots surrounded by a reddish area (arrows). b Erosions were identified as
small nodules with central umbilications mimicking octopus’ suckers that were observed groups in the antrum
Because the distinction between erosion and tiny shallow ulcer was arbitrary, tiny shallow ulcer might be included in erosion. Sample pictures for typical erosive gastritis are shown in Fig. 1. ‘‘Acute gastritis’’ was diagnosed for so-called acute gastric mucosal lesion (AGML) which consisted of multiple and wide-ranging erosions and ulcers often presented with hemorrhages and clots. ‘‘Chronic gastritis’’ was distinguished from ‘‘erosive gastritis’’ simply by the absence of erosive lesions. Chronic gastritis included atrophic gastritis, metaplastic gastritis, enlarged fold gastritis, and superficial gastritis without erosive lesion. Because acute gastritis was rare and chronic gastritis was a vague finding, we excluded them from the analysis.
percentages. Kappa statistic for multiple raters was calculated following the procedure reported by Chen et al. [18]. Agreement was considered poor if \0.2, fair if \0.4, moderate if \0.6, substantial if \0.8 or good if [0.8. For inter-group (or two-group) comparisons, continuous variables were analyzed using the Student’s t test, and categorical variables using the v2 test. Associations between EEG and other parameters were first analyzed by simple logistic regression analysis and then by multivariate stepwise logistic regression analysis. Variables were selected by the step-wise method with a P value of 0.25 or less before being entered into the multivariate analysis. Odds ratio (OR) was estimated and expressed with 95% confidence interval (CI). Variables included in the analysis were sex, age, BMI, adiponectin, smoking habit (current, past, and non-smoker), alcohol habit (yes or no), blood pressure, HDL and LDL cholesterol, triglyceride, FPG, IRI, reflux esophagitis, and duodenitis. All data analysis was performed with the JMP 8 statistical package (Statistical Analysis Systems Inc, Cary, NC). A P value of less than 0.05 was considered statistically significant.
2.
3.
In this study, we picked up ‘‘erosive gastritis’’ from the computer database as the primary finding, and the following four findings as secondary findings: ‘‘reflux esophagitis,’’ ‘‘gastroduodenal ulcer,’’ ‘‘ulcer scar,’’ and ‘‘duodenitis.’’ Because histopathologic examination was not conducted, we termed erosive gastritis ‘‘endoscopic erosive gastritis’’ (EEG) in this study. Reflux esophagitis was defined as endoscopic esophagitis, represented by grades M to D in the Los Angeles classification [17]. Duodenitis was defined as small red spots in the duodenum. Because the primary finding of this study was defined endoscopically, kappa statistic was calculated using representative images of endoscopic erosive gastritis to assure inter-observer variability. Statistical Analysis Continuous variables are presented as mean ± SD and categorical variables are displayed as frequencies and
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Results Baseline Characteristics A total of 2,400 Japanese were enrolled (men/women, 1,537/868; mean age ± standard deviation (SD), 55.1 ± 11.2 years). Among them, 248 (10.3%) had EEG. Kappa statistic for diagnosis of EEG indicated ‘substantial (0.79)’ agreement among the endoscopists who were involved in this study. Clinical characteristics were compared between subjects with EEG (N = 248) and without EEG (N = 2,152) (Table 1). EEG was more prevalent in males (P = 0.001) and non- or past-smokers (non to
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current and past smokers, P = 0.0041; current to past and non smokers, P = 0.0002). BMI, waist circumference, systolic (SBP) and diastolic blood pressure (DBP), TG, and IRI were significantly higher, and adiponectin was significantly lower in subjects with EEG.
esophagitis and duodenitis were significantly higher in subjects with EEG. The prevalence of gastroduodenal ulcers and ulcer scars was not different between groups.
Comparison of Secondary Endoscopic Findings
Sixty-one percent and 22% of EEG was found in the antrum and the body (upper third 10%, middle third 3%, lower third 9%), respectively. The remaining 17% of EEG lacked the information of the location. High prevalence of
Secondary endoscopic findings were compared between subjects with and without EEG (Table 2). Rates of reflux
Location of Erosive Gastritis
Table 1 Comparison of the clinical characteristics between subjects with and without EEG Term
With EEG (n = 248)
Without EEG (n = 2,152)
P-value
Sex, Male/total
182/248
1,350/2,152
0.001
Age, years
55.4 ± 10.2
55.1 ± 11.3
NS
BMI, kg/m2
23.5 ± 3.1
22.6 ± 3.1
\0.0001
Adiponectin, lg/ml
8.7 ± 4.7
10.1 ± 5.7
0.0002
Smoking, current/Past/Non
22/82/144
398/720/1,034
Non/current and past
144/104
1,034/1,118
0.0041
Current/past and non Alcohol drinker
22/226 45/248
398/1,754 460/2,152
0.0002 NS
WC, cm
84.7 ± 8.9
82.7 ± 9.0
0.0007
SBP, mmHg
128.2 ± 15.4
124.6 ± 15.5
0.0005
DBP, mmHg
80.4 ± 10.0
77.5 ± 10.4
\0.0001
62.9 ± 15.1
64.3 ± 16.3
NS
Blood pressure
Lipids HDL-C, mg/dl LDL-C, mg/dl
128.1 ± 29.4
125.3 ± 30.7
NS
TG, mg/dl
135.4 ± 93.7
120.2 ± 94.6
0.0170
Diabetes FPG, mg/dl
98.0 ± 19.0
95.9 ± 17.1
NS
IRI, lU/ml
6.3 ± 3.6
5.7 ± 3.7
0.0204
Data are given as mean ± standard deviation (SD) NS not significant, EEG endoscopic erosive gastritis, BMI body mass index, WC waist circumference, SBP systolic blood pressure, DBP diastolic blood pressure, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, TG triglycerides, FPG fasting plasma glucose, IRI immunoreactive insulin
Table 2 Comparison of secondary endoscopic findings between groups with and without EEG Term
With EEG (n = 248)
Without EEG (n = 2,152)
P-value
Reflux esophagitis (%)
37 (14.9)
199 (9.2)
0.0073
Duodenitis (%)
17 (6.9)
65 (3.0)
0.0047
Ulcer (%)
9 (3.6)
52 (2.4)
NS
Stomach
4
30
Duodenum
5
22
Ulcer scar (%)
22 (8.8)
180 (8.3)
Stomach
7
87
Duodenum
15
93
NS
NS not significant, EEG Endoscopic erosive gastritis
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Table 3 Logistic regression analysis Term
Simple Estimate
Multiple SE
P-value 0.0010
Estimate
SE
P-value
0.0457
0.0247
NS
Sex
0.2468
0.0752
Age
0.0024
0.006
NS
BMI
0.0865
0.0204
\0.0001
-0.0535
0.0147
0.0003
-0.0419
0.0168
0.0125
0.387
0.1356
0.0043
0.1896
0.1477
NS
0.8463 -0.1007
0.2301 0.0865
0.0002 NS
0.6906
0.2493
0.0056
Adiponectin Smoking Non vs current and past Current vs past and non Alcohol
0.0266
0.0064
\0.0001
HDL-C
-0.0065
0.0043
NS
LDL-C
0.0029
0.0022
NS
TG
0.0013
0.0005
0.0217
FPG
0.0062
0.0035
NS
IRI
0.0352
0.0154
0.0219
Reflux esophagitis
0.5107
0.1950
0.0088
Duodenitis
0.8599
0.2811
0.0022
DBP
0.0194
0.0069
0.0051
-0.0056
0.0051
NS
0.5881
0.2874
0.0407
NS not significant, EEG endoscopic erosive gastritis, BMI body mass index, DBP diastolic blood pressure, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, TG triglycerides, FPG fasting plasma glucose, IRI immunoreactive insulin
EEG in the antrum suggests that most of EEG were verrucous gastritis or gastritis varioliformis.
Adiponectin and EEG The results of the logistic regression analysis are shown in Table 3. Among the variables, the combination of BMI and waist circumference, SBP, and DBP, as well as total cholesterol and LDL-cholesterol were dependent on each other. Therefore, among these parameters, BMI, DBP and LDL cholesterol were selected as representative factors. Simple logistic regression analysis revealed that sex, BMI, adiponectin, smoking, DBP, TG, IRI, reflux esophagitis, and duodenitis were significantly correlated with EEG. Stepwise multiple logistic regression analysis revealed that adiponectin (OR 0.96; 95% CI 0.93–0.99), smoking (smoker VS past and non smoker) (0.50; 95% CI 0.30–0.80), DBP (OR 1.02; 95% CI 1.01–1.03), and duodenitis (OR 1.8; 95% CI 1.00–3.09) were significantly and independently correlated with EEG. The correlation between EEG and adiponectin is shown in Fig. 2. Adiponectin levels were divided into quartiles (Q1, 1.6–6.0; Q2, 6.1–8.5; Q3, 8.6–12.2; Q4, 12.3–73.6 lg/ ml). Each group included 25% of study subjects. The rate of EEG gradually increased as the adiponectin level decreased.
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Fig. 2 Association of serum adiponectin levels and endoscopic erosive gastritis (EEG). Adiponectin levels were divided into quartiles (Q1, 1.6–6.0; Q2, 6.1–8.5; Q3, 8.6–12.2; Q4, 12.3–73.6 lg/ml). Each quartile includes 600 study subjects. Number of patients with EEG in each quartile was 84 (34%) in Q1, 67 (27%) in Q2, 49 (20%) in Q3, and 48 (19%) in Q4
Discussion The results of this study indicate that a low serum adiponectin level is associated with an increased prevalence of endoscopic erosive gastritis in Japanese subjects. Because the subjects were attendants of a health check-up examination, they may well reflect the general population. Our starting hypothesis was that a low serum adiponectin level is a risk factor for gastritis. After adjusting for other factors including sex, age, BMI, smoking habit, alcohol
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consumption, blood pressure, cholesterol, triglycerides, glucose, insulin, and other endoscopic findings of reflux esophagitis and duodenitis, we showed that adiponectin remained a significant and independent factor that influenced the frequency of EEG. A higher BMI was associated with an increased rate of erosive gastritis in our study, consistent with recent reports [3–5]. This finding indicates that obesity increases the risk of erosive gastritis. The following three mechanisms have been considered that may explain the mechanism of obesity-related gastritis. First, physical changes in obese subjects could be involved. Obesity is associated with increased intra-abdominal pressure and impaired gastric emptying [19]. These changes are thought to be causal mechanisms for increased rates of GERD in obese subjects [20, 21], and could also play causal roles in erosive gastritis. Second, poor life habits of obese people might be involved. Food habits such as binging, excess food intake, and food restriction in obese subjects might be associated with increased gastrointestinal symptoms and gastric diseases [5, 22, 23]. A third and emerging mechanism is dysregulation of the hormonal factors ghrelin and leptin [24, 25]. The precise mechanism for the relationship between obesity and gastritis, however, is unknown. We focused on hypoadiponectinemia in obese subjects and found that low serum adiponectin is a risk factor for erosive gastritis independent of BMI. Hypoadiponectinemia could be a new mechanism as a causative role in obesity-related gastritis. Adiponectin has been intensively investigated in relation to obesity and metabolic disorders [9]. We have investigated adiponectin in cardiovascular and gastrointestinal diseases. In colitis, adiponectin protects intestinal tissue by inhibiting chemokine production and the subsequent inflammatory responses, including infiltration of macrophages and the release of proinflammatory cytokines [12]. The inhibitory effect of adiponectin on macrophages has also been demonstrated in pancreatitis [13]. Adiponectin induces the expression of cyclooxygenase 2 and increases the production of prostaglandins in the heart, protecting it from ischemic injury [26]. In the stomach, the integrity and restoration of gastric mucosa is mainly maintained by prostaglandins, and inflammatory cells play similar roles as in colitis at the site of gastritis [27, 28]. From these findings and the results of the present study, we propose that adiponectin protects the gastric mucosa from gastritis through increasing prostaglandin production and suppressing excess inflammatory cell reactions, and this property may be involved in the mechanism for the relationship of obesity and erosive gastritis. We analyzed the secondary endoscopic findings and the location of gastritis to characterize EEG in this study. Erosive gastritis, in general, includes irritation- or toxicityinduced gastritis, such as that caused by non-steroidal
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anti-inflammatory drugs, alcohol, and steroids, and gastric acid-related gastritis [29]. In this study, subjects with EEG accompanied reflux esophagitis and duodenitis more often than those without. This finding suggests that erosive gastritis in this study may be acid-related, because gastric acid plays a significant role in the pathogenesis of reflux esophagitis [30, 31]. In the analysis of the location of EEG, we found that 61% of EEG was present in the gastric antrum. This finding indicates that antral verrucous gastritis may comprise a large proportion of EEG in this study. Because Tatsuta et al. [32] reported that erosive gastritis in the antrum was associated with high gastric acid output, this finding again supports our speculation that EEG in this study might partially be acid-related. However, further investigations are necessary to confirm this speculation. In this study, non-smokers tended to have more EEG. Serum adiponectin levels are reported to be lower in heavy smokers compared with never smokers [33], which seems to contradict our results. There is, however, one report that smoking habit exacerbates atrophic gastritis [34]. Thus, it might be that in our study, smokers who had more atrophic gastritis rather than erosive gastritis tended to be in the group without EEG because their gastric acid output was lower. Atrophic gastritis, however, was not investigated in this study, so this issue remains unclear and requires further study. Our study has several limitations. First, it is a retrospective cross-sectional study. Because our study included more than 2,000 individuals who were not selected patients but participants of a routine health check-up program, the results of our study may represent the general population. Second, endoscopic data review and histopathologic confirmation of the endoscopic findings were not obtained. Third, we could not obtain data regarding H. Pylori infection or medication use. H. Pylori is a strong factor for almost all gastric diseases [35]. We presume, however, that the influence of H. Pylori infection might be moderate in this study, because the prevalence of gastric ulcers and ulcer scars, which are closely associated with H. pylori infection, was comparable in participants with and without EEG. Two studies by Japanese investigators reported that BMI is not associated with H. pylori infection status, supporting this speculation [36, 37]. In conclusion, lower serum level of adiponectin may increase the risk of endoscopic erosive gastritis, independently of BMI. Further investigation should be facilitated to clarify the role of hypoadiponectinemia in endoscopic erosive gastritis. Acknowledgments The authors thank Shoji Ishitani at Sumitomo Hospital for the assiduous effort in data collection from the annual health checkup records. Conflict of interest The authors declare no conflict of interest and no grant support or other financial arrangement with any of the commercial entities mentioned in this report.
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