台灣男性胃賁門腺癌的相關危險因素探討

Abstract

背景：自1970年後，全世界性胃癌的發生率及死亡率雖已有逐漸下降的趨勢，但其仍位居人類常見癌症的第四位，以及癌症死因的第二位，故其對人類健康的威脅仍不容小覷。正當胃癌發生率逐漸下降之際，「胃賁門腺癌」的發生率卻戲劇性地逐漸上升，特別是在西方已開發國家（北美及歐洲等國家）的發生率甚至有高達5至6倍的成長速率。近年來，中國大陸及其愈加都市化（上海、北京）的地區亦見有增加的現象，除了顯見「胃賁門腺癌」與其他部位之胃癌有不同的癌症致因外；尚發現「胃賁門腺癌」現已悄悄地成為人類健康的新興問題，雖至今其仍為罕見疾病。而胃賁門腺癌發生率不減反增的趨勢，加上其另一個引人注目的特徵是罹病傾向以男性較具優勢，以上兩者之發生原因至今仍未明。且在臨床上，由於早期的胃賁門腺癌通常無明顯症狀，而進行性之胃賁門腺癌的5年存活率僅為14.55%，加上目前又缺乏適當的篩檢工具，故欲有效控制胃賁門腺癌，唯有從「預防」著手，因此鑑別胃賁門腺癌的高危險因素及流行病學調查就顯得格外地重要了。分析過去的研究，可能是因為胃賁門腺癌是罕見疾病，故常將男女性的暴露資料合併計算，如此恐將造成危險致因之相關性的稀釋，並造成結果的扭曲，且目前許多流行病學研究均強調「環境因素」對胃賁門腺癌發生的重要性。由於台灣的社會生活型態正好介於歐美與中國大陸之間，就探討一個會受環境及社經地位因素影響的疾病而言，提供台灣的相關研究經驗，將有助於世人相關胃賁門腺癌之致因探討及有效防治策略擬定之非常重要的關鍵資訊。但由於台灣目前相關胃賁門腺癌之分析性流行病學研究並不多見，是故相關台灣的胃賁門腺癌流行病學研究，實是非常重要且有趣的研究課題。 方法：本研究乃是以醫院為基礎的病例對照研究法（Hospital-based case-control study）來進行胃賁門腺癌相關危險因素探討之流行病學調查。研究對象為南台灣的一家醫學中心之住院病例經醫師之臨床診斷及經內視鏡檢及病理切片證實肯定為原發性之胃賁門腺癌男性患者為病例組，再經性別、年齡（± 3歲）、及住院時間（± 2 週）之配對選取家醫科健檢之住院病患為對照組，但若其罹患有胃部相關之疾病及其他癌症等除外，並以病例組與對照組為1：5的比例來進行樣本數的收集，均採以存活之個案，且事先均取得案例之同意。研究對象選取後，即由一受訓之訪談員以面對面之訪談方式進行研究對象相關問卷資料的蒐集以及血液樣本的採集。本問卷採結構式問卷，收集所有相關生活型態、飲食暴露、幽門螺旋桿菌的感染、家族病史及其他環境暴露因素等可能的相關危險因素的暴露情形，且相關人口學特徵、生活型態及環境暴露頻率等因素，多以範疇類別方式來進行資料的收集，藉以降低回溯性記憶偏差（recall bias）的產生。並配合利用非侵襲性方法－血清抗體檢驗法來進行幽門螺旋桿菌感染的診斷，即是以酵素連接免疫吸附檢定（enzyme linked immunosorbent assay, ELISA）來檢測血清抗幽門螺旋桿菌IgG的抗體效價，然後再針對IgG抗體呈現陽性反應者續以ELISA進行幽門螺旋桿菌細胞毒素相關基因A菌株（cytotoxin-associated gene strain, CagA strain）的檢測。研究時間乃自民國89年1月起至98年9月底止。所有的資料，都是以第七版之STATA統計軟體來進行分析，而所有的分析均調整了年齡及教育程度因素，以盡可能減少混淆因素的影響，並利用條件式的多變項邏輯斯迴歸分析（經調整干擾因素之作用後），以分析釐清國人男性胃賁門腺癌之相關危險因素。 結果：共有246名案例進行分析比較，病例組共有41例的原發性胃賁門腺癌男性病患，而對照組則為205例。在單變數分析方面發現：生活型態－飯後工作或運動相較於對照組有3.26倍罹患胃賁門腺癌之高危險性（95% CI 1.31∼8.11）及抽菸有2.28倍罹患胃賁門腺癌之高危險性（95% CI 1.05∼4.96）；環境因子－幽門螺旋桿菌感染情形顯示病例組相較於對照組有顯著性2.69倍罹患胃賁門腺癌之高危險性（95% CI 1.30∼5.53）存在；在飲食暴露方面，則發現：鹽漬食品（OR = 2.51，95% CI 1.08∼6.11）等因素均具有較高的罹患胃賁門腺癌的危險性。而每天食用新鮮蔬菜（OR = 0.28，95% CI 0.09∼0.80）、水果（OR = 0.19，95% CI 0.04∼0.89）相較於沒有每天食用者，及以米飯為主食（OR = 0.53，95% CI 0.30∼0.85）等多項因素與胃賁門腺癌均具有顯著性的負相關。其他如營養補充品、及家族病史等因素，均未見其與胃賁門腺癌的顯著性相關。經multivariate conditional logistic regression model分析結果，最後發現：飯後工作或運動與胃賁門腺癌的發生呈現中度相關（OR = 3.18，95% CI 1.23∼9.36），及幽門螺旋桿菌感染（OR = 2.93，95% CI 1.42∼6.01）與胃賁門腺癌的發生呈現弱相關。而每日食用新鮮的蔬菜（OR = 0.22，95% CI 0.06∼0.83）、水果（OR = 0.28，95% CI 0.09∼0.79）及以米飯為主食者（OR = 0.48，95% CI 0.24∼0.93）則與胃賁門腺癌間呈現顯著性的負相關，具有保護效應。 結論：飯後30分鐘內若從事激烈工作或運動、及幽門螺旋桿菌感染是胃賁門腺癌發生的主要相關危險因素，但幽門螺旋桿菌CagA菌株陽性反應者卻與胃賁門腺癌的發生無關。而每日攝取新鮮的蔬菜、水果及以米飯為主食，將可有效降低胃賁門腺癌發生的危險性。

Background: The gastric cardiac adenocarcinoma (GCA) has attracted considerable attention recently as a consequence of the rapid increase by five to six folds in incidence, especially among white males, while the overall rate of gastric cancer has markedly declined in western countries. Recent studies in China have also shown a statistically significant increasing trend of the disease in the last two decades. Another striking feature is the strong male predominance (the sex ratio of male/female as 6:1) among the patients. However, no established risk factors have well explained the male predominance. As the reasons for these variations of incidence remain uncertain, there emerges a critical need for epidemiological studies to identify risk factors in male as well as risk factors that might account for the rapid increases in incidence, although it is very rare. Previous studies evaluating the etiology of the GCA generally merged with data of both genders, which may distort the findings and dilute the association. Methods: A hospital-based case-control study of matched pairs was derived from 2000 to 2009 in Kaohsiung City, Taiwan, to explore the risk factors of GCA associated with lifestyles, dietary habits, H. pylori infection, family history and other environmental exposure factors. All cases were newly confirmed as primary GCA. For each case identified, five controls were selected, matching with age (± 3 years), sex, and admission date (± 2 weeks), from the inpatients free of cancer in the Family Medicine Departments at the same hospital, including the inpatients who received a general health check-up. Subjects with stomach-related diseases were excluded. With consent from subjects, trained professional interviewers performed face-to-face interviews at the hospital using a structured questionnaire and a blood sample was taken from eatch of the subjects for the determination of H. pylori infection. Serums were evaluated for immunoglobulin G antibodies against H. pylori whole-cell and cytotoxin-assoicated gena A antigens（CagA）by enzymelinked immunoborbent assays（ELISA）. All data were analyses using STATA 7.0 statistical software. Conditional logistic regression models were used to estimate odds ratio (OR) and 95% confidence interval (95% CI) for the associations between GCA and the covariates of interest. All analyses were performed controlling for age and education level to minimize the possible confounding effects. The multivariate analysis was performed with no interaction terms to identify factors with the greatest impact on the fit of the model predicting the risk of GCA, taking into account other related exposure factors and covariates. Results: All participants recruited for this study were men, consisting of 41 cases and 205 controls. Cases were older than controls, but not significant (average age: 64.53±2.17 vs. 63.27±1.73 years, respectively), but not statistically significant (P = 0.28). Results of the univariate analysis showed that the significant factors associated with the etiology of GCA included working or exercising after meals (OR = 3.26, 95% CI = 1.31∼8.11), cigarette smoking (OR = 2.28, 95% CI = 1.05∼4.96), infection of H. pylori (OR = 2.69, 95% CI = 1.30∼5.53), consumption of salted food (OR = 2.51, 95%CI = 1.08∼6.11), consumption of fresh vegetables (OR = 0.28, 95% CI = 0.09∼0.80), consumption of fruits (OR = 0.19, 95% CI = 0.04∼0.89), and rice as principal food (OR = 0.53, 95% CI = 0.30∼0.85). This study, failed to find any nutritional supplement intake and family history in association with GCA. Multivariate conditional logistic regression models indicated that a significantly elevated risk of contracting GCA was associated with working or exercising after meals (OR = 3.18, 95% CI = 1.23∼9.36) and H. pylori infection (OR = 2.93, 95% CI = 1.42∼6.01). In contrast, the consumption of fresh vegetables (OR = 0.22, 95% CI = 0.06∼0.83), fruits (OR = 0.28, 95% CI = 0.09∼0.79) and rice as principal food (OR = 0.48, 95% CI = 0.24∼0.93) remained as significant beneficial factors associated with GCA. Conclusions: Working or exercising after meals and H. pylori infection are important independent risk factors for GCA, but Cag+A strains of H. pylori are not related with this cancer. The consumption of rice as principal food, as well as consumption of fresh vegetables and fruits may well reduce the GCA risk.