台灣地區社區肝癌篩檢

Abstract

肝細胞癌是全世界發生率第五位以及死亡率第三位的癌症，也是台灣地區癌症發生率的第一位以及死亡率第二位。肝細胞癌主要的危險因數包括B型肝炎與C型肝炎病毒感染、酒精、黃麴毒素、糖尿病與肥胖等。除了危險因數的介入預防外，肝細胞癌的預防也以早期篩檢早期治療為主要策略之一。 台灣肝細胞癌的發生率與死亡率在過去二十年來均有上昇的趨勢，特別是在1991年之後。如果肝細胞癌的死亡增加是因為存活率差，肝細胞癌的治療就必須設法改善；如果是因為肝細胞癌的發生增多，早期偵測出肝細胞癌個案便相當重要。本論文第一部份，在探討台灣地區肝細胞癌死亡率的上昇原因，本研究收集1985至1998年間，年齡20-79歲的肝細胞癌(ICD=155.0)死亡個案41,150 名與肝細胞癌發生個案51,201名進行分析；並以Poisson迴歸進行年齡與出生世代之交互分析。結果發現，肝細胞癌發生率的上昇，特別是在50歲以上的族群，是台灣地區近年來肝細胞癌死亡率上昇的主要原因，針對高危險群早期篩檢肝細胞癌便成為重要的公共衛生課題。（第三章） 在肝細胞癌的危險因子研究方面，除了B型肝炎與C型肝炎外，肥胖與糖尿病也已在西方國家被許多研究證明與肝細胞癌的發生有高度相關。台灣地區近幾十年來生活形態逐漸西化，從早期預防的觀點而言，慢性病特別是代謝症候群與B型肝炎或C型肝炎之間的相關或交互作用，值得加以探討。本論文第二部分，收集1999至2002年間參加基隆社區複合式篩檢，年齡30-79歲民眾共53,528 名，將其B型肝炎表面抗原、C型肝炎抗體以及代謝症候群之相關因子如空腹血糖、血壓、高密度膽固醇、三酸甘油脂與腰圍資料，利用羅吉斯迴歸分析估計相對危險比及其百分之九十五信賴區間。結果顯示，B型肝炎表面抗原陽性，多與代謝症候群的相關因子之間呈現負相關；而C型肝炎抗體陽性，則與代謝症候群的相關因子之間則有或正或負的相關性存在，如C型肝炎抗體陽性者有較高比率的高密度膽固醇偏低，以及三酸甘油脂偏高。此種相關是否意味著B型肝炎與C型肝炎病毒在非酒精性脂肪肝病的病理機轉上有不同的作用，值得進一步研究。（第四章） 至於在肝細胞癌的次段預防方面，對於肝細胞癌的篩檢模式仍存有許多爭論。本論文第三部份，係以社區為基礎的隨機分派臨床試驗，針對非肝硬化的高危險群民眾，使用腹部超音波與甲型胎兒蛋白進行肝細胞癌篩檢，比較間隔6個月（密集篩檢組）與間隔12個月（非密集篩檢組）之成效差異。本研究邀請台灣地區6個鄉鎮年齡38–72歲，共4,319名非肝硬化的高危險群民眾（下列至少一項陽性：B型肝炎表面抗原陽性、C型肝炎抗體陽性、甲型胎兒蛋白大於或等於20 ng/mL、aspartate transaminase (GOT) 大於或等於40 IU/L、alanine transaminase (GPT) 大於或等於45 IU/L ）參與本研究。按居住地、年齡、性別以及B型肝炎表面抗原狀態，隨機分派為篩檢間隔6個月與12個月兩組。自1999年9月開始追蹤至2004年12月底止，接受定期腹部超音波與甲型胎兒蛋白篩檢，主要評估密集篩檢組與非密集篩檢組的死亡率差異。結果顯示，這兩組在累積全死因死亡率、累積肝細胞癌死亡率均無統計學上顯著差異。藉由本篇研究結果，定期規律接受肝細胞癌篩檢是改善高危險群個案存活率之重要因素。（第五章)

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm, and the third most common cause of cancer-related death in the world. In Taiwan, HCC is also one of the most common neoplasm and the first leading cause of cancer death in recent decades. The risk factors of HCC include mainly hepatitis B infection (HBV), hepatitis C infection (HCV), alcohol use, aflatoxin, diabetes (DM) and obesity, etc. In addition to risk factors avoidance, early detection is the major strategy of intervention to prevent from HCC. Both HCC mortality and incidence are noted to increase in the past two decades from national health statistics in Taiwan and a rapid rise in mortality from HCC has been observed in subjects aged 20 years and over since 1991. If the cause of increasing mortality of HCC is due to poor survival from HCC mainly, then improvement of treatment should be encouraged. On the contrary, if the cause is due to increasing incidence of HCC, then early detection for HCC would be mandatory. Therefore, the aim of the first part (Chapter 3) of this thesis study is to delineate the cause of rising mortality of HCC. We collected a total of 41,150 deaths and 51,201 incident HCC cases (ICD 9 code 155.0) aged 20-79 years between 1985 and 1998. Trends in HCC mortality rates were decomposed into two parts, the annual case-fatality rates and HCC incidence rates by age. Poisson regression was used to distinguish a cohort effect from a time period effect on the incidence of HCC. The results disclosed increased incidence, particularly in individuals over 50, rather than poor survival, accounts for the rapid rise in mortality from HCC in Taiwan. Thus early detection for HCC is very important regarding HCC prevention. As to the risk factors of HCC, in addition to hepatitis B and hepatitis C, obesity and DM have also been proven to be highly associated with HCC in the western society. Because the lifestyle change in Taiwan moves more like the West, the possible changing of risk factors for HCC and the interactions between chronic diseases and hepatitis B/C deserves to be elucidated from the viewpoint of early prevention. It is timely to explore the associations between chronic diseases, particularly the factors related to metabolic syndrome (MS), and risk factors of HCC, especially hepatitis B and hepatitis C in Taiwan. The second part (Chapter 4) of this thesis study aims to see the relationship between MS and hepatitis B surface antigen (HBsAg), hepatitis C antibody (anti-HCV) status simultaneously with the help from using a large population-based data from Keelung Community Integrated Screening program (KCIS). A population-based cross-sectional study design was adopted with a total of 53,528 subjects being enrolled from KCIS. Evidence of past hepatitis B/C infection, acquired during childhood or as a young adult, was identified during the two-stage liver cancer screening part of the process. Information on biochemical markers and anthropometric measures related to MS, such as fasting blood sugar, triglyceride (TG) and high-density lipoprotein (HDL-C), abdominal circumference (WC) and blood pressure (BP), were collected routinely whilst screening for hypertension, type 2 DM, and hyperlipidemia. Logistic regression was used to estimate odd ratios (OR) and related 95% confidence interval (CI) for the associations between MS and hepatitis B/C infection. The results showed that there is an inverse association between MS and HBV infection whereas the association was heterogeneous for HCV infection with a positive association with abnormal HDL-C but an inverse association with hypertriglyceridemia. It needs further studies to clarify the potential different pathogenesis mechanism of non-alcoholic fatty liver diseases from hepatitis B and hepatitis C. With regards to the secondary prevention of HCC, there are still lots of debates about screening for HCC. The third part (Chapter 5) of this thesis study wishes to demonstrate the efficacy of HCC screening program in terms of different strategy of screening interval using community-based randomized clinical trial. 4,319 non-liver cirrhotic subjects aged 38–72 years from 6 townships in Taiwan with at least 1 positive result from 5 markers including HBsAg positive, anti-HCV positive, alpha-fetoprotein (AFP) ≧ 20 ng/mL, aspartate transaminase (GOT) ≧ 40 IU/L, and alanine transaminase (GPT) ≧ 45 IU/L were invited to participate this randomised trial from September 1, 1999 and follow up until December 31, 2004. Repeated abdominal sonography (US) screening was offered to these subjects through randomised to two different screening intervals strategies, 6 months and 12 months respectively. The primary end point was to assess the effect of intensive strategy on mortality reduction compared with regular strategy. The results disclosed there was no difference between 6 months and 12 months screening interval strategies for HCC screening among non-cirrhotic high risk groups in hepatitis B hyperendemic area. Besides, no matter 6 months or one year screening interval for HCC screening among those who at high risk of HCC, the best way for high risk groups to prevent from HCC is to follow up regularly.