以人群為基礎之幽門螺旋桿菌篩檢與治療來預防胃癌及根除治療後之個人監測

Population-based screening and treatment of Helicobacter pylori to prevent gastric cancer and the post-eradication individual surveillance

江宗賢(Tsung-Hsien Chiang)

指導教授 ： 吳明賢

共同指導教授 ： 孫家棟(Chia-Tung Shun)

國立臺灣大學/醫學院/臨床醫學研究所/博士(2020年)

https://doi.org/10.6342/NTU202004296

摘要

胃癌是全球主要的健康威脅，估計每年在全球造成超過80萬人死亡。馬祖列島是我國胃癌發生高風險區域，也因此，如果有可使用之胃癌風險特異性的生物標誌物（例如血清胃蛋白酶原（PG））來識別將來發生胃癌之高風險族群，進而安排後續之內視鏡監測，則可以有效降低胃癌的死亡率。在1995年至1998年間，在馬祖地區曾進行一項以PG為主之胃癌篩檢計劃，而我們運用當時的PG檢測結果來檢視16年後(2010年)，其與發生胃癌死亡的關聯性。結果顯示PG-I <30μg/ L〔風險比率：3.27（95％信賴區間：1.11-9.61）〕和PG-I <30μg/ L或PG-I / II比<3〔風險比率：3.45（95％信賴區間：1.18-10.12）〕與胃癌死亡的風險顯著相關。目前已知幽門螺旋桿菌感染是造成胃癌最重要的病因，而根除這種病原體則可能是減輕胃癌負擔的一種策略。因為根除幽門螺旋桿菌在具有不同水平的胃癌風險和不同臨床情況的人群中獲益的程度尚不清楚，因此我們對隨機對照試驗和觀察性研究進行了系統性的回顧和統合分析，以研究根除幽門螺旋桿菌對胃癌發生率的影響。此統合分析所納入的文獻包括二十四篇符合條件的研究（22篇研究論文和2篇摘要）（總共為48,064人/ 340,255人年，且共有715例胃癌）。結果顯示，根除治療後對無症狀幽門螺旋桿菌感染者（胃癌發生率，0.62； 95％信賴區間：0.49-0.79）與已經由內視鏡切除早期胃癌後的幽門螺旋桿菌感染者（胃癌發生率，0.46； 95％信賴區間：0.35-0.60）皆提供了顯著預防胃癌發生的益處。
儘管目前研究已提出大規模根除幽門螺旋桿菌可作為消除胃癌發生的可行策略，但其對於基於以人群為基礎之幽門螺旋桿菌篩檢與治療後的長期效果仍不清楚。馬祖列島是我國胃癌發生高風險區域，針對該區域年齡大於30歲的居民以幽門螺旋桿菌的大規模根除來達到防治胃癌計畫始於2004年；而直到2018年為止，該地區已進行了6輪的大規模幽門螺旋桿菌篩檢與根除治療。與1995年至2003年的非除菌之歷史控制時期相比，我們發現，在除菌計畫進行後能有效降低胃癌的發生率〔胃癌發生率：0.53（95％信賴區間：0.30-0.69）〕。不過對於胃癌死亡率的影響，則須更長時期的追蹤才能看到效益。在大規模的幽門螺旋桿菌根除治療後，接著，我們於2015年至2018年間亦進行一前瞻篩檢計畫，包含第一階段血清學檢查（PG-1，PG-II，幽門螺旋桿菌免疫球蛋白G和胃泌素17）和第二階段內視鏡檢查。而指標性病變則包括了胃癌及萎縮性胃炎與腸化生之癌前病變，來評估血清學檢測對於幽門螺旋桿菌根除治療後來識別胃癌或癌前病變之效益。以分別根據正似然比和負似然比“排除”和“排除”風險。此外，對於有接受內視鏡檢查的居民，我們也檢測了胃黏膜組織中之microRNA-124a-3的甲基化程度，以驗證表觀遺傳標記對於胃癌風險預測的表現。結果顯示，PG檢查可以適度預測萎縮性胃炎〔陽性概似比：4.11（95％信賴區間：2.92-5.77）；陰性概似比：0.14（95％信賴區間：0.10–0.19）〕。胃泌素17則無效（陽性概似比：0.66；陰性概似比：1.20）。但是，PG檢測仍無法很好地整體預測指標性病變〔陽性概似比：2.04（95％信賴區間：1.21-3.42）；陰性概似比：0.57（95％信賴區間：0.34-0.95）〕。而表觀遺傳標記中的DNA甲基化程度則對於預測指標性病變更具識別度〔陽性概似比：3.89（95％信賴區間：2.32-6.54）；陰性概似比：（95％信賴區間：0.15-0.42）〕。
目前常規的根除幽門螺旋桿菌通常需要7-14天的療程，包括有效的抑胃酸劑和2至3種抗生素的使用。儘管充分的胃酸抑制能達到優化抗生素的殺菌作用，但是胃酸的抑制與否對鉍劑的殺菌作用有何影響尚不明確。我們運用隨機分派的設計，藉由穿透式射電子顯微鏡來直接觀察胃黏膜組織上幽門螺旋桿菌的形態學變化，並證明了鉍劑在胃內的治療幽門螺旋桿菌時的即時毒性作用與胃酸抑制與否無關。

關鍵字

胃癌 ； 幽門螺旋桿菌 ； 胃蛋白酶原 ； 篩檢 ； 甲基化 ； 鉍劑 ； 穿透式射電子顯微鏡

並列摘要

Gastric cancer is a major global health threat and causing an estimated >800,000 deaths per year globally. Therefore, endoscopic surveillance would be effective and efficient in reducing gastric cancer mortality if a biomarker such as serum pepsinogen (PG) is available to identify high-risk individuals and if the biomarker also is specific to gastric cancer risk. Between 1995 and 1998, a gastric cancer-screening program was conducted in Matsu Islands: The first stage involved PG testing, and the second stage involved upper endoscopy; then, we monitor gastric cancer death until 2010 in relation to previous PG testing. After 16 years of follow-up, the results showed that PG-I <30 μg/L and PG-I <30 μg/L or PG-I/II ratio <3 were significantly associated with the risk of gastric cancer death (hazard ratio (HR), 3.27; 95% CI, 1.11-9.61 and HR, 3.45; 95% CI, 1.18-10.12, respectively). As we know, Helicobacter pylori is the most important etiologic factor for gastric cancer, and eradicating this pathogen might represent a strategy to reduce the burden of gastric cancer. The magnitude of benefit of H. pylori eradication in populations with different levels of gastric cancer risk and in different clinical scenarios is unclear. We performed a systematic review and meta-analysis of randomized controlled trials and observational studies to investigate the effects of H. pylori eradication on the incidence of gastric cancer. Twenty-four eligible studies (22 research manuscripts and 2 abstracts) were included in our meta-analysis (715 incident gastric cancers among a total of 48,064 individuals/340,255 person-years). Eradication provided significant benefit for asymptomatic infected individuals (pooled incidence rate ratio, 0.62; 95% confidence interval (CI): 0.49-0.79) and individuals after endoscopic resection of gastric cancers (pooled incidence rate ratio, 0.46; 95% CI: 0.35-0.60).
Although mass eradication of H. pylori has been proposed as a means to eliminate gastric cancer, its long-term effects for population-based cohort approach remain unclear. Mass eradication of H. pylori infection was launched in 2004 and continued until 2018 for a high-risk Taiwanese population aged 30 years or older dwelling on Matsu Islands with prevalent H. pylori infection. Test-positives for the 13C-urea breath test underwent eradication therapy. After 6 rounds of mass screening and eradication, we evaluated the effectiveness of the mass eradication in reducing two main outcomes, incidence and mortality rates of gastric cancer, until the end of 2016 and 2018, respectively. Compared with the historical control period from 1995 to 2003, the effectiveness in reducing gastric cancer incidence during the chemoprevention period was 53% (95% CI: 30-69%, P<0.001) and a significant reduction in mortality is likely to be achieved with a longer follow-up period. After mass eradication, another prospective screening program involving first-stage serological tests (PG-I, PG-II, H. pylori immunoglobin G, and gastrin-17) and second-stage endoscopic examination was launched in 2015-2018 in Matsu Islands also. We defined index lesions including gastric cancer or extensive premalignant lesions, and evaluated the performance of the serological tests to “rule in” and “rule out” the risk based on positive and negative likelihood ratios, respectively. Besides, the methylation levels of microRNA-124a-3 in the stomach were measured to indicate genetic damage. The results showed that PG testing could moderately predict atrophic gastritis [positive likelihood ratio: 4.11 (95% CI: 2.92-5.77); negative likelihood ratio: 0.14 (0.10–0.19)]. Gastrin-17 was not useful (0.66 and 1.20, respectively). However, PG testing poorly predicted the index lesions [2.04 (1.21–3.42) and 0.57 (0.34–0.95)]. DNA methylation levels in the post-eradication mucosa was more discriminative for predicting index lesions [3.89 (2.32–6.54) and 0.25 (0.15–0.42)].
Eradication of H. pylori typically requires a treatment course of 7-14 days, consisting of a potent acid suppressant and 2 to 3 kinds of antibiotics. Although adequate acid suppression is required to optimize the antibiotic effects, whether this will or will not affect the effectiveness of bismuth salts remains unclear. We used a randomized design to test the hypothesis whether the bactericidal effect of colloidal bismuth subcitrate (CBS) on the H. pylori would be affected by the intra-gastric pH, a typical condition when the eradication therapy is administered, through the direct observation of morphological changes of H. pylori using the transmission electron microscopy in the absence of antibiotics. We demonstrated that an immediate toxic effect of CBS treatment on H. pylori is documented, which is independent from the intra-gastric acidity.

並列關鍵字

gastric cancer ； Helicobacter pylori ； pepsinogen ； screening ； methylation ； bismuth ； transmission electron microscopy

參考文獻

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