長期重複測量之B型肝炎病毒量與肝癌/肝硬化風險之相關研究

Long-term Repeated Measurements of Hepatitis B viral Load and the Risks of Hepatocellular Carcinoma/Liver Cirrhosis

陳春妃(Chuen-Fei Chen)

指導教授 ： 陳建仁 ； 李文宗

國立臺灣大學/公共衛生學院/流行病學與預防醫學研究所/博士(2011年)

https://doi.org/10.6342/NTU.2011.02957

摘要

中文摘要
本論文以下列兩個子研究探討血清中B型肝炎病毒量的長期變化趨勢與肝癌及肝硬化危險性之相關。
研究一：血清中B型肝炎病毒量的長期變化趨勢與肝癌危險性之長期追蹤研究
背景 在慢性B型肝炎自然史的過程中，血清中肝炎病毒量可能會有很大的變化。然而，過去研究大多著重於探討單一個時間點而非多個時間點重複測量之B型肝炎病毒量與肝癌之相關。因此，本研究乃利用前瞻性之世代追蹤研究探討血清中B型肝炎病毒量的長期變化趨勢與肝癌風險的相關。
方法 本研究共追蹤3,160名30至65歲且無肝癌既往史之研究個案，並檢測其進入研究時以及肝癌發生之前追蹤過程中，重複測量的血清中B型肝炎病毒量與丙胺酸轉胺脢濃度。肝癌的確認乃經由追蹤檢查以及癌症登記檔和死亡檔之資料連結。以群體軌跡模型來探索11年的追蹤過程中，血清中B型肝炎病毒量存在哪些顯著不同的長期變化趨勢。以Cox氏比例危害複迴歸模式，估計血清中B型肝炎病毒量的各種長期變化趨勢發生肝癌的相對危險性及其95%信賴區間。
結果 經由38,330人年的追蹤, 共有81名個案新發生肝細胞癌，發生率為每十萬人年211.3人。在調整年齡、性別、抽菸及喝酒習慣、丙胺酸轉胺脢濃度的長期變化趨勢與B型肝炎基因型後，血清中B型肝炎病毒量在追蹤過程中自然下降到小於10,000 copies/mL的個案，其肝癌的發生率僅較參考組（血清中B型肝炎病毒量在進入研究時就小於10,000 copies/mL的個案）稍微高一些，但未達統計上之顯著差異（相對危險性：2.25； 95%信賴區間：0.68–7.37）。相較於參考組，長期血清中B型肝炎病毒量持續在10,000–100,000 copies/mL者，其發生肝癌的相對危險性（95%信賴區間）為3.12（1.09–8.89）；下降至或持續在100,000–1,000,000 copies/mL者，其發生肝癌的相對危險性（95%信賴區間）為8.85（3.85–20.35）；下降至或持續在1,000,000–10,000,000 copies/mL者，其發生肝癌的相對危險性（95%信賴區間）為16.78（7.33–38.39）。在調整年齡、性別、抽菸及喝酒習慣、B型肝炎病毒量濃度的長期變化趨勢與B型肝炎基因型後，丙胺酸轉胺脢濃度的長期變化趨勢與肝癌的發生率有一個顯著的劑量效應（P<.001）。
結論 血清中B型肝炎病毒量與丙胺酸轉胺脢濃度兩者之長期變化趨勢皆可獨立預測發生肝癌的危險性。血清中B型肝炎病毒量於追蹤過程中自然下降至小於10,000 copies/mL，可顯著下降肝癌的發生危險性。建議臨床對慢性B型肝炎病患的處置，應定期追蹤檢測血清中B型肝炎病毒量與丙胺酸轉胺脢濃度。

研究二：血清中B型肝炎病毒量的長期變化趨勢與肝硬化危險性之長期追蹤研究
背景 慢性B型肝炎可導致肝硬化。慢性B型肝炎感染是ㄧ個隨血清中肝炎病毒量變化的動態致病過程。本研究乃利用前瞻性之世代追蹤研究釐清血清中B型肝炎病毒量的長期變化趨勢與肝硬化風險的相關。
方法 本研究共追蹤3,106名30至65歲且無肝硬化既往史之研究個案，並檢測其進入研究時以及肝硬化發生之前追蹤過程中，重複測量的血清中B型肝炎病毒量與丙胺酸轉胺脢濃度。追蹤過程以腹部超音波診斷肝硬化，並串聯全民健康保險檔，由專科醫師查閱病歷，以確保肝硬化新發個案確診之完整性。透過群體軌跡模型來探索11年的追蹤過程中，血清中B型肝炎病毒量存在哪些顯著不同的長期變化趨勢。以Cox氏比例危害複迴歸模式，估計血清中B型肝炎病毒量的各種長期變化趨勢發生肝硬化的相對危險性及其95%信賴區間。
結果 經由36,923人年的追蹤, 共有262名個案新發生肝硬化，發生率為每十萬人年 709.6人。在調整年齡、性別、抽菸及喝酒習慣、丙胺酸轉胺脢濃度的長期變化趨勢與B型肝炎基因型後，血清中B型肝炎病毒量在追蹤過程中自100,000 copies/mL自然下降到小於10,000 copies/mL的個案，其發生肝硬化的危險性僅較參考組（血清中B型肝炎病毒量在進入研究時就小於10,000 copies/mL的個案）稍微高一些，但未達統計上之顯著差異（相對危險性：1.38；95%信賴區間：0.87–2.18）。相較於參考組，血清中B型肝炎病毒量在追蹤過程中從10,000,000 copies/mL自然下降到小於10,000 copies/mL的個案；其發生肝硬化的相對危險性（95%信賴區間）為2.46（1.19–5.13）；長期血清中B型肝炎病毒量持續在100,000–1,000,000 copies/mL的個案，其發生肝硬化的相對危險性（95%信賴區間）為2.92 （1.94–4.39）；在追蹤過程中從10,000,000 copies/mL自然下降到小於1,000,000 copies/mL的個案，其發生肝硬化的相對危險性（95%信賴區間）為4.10（2.51–6.72）；持續在1,000,000–10,000,000 copies/mL 其發生肝硬化的相對危險性（95%信賴區間）為4.81（2.94–7.87）。在調整年齡、性別、抽菸及喝酒習慣、B型肝炎病毒量濃度的長期變化趨勢與B型肝炎基因型後，丙胺酸轉胺脢濃度的長期變化趨勢與發生肝硬化的危險性有一個顯著的劑量效應（P<.001）。
結論 血清中B型肝炎病毒量與丙胺酸轉胺脢濃度兩者之長期變化趨勢皆可獨立預測發生肝硬化的危險性。進入研究時血清中B型肝炎病毒量相同的個案，其隨後發生肝硬化的危險性並不相同；換句話說，追蹤過程中血清中B型肝炎病毒量下降愈多者，其未來發生肝硬化的危險性就越低。血清中B型肝炎病毒量於追蹤過程中自然下降至小於10,000 copies/mL的個案，其隨後發生肝硬化的危險性也不相同，需視其進入研究時的血清中B型肝炎病毒量而定。建議臨床對慢性B型肝炎病患的處置應定期追蹤檢測血清中B型肝炎病毒量與丙胺酸轉胺脢濃度。

關鍵字

慢性B型肝炎 ； 肝癌 ； 肝硬化 ； B型肝炎病毒量 ； 丙胺酸轉胺脢 ； 群體軌跡模型 ； 長期追蹤研究

並列摘要

Abstract
This thesis consists of two component studies to investigate long-term changes in serum levels of hepatitis B virus (HBV) DNA and the risks of hepatocellular carcinoma and liver cirrhosis.
PART 1: Long-term Changes in HBV DNA Predict Risk of Hepatocellular Carcinoma
Background & Aims: Serum HBV DNA levels may vary markedly in the natural progression of chronic hepatitis B. It is not clear whether risk for hepatocellular carcinoma can be accurately determined from long-term changes in serum levels of HBV DNA or alanine aminotransferase (ALT).
Methods: We measured serum levels of HBV DNA and ALT at enrollment and during follow-up analysis of 3,160 participants in the REVEAL-HBV study. Development of hepatocellular carcinoma was determined from follow-up examinations and computerized linkage with National Cancer Registry and National Death Certification profiles. The group-based trajectory model was used to identify distinctive groups of long-term changes in serum HBV DNA levels over 11 years of follow-up. Multivariate-adjusted hazard ratios [HRs] and 95% confidence intervals [CI] were estimated using Cox regression models.
Results: During 38,330 person-years of follow-up, 81 participants developed hepatocellular carcinoma (incidence rate, 211.3/100,000 person-years). The hepatocellular carcinoma risk was only slightly higher for participants whose follow-up levels of HBV DNA spontaneously decreased to <10,000 copies/mL, compared to those with baseline levels of HBV DNA <10,000 copies/mL (reference group; HR, 2.25; 95% CI, 0.68–7.37). Compared with the reference group, the HRs (95% CI) for long-term levels of HBV DNA that persisted at 10,000–100,000 copies/mL, decreased to/persisted at 100,000–1,000,000 copies/mL, or decreased to/persisted at 1,000,000–10,000,000 copies/mL were 3.12 (1.09–8.89), 8.85 (3.85–20.35), and 16.78 (7.33–38.39), respectively. A gradient in ALT level was significantly associated with hepatocellular carcinoma risk: from all low normal, to ever high normal, to transient abnormal, to persistent abnormal (Ptrend<.001).
Conclusions: Long-term changes in serum levels of HBV DNA and ALT are independent predictors of risk for hepatocellular carcinoma. Spontaneous decrease of HBV DNA to <104 copies/mL is associated with a significantly lowered risk of hepatocellular carcinoma. Regular monitoring of levels of HBV DNA and ALT is important in clinical management of chronic carriers of HBV.

PART 2: Long-term Changes in HBV DNA Predict Risk of Liver Cirrhosis
Background & Aims: Chronic hepatitis B may lead to the development of liver cirrhosis. Chronic hepatitis B is a dynamic disorder with dynamic change of serum HBV DNA level. There is little known about the impact of long-term sequential changes in HBV viral load and ALT on subsequent liver cirrhosis risk.
Methods: We measured serum levels of HBV DNA and ALT at enrollment and during follow-up analysis of 3,106 participants in the REVEAL-HBV study. Development of liver cirrhosis was determined by ultrasounds. To confirm the complete ascertainment of cirrhosis cases, we conducted data linkage to the National Health Insurance profiles in Taiwan. The group-based trajectory model was used to identify distinctive groups of long-term changes in serum HBV DNA levels over 11 years of follow-up. Multivariate-adjusted hazard ratios [HRs] and 95% confidence intervals [CI] were estimated using Cox regression models.
Results: During 36,923 person-years of follow-up, 262 participants developed liver cirrhosis (incidence rate, 709.6/100,000 person-years). The liver cirrhosis risk was only slightly higher for participants whose follow-up levels of HBV DNA spontaneously decreased from 100,000 copies/mL to <10,000 copies/mL, compared to those with baseline levels of HBV DNA <10,000 copies/mL (reference group; HR, 1.38; 95% CI, 0.87–2.18). Compared with the reference group, the HRs (95% CI) for long-term levels of HBV DNA that decreased from >10,000,000 copies/mL to <10,000 copies/mL, persisted at 100,000–1000,000 copies/mL, decreased from >10,000,000 copies/mL to 100,000–1,000,000 copies/mL, or persisted at 1,000,000–10,000,000 copies/mL were 2.46 (1.19–5.13), 2.92 (1.94–4.39), 4.10 (2.51–6.72),and 4.81 (2.94–7.87), respectively. A gradient in ALT level was significantly associated with liver cirrhosis risk: from all low normal, to ever high normal, to transient abnormal, to persistent abnormal (Ptrend<.001).
Conclusions: Long-term changes in serum levels of HBV DNA and ALT are independent predictors of risk for liver cirrhosis. For participants with the same HBV DNA levels at enrollment, greater decreases in serum HBV DNA during the follow-up were associated with lower risk of liver cirrhosis. Participants with spontaneous viral load reduction to <104 copies/mL during follow-up had different risks of liver cirrhosis depending on their HBV DNA levels at enrollment. Regular monitoring of levels of HBV DNA and ALT is important in clinical management of chronic carriers of HBV.

並列關鍵字

chronic hepatitis B ； hepatocellular carcinoma ； liver cirrhosis ； HBV DNA ； ALT ； group-based trajectory model ； long-term follow-up study

參考文獻

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