의학석사학위논문 The Association Between Helicobacter pylori Seropositivity and Colorectal Adenoma : A Case-Control Study 혈청 Helicobacter pylori 양성과 대장의선종성용종과

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1 저작자표시 2.0 대한민국 이용자는아래의조건을따르는경우에한하여자유롭게 이저작물을복제, 배포, 전송, 전시, 공연및방송할수있습니다. 이차적저작물을작성할수있습니다. 이저작물을영리목적으로이용할수있습니다. 다음과같은조건을따라야합니다 : 저작자표시. 귀하는원저작자를표시하여야합니다. 귀하는, 이저작물의재이용이나배포의경우, 이저작물에적용된이용허락조건을명확하게나타내어야합니다. 저작권자로부터별도의허가를받으면이러한조건들은적용되지않습니다. 저작권법에따른이용자의권리는위의내용에의하여영향을받지않습니다. 이것은이용허락규약 (Legal Code) 을이해하기쉽게요약한것입니다. Disclaimer

2 의학석사학위논문 The Association Between Helicobacter pylori Seropositivity and Colorectal Adenoma : A Case-Control Study 혈청 Helicobacter pylori 양성과 대장의선종성용종과의연관성 : 환자대조군연구 2013 년 2 월 서울대학교대학원 의학과내과학과정 박소연

3 A thesis of the Master s degree 혈청 Helicobacter pylori 양성과 대장의선종성용종과의연관성 : 환자대조군연구 The Association Between Helicobacter pylori Seropositivity and Colorectal Adenoma : A Case-Control Study February 2013 The Department of Internal Medicine, Seoul National University College of Medicine So Youn Park

4 혈청 Helicobacter pylori 양성과 대장의선종성용종과의연관성 : 환자대조군연구 지도교수김주성 이논문을의학석사학위논문으로제출함 2012 년 10 월 서울대학교대학원 의학과내과학전공 박소연 박소연의의학석사학위논문을인준함 2013 년 2 월 위원장정승용 ( 인 ) 부위원장김주성 ( 인 ) 위원김상균 ( 인 )

5 학위논문원문제공서비스에대한동의서 본인의학위논문에대하여서울대학교가아래와같이학위논문제공하는것에 동의합니다. 1. 동의사항 1 본인의논문을보존이나인터넷등을통한온라인서비스목적으로복제할경우저작물의내용을변경하지않는범위내에서의복제를허용합니다. 2 본인의논문을디지털화하여인터넷등정보통신망을통한논문의일부또는전부의복제 배포및전송시무료로제공하는것에동의합니다. 2. 개인 ( 저작자 ) 의의무 본논문의저작권을타인에게양도하거나또는출판을허락하는등동의내용을 변경하고자할때는소속대학 ( 원 ) 에공개의유보또는해지를즉시통보하겠습니다. 3. 서울대학교의의무 1 서울대학교는본논문을외부에제공할경우저작권보호장치 (DRM) 를사용하여야합니다. 2 서울대학교는본논문에대한공개의유보나해지신청시즉시처리해야합니다. 논문제목 : The Association Between Helicobacter pylori Seropositivity and Colorectal Adenoma : A Case-Control Study 학위구분 : 석사학과 : (Department) 의학과내과학학번 : (Student number) 연락처 : (Contact info) chatchat222@gmail.com 저작자 : (Name) 박소연 ( 인 ) 제출일 : 2013 년 2 월 4 일 서울대학교총장귀하

6 ABSTRACT Introduction: Several studies on the association between Helicobacter pylori (H. pylori) infection and colorectal adenoma have been reported recently. But the results have been controversial. The aim of this study is to examine whether H. pylori seropositivity is associated with colorectal adenoma. Methods: Individuals who underwent screening colonoscopy were recruited. After colonoscopy, the subjects were grouped into two groups: subjects with colorectal adenoma (cases) and subjects whose colonoscopic findings were normal (controls). Individuals with hyperplastic or malignant polyp were excluded. All subjects were questioned about smoking, alcohol, weekly exercise, diabetes mellitus, hypertension, medication history and a family history of colorectal cancer. Subjects underwent various anthropometric and laboratory tests including serum IgG antibody against H. pylori. Results: Total 1,780 age and sex matched subjects were allocated in each group: 890 in case and 890 in control group. The mean age of subjects was 55.5±7.6 years and 1,358 (76.3%) were male. The H. pylori serology was positive for 1,035 (58.1%) and negative for 745 (41.9%) subjects. By univariate analysis, the prevalence of H. pylori was slightly higher in the adenoma group than in the control group, but this association was not statistically significant (OR, 1.19; 95% CI, ; P=0.074). Hypertension, smoking, alcohol, abdominal obesity, obesity, triglyceride and a family history of colorectal cancer were significantly higher in the adenoma group than control group. Multivariate analysis to adjust for possible confounders i

7 revealed that H. pylori infection was not a significant risk factor for colorectal adenoma (OR, 1.20; 95% CI, ; P=0.075). H. pylori infection was not associated with the characteristics of colorectal adenoma such as number, size, location or advanced adenoma (size> 1cm, high grade dysplasia, villous component). Conclusions: In this large-scale case-control study, the association of H. pylori seropositivity and colorectal adenoma was not statistically significant, so H. pylori infection might not be a risk factor for colorectal adenoma. Further studies are necessary for the identification of association with H. pylori infection and colorectal adenoma Keywords: Colorectal adenoma; Helicobacter pylori Student number: ii

8 CONTENTS Abstract... i Contents... iii List of Tables... iv Introduction... 1 Methods... 2 Results... 5 Discussion References Abstract in Korean iii

9 LIST OF TABLES Table Table Table Table iv

10 Introduction Colorectal cancer is the second most common cause of cancer in women and the third most common in men in 2008 with it being the fourth most common cause of cancer death.(1) Colorectal cancer incidence rates have rapidly increased in Eastern Asia, an area historically at low risk. Colorectal adenoma is the premalignant lesion in colorectal cancer. It develops into colorectal carcinoma through the adenoma-to-carcinoma sequence.(2) Colorectal neoplasms may be caused by dietary factors, smoking, alcohol consumption and genetic factors, but the exact etiology is still unknown.(3) Identification of the etiology of colorectal neoplasms may be essential for its prevention and treatment. Helicobacter pylori (H. pylori) is a Gram-negative, microaerophilic bacterium that infects the gastric mucosa and causes inflammation and several gastric diseases, such as peptic ulcer, gastric cancer and gastric lymphoma of mucosa-associated lymphoid tissue. In 1994, H. pylori was classified as a type I carcinogen for humans by the IARC/WHO due to the association between H. pylori and gastric cancer.(4) The association of H.pylori infection and colorectal adenoma, the precancerous lesion of colorectal adenocarcinoma, has been examined in recent decades. Several studies have suggested that hypergastrinemia induced by H. pylori is associated with intestinal mucosal cell proliferation, which increases the growth of cancer cell line resulting in colorectal adenoma and 1

11 adenocarcinoma.(5, 6) But the pathogenic mechanisms regarding H. pylori`s contribution to colonic neoplasms have yet to be clarified. Some epidemiologic studies have observed an increased prevalence of colorectal adenomas in patients infected with H.pylori(7-12) while others report a negative association.(13-15) Moreover, few large-scale population-based epidemiological studies have demonstrated that the association with colorectal adenomas and H. pylori infection. The purpose of this research was to examine the association between colorectal adenomas and H. pylori infection in healthy individuals whom we consider to reflect the general population. Methods This was a cross-sectional, age-sex matched case-control study. Initially, 4,276 subjects underwent colonoscopy for screening at Seoul National University Hospital Healthcare System Gangnam Center during a routine health check-up from January 2006 to December They also underwent various anthropometric and laboratory tests including serum IgG antibody against H. pylori. The sample frame included 3,585 subjects who were eligible for the following exclusion criteria: age>75 years or <40 years; incomplete colonoscopic examination; diagnosis of colorectal cancer in this check-up; a history of colonic disease, such as colorectal adenomatous polyps, 2

12 cancer, inflammatory bowel disease and bowel resection; a colonic examination including colonoscopy, sigmoidoscopy or barium enema in the previous 10 years; symptoms like rectal bleeding, severe lower abdominal pain or change in bowel habits. 1,159 (32.3%) subjects had colorectal adenomas in them. Subjects who had hyperplastic polyps in the control group were excluded. We formed the adenoma group and the control group on subjects who underwent H. pylori serology testing. We matched the two group for age and sex which are considered major confounders on colorectal adenoma. Finally, 1,780 age and sex matched subjects were allocated to each group: 890 in the case and 890 in the control group. The Institutional Review Board of Seoul National University Hospital approved the research protocol, and the study was conducted in accord with the Helsinki Declaration. Subjects were questioned about weekly exercise, alcohol consumption, current smoking, medical history of diabetes mellitus or hypertension, medication history (aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS)) and a family history of colorectal cancer. Height, weight and waist circumference were measured. Venous samples to measure total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, fasting glucose level, high sensitivity C-reactive protein (hs-crp) and IgG antibody against H. pylori were drawn after an overnight fasting. IgG antibodies to H. pylori were detected using a rapid enzyme linked immunosorbent assay (EIA WELL; REF K5HPG kit; RADIM, Roma, Italia). The sensitivity and specificity of the method were 95.8% and 96.2%, according to the manufacturer`s statement. (For more information see: 3

13 Abdominal obesity was defined by the Regional Office for the Western Pacific Region of the World Health Organization WC criteria based on the ATP III-WPRO. Fasting glucose, triglyceride and HDL cholesterol were categorized by the criteria of metabolic syndrome of NCEP ATP III. Colonoscopies were performed by experienced gastroenterologists (FICE 4400 series, Fujinon, Japan). The location, sizes, numbers and types of all adenomatous polyps were recorded. Locations were categorized as proximal colon (including the cecum, ascending colon or transverse colon) and distal colon (including the splenic flexure, descending colon, sigmoid colon or rectum). Colorectal adenoma was defined as an adenoma in the colorectum regardless of grading of villous component. Hyperplastic or malignant polyps were excluded. Advanced adenoma was defined as an adenoma of diameter 10mm, adenoma with high-grade dysplasia or containing >25% villous features. Statistical analysis We compared the case and control group. Continuous variables were analyzed using the Student`s t test and expressed as means±s.d.. Categorical variables were analyzed using the chi-square test or univariate analysis. We computed odds ratios (OR) and 95% confidence interval (95% CI) using conditional logistic regression. In the multivariate conditional logistic regression models, we included variables with P<0.10 in the univariate analysis to identify independent predictors of colorectal adenoma after adjusting for other variables. P values of <0.05 were considered statistically 4

14 significant. Statistical analysis was carried out using SPSS 12.0 (SPSS, Chicago, IL, USA) and STATA 12.0 (Stata Corp, College Station, TX, USA). Results 1. Baseline characteristics of the study subjects The study sample included 1,780 age and sex matched subjects allocated in each group: 890 in adenoma (case) and 890 in normal (control) group. The mean age of all 1,780 subjects was 55.5±7.6 years and each group contained 679(76.3%) men. The H. pylori serology was positive for 1,035 (58.1%) and negative for 745 (41.9%) subjects. The rates of current smoking, alcohol consumption, hypertension and family history of colorectal cancer were higher in the adenoma group than in the control group. In addition, waist circumference, body mass index and triglyceride levels were higher and HDL cholesterol levels were lower in the adenoma group. The two groups did not differ in the frequency of diabetes mellitus, exercise ( 3 per week), regular aspirin use, regular NSAID use and the levels of total cholesterol, fasting glucose, hs-crp. There were 499 (56.1%) H. pylori seropositive subjects in the control group and 536 (60.2%) in the adenoma group. The difference was not statistically significant (P=0.074) (Table 1). 5

15 Table 1. Comparisons of the baseline characteristics of the adenoma and control groups Control group (N=890) Adenoma group (N=890) P Age (years) 55.5± ± Male, N (%) 679 (76.3) 679 (76.3) H. pylori seropositivity, N (%) 499 (56.1) 536 (60.2) Current smoking, N (%) 182 (20.4) 239 (26.9) Alcohol consumption, N (%) 138 (15.5) 172 (19.3) Hypertension, N (%) 244 (27.4) 298 (33.5) Diabetes mellitus, N (%) 99 (11.1) 99 (11.1) Family history of colorectal 22 (2.5) 38 (4.3) cancer, N (%) Regular aspirin use, N (%) 143 (16.1) 136 (15.3) Regular NSAID use, N (%) 21 (2.4) 20 (2.2) Exercise ( 3 per week), N (%) 129 (14.5) 110 (12.4) Waist circumference (cm) 85.9± ±7.3 < Body mass index (kg/m 2 ) 23.7± ±2.6 < Total cholesterol (mg/dl) 196.6± ± Triglyceride (mg/dl) 112.3± ±74.2 <0.001 HDL cholesterol (mg/dl) 53.2± ±12.8 <0.001 Fasting glucose (mg/dl) 100.2± ±

16 hs-crp (mg/l) 0.1± ± H. pylori, Helicobacter pylori; HDL cholesterol, high-density lipoprotein cholesterol; hs-crp, high sensitivity C-reactive protein. Results are expressed as mean±s.d. or N (%). 2. H. pylori seropositivity and colorectal adenoma According to univariate analysis, the prevalence of H. pylori was slightly higher in the adenoma group than the control group, but this association was not statistically significant (OR, 1.19; 95% CI, ; P=0.074). Hypertension, current smoking, alcohol consumption, abdominal obesity (waist circumference), obesity, triglyceride level and a family history of colorectal cancer were significant positive risks for adenoma. Multivariate analysis after adjusting for the variables with P<0.10 in the univariate analysis revealed that H. pylori infection was not a significant risk factor for colorectal adenoma (OR, 1.20; 95% CI, ; P=0.075). Current smoking, obesity, triglyceride level and a family history of colorectal cancer were statistically significant risk factors of colorectal adenoma (Table 2). Table 2. Risks for colorectal adenoma Univariate analysis Multivariate analysis a OR (95% CI) P OR (95% CI) P H. pylori seropositivity 1.19 ( ) ( ) Hypertension 1.35 ( ) ( )

17 Diabetes mellitus 1.00 ( ) Current smoking 1.52 ( ) ( ) Alcohol consumption 1.31 ( ) ( ) Waist circumference 1.60 ( ) ( ) (Male>90cm, Female>80cm) Obesity (Body mass 1.70 ( ) ( ) index 25kg/m 2 ) Triglyceride 1.72 ( ) ( ) ( 150mg/dl) HDL cholesterol 1.24 ( ) ( ) (Male<40mg/dl, Female<50mg/dl) Fasting glucose 1.10 ( ) ( 110mg/dl) Family history 1.84 ( ) ( ) of colorectal cancer Regular aspirin use 0.94 ( ) Regular NSAID use 0.95 ( ) Exercise ( 3 per week) 0.83 ( ) OR, odds ratio; CI, confidence interval; H. pylori, Helicobacter pylori; HDL cholesterol, high-density lipoprotein cholesterol. a Adjusted for the variables with P<0.10 in the univariate analysis. 3. H. pylori seropositivity and characteristics of colorectal 8

18 adenoma in the adenoma group We performed a sub-group analysis about H. pylori seropositivity and characteristics of colorectal adenoma in the adenoma group. The H. pylori serology was positive for 536 (60.2%) and negative for 354 (39.8%) subjects. H. pylori seropositivity was not associated with the characteristics of colorectal adenoma such as size (<1cm vs. 1cm), number (1 or 2 vs. 3), location (only distal vs. any proximal colon), pathology (tubular vs. tubulovillous or villous), dysplasia (low grade vs. high grade) or advanced adenoma (size 1cm, villous component or high-grade dysplasia) (Table 3). Multivariate analysis also showed that H. pylori infection was unrelated with the characteristics of colorectal adenoma (Table 4). Table 3. Colorectal adenoma characteristics in the adenoma group H. pylori (-) group N=354 (39.8%) H. pylori (+) group N= 536 (60.2%) P Adenoma 1cm in size 37 (10.5) 50 (9.3) Multiple ( 3) adenoma 56 (15.8) 103 (19.2) Any proximal adenoma 230 (65.0) 356 (66.4) Tubulovillous/villous 11 (3.1) 17 (3.2) adenoma Adenoma with 4 (1.1) 5 (0.9)

19 high-grade dysplasia Advanced adenoma a 38 (8.9) 58 (10.4) Results are expressed as N (%). a Size 1cm, villous component or high-grade dysplasia. Table 4. Multivariate analysis for the association of H. pylori seropositivity and colorectal adenoma characteristics OR (95% CI) P Adenoma 1cm in size 0.83 ( ) Multiple ( 3) adenoma 1.28 ( ) Any proximal adenoma 1.02 ( ) Tubulovillous/villous adenoma 1.05 ( ) OR, odds ratio; CI, confidence interval Discussion In this study, H. pylori seropositivity was slightly higher in the adenoma group than control group, but this association was not statistically significant. So H. pylori infection might not be a risk factor for colorectal adenoma. H. pylori seropositivity was not associated with the characteristics of colorectal adenoma. 10

20 There are possible explanations for the putative relationship between H. pylori infection and colorectal neoplasm. A few studies have suggested that fecal shedding of H. pylori and its antigens means H. pylori moves through the intestine in direct contact with colonic mucosa.(16, 17) Others identified H. pylori DNA in colorectal adenoma and adenocarcinoma specimens.(18, 19) But its direct association with colorectal neoplasm development seems less plausible because H. pylori has a specific affinity for the gastric mucosa. Another mechanism is that persistent H. pylori exposure may result in transformation of gastric cells into gastrin-producing cells, which induce hypergastrinemia.(20, 21) Gastrin has a trophic effect on colorectal mucosa and is related to expression of inflammatory mediators like COX-2 and IL-8, whose inhibition can contribute to the prevention of colorectal cancer development.(22) H. pylori strains expressing the cytoxin-associated gene (CagA) results in enhanced inflammatory response and higher gastrin levels compared to CagA- strains.(23) Several epidemiologic studies have examined the association between H. pylori and colorectal adenomas. Recently, a case-control study by Inoue et al. showed that H. pylori seropositivity increased the risk of colorectal adenomas (OR, 2.52; 95% CI, ).(11) Hong et al. suggested that H. pylori seropositivity was a risk factor for any proximal adenoma (OR, 1.50; 95% CI ), but not for only distal adenoma (OR, 1.07; 95% CI, )(12). On the other hand, a prospective study by Robertson et al. showed that H. pylori seropositivity was not associated with an increased risk for recurrent adenoma development (RR, 0.76; 95% CI, ).(14) Abbass et al. found 11

21 that the higher prevalence of colon adenoma in H. pylori positive patients was not statistically significant (P=0.52).(15) The discrepant results of previous studies about the relationship between H. pylori seropositivity and colorectal adenomas might have been due to small sample size, sample bias, insufficient adjusting of confounding factors and race differences with a varying frequency of CagA+ H. pylori.(24) This study has several advantages. It was a large sample size, case-control study and we used a healthy population that was considered to approximate the general population. Furthermore, age and sex matching was carried out because age and sex were well known risk factors for colorectal adenoma. We carried out a conditional logistic regression analysis adjusting with many possible confounding factors. In our study, H. pylori seropositivity is slightly higher in colorectal adenoma subjects, but not statistically significant. Previous epidemiologic studies showed controversial results. It means that the other unknown mechanisms or factors cause the negative association between H. pylori and colorectal neoplasm could present. Besides, the regional distribution of colorectal cancer does not mirror that of gastric cancer and in Asia, there are converse trends over time for the two cancers.(25) In Western countries, the frequency of H. pylori infection is lower but colorectal adenomas are higher than Eastern countries. And in Asia, H. pylori infection is decreasing, but the occurrence of colorectal adenomas is increasing over time. This study has some limitations. First, we measured H. pylori infection only by H. pylori antibodies in human serum, which may not represent actual H. 12

22 pylori infection and recent eradication of H. pylori by treatment. Past historical data of diagnosis and treatment of H. pylori infection were not included in this study. Second, our study lacks information on H. pylori CagA status and serum gastrin levels. Third, this study is a cross-sectional casecontrol design. So the temporal sequence of H. pylori infection and colorectal adenoma cannot be determined nor could the pathologic mechanisms underlying the association between colorectal adenoma and H. pylori infection be identified. In conclusion, the association of H. pylori seropositivity and colorectal adenoma was not statistically significant, so H. pylori infection might not be a risk factor for colorectal adenoma in this large-scale, age-sex matched casecontrol study. A large-scale prosepective study including H. pylori CagA status and serum gastrin levels is necessary for the identification of association with H. pylori infection and colorectal neoplasm. Clarifying the pathophysiological role of H. pylori in the development of colorectal neoplasm is also needed. 13

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27 국문초록 서론 : Helicobacter pylori (H. pylori) 감염과대장의선종성용종과의연관성에대해서최근여러연구가있어왔으나연구결과들은상반된결과들이보고되었다. 본연구에서는혈청 H. pylori 양성과대장의선종성용종과의연관성에대해알아보고자하였다. 방법 : 검진목적의대장내시경을받은수진자들을대상으로하였다. 대장내시경을받은후, 수진자들은대장에선종성용종이있는군 ( 환자군 ) 과정상인군 ( 대조군 ) 으로나뉘었다. 과증식성용종이나악성용종이있는수진자들은제외되었다. 수진자들을대상으로흡연여부, 음주력, 운동력, 당뇨, 고혈압, 약제복용력, 대장암의가족력을조사하였다. 이들에게다양한신체계측및혈액검사를하였고 H. pylori 감염은 ELISA를이용한항헬리코박터항체 IgG를측정하여진단하였다. 결과 : 총 1,780명이분석에포함되었으며성별과연령을매칭하여각각 890명의선종군과대조군으로구분하였다. 평균연령은 55.5±7.6세였고, 1,358명 (76.3%) 이남성이었다. H. pylori 양성인수진자가 1,035명 (58.1%), 음성인수진자가 745명 (41.9%) 이었다. 단변량분석에서 H. pylori 양성률은대조군에비해선종군에서약간더높았으나이러한연관성은통계적으로유의하지않았다 (OR, 1.19; 95% CI, ; P=0.074). 고혈압, 흡연, 음주, 복부비만, 비만도, 중성 18

28 지방수치, 대장암의가족력은대조군에비해선종군에서유의미하게더높았다. 대장선종의위험인자를보정한다변량분석에서 H. pylori 감염은대장의선종성용종의중요한위험인자가아니었다 (OR, 1.20; 95% CI, ; P=0.075). H. pylori 감염과선종의수, 크기, 위치, 진행성선종의발생은통계적으로유의한연관성을보이지않았다. 결론 : 본대단위환자-대조군연구에서 H. pylori 양성률은대조군에비해선종군에서약간더높았으나이러한연관성은통계적으로유의하지않았다. H. pylori 감염과대장의선종성용종과의연관성을밝히기위해추가적인연구가필요하겠다 주요어 : 헬리코박터파일로리, 대장선종학번 :