Hyperglycemia Increases Risk of Gastric Cancer Posed by Helicobacter pylori Infection : A Population-Based Cohort Study FUMIE IKEDA,* YASUFUMI DOI,‡ KOJI YONEMOTO,* TOSHIHARU NINOMIYA,* MICHIAKI KUBO,* KENTARO SHIKATA,* JUN HATA,* YUMIHIRO TANIZAKI,* TAKAYUKI MATSUMOTO,‡ MITSUO IIDA,‡ and YUTAKA KIYOHARA* *Department of Environmental Medicine and ‡Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan GASTROENTEROLOGY 2009;136:1234–1241 소화기내과 R3 박현진

Introduction Stomach cancer –Markedly decreased incidence and mortality during the past 75 years –The 2nd most common cause of cancer-related mortality in the world The risk factors of gastric cancer –The long-term ingestion of high concentrations of nitrates in dried, smoked, and salted foods –Gastric ulcer or adenomatous polyp –An extreme hypertrophy of gastric rugal folds –Blood group A > Blood group O –A germline mutation in the E-cadherin gene  Helicobacter pylori infection A well-known and strong risk factor for gastric cancer Prevalence : Japan > Western countries Especially in middle-aged and elderly individuals Causing chronic gastritis, loss of gastric acidity, and bacterial growth The only etiologic factor of gastric cancer?  Helicobacter pylori infection A well-known and strong risk factor for gastric cancer Prevalence : Japan > Western countries Especially in middle-aged and elderly individuals Causing chronic gastritis, loss of gastric acidity, and bacterial growth The only etiologic factor of gastric cancer?

Introduction Diabetes mellitus and malignant neoplasm –Only very few studies have been published. –Fasting plasma glucose and gastric cancer Impact of fasting plasma glucose levels on gastric cancer incidence in a general Japanese population : the Hisayama Study Yamagata H, et al. D iabetes Care 2005; 28:789–794 Fasting serum glucose level and cancer risk in Korean men and women. Jee SH, Ohrr H, Sull JW, et al. JAMA 2005;293:194– 202 Fasting blood glucose and cancer risk in a cohort of more than 140,000 adults in Austria. Rapp K, Schroeder J, Klenk J, et al. Diabetologia 2006;49: –HbA1c and Gastric cancer HbA1c : reflects long-term glycemic control No studies have evaluated the impact of HbA1c levels on the development of gastric cancer.

Purpose A prospective investigation of the relationship between HbA1c levels and gastric cancer occurrence in a general Japanese population, taking H. pylori infection as well as other risk factors into consideration. HbA1C levels

Subjects and Methods Study population –A population-based prospective study from 1961 –Hisayama, Fukuoka metropolitan area of Kyushu Island, Japan. –The age and occupation : almost identical to those of Japan –A screening survey : from 1988  132 : gastrectomy or gastric cancer  2 : HbA1c levels measurement (-)  5 : death during the screening 3390 Hisayama residents in 1988(40 years or over) 2742(80.9%) : informed consent 3390 Hisayama residents in 1988(40 years or over) 2742(80.9%) : informed consent Total 2603 subjects men, 1533 women, mean age : 59 years Total 2603 subjects men, 1533 women, mean age : 59 years

Subjects and Methods Follow-up survey –For 14 years, from December 1988 to November 2002 –Health status check-up : once yearly –Identification of new occurrences of gastric cancer 1. Interview : medical history and annual mass screening history 2. Radiographic and endoscopic study with biopsy 3. Autopsy : 442(76.1%)/581 subjects who died during the follow-up period –Diagnosis of gastric cancer By histologic examination of tissue Pathologic diagnosis : Japanese Gastric Cancer Association Histologic classification : Laurén classification –Dropped out : only 1 subject

Subjects and Methods Laboratory testing –HbA1c : High-performance liquid chromatography (HLC-723Hb) –Plasma glucose levels : glucose-oxidase method Assessment of the independent effect of HbA1c on gastric cancer –(1) Serum IgG antibodies to H pylori : positive or negative –(2) Information about history of peptic ulcer disease, alcohol intake, and smoking habits (current use or not) –(3) Height, weight and the body mass index –(4) Serum cholesterol levels –(5) Data on dietary factors The daily nutrient intakes, including total energy, total fat, salt, vitamin A, vitamin B-1, vitamin B-2, vitamin C, and dietary fibers

Subjects and Methods Statistical Analysis –HbA1c Normal range : 4.0%– 6.0% (American Diabetes Association’s guideline) Classification of baseline HbA1c level : 1% interval( 7.0% ) –Age- and sex-adjusted risk factors : the analysis of covariance method –Trends across HbA1c levels : multiple regression analysis –Age- and sex-adjusted incidence rates : the person-year method –The Cox proportional hazards model The age- and sex- or multivariate-adjusted hazard ratios (HRs) 95% confidence intervals (CIs) –The multivariate analysis Age, sex, H. pylori seropositivity, history of peptic ulcer disease, body mass index, serum cholesterol, alcohol intake, smoking habits, and dietary factors –The χ2 test The effect of the interaction between HbA1c and H pylori infection

Results

Age- and Sex- adjusted incidence rate of gastric cancer

Results Age- and Sex- adjusted HR and 95% CI of Gastric cancerMultivariate - adjusted HR and 95% CI of Gastric cancer

Results Multivariate adjusted splines for hemoglobin A1c (%) and gastric cancer risk 5.3% 5.5% 6.5%

Results

Conclusion The first population-based cohort study An elevated HbA1c level, namely, casual hyperglycemia, is an independent risk factor for gastric cancer occurrence and is a possible cofactor increasing the risk of cancer posed by H pylori infection.