肝纖維化與慢性C型肝炎之臨床表徵之關聯性

Association of liver fibrosis with the clinical features in chronic hepatitis C

Batbold Batsaikhan(Batbold Batsaikhan)

指導教授 ： 戴嘉言

高雄醫學大學/醫學院/醫學研究所博士班/博士(2018年)

摘要

全球有超過1.7億人感染Ｃ型肝炎病毒（HCV），佔世界人口的2.8-3％，是全球健康的嚴重負擔。台灣和蒙古是HCV感染的流行地區。因此，HCV感染是重度纖維化，肝硬化和肝細胞癌的主要原因之一。近幾十年來，HCV感染及其併發症仍然是大眾面臨的主要威脅。然而，藉由強效直接作用抗病毒藥物（direct acting antiviral）治癒HCV患者是可能的，以干擾素為基底的治療仍將維持為標準治療，特別是在經濟上低開發國家。對於預防臨床醫學的併發症，HCV相關的肝病進展和晚期肝纖維化的相關因素的研究是迫切需要的。我們開發了新的非侵入性，簡單的生物標誌物來預測慢性Ｃ型肝炎（CHC）患者的纖維化嚴重度：這一新的評分方法含有血清介白素-4（interleukin-4; IL-4）細胞激素濃度。我們發現高血清IL4濃度與重度肝纖維化密切相關，並且血清IL4，鐵蛋白（ferritin）,谷氨酰草酰乙酸轉氨酶（glutamyl oxaloacetic transaminase）值和患者年齡的組合對於預測CHC中的重度纖維化具有高度價值。我們的研究開發了新的評分方法以預測重度肝纖維化，此方法可能取代對個體有併發症的肝臟活檢。我們還發現血清鐵蛋白值升高與肝臟脂肪變性以及重度纖維化有關。性別特異性血清鐵蛋白值增加1.5倍可能有助於預測肝臟脂肪變性和纖維化。因此，我們研究了進行肝臟活檢的CHC患者中重度肝纖維化和冷凝球蛋白血症（cryoglobulinemia）之間的顯著相關性。有趣的是，這個結果在沒有肝臟活檢的CHC患者中是相同的（藉由FIB4（> 3.25）指數評估）。這是第一項使用FIB4評分來預測患有冷凝球蛋白血症的CHC患者纖維化的研究。我們還研究了以干擾素為基底標準抗病毒治療後的持續性冷凝球蛋白血症與重度纖維化有關。持續病毒學反應（sustained virologic response ；SVR）者且有持續性冷凝球蛋白血症的患者更可能患有重度纖維化。另外我們證實了干擾素抗病毒治療後血清脂質顯著增加。 HCV感染與低脂質相關，並且在治療後SVR患者中顯著增加，然而重度纖維化患者則無增加。我們所有的研究結果都提供了對重度纖維化的追蹤策略、監測和治療方案的見解。

關鍵字

慢性丙型肝炎

並列摘要

Globally over 170 millions of people infected with Hepatitis C virus (HCV) as a prevalence of 2.8-3% of World population and it is serious burden of global health, Taiwan and Mongolia is an endemic areas for HCV infection. Therefore HCV infection is one of the major cause of advanced fibrosis, cirrhosis and hepatocellular carcinoma. Thus, HCV infection and its complications remain the leading threat for public in recent decades. However it is possible to treat HCV patients by powerful direct acting antivirals, interferon based treatment will still remain in standard care especially in economically non developed countries. There is an urgent need to investigate that HCV related liver disease progression and related factors for advanced liver fibrosis is necessary to prevent the complications for clinicians. My colleagues and I have developed new non-invasive, simple biomarker to predict advanced fibrosis in chronic hepatitis C (CHC) patients and this new score contains serum Interleukin-4 (IL4) cytokine level. We studied that high serum IL4 level is strongly associated with advanced liver fibrosis and the combination of serum IL4, ferritin, glutamyl oxaloacetic transaminase levels and patient’s age had strong value to predict advanced fibrosis in CHC. Our study developed new score to predict advanced liver fibrosis for possibility to replace liver biopsy which this procedure have several complications to individuals. We also identified that an elevated serum ferritin level was associated with liver steatosis as well as advanced fibrosis. Sex specific 1.5 fold increase of serum ferritin level may be useful for predicting liver steatosis also fibrosis. Therefore we investigated the significant association between advanced liver fibrosis and cryoglobulinemia in CHC patients who undergo liver biopsy. Interestingly this result was the same in CHC patient without liver biopsy (assessed by FIB4 (>3.25) index). It is the first study used FIB4 score to predict fibrosis in CHC patients with cryoglobulinemia. We also investigated the persistent cryoglobulinemia after interferon based, standard antiviral treatment is associated with advanced fibrosis. Patients with sustained virologic response (SVR) and persistent cryoglobulinemia are more likely to have advanced fibrosis. We confirmed that significant increase of serum lipid profiles after interferon based antiviral treatment. HCV infection is associated with low lipids and it is significantly increased in SVR patients after the treatment. However patients with advanced fibrosis did not increased. All our study results provides the insight of carefully follow up strategy, monitoring and treatment options in advanced fibrosis.

並列關鍵字

Chronic hepatitis C ； fibrosis ； cryoglobulinemia ； serum ferritn ； , HCV treatment ； lipid metabolism

參考文獻

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