Original Article
Family history is an independent risk factor for the progression of gastric atrophy among patients with Helicobacter pylori infection
United European Gastroenterology Journal 2017, Vol. 5(1) 32–36 ! Author(s) 2017 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2050640616642341 journals.sagepub.com/home/ueg
Toshihiro Nishizawa1,2,3, Hidekazu Suzuki4, Kosuke Sakitani1,5, Hiroharu Yamashita1,6, Shuntaro Yoshida1,7, Keisuke Hata1,8, Takamitsu Kanazawa1,9, Naoto Fujiwara7, Takanori Kanai3, Naohisa Yahagi2 and Osamu Toyoshima1
Abstract Background and aim: Risk factors for progression of gastric atrophy have not been fully elucidated. The aim of this study was to evaluate the risk factors for the development of atrophic gastritis in patients with Helicobacter pylori (H. pylori ) infection. Methods: We reviewed 206 H. pylori-infected patients retrospectively. Endoscopic gastric atrophy was classified into closedand open-type. We conducted univariate and multivariate logistic regression analyses on the contribution of age, sex, body mass index, past history of cancer, the first-degree family history of gastric cancer, habitual smoking and alcohol drinking, and endoscopic findings of gastric ulcer or duodenal ulcer for open-type gastric atrophy. Results: On multivariate analysis, age (odds ratio ¼ 1.079, 95% confidence interval ¼ 1.048–1.11, p < 0.001), family history of gastric cancer (odds ratio ¼ 3.967, 95% confidence interval ¼ 1.414–10.6, p ¼ 0.006) and duodenal ulcer (odds ratio ¼ 0.834, 95% confidence interval ¼ 0.711–0.977, p ¼ 0.024) were the factors independently associated with open-type gastric atrophy. Conclusions: A first-degree family history of gastric cancer, absence of duodenal ulcer, and old age were independent risk factors for the progression of gastric atrophy among H. pylori-infected patients. Careful examination with upper gastrointestinal endoscopy is necessary in patients with such risk factors.
Keywords Atrophic gastritis, gastric cancer, H. pylori, family history, duodenal ulcer Received: 17 November 2015; accepted: 8 March 2016
1
Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo, Japan Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Tokyo, Japan 3 Division of Gastroenterology and Hepatology, Department Of Internal Medicine, Keio University School of Medicine, Tokyo, Japan 4 Medical Education Center, Keio University School of Medicine, Tokyo, Japan 5 Division of Gastroenterology, The Institute for Adult Disease, Asahi Life Foundation, Tokyo, Japan 6 Department of Gastrointestinal Surgery, The University of Tokyo, Tokyo, Japan 7 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 8 Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan 9 Department of Surgery, The Fraternity Memorial Hospital, Tokyo, Japan 2
Introduction Gastric cancer is one of the major causes of cancer deaths in the world.1 Progression of gastric atrophy is one of the risk factors for gastric cancer among patients with Helicobacter pylori (H. pylori) infection.2,3 Although H. pylori infection seems to be a prerequisite for atrophic gastritis, not all H. pyloriinfected patients will develop atrophic gastritis. Moreover, while some patients do progress to gastric cancer, others do not. Risk factors for the progression of gastric atrophy have not been fully elucidated. The aim of this study was to evaluate the risk factors for the development of atrophic gastritis in H. pyloriinfected patients.
Corresponding author: Toshihiro Nishizawa, Division of Gastroenterology and Hepatology Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Email: [email protected]
Nishizawa et al.
Methods Subjects Patients (N ¼ 10,251) who underwent upper gastrointestinal endoscopy between January 2009 and December 2012 in Toyoshima endoscopy clinic were retrospectively reviewed. Five patients with gastric cancer history and a previous gastric surgery were excluded from the present study. H. pylori negative patients (n ¼ 1563) and 675 patients who had received H. pylori eradication therapy were also excluded, despite failed eradication therapy; 8418 patients with an unclear status of H. pylori infection were also excluded.
Status of H. pylori infection The status of H. pylori infection was assessed by13 Curea breath test, stool antigen analysis, or H. pylorispecific immunoglobulin G antibodies in the serum.4 H. pylori infection was confirmed when any one of these tests was positive.
33 endoscopically identified duodenal ulcer or ulcer scar were classified into the duodenal ulcer group.
Statistical analysis We evaluated the effects of age, sex, BMI, past history of cancer, the first-degree family history of gastric cancer, habitual smoking, habitual alcohol drinking, gastric ulcer and duodenal ulcer on atrophic gastritis. The clinical parameters were analyzed by a univariate logistic regression analysis. The predictors found to be associated with open-type gastric atrophy on univariate analysis (p < 0.1) were subsequently assessed by a multiple logistic regression method to identify independent factors. Age and BMI were included as continuous variables in the univariate and multivariate logistic regression method. A p value of less than 0.05 was considered statistically significant. The data were analyzed using the Stat Mate IV software (ATOMS, Tokyo, Japan).
Ethics Questionnaire All patients had provided detailed prior information and answered a structured questionnaire to assess personal and clinical data under the supervision of a well-trained interviewer. The questionnaire included questions on age, sex, body mass index (BMI), past history of cancer, the first-degree family history of gastric cancer, habitual smoking and habitual alcohol drinking.
Endoscopic diagnosis Upper gastrointestinal endoscopy was performed by eight experienced endoscopists (OT, KS, HY, SY, KH, TK, SM, YI in Toyoshima endoscopy clinic). Endoscopic studies have reported that the area of atrophy in patients with chronic atrophic gastritis extends from the antrum to the corpus.5,6 Kimura and Takemoto divided gastric mucosal atrophy into six stages (C-I, C-II, C-III, O-I, O-II and O-III) based on the endoscopic evaluation.7 It has been clarified that mucosal atrophy progresses sequentially from C-I to O-III. This endoscopic classification was consistent with the Sydney system of classification of gastric atrophy.8 We defined gastric mucosal atrophy of stages CI–C-III as closed-type and that of stages O-I–O-III as open-type.9 Patients with an endoscopically identified gastric ulcer or ulcer scar were classified into the gastric ulcer group. An ulcer was defined as a localized defect in the gastric mucosa of at least 5 mm diameter and with perceptible depth, whereas smaller lesions were considered as erosions.10 Similarly, patients with an
The study was conducted with the approval of the Ethics Committee of external organization, and informed consent was obtained from all patients. The clinical trial registration number of the University Hospital Medical Information Network was R000018541.
Results A total of 10,251 patients underwent upper gastrointestinal endoscopy. H. pylori infection status was confirmed in 1839 patients. We investigated 206 patients, after excluding 953 patients without H. pylori infection, 675 patients after H. pylori eradication and five patients with previous gastric surgery. Table 1 shows the characteristics of the 206 patients investigated. Among the patients, 114 had open-type gastric atrophy and 92 had closed-type gastric atrophy. Table 2 shows the univariate and multivariate analysis for open-type gastric atrophy. On univariate analysis, old age (odds ratio ¼ 1.083, p < 0.001), high BMI (odds ratio ¼ 1.10, p ¼ 0.036), family history of gastric cancer (odds ratio ¼ 3.41, p ¼ 0.005), duodenal ulcer (odds ratio ¼ 0.30, p ¼ 0.002), male sex (odds ratio ¼ 1.765, p ¼ 0.066),] and history of cancer (odds ratio ¼ 3.33, p ¼ 0.054) were associated with open-type gastric atrophy. On multivariate analysis, age (odds ratio ¼ 1.079, 95% confidence interval (CI) ¼ 1.048– 1.11, p < 0.001), family history of gastric cancer (odds ratio ¼ 3.967, 95% CI ¼ 1.414–10.6, p ¼ 0.006) and duodenal ulcer (odds ratio ¼ 0.834, 95% CI ¼ 0.711– 0.977, p ¼ 0.024) were factors independently associated with open-type gastric atrophy.
34
United European Gastroenterology Journal 5(1)
Discussion A first-degree family history of gastric cancer, absence of duodenal ulcer, and old age were independent risk factors for the progression of gastric atrophy among H. pylori-infected patients. Some studies showed that the first-degree relatives of patients with gastric cancer and H. pylori infection have an increased risk of atrophic gastritis.11–14 However, other studies have failed to show a significant association.15–19 A recent meta-analysis reported the risk of first-degree relatives developing gastric cancer in comparison with controls who had no family history of gastric cancer. For gastric atrophy and H. pylori prevalence, the pooled odds ratios with 95% CI were 2.20 (1.266–3.824) and 1.925 (1.419–2.611), respectively.20 First-degree relatives of gastric cancer patients had a
Table 1. Characteristics of patients included in the present study All Characteristics Age Sex, male Body mass index History of cancer Family history Smoking Alcohol drinking Gastric ulcer Duodenal ulcer
N ¼ 206 a
53 14 98 (48%) 21 3.3a 19 (9.2%) 32 (16%) 71 (34%) 108 (52%) 35 (17%) 35 (17%)
Closed-type atrophy
Open-type atrophy
n ¼ 92
n ¼ 114 a
46 12 38 (41%) 21 3.1a 4 (4.3%) 7 (7.6%) 34 (37%) 48 (52%) 17 (18%) 24 (26%)
58 13a 60 (53%) 22 3.4a 15 (13%) 25 (22%) 37 (32%) 60 (53%) 18 (16%) 11 (9.6%)
a
Mean standard deviation.
significantly higher risk for developing gastric atrophy, and this paralleled with a significantly higher risk of harboring H. pylori. Most studies did not match the population by H. pylori infection status, although one study matched that in order to reduce confounding effects of H. pylori infection status.18 Therefore, the role of family history as a risk factor for atrophic gastritis was not conclusive. The present study of H. pyloriinfected patients clearly showed that family history was an independent risk factor for atrophic gastritis. Tsukui et al. also reported that the presence of duodenal ulcers reduced the risk for atrophic gastritis in dyspeptic patients.21 Some reports showed that the presence of duodenal ulcer reduced the risk of gastric cancer.9,22,23 Lu et al. reported that the presence of dupA gene was related to increased risk of duodenal ulcers, as well as that it provided increased protection against gastric atrophy and gastric cancer.24 A recent meta-analysis confirmed the importance of the dupA gene for duodenal ulcers,25 in line with our present study. Our study showed that old age was an independent risk factor for the progression of gastric atrophy. It is believed that H. pylori infection is acquired during early childhood in the majority of the infected individuals. Therefore, aging reflects the duration of H. pylori infection. We previously reported significant improvements in gastric atrophy after H. pylori eradication therapy, especially in the earlier phase of infection.26–28 These results indicate that early eradication would be desirable. The present study has several limitations. First, we did not assess other factors such as daily salt and nitrite/N-nitrosodimethylamine intake.29 Dietary salt intake is directly associated with risk of gastric cancer,30 and high consumption of nitrites and
Table 2. Univariate and multivariate analysis for open-type gastric atrophy Univariate analysis
Multivariate analysis
Variables
Odds ratio
95% CI
p value
Odds ratio
95% CI
p value
Agea Sex, male Body mass index History of cancer Family history Smoking Alcohol drinking Gastric ulcer Duodenal ulcer
1.083 1.765 1.1 3.333 3.41 0.82 1.019 0.827 0.3
1.054–1.113 1.003–3.105 1.10–1.20 1.066–10.42 1.40–8.30 0.460–1.470 0.588–1.765 0.399–1.714 0.14–0.66
Family history is an independent risk factor for the progression of gastric atrophy among patients with Helicobacter pylori infection
United European Gastroenterology Journal 2017, Vol. 5(1) 32–36 ! Author(s) 2017 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2050640616642341 journals.sagepub.com/home/ueg
Toshihiro Nishizawa1,2,3, Hidekazu Suzuki4, Kosuke Sakitani1,5, Hiroharu Yamashita1,6, Shuntaro Yoshida1,7, Keisuke Hata1,8, Takamitsu Kanazawa1,9, Naoto Fujiwara7, Takanori Kanai3, Naohisa Yahagi2 and Osamu Toyoshima1
Abstract Background and aim: Risk factors for progression of gastric atrophy have not been fully elucidated. The aim of this study was to evaluate the risk factors for the development of atrophic gastritis in patients with Helicobacter pylori (H. pylori ) infection. Methods: We reviewed 206 H. pylori-infected patients retrospectively. Endoscopic gastric atrophy was classified into closedand open-type. We conducted univariate and multivariate logistic regression analyses on the contribution of age, sex, body mass index, past history of cancer, the first-degree family history of gastric cancer, habitual smoking and alcohol drinking, and endoscopic findings of gastric ulcer or duodenal ulcer for open-type gastric atrophy. Results: On multivariate analysis, age (odds ratio ¼ 1.079, 95% confidence interval ¼ 1.048–1.11, p < 0.001), family history of gastric cancer (odds ratio ¼ 3.967, 95% confidence interval ¼ 1.414–10.6, p ¼ 0.006) and duodenal ulcer (odds ratio ¼ 0.834, 95% confidence interval ¼ 0.711–0.977, p ¼ 0.024) were the factors independently associated with open-type gastric atrophy. Conclusions: A first-degree family history of gastric cancer, absence of duodenal ulcer, and old age were independent risk factors for the progression of gastric atrophy among H. pylori-infected patients. Careful examination with upper gastrointestinal endoscopy is necessary in patients with such risk factors.
Keywords Atrophic gastritis, gastric cancer, H. pylori, family history, duodenal ulcer Received: 17 November 2015; accepted: 8 March 2016
1
Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo, Japan Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Tokyo, Japan 3 Division of Gastroenterology and Hepatology, Department Of Internal Medicine, Keio University School of Medicine, Tokyo, Japan 4 Medical Education Center, Keio University School of Medicine, Tokyo, Japan 5 Division of Gastroenterology, The Institute for Adult Disease, Asahi Life Foundation, Tokyo, Japan 6 Department of Gastrointestinal Surgery, The University of Tokyo, Tokyo, Japan 7 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 8 Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan 9 Department of Surgery, The Fraternity Memorial Hospital, Tokyo, Japan 2
Introduction Gastric cancer is one of the major causes of cancer deaths in the world.1 Progression of gastric atrophy is one of the risk factors for gastric cancer among patients with Helicobacter pylori (H. pylori) infection.2,3 Although H. pylori infection seems to be a prerequisite for atrophic gastritis, not all H. pyloriinfected patients will develop atrophic gastritis. Moreover, while some patients do progress to gastric cancer, others do not. Risk factors for the progression of gastric atrophy have not been fully elucidated. The aim of this study was to evaluate the risk factors for the development of atrophic gastritis in H. pyloriinfected patients.
Corresponding author: Toshihiro Nishizawa, Division of Gastroenterology and Hepatology Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Email: [email protected]
Nishizawa et al.
Methods Subjects Patients (N ¼ 10,251) who underwent upper gastrointestinal endoscopy between January 2009 and December 2012 in Toyoshima endoscopy clinic were retrospectively reviewed. Five patients with gastric cancer history and a previous gastric surgery were excluded from the present study. H. pylori negative patients (n ¼ 1563) and 675 patients who had received H. pylori eradication therapy were also excluded, despite failed eradication therapy; 8418 patients with an unclear status of H. pylori infection were also excluded.
Status of H. pylori infection The status of H. pylori infection was assessed by13 Curea breath test, stool antigen analysis, or H. pylorispecific immunoglobulin G antibodies in the serum.4 H. pylori infection was confirmed when any one of these tests was positive.
33 endoscopically identified duodenal ulcer or ulcer scar were classified into the duodenal ulcer group.
Statistical analysis We evaluated the effects of age, sex, BMI, past history of cancer, the first-degree family history of gastric cancer, habitual smoking, habitual alcohol drinking, gastric ulcer and duodenal ulcer on atrophic gastritis. The clinical parameters were analyzed by a univariate logistic regression analysis. The predictors found to be associated with open-type gastric atrophy on univariate analysis (p < 0.1) were subsequently assessed by a multiple logistic regression method to identify independent factors. Age and BMI were included as continuous variables in the univariate and multivariate logistic regression method. A p value of less than 0.05 was considered statistically significant. The data were analyzed using the Stat Mate IV software (ATOMS, Tokyo, Japan).
Ethics Questionnaire All patients had provided detailed prior information and answered a structured questionnaire to assess personal and clinical data under the supervision of a well-trained interviewer. The questionnaire included questions on age, sex, body mass index (BMI), past history of cancer, the first-degree family history of gastric cancer, habitual smoking and habitual alcohol drinking.
Endoscopic diagnosis Upper gastrointestinal endoscopy was performed by eight experienced endoscopists (OT, KS, HY, SY, KH, TK, SM, YI in Toyoshima endoscopy clinic). Endoscopic studies have reported that the area of atrophy in patients with chronic atrophic gastritis extends from the antrum to the corpus.5,6 Kimura and Takemoto divided gastric mucosal atrophy into six stages (C-I, C-II, C-III, O-I, O-II and O-III) based on the endoscopic evaluation.7 It has been clarified that mucosal atrophy progresses sequentially from C-I to O-III. This endoscopic classification was consistent with the Sydney system of classification of gastric atrophy.8 We defined gastric mucosal atrophy of stages CI–C-III as closed-type and that of stages O-I–O-III as open-type.9 Patients with an endoscopically identified gastric ulcer or ulcer scar were classified into the gastric ulcer group. An ulcer was defined as a localized defect in the gastric mucosa of at least 5 mm diameter and with perceptible depth, whereas smaller lesions were considered as erosions.10 Similarly, patients with an
The study was conducted with the approval of the Ethics Committee of external organization, and informed consent was obtained from all patients. The clinical trial registration number of the University Hospital Medical Information Network was R000018541.
Results A total of 10,251 patients underwent upper gastrointestinal endoscopy. H. pylori infection status was confirmed in 1839 patients. We investigated 206 patients, after excluding 953 patients without H. pylori infection, 675 patients after H. pylori eradication and five patients with previous gastric surgery. Table 1 shows the characteristics of the 206 patients investigated. Among the patients, 114 had open-type gastric atrophy and 92 had closed-type gastric atrophy. Table 2 shows the univariate and multivariate analysis for open-type gastric atrophy. On univariate analysis, old age (odds ratio ¼ 1.083, p < 0.001), high BMI (odds ratio ¼ 1.10, p ¼ 0.036), family history of gastric cancer (odds ratio ¼ 3.41, p ¼ 0.005), duodenal ulcer (odds ratio ¼ 0.30, p ¼ 0.002), male sex (odds ratio ¼ 1.765, p ¼ 0.066),] and history of cancer (odds ratio ¼ 3.33, p ¼ 0.054) were associated with open-type gastric atrophy. On multivariate analysis, age (odds ratio ¼ 1.079, 95% confidence interval (CI) ¼ 1.048– 1.11, p < 0.001), family history of gastric cancer (odds ratio ¼ 3.967, 95% CI ¼ 1.414–10.6, p ¼ 0.006) and duodenal ulcer (odds ratio ¼ 0.834, 95% CI ¼ 0.711– 0.977, p ¼ 0.024) were factors independently associated with open-type gastric atrophy.
34
United European Gastroenterology Journal 5(1)
Discussion A first-degree family history of gastric cancer, absence of duodenal ulcer, and old age were independent risk factors for the progression of gastric atrophy among H. pylori-infected patients. Some studies showed that the first-degree relatives of patients with gastric cancer and H. pylori infection have an increased risk of atrophic gastritis.11–14 However, other studies have failed to show a significant association.15–19 A recent meta-analysis reported the risk of first-degree relatives developing gastric cancer in comparison with controls who had no family history of gastric cancer. For gastric atrophy and H. pylori prevalence, the pooled odds ratios with 95% CI were 2.20 (1.266–3.824) and 1.925 (1.419–2.611), respectively.20 First-degree relatives of gastric cancer patients had a
Table 1. Characteristics of patients included in the present study All Characteristics Age Sex, male Body mass index History of cancer Family history Smoking Alcohol drinking Gastric ulcer Duodenal ulcer
N ¼ 206 a
53 14 98 (48%) 21 3.3a 19 (9.2%) 32 (16%) 71 (34%) 108 (52%) 35 (17%) 35 (17%)
Closed-type atrophy
Open-type atrophy
n ¼ 92
n ¼ 114 a
46 12 38 (41%) 21 3.1a 4 (4.3%) 7 (7.6%) 34 (37%) 48 (52%) 17 (18%) 24 (26%)
58 13a 60 (53%) 22 3.4a 15 (13%) 25 (22%) 37 (32%) 60 (53%) 18 (16%) 11 (9.6%)
a
Mean standard deviation.
significantly higher risk for developing gastric atrophy, and this paralleled with a significantly higher risk of harboring H. pylori. Most studies did not match the population by H. pylori infection status, although one study matched that in order to reduce confounding effects of H. pylori infection status.18 Therefore, the role of family history as a risk factor for atrophic gastritis was not conclusive. The present study of H. pyloriinfected patients clearly showed that family history was an independent risk factor for atrophic gastritis. Tsukui et al. also reported that the presence of duodenal ulcers reduced the risk for atrophic gastritis in dyspeptic patients.21 Some reports showed that the presence of duodenal ulcer reduced the risk of gastric cancer.9,22,23 Lu et al. reported that the presence of dupA gene was related to increased risk of duodenal ulcers, as well as that it provided increased protection against gastric atrophy and gastric cancer.24 A recent meta-analysis confirmed the importance of the dupA gene for duodenal ulcers,25 in line with our present study. Our study showed that old age was an independent risk factor for the progression of gastric atrophy. It is believed that H. pylori infection is acquired during early childhood in the majority of the infected individuals. Therefore, aging reflects the duration of H. pylori infection. We previously reported significant improvements in gastric atrophy after H. pylori eradication therapy, especially in the earlier phase of infection.26–28 These results indicate that early eradication would be desirable. The present study has several limitations. First, we did not assess other factors such as daily salt and nitrite/N-nitrosodimethylamine intake.29 Dietary salt intake is directly associated with risk of gastric cancer,30 and high consumption of nitrites and
Table 2. Univariate and multivariate analysis for open-type gastric atrophy Univariate analysis
Multivariate analysis
Variables
Odds ratio
95% CI
p value
Odds ratio
95% CI
p value
Agea Sex, male Body mass index History of cancer Family history Smoking Alcohol drinking Gastric ulcer Duodenal ulcer
1.083 1.765 1.1 3.333 3.41 0.82 1.019 0.827 0.3
1.054–1.113 1.003–3.105 1.10–1.20 1.066–10.42 1.40–8.30 0.460–1.470 0.588–1.765 0.399–1.714 0.14–0.66
