臺灣博碩士論文加值系統

背景:慢性C型肝炎一直以來都是肝病治療上相當棘手的課題。目前慢性C型肝炎的標準治療處方為長效型干擾素(pegylated interferon)併用口服雷巴威林(Ribavirin)。自從此處方治療以來，已發現有諸多因素影響著治療效果。例如：年齡、肝臟纖維化程度、第一基因型之慢性C型肝炎等，依目前所採用的標準治療而言，上列因素均已證實和病毒治療的低反應度有關。在接受抗病毒治療的病人之中，本研究整合分析130位病患的臨床表現與生化資料，期望能在台灣中部的慢性C型肝炎的族群中，尋找出可預測其療效持續有效病毒反應(sustained virological response ，SVR ) 之重要因子。
病人與方法: 共有130位在接受抗病毒治療之慢性C型肝炎病患納入本研究之中。除了傳統生物化學的資料分析之外， 本研究測量了粒線體去氧核醣核酸之複製數目(copy number of mitochondrial DNA)，並以△Ct 來估算它的DNA氧化傷害。
本研究收集彰化基督教醫院於2003年至2004年間所有接受長效型干擾素(pegylated interferon)併用口服雷巴威林(Ribavirin)治療之第一基因型之慢性C型肝炎病人的血液採樣，據以分析粒線體去氧核醣核酸之複製數目(copy number of mitochondrial DNA)與治療效果指標中之持續有效的病毒反應(SVR )的關聯性。
結果: 在所分析的90位達到持續有效的病毒反應 (SVR)與40為病患未達到持續有效的病毒反應 (sustained virological response ，SVR) 的病患當中，我們發現治療前的年齡、性別、高血壓、高血脂與持續有效的病毒反應 (SVR)並無相關性存在。而在持續有效的病毒反應 (SVR)一組中，有較高的血色素(hemoglobin 14.74g/dL vs 13.97g/dL, p <0.05)與血小板(platelet count 180.97 vs 148.58, p <0.05)。而在持續有效的病毒反應 (SVR)一組中，第一基因型比例較低(65.89% vs 76.56%, p = 0.39 )。此外，在持續有效的病毒反應 (SVR)一組中，粒線體去氧核醣核酸之複製數目(copy number of mitochondrial DNA)明顯偏高(190.46 vs 138.83 , p < 0.05 )。至於△Ct則兩組明顯差異。
結論: 在較差的持續有效的病毒反應 (SVR)的預測因子之中，除了傳統已知的因子之外，本研究發現粒線體去氧核醣核酸之複製數目(copy number of mitochondrial DNA)偏低與較差的持續有效的病毒反應 (SVR)有關。

Background: Hepatitis C leads to serious to patients with chronic infection. Interferon based therapy is now the golden standard therapy for this chronic infection. Several factors such as old age, advanced liver fibrosis and genotype 1 hepatitis C infection are reported to be associated with decreased virological response to current standard therapy. We retrospectively analyze the clinical features and biological data of 130 patients received antiviral therapy in our institution and try to find out clinical factors to predict decreased SVR(sustained virological response) in our patient group.
Material and Method: A total of 130 patients with chronic hepatitis C received antiviral therapy in our institution were included in our study. In addition to clinical biochemistry data, we measure the mitochondria DNA copy number and determine its oxidative DNA damage with △Ct in these patients.
Result: 90 patients achieved sustained viral response (SVR) and 40 patients didn’t achieve SVR in this study. Clinical factors, such as age, sex, hypertension, hyperlipidemia are not associated with SVR in this cohort. Both higher hemoglobin level (14.74g/dL vs 13.97g/dL, p &lt;0.05) and platelet count (180.97 vs 148.58, p &lt;0.05) are found among the SVR group patients. The genotype 1 patients have a trend for lower SVR compared with non-genotype 1 patients (65.89% vs 76.56%, p = 0.39 ). A high mtDNA copy number is found in the SVR patient (190.46 vs 138.83 , p &lt; 0.05 ). There is no difference of ?媒t between these two group of patients.
Conclusion: In addition to traditional factors associated with decreased SVR in chronic hepatitis C patients. We found a low mtDNA copy number is also associated with decreased SVR in our patient group.

英文縮寫 IV
中文摘要 V
英文摘要 VII
壹、導論 1
一、慢性C型肝炎的盛行率與預後 1
二、慢性C型肝炎的宿命 1
三、慢性C型肝炎的治療. 2
四、慢性C型肝炎對肝細胞的傷害 2
五、粒線體的角色. 2
六、粒線體功能受損的相關病變. 3
七、氧化壓力(Oxidative stress)與粒線體功能 3
八、C型肝炎的氧化壓力機轉. 4
九、粒線體功能在C型肝炎治療中的角色 5
貳、研究構想 6
參、研究材料與方法 7
甲、病人收集 7
一、收取來源 7
二、收取條件 7
三、排除條件 7
乙、方法 7
一、白血球DNA分離 7
二、測定人類白血球中的mtDNA複製數 8
三、粒線體DNA氧化壓力測定 9
丙、分析統計方法 10
肆、結果 11
一、基本條件 11
二、週邊血球與血清生化 11
三、C型肝炎病毒的基因型 11
四、肝臟的組織病理學 11
五、粒線體功能 12
伍、討論 13
一、基本條件 13
二、血清生化 14
三、週邊血球 14
四、C型肝炎病毒的基因型 15
五、粒線體去氧核醣核酸的功能 15
陸、結論 17
柒、參考文獻 18
捌、表 26
玖、附表 28
拾、圖 33
拾壹、附圖 41

1.Strader DB, Wright T, Th omas DL, Seeff LB (2004) Diagnosis,management, and treatment of hepatitis C. Hepatology 39:1147–71
2.Hnatyszyn HJ. Chronic hepatitis C and genotyping: the clinical significance of determining HCV genotypes. Antivir Ther 2005; 10: 1–11.
3.Poynard T, Yuen MF, Ratziu V, Lai CL. Viral hepatitis C. Lancet 2003; 362: 2095–100.
4.Seeff LB. Natural history of chronic hepatitis C. Hepatology. 2002; 36(suppl 5):35–46.
5.Marcellin P, Boyer N, Gervais A, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med 1997; 127:875–81.
6.Marcellin P, Asselah T, Boyer N. Fibrosis and disease progression in hepatitis C. Hepatology. 2002;36(suppl 5):47–56
7.Einav S, Koziel MJ. Immunopathogenesis of hepatitis C virus in the immunosuppressed host. Transpl Infect Dis. 2002;4:85–92.
8.Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C: the OBSVIRC,METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349:825–832.
9.Roudot-Thoraval F, Bastie A, Pawlotsky JM, et al. Epidemiological factors affecting the severity of hepatitis C virus-related liver disease: a French survey of 6,664 patients. The Study Group for the Prevalence and the Epidemiology of Hepatitis C Virus. Hepatology. 1997;26:485–490.
10.Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med 2007; 147: 677–84.
11.Niederau C, Lange S, Heintges T, et al. Prognosis of chronic hepatitis C: results of a large prospective cohort study. Hepatology 1998; 28: 1687–95.
12.Foster GR, Fried MW, Hadziyannis SJ, et al (2007) Prediction of sustained virological response in chronic hepatitis C patientstreated with peginterferon alfa-2a (40 KD) and ribavirin.Scand J Gastroenterol 42: 247–55
13.Hofer H, Gurguta C, Bergholz U, Steindl-Munda P, Ferenci P(2006) Standard interferon-alpha in combination with ribavirinfor hepatitis C patients with advanced liver disease andthrombocytopenia. Wien Klin Wochenschr 118: 595–600
14.Ferenci P, Laferl H, Scherzer TM, et al (2010) Peginterferonalfa-2a/ribavirin for 48 or 72 weeks in hepatitis C genotypes1 and 4 patients with slow virologic response. Gastroenterology138: 503–12, 512.e1. Epub 2009 Nov 10
15.Okuda M, Li K, Beard M, Showalter L, Scholle F, Lemon S.Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein.Gastroenterology 2002; 122:366–375.
16.De Mendoza C, Sa´nchez-Conde M, Timmermans E, Buitelaar M, de Baar M, Gonzalez-Lahoz J, Soriano V. Mitochondrial DNA depletion in HIV-infected patients is more pronounced with chronic hepatitis C and enhanced following treatment with pegylated nterferon plus ribavirin. Antiviral Ther 2005; 10:557–561
17.Ballesteros A, Miro O, Lopez S, Fuster D, Videla S, Marrinez E, Clotet B, Tutal C. Mitochondrial effects of a 24-week course of pegylated interferon plus ribavirin in asymptomatic HCV/HIV co-infected patients on long-term treatment with didanosine, stavudine or both. Antiviral Ther 2004; 9:969–977
18.Hoek JB, Cahill A, Pastorino JG. Alcohol and mitochondria: a dysfunctional relationship. Gastroenterology. 2002;122:2049–2063.
19.Hoek JB, Pastorino JG. Ethanol, oxidative stress, and cytokine-induced liver cell injury. Alcohol. 2002;27:63–68.
20.Sun AY, Ingelman-Sundberg M, Neve E, et al. Ethanol and oxidative stress. Alcohol Clin Exp Res. 2001;25(suppl):237–243.
21.Barbaro G, Di Lorenzo G, Ribersani M, et al. Serum ferritin and hepatic glutathione concentrations in chronic hepatitis C patients related to the hepatitis C virus genotype. J Hepatol. 1999;30:774–782.
22.Cardin R, Saccoccio G, Masutti F, et al. DNA oxidative damage in leukocytes correlates with the severity of HCV-related liver disease: validation in an open population study. J Hepatol. 2001;34:587– 592.
23.Paradis V, Kollinger M, Fabre M, et al. In situ detection of lipid peroxidation by-products in chronic liver diseases. Hepatology. 1997;26: 135–142.
24.Valgimigli M, Valgimigli L, Trere D, et al. Oxidative stress EPR measurement in human liver by radical-probe technique: correlation with etiology, histology and cell proliferation. Free Radic Res. 2002;36:939–948.
25.Barbaro G, Di Lorenzo G, Asti A, et al. Hepatocellular mitochondrial alterations in patients with chronic hepatitis C: ultrastructural and biochemical findings. Am J Gastroenterol. 1999;94:2198–2205.
26.Rigamonti C, Mottaran E, Reale E, et al. Moderate alcohol consumption increases oxidative stress in patients with chronic hepatitis C. Hepatology. 2003;38:42–49
27.Revuelta MP. Cumulative insults to mitochondrial function may promote the emergence of syndrome X and diabetes mellitus in HIV/HCV co-infected patients. Mitochondrion 2004; 4:175–184.10.
28.Rolo AP, Palmeira CM. Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress. Toxicol Appl Pharmacol. 2006 Apr 15;212(2):167-78. Epub 2006 Feb 20. Review.
29.Rigamonti C, Mottaran E, Reale E, et al. Moderate alcohol consumption increases oxidative stress in patients with chronic hepatitis C. Hepatology. 2003;38:42–49.
30.Masaaki Korenaga, MD, PhD, Michiari Okuda, MD, PhD, Kazuhiro Otani, MD, PhD, Ting Wang, PhD, Yanchun Li, PhD, and Steven A. Weinman, MD, PhD. Mitochondrial Dysfunction in Hepatitis C. J Clin Gastroentero. 2005:S162-S166
31.Moriya K, Nakagawa K, Santa T, et al. Oxidative stress in the absence of inflammation in a mouse model for hepatitis c virus-associated hepatocarcinogenesis. Cancer Res. 2001;61:4365–4370.
32.Okuda M, Showalter LA, Otani K, et al. Alcohol-HCV interactions in transgenic mice expressing viral proteins in the liver. In: Okita K, ed. HCV/Oxidative Stress and Liver Disease. Tokyo: Springer-Verlag, 2003:1–7.
33.Visnegarwala F, Chen L, Raghavan S, Tedaldi E. Prevalence of diabetes mellitus and dyslipidemia among antiretroviral-naïve patients coinfected with HCV and HIV-1 compared to patientswithout coinfection. J Infect 2005; 50:331–337.
34.I.Carmen de Mendozaa, Luz Martin-Carboneroa, Pablo Barreiroa, Michel de Baarb, Natalia Zahoneroa, Sonia Rodriguez-Novoaa, Jose´ Miguel Benitoa, Juan Gonza´lez-Lahoza and Vincent Soriano. Mitochondrial DNA depletion in HIV-infectedpatients with chronic hepatitis C and effect ofpegylated interferon plus ribavirin therapy. AIDS 2007, 21:583–588
35.Bin Gao, Feng Hong, and Svetlana Radaeva. Host Factors and Failure of Interferon-α Treatment in Hepatitis C Virus. HEPATOLOGY 2004, 39:880–890
36.Rosario Gonzalez-Casas, E Anthony Jones, and Ricardo Moreno-Otero. Spectrum of anemia associated with chronic liver disease. World J Gastroenterol. 2009 Oct 7;15(37):4653-8.
37.Caldwell SH, Hoffman M, Lisman T, Macik BG, Northup PG, Reddy KR, Tripodi A, Sanyal AJ. Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management. Hepatology. 2006;44:1039–1046.
38.Gonzalez-Casas R, Garcia-Buey L, Jones EA, Gisbert JP, Moreno-Otero R. Systematic review: hepatitis-associated aplastic anaemia--a syndrome associated with abnormal immunological function. Aliment Pharmacol Ther. 2009;30:436–443
39.Aster RH. Pooling of platelets in the spleen: role in the pathogenesis of ‘‘hypersplenic’’ thrombocytopenia. J Clin Invest. 1966;45:645–57.
40.Peck-Radosavljevic M. Hypersplenism. Eur J Gastroenterol Hepatol. 2001;13:317–23.
41.Bolognesi M, Merkel C, Sacerdoti D, Nava V, Gatta A. Role of spleen enlargement in cirrhosis with portal hypertension. Dig Liver Dis. 2002;34:144–50.
42.Adinolfi LE, Giordano MG, Andreana A, Tripodi MF, Utili R, Cesaro G, et al. Hepatic fibrosis plays a central role in the pathogenesis of thrombocytopenia in patients with chronic viral hepatitis. Br J Haematol. 2001;113:590–5.
43.Karasu Z, Tekin F, Ersoz G, Gunsar F, Batur Y, Ilter T, et al. Liver fibrosis is associated with decreased peripheral platelet count in patients with chronic hepatitis B and C. Dig Dis Sci. 2007;52:1535–9.