1、病毒性肝炎合并脂肪肝的治疗策略,病毒性肝炎合并脂肪肝的流行病学 慢性乙型肝炎合并脂肪肝的危害和治疗策略 慢性丙型肝炎合并脂肪肝的危害和治疗策略,目 录,全球和中国肝病的病因分布,Wang FS, et al. Hepatology. 2014 ;60(6):2099-108,HBV感染和脂肪肝是我国最主要的肝病病因。,14%-71%的慢乙肝患者合并脂肪肝,Raluca Pais, et al. Clin Liver Dis 18 (2014) 165178,欧洲和中东地区,亚太地区,40-86%的慢性丙型肝炎患者合并脂肪肝,T Asselah, et al. Gut 2006;55:12313
2、0,中国慢性乙型肝炎和慢性丙型肝炎患者 脂肪肝的流行情况,Raluca Pais, et al. Clin Liver Dis 18 (2014) 165178,合并脂肪肝 对慢性病毒性肝炎患者临床预后的影响,肝硬化 风险,肝细胞癌 风险,范建高. 中华肝脏病杂志; 2009;17(11):801-805,问 题,如何正确理解病毒肝与脂肪肝之间的关系？如何治疗病毒肝合并脂肪肝的患者？,病毒性肝炎（乙型、丙型） 脂肪肝 ？,病毒性肝炎（乙型、丙型） + 脂肪肝 ？,以治疗脂肪肝为主？,以治疗病毒肝为主？,双管齐下？,病毒性肝炎合并脂肪肝的流行病学 慢性乙型肝炎合并脂肪肝的危害和治疗策略 慢性丙型
3、肝炎合并脂肪肝的危害和治疗策略,目 录,肝脏在肥胖相关并发症发病机制中的 关键角色,Thomas Karlas, et al. Best Practice 27:195208,HBV 感染与代谢综合征：事实还是虚构？,Chia-Chi Wang, et al. J Gastroenterol Hepatol. 2014 Aug 5. doi: 10.1111/jgh.12700. Epub ahead of print,HBV感染与代谢综合征的相互关系： 临床研究汇总,Chia-Chi Wang, et al. J Gastroenterol Hepatol. 2014 Aug 5. doi:
4、 10.1111/jgh.12700. Epub ahead of print,慢性HBV感染与代谢综合征相关性的荟萃分析,Chia-Chi Wang, et al. J Gastroenterol Hepatol. 2014 Aug 5. doi: 10.1111/jgh.12700. Epub ahead of print,OR= 0.82,合并代谢综合征(包括脂肪肝) 对HBV肝病进展的影响,肝纤维化 肝硬化,风险,HBV携带者合并超声下脂肪肝 对肝脏损伤具有协同作用,Yu-Cheng Lin, et al. World J Gastroenterol 2007 ; 13(12): 18
5、05-1810,A cross-sectional retrospective analysis of health records including medical history, physical examination, abdominal sonogram, blood biochemistry and hepatic virological tests. We utilized the Students t-test, chi-square, multivariate logistic regression and synergy index to assess risks fo
6、r LD.,合并NAFLD的CHB患者肝酶和肝组织学分期比不合并NAFLD的CHB升高,Arezoo Estakhri, et al. Open Journal of Gastroenterology, 2012, 2:18-21,retrospectively evaluated 94 “eAg” negative CHB patients (with NAFLD: 44, without NAFLD: 50). In the NAFLD group, increase in AST, ALT, stage (P = 0.002), grade, and total score of liv
7、er biopsy were independently related to non-alcoholic fatty liver disease, while HBV-DNA viral load did not correlate with the presence of a fatty liver.,慢性病毒性肝炎合并脂肪肝的治疗策略,整体治疗的前提： 脂肪肝的基础治疗,最根本的治疗： 抗病毒治疗,重要组成部分： 保肝药物,改变生活方式 治疗原发病和去除相关危险因素：肥胖、2型糖尿病,抗病毒药物,保肝药物一般可选用多烯磷酯酰胆碱、水飞蓟素等1-2种，治疗半年至1年以上。,施军平, 等.
8、实用肝脏病杂志, 2008; 11(4):278-280,通过健康宣教以及心理和行为修正治疗， 做到“合理膳食、增加运动、节制饮酒、慎用肝毒药物以及避免接触肝毒物质”。,改变生活方式,施军平, 等. 实用肝脏病杂志, 2008; 11(4):278-280,应用IFN-类抗病毒治疗时，ALT10ULN，TBIL50mol/L的患者；或使用过程中ALT或AST继续上升10ULN 应用NUCs过程中少数ALT持久波动或ALT复升（除外耐药因素）者（必要时寻找其他病因，相应处置） 使用抗病毒药物正规治疗中，ALT、AST仍异常者（必要时寻找其他病因，相应处置） ALT、AST异常，但暂不宜应用IFN
9、-及NUCs治疗的CHB、CHC、肝硬化代偿或失代偿患者。,抗炎保肝类药物治疗病毒性肝炎合并脂肪肝,中华医学会感染病学分会，肝脏炎症及其防治专家共识专家委员会. 中国实用内科杂志, 2014;34(2): 152-162,针对病毒感染合并脂肪肝的患者，是否适用？,抗炎保肝药物显著改善 乙肝合并脂肪肝患者的肝生化指标,选择病毒性肝炎合并脂肪肝136例，慢性乙肝112例，慢性丙肝22例，急性乙肝2例 对照组:一般治疗+肝炎治疗；治疗组:一般治疗+肝炎治疗+多烯磷脂酰胆碱胶囊 2片/次 3次/日；疗 程:3个月,姜宁华.易善复治疗病毒性肝炎合并脂肪肝临床疗效评估. 中国现代应用药学.2004;21(
10、3):235-7,抗炎保肝药物治疗 显著改善乙肝合并脂肪肝患者的影像学,选择病毒性肝炎合并脂肪肝136例，慢性乙肝112例，慢性丙肝22例，急性乙肝2例 对照组:一般治疗+肝炎治疗；治疗组:一般治疗+肝炎治疗+多烯磷脂酰胆碱胶囊 2片/次 3次/日；疗 程:3个月,组间比较，p0.05,姜宁华.易善复治疗病毒性肝炎合并脂肪肝临床疗效评估. 中国现代应用药学.2004;21(3):235-7,合并代谢综合征对HBV肝病进展有影响(如可能增加肝纤维化、肝硬化风险)； HBV感染合并NAFLD对肝细胞损伤有协同作用，患者肝酶和肝组织学分期比不合并NAFLD的CHB高； 对于慢乙肝合并脂肪肝的患者，脂
11、肪肝的基础治疗是前提，抗病毒治疗是根本、保肝药物治疗是重要组成部分； 抗炎保肝类药物能有效改善乙肝合并脂肪肝的患者肝功能和影像学。,小结：慢性乙型肝炎合并脂肪肝的 治疗策略,病毒性肝炎合并脂肪肝的流行病学 慢性乙型肝炎合并脂肪肝的危害和治疗策略 慢性丙型肝炎合并脂肪肝的危害和治疗策略,目 录,HCV在脂肪肝发生过程中的作用,Anish Patel, and Stephen A. Harrison. Gastroenterology & Hepatology Volume 8, Issue 5 May 2012: 305-312,HCV感染患者 促炎性细胞因子分泌显著增多,A total of
12、28 consecutive nondiabetic patients with chronic hepatitis C were included in the study (anti-HCV). Fourteen patients with chronic hepatitis other than HCV infection served as the control group (anti-HCV). Both groups were closely matched by the main clinical variables associated with insulin resist
13、ance and the degree of liver fibrosis.,ALBERT LECUBE, et al. Diabetes Care 2006; 29:10961101,促炎因子与胰岛素抵抗发生有关,A total of 28 consecutive nondiabetic patients with chronic hepatitis C were included in the study (anti-HCV). Fourteen patients with chronic hepatitis other than HCV infection served as the c
14、ontrol group (anti-HCV). Both groups were closely matched by the main clinical variables associated with insulin resistance and the degree of liver fibrosis.,ALBERT LECUBE, et al. Diabetes Care 2006; 29:10961101,稳态胰岛素评价指数：HOMA-IR,代谢组学分析： 丙肝患者和对照组存在差别,Classification of urine samples based on P functi
15、on scores obtained through the metabonomics analysis of the 1H NMR spectra model of 66 individuals,M. M. G. Godoy, et al. Journal of Viral Hepatitis, 2010, 17, 854858,丙肝患者的核磁共振代谢组学,FFA促进HCV在肝细胞复制,Immunohistochemical staining for HCV core antigen in the infected Huh 7.5 cells in the presence of diffe
16、rent concentrations of FAA after 15 days,HCV infected Huh-7.5 cells were cultured with a mixture of saturated (palmitate) and unsaturated (oleate) long-chain free fatty acids (FFA). Intracytoplasmic fat accumulation in these cells was visualized by Nile red staining and electron microscopy then quan
17、tified by microfluorometry. The effect of FFA treatment on HCV replication and IFN- antiviral response was measured by flow cytometric analysis, Renilla luciferase activity, and real-time RT-PCR,Feyza Gunduz, et al. Virology Journal 2012, 9:143,游离脂肪酸降低IFN对HCV的治疗作用,HCV infected Huh-7.5 cells were cul
18、tured with a mixture of saturated (palmitate) and unsaturated (oleate) long-chain free fatty acids (FFA). Intracytoplasmic fat accumulation in these cells was visualized by Nile red staining and electron microscopy then quantified by microfluorometry. The effect of FFA treatment on HCV replication a
19、nd IFN- antiviral response was measured by flow cytometric analysis, Renilla luciferase activity, and real-time RT-PCR,Feyza Gunduz, et al. Virology Journal 2012, 9:143,IR降低抗病毒治疗病毒学应答率：EVR,HOMA：稳态模式评估法，Homeostasis Model Assessment，用于评估胰岛素抵抗。,J . J . BLONSKY & S. A. HARRISON. Aliment Pharmacol Ther 2
20、7, 855865,To conduct a systematic, evidence-based review of the epidemiology, pathophysiology and potential treatments of coexistent NAFLD and CHC. The terms such as hepatitis C, fatty liver, NAFLD, nonalcoholic steatohepatitis and steatosis were searched on PubMed up to January 2008. References fro
21、m selected articles and pertinent abstracts were also included.,IR降低抗病毒治疗病毒学应答率：SVR,HOMA：稳态模式评估法，Homeostasis Model Assessment，用于评估胰岛素抵抗。,J . J . BLONSKY & S. A. HARRISON. Aliment Pharmacol Ther 27, 855865,To conduct a systematic, evidence-based review of the epidemiology, pathophysiology and potenti
22、al treatments of coexistent NAFLD and CHC. The terms such as hepatitis C, fatty liver, NAFLD, nonalcoholic steatohepatitis and steatosis were searched on PubMed up to January 2008. References from selected articles and pertinent abstracts were also included.,脂肪肝分级不同， 肝细胞癌累积发生率差异显著,P = 0.0002 between
23、 grade 2 and grade 1 or grade 0).,Atsushi Tanaka, et al. World J Gastroenterol 2007 October 21; 13(39): 5180-5187,获得持久病毒学应答的CHC患者的HCC累积发生率,Grade 2，Grade 1，Grade 0 指肝脂肪变分级,小结：与NAFLD的相互关系,胰岛素抵抗相关 IR影响抗病毒疗效,脂肪肝分级与CHC患者肝细胞癌风险相关,改变生活方式，包括运动和减重：但在HCV合并脂肪肝人群中尚缺乏正规的临床研究数据。1 抗病毒治疗。2 抗炎保肝类药物：保护肝细胞、拮抗氧应激脂质过氧化、
24、抗炎、抗凋亡、抗纤维化，还避免使用减肥和调脂药物诱发的肝胆损伤。2 胰岛素增敏剂：改善胰岛素抵抗；提高持久病毒学应答率？需要进一步临床研究的证明。1 他汀类药物：用于CHC合并脂肪肝的治疗需要更大型、前瞻性、随机研究数据评估。1,慢性病毒性肝炎合并脂肪肝的治疗现状,Anish Patel, and Stephen A. Harrison. Gastroenterology 11(4):278-280,多项研究提示 改变生活方式有效改善脂肪肝,Valerio Nobili, et al. BMC Medicine 2011, 9:70,通过生活方式干预代谢综合征 对抗病毒疗效的影响,Tarant
25、ino G, et al. Gut. 2006;55:585,病毒学应答率，HCV-RNA 2 log 10,n=17,n=15,All patients were offered standard combined antiviral therapy Peg-interferon alpha 2b 1.5 mg/kg body weight/weekly and ribavirin 10001200 mg/daily) for at least three months for non-responders (same virological load before and after) a
26、nd for 12 months if responders or partial responders (decrease in HCV-RNA 2 log 10),P=0.035 X2,有效的抗病毒治疗 显著改善基因3型丙肝患者脂肪肝情况,L Castera, et al. Gut 2004;53:420424,A total of 151 patients (37 with HCV genotype 3; 114 with HCV non-3 genotypes) were selected to study the relationship between steatosis evol
27、ution and HCV clearance after antiviral treatment in patients with chronic hepatitis C and paired liver biopsies,Improvement was defined as a decrease of at least one grade between the two biopsies; stability was defined as identical grades between the two biopsies; worsening of steatosis was define
28、d as an increase of at least one grade between the two biopsies,抗病毒治疗后与脂肪肝改善相关的 独立影响因素,L Castera, et al. Gut 2004;53:420424,A total of 151 patients (37 with HCV genotype 3; 114 with HCV non-3 genotypes) were selected to study the relationship between steatosis evolution and HCV clearance after antiv
29、iral treatment in patients with chronic hepatitis C and paired liver biopsies,服用胰岛素增敏剂二甲双胍 有效改善基因1型丙肝患者胰岛素抵抗,Peg 干扰素-+利巴韦林+二甲双胍 Peg 干扰素-+利巴韦林,Jian-Wu Yu, et al. International Journal of Infectious Diseases 2012;16 :e436e441,P0.01,胰岛素增敏剂 能否提高抗病毒治疗应答率？,Kathrin Overbeck, et al. Journal of Hepatology 20
30、08;49 :295298,胰岛素增敏剂吡格列酮 对抗病毒疗效的影响与丙肝基因型的关系,Mahmoud Khattab, et al. Liver Int. 2010 Mar;30(3):447-54,Ninety-seven previously untreated patients with CHC and IR were randomly assigned into two arms; (arm A; n = 48) were given pioglitazone 30 mg/day combined with peginterferon (Peg-IFN)-a-2b/ ribaviri
31、n (RBV) for 48 weeks, and (arm B; n = 49) were given standard of care (Peg-IFN-a-2b/RBV for 48 weeks); HOMA index and hepatitis C virus RNA (HCV RNA) levels were measured at baseline, during therapy and follow-up,胰岛素增敏剂二甲双胍对基因1型丙肝 患者抗病毒治疗疗效的影响,prospective, multicentered, randomized, double-blinded,
32、placebo-controlled trial in 19 Spanish hospitals, including 123 consecutive patients with genotype 1 chronic hepatitis C and insulin resistance. Patients were randomized to receive either metformin (arm A; n =59) or placebo (arm B; n =64) in addition to peginterferon alfa-2a (180 g/week) and ribavir
33、in (1000-1200 mg/day). The primary end point was SVR,Manuel Romero-G omez, et al. HEPATOLOGY 2009;50:1702-1708,他汀对丙肝抗病毒治疗疗效的影响,Ben Verpaalen, et al. Antiviral Research 2014;105: 9299,保肝药物的治疗作用,保护肝细胞,拮抗氧化应激/脂质过氧化,抗纤维化,抗凋亡,避免使用减肥和调脂药物诱发的肝胆损伤,施军平, 等. 实用肝脏病杂志, 2008; 11(4):278-280,应按照循证医学的原则选用，以提高疗效。 不宜同
34、时应用过多特别是同类抗炎保肝药物，以免加重肝脏负担及药物间相互作用。 大多数药物以口服给入。但肝衰竭时多以静脉给药为主，对肝炎突发患者常见静脉滴注后改用口服的序贯疗法。 用药期间应定期观察患者的症状、体征和肝功能变化，必要时及时调整用药方案。 部分药物有一定不良反应。用于肝衰竭时尤应谨慎并注意鉴别，以免误判误诊。,抗炎保肝药物的用药原则,中华医学会感染病学分会，肝脏炎症及其防治专家共识专家委员会.中国实用内科杂志, 2014; 34(2):152-162,多烯磷脂酰胆碱联合干扰素 有效提高慢性丙肝患者生化应答率(24w),Niederau C et al: Hepato Gastroenter
35、ology 1998;45:797-804,ALT降低50%有效 P=0.016,治疗24周时，慢性丙肝患者的生化（ALT）应答率,ALT降低50%的病人比例,试验发现， IFN+PPC组比 IFN+安慰剂组可实现更好的ALT治疗反应率。在 24周时， ALT降低50%的病人比例IFN+PPC组显著多于IFN+安慰剂组。表明，多烯磷脂酰胆碱胶囊可以改善病毒性肝炎患者的肝功能水平，有效治疗病毒性肝炎。,基础治疗: a-干扰素Hep.B: 5 mio I.U. s.c. 3x 每周，24周，Hep.C: 3 mio I.U. s.c. 3x 每周，24周。试验药物:3 x 2 胶囊， PPC 每日
36、使用 (1.8 g/天)或 3x 2 胶囊，安慰剂每日使用24周，有效者（ALT 下降 50）继续治疗24周，176 病人完成试验: Hep.B. 22/25（47）， Hep.C 70/59（129）,多烯磷脂酰胆碱联合干扰素48周时 慢性丙肝患者ALT复常率,Niederau C et al: Hepato Gastroenterology 1998;45:797-804,P=0.06,治疗24周时ALT降低50的病人，停用IFN，继续使用PPC（每日3次，每次2粒）或安慰剂治疗，第48周时的ALT复常率,ALT正常的病人比例,基础治疗: a-干扰素Hep.B: 5 mio I.U. s.
37、c. 3x 每周，24周，Hep.C: 3 mio I.U. s.c. 3x 每周，24周。试验药物:3 x 2 胶囊， PPC 每日使用 (1.8 g/天)或 3x 2 胶囊，安慰剂每日使用24周，有效者（ALT 下降 50）继续治疗24周，176 病人完成试验: Hep.B. 22/25（47）， Hep.C 70/59（129）,HCV与脂肪肝在发病机理上相互促进； NAFLD合并HCV和IR降低抗病毒治疗的病毒学应答率； 治疗策略包括针对脂肪肝的基础治疗、抗病毒治疗和保肝治疗等； 胰岛素增敏剂和他汀类对抗病毒治疗效果的影响尚需进一步的研究； 抗炎保肝药物如多烯磷脂酰胆碱，联合干扰素能提高干扰素治疗丙肝的疗效。,小结：丙肝合并脂肪肝的危害和 治疗策略,病毒性肝炎合并脂肪肝非常常见。 病毒性肝炎合并脂肪肝增加肝硬化和肝细胞癌风险。 慢性病毒性肝炎合并脂肪肝的治疗策略包括： 针对脂肪肝的基础治疗前提 抗病毒药物治疗根本 保肝药物治疗重要组成部分,总 结,谢 谢 聆 听 ！,
