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  • 學位論文

探討B型肝炎表面抗原濃度對B型肝炎帶原者長期預後的影響:以醫院為基礎的B型肝炎帶原者之世代研究

Role of Hepatitis B Surface Antigen Level in Long-term Outcomes of Hospital-based Hepatitis B Virus Carriers

指導教授 : 高嘉宏 劉俊人

摘要


慢性B型肝炎是產生肝癌的危險因子。過去的文獻已經指出,當病患血清中的病毒量越高,產生慢性肝炎、肝硬化及肝癌的風險性越大。然而對於病毒量小於2000 IU/mL的患者,血清中病毒量並無法預測這些併發症的發生。 近年來,定量血清中表面抗原濃度,已成為一項新的生物指標。最近的研究指出,在免疫耐受期當中,表面抗原濃度最高;在免疫清除期時,濃度會開始緩慢下降;於免疫清除期結束,進入e抗原陰性時期後,不活動帶原者的血清表面抗原濃度將會降到最低;但對於產生e抗原陰性之慢性肝炎患者,血清表面抗原濃度則相對較高。在盛行病毒基因型B或C的亞太地區,不論是低病毒量之患者,或是產生自發性e抗原血清轉換的患者,可以觀察到當病患的血清表面抗原濃度越低,日後血清表面抗原消失的機率將會越高。而表面抗原濃度在10-100 IU/mL可以預測未來表面抗原消失的機率。至於血清表面抗原濃度和B型肝炎疾病進展的相關研究,則相對闕如。 在這份研究報告中,我們利用以醫院為基礎的世代研究的族群,來探討表面抗原濃度是否能輔助血清中病毒量,來預測與B型肝炎相關之併發症的發生。我們第一部份的研究指出,對於預測肝癌的發生,B型肝炎病毒量是一個比表面抗原濃度更準確的指標,然而對於e抗原陰性且病毒量小於2000 IU/mL的患者 (低病毒量),表面抗原濃度大於1000 IU/mL,是唯一和肝癌發生有關的病毒因子。此外,我們利用同一個研究族群,進一步發現在低病毒量的患者,表面抗原濃度大於1000 IU/mL也和病毒複製的活化、慢性肝炎的發生、慢性肝炎急性發作、以及肝硬化等早期的慢性B型肝炎的併發症有關。 除了在低病毒量之患者外,我們也分別在e抗原陰性之中病毒量的患者(病毒量介於2000到20,000 IU/mL),以及高病毒量的患者(病毒量大於20,000 IU/mL),檢視表面抗原和肝癌發生的關係,在中病毒量的患者中,表面抗原濃度100以及1000 IU/mL,可以用來區分中病毒量患者的肝癌風險,然而對於高病毒量的患者,表面抗原濃度則不具有預測力,最後我們利用血清中病毒量配合表面抗原,來預測肝癌之發生,發現其預測能力較單獨使用病毒量尤佳。 綜上所述,我們相信使用血清中病毒量配合監測表面抗原的濃度,能讓我們對於照護病患的思考流程更臻完美。未來,將需要更多的證據來驗證此項發現,並且期待能於臨床實務上形成可以應用的準則,甚至嘉惠接受抗病毒藥物治療的族群。如此一來,方能達成所謂個人化醫療之願景。

並列摘要


Patients with chronic hepatitis B virus (HBV) infection have a high risk for developing hepatocellular carcinoma (HCC). Patients with a higher level of HBV DNA level have increased risks of hepatitis activity, cirrhosis, and HCC. However, in patients with HBV DNA level <2000 IU/mL, the viral load plays a little role in predicting these adverse events. Recently, using commercial quantitative assays, quantitative HBsAg (qHBsAg) has improved our understanding and management of chronic hepatitis B. Recent studies have shown that HBsAg level is highest in immune tolerance phase, starts to decline during immune clearance phase and decreases slowly but progressively after HBeAg seroconversion. HBsAg level is lowest in those with inactive carrier state but higher in those who develop HBeAg-negative hepatitis. In the Asian-Pacific region where HBV genotype B and C are dominant, HBeAg-negative carriers with a low viral load and spontaneous HBeAg seroconverters, HBsAg levels of 10-100 IU/mL may predict HBsAg loss over time, which is marker for HBV cure. However, little is known about whether higher levels of HBsAg increase the risk for disease progression in HBV carriers. In this dissertation, we used a hospital-based cohort study to investigate whether HBsAg level could complement HBV DNA level in predicting HBV-related adverse events. Our results showed that HBV DNA level, compared to HBsAg level, served as a better predictor for HCC. However, in HBeAg-negative patients with HBV DNA level <2000 IU/mL (low viral load), HBsAg level is the only viral factor associated with HCC development. In addition, we used the same cohort and found that HBsAg level ≥1000 IU/mL was associated with HBV-related complications, including HBV DNA relapse, hepatitis activity and cirrhosis development in lowly viremic patients. In other words, in patients with HBV DNA level <2000 IU/mL, HBsAg level >1000 IU/mL is associated with the HBV-related complications in every step of disease progression. In addition to patients with low viral loads, we also investigated the role of HBsAg in HBeAg-negative patients with HBV DNA level between 2000-20,000 IU/mL (intermediate viral load) and HBeAg-negative patients with HBV DNA level ≥20,000 IU/mL (high viral load). We found that HBsAg levels of 100 and 1000 IU/mL can further stratify HCC risk in patients with intermediate viral loads but HBsAg level played little role in patients with high viral loads. Finally, we tried to combine HBsAg and HBV DNA levels as a combined biomarker to predict HCC risk in the overall HBeAg-negative cohorts. The combined biomarker served as a better predictor for HCC than using HBV DNA level alone. Taking these lines of evidence together, qHBsAg can complement HBV-DNA to improve the management of CHB patients in our daily clinical practice. However, our results need to be validated by other large cohorts and the clinical utility of qHBsAg in patients receiving anti-viral therapy awaits further studies.

參考文獻


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被引用紀錄


洪憶雯(2016)。肝病防治方法之關鍵因素〔碩士論文,國立虎尾科技大學〕。華藝線上圖書館。https://www.airitilibrary.com/Article/Detail?DocID=U0028-1806201612571000

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