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1、Hepatic Steatosis and Viral Hepatitis co-factor or bystander?宓余强宓余强 天津市传染病医院天津市传染病医院 天津市肝病医学研究所天津市肝病医学研究所NAFLD流行情况Aliment Pharmacol Ther 2011; 34: 274285101020202020333310102929（10 years10 years）Science. 2011 June 24; 332(6037): 15191523.4 42727HBV流行情况2009年天津市肝病年会HCV流行情况2009年天津市肝病年会Liver Internation
2、al (2011)：61-80HCVHCV与NAFLDNAFLDHCV感染者感染者HS患病率及临床特点患病率及临床特点Angulo P. Archives of Medical Research 2007;38:621-7.HCVHCV基因分型与肝脂肪基因分型与肝脂肪变3型1型/4型检出率70%30%危险因素HCV-RNA肥胖和IR加剧肝损伤是是降低SVR否是SVR后脂肪变消退有所减轻?减肥后脂肪变有所减轻？消退HCVHCV与与NAFLDNAFLDHCV病毒蛋白诱导的脂代谢紊乱的机制病毒蛋白诱导的脂代谢紊乱的机制固醇调节元件结合蛋白 微粒体三酰甘油转移蛋白 过氧化体增殖剂激活的受体 蛋白酶体激
3、活剂PA28亚单位 HCV与IR Cancer 2009;115:565161. IRS-1 2、 TNF-a、 PI3-K、 Akt、 SREBPPI3K-AktPI3K-Akt信号通路信号通路HCV病毒蛋白诱导的病毒蛋白诱导的HE,IR,HCC的机制的机制 NAFLDNAFLD与与CHCCHC肝纤维化肝纤维化Author, yearAuthor, yearPatientPatients (n)s (n)Characteristics associated with fibrosis (Characteristics associated with fibrosis (P P) )Cross
4、 2009Cross 2009122122Hepatic steatosis (0.006)Hepatic steatosis (0.006)Hourigan 2004Hourigan 2004148148Hepatic steatosis (0.03)Hepatic steatosis (0.03)Adinolfi 2001Adinolfi 2001180180Hepatic steatosis (0.001), age (0.001)Hepatic steatosis (0.001), age (0.001)Hui 2003Hui 2003260260HOMA-IR (0.001)HOMA
5、-IR (0.001)Poynard 2003Poynard 200314281428Hepatic steatosis (0.007)Hepatic steatosis (0.007)Ratziu 2003Ratziu 2003710710Hyperglycemia (0.01), BMI (0.01),Hyperglycemia (0.01), BMI (0.01),steatosis (0.01)steatosis (0.01)Sanyal 2003Sanyal 2003144144BMI (0.003), cytologic ballooning (0.003),BMI (0.003)
6、, cytologic ballooning (0.003),diabetes (0.03)diabetes (0.03)Younossi 2004Younossi 2004120120Superimposed NASH (0.001)Superimposed NASH (0.001)Rubbia-Brandt Rubbia-Brandt 20042004755755Hepatic steatosis (0.001 in genotype 3)Hepatic steatosis (30 kg/mBMI30 kg/m2 2 ( ( 0.01), cirrhosis (0.01),0.01), c
7、irrhosis (0.01),genotype 1 (0.01)genotype 1 (0.01)Poynard 2003Poynard 200314281428BMI, hepatic steatosis (0.001)BMI, hepatic steatosis (0.001)Sanyal 2003Sanyal 2003144144Presence of NAFLD (0.01)Presence of NAFLD (33% (0.001)Steatosis33% (0.001)Factors associated with poor response to antiviral thera
8、py in Factors associated with poor response to antiviral therapy in hepatitis C virushepatitis C virusNAFLDNAFLD与与SVRSVRLiver International 2009; 29 (s2): 312Romero-Gomez.Gastroenterology 2005; 128: 63641.Aliment Pharmacol Ther 27, 855865Degree of insulin resistance and effect on EVR and SVRHCVHCV与与
9、AFLDAFLDHost factors influencing HCV SVRHost factors influencing HCV SVR细胞激酶信号-3抑制剂 胰岛素受体底物-1 信号转导及转录活化因子 Virus-related mechanisms for decreased SVRVirus-related mechanisms for decreased SVRHCVHCV与与AFLDAFLDPioglitazone with Peg-IFN -2a and RBV in HCV Genotype 1 Patients (Placebo-controlled RCT)Virol
10、ogic Response (%)Placebo-controlled, double-blind, randomized trial: CHC genotype 1 with HOMA 2 (n = 20 in each group)Pioglitazone 30 mg/day for 48 weeksConjeevaram H, et al. AASLD 59th Annual Meeting, San Francisco, CA, 2008 Metformin with Peg-IFN -2a and RBV in Treatment-nave HCV Genotype 1 Patien
11、ts with IR (TRIC-1)Virologic Response (%)Multicenter, randomized trial: CHC genotype 1 with HOMA 2 (n = 125)Metformin 425 mg tid x 4 wks then 850 mg tid x 44 wksRomero-Gomez M, et al. AASLD 59th Annual Meeting, San Francisco, CA, 2008 Rosuvastatin reduces nonalcoholic fatty liver disease in patients
12、 with CHC treated with -interferon and ribavirinHepat Mon. 2011;1111(2):92-98Conclusions: In HCV patients with NAFLD, the addition of rosuvastatin to interferon and ribavirin significantly reduces viremia, steatosis, and fibrosis without causing side effectsHepatic Steatosis and Hepatitis C co-facto
13、rHBVHBV与NAFLDNAFLD葡萄牙学者4100例例HBV感染者感染者荟萃分析：（1）HS患病率：29.6%（普通人群类似，低于HCV感染者）（2）高危因素：男性，BMI, 肥胖，糖尿病等（3）无关因素：转氨酶，HBeAg,基因型，肝组织学等HBVHBV与与NAFLDNAFLDJournal of Gastroenterology and Hepatology 26 (2011) 13611367Journal of Gastroenterology and Hepatology 26 (2011) 13611367HBVHBV与与NAFLDNAFLDJournal of Gastroe
14、nterology and Hepatology 26 (2011) 13611367HBVHBV与与NAFLDNAFLDSteatosis in CHB: lack of associations with HBV replication and disease severityAuthorsAssociation with HBeAg or HBV DNA?Worsens fibrosis severity?Elloumi et al. 2008Shi et al. 2008Peng et al. 2008Yun et al. 2009Kumar et al. 2009Minakari e
15、t al. 2009Persico et al. 2009Wong GL et al. 2009NoNoNoNoNoNoNot mentionedNot mentionedNo NoNoNoNoNoNoYesHBVHBV与与NAFLDNAFLDo of fl li iv ve er rc ci ir rr rh ho os si is si in nC CH HB B. .Metabolic syndrome is an independent risk factor Metabolic syndrome is an independent risk factor of liver cirrh
16、osis in CHBof liver cirrhosis in CHB HBVHBV与与NAFLDNAFLDBiochem. J. (2008) 416, e15e17肝脂肪变对CHB抗病毒治疗SVR的影响 无肝细胞脂肪变性或仅发生局限性脂肪变性的无肝细胞脂肪变性或仅发生局限性脂肪变性的CHBCHB患者对聚乙二醇患者对聚乙二醇干扰素治疗的反应较佳，能够长时间保持干扰素治疗的反应较佳，能够长时间保持HBVHBV的低复制状态。的低复制状态。Kau A,et al. J Hepatol. 2008 Oct;49(4):634-51Mehmet Cindoruk,J Clin Gastroenter
17、ol,2007,513-5170%10%20%30%HBeAg+HBeAg+40%肝脂肪变肝脂肪变无肝脂肪变无肝脂肪变HBeAg -HBeAg - HBVHBV与与NAFLDNAFLD影响影响Peg-IFN抗抗HBV治疗治疗SVR的因素的因素Mehmet Cindoruk,MD,et al.J Clin Gastroenterol. 2007,41（ 5）:513-517影响影响Peg-IFN抗抗HBV治疗治疗SVR的因素的因素-98wksSHI JP, EASL/NASH,2009我们的工作CHB患者合并脂肪变性发生率情况33.4%33.4%（422/1263422/1263）HBVHBV与
18、与NAFLDNAFLD宓余强，刘勇钢，徐亮等. 中华肝脏病杂志 2009;第11期HBVHBV与与NAFLDNAFLD组 别例数BMI (kg/m2)FPG (mmol/L)TG (mmol/L)TC (mmol/L)肝脂肪变组11425.133.355.391.241.581.044.591.26无肝脂肪变组11321.993.144.910.881.200.474.161.04t值6.8112.7333.0632.340P值 0.01 0.01 0.01 0.05 0.05 0.05 0.05 0.05HBVHBV与与NAFLDNAFLD 肝脂肪变组与无脂肪变组肝脂肪变组与无脂肪变组CHB
19、CHB患者血清患者血清HBV DNAHBV DNA滴度的比较（例，滴度的比较（例，% %）宓余强，刘勇钢，徐亮等. 中华肝脏病杂志 2009;第11期组 别例数 105 拷贝/ml肝脂肪变组10127（26.7%）15（14.9%）59（58.4%）无肝脂肪变组9512（12.6%）18（18.9%）65（68.4%）2值6.154P值 0.05HBV-DNA肝脂肪变组与无脂肪变组肝脂肪变组与无脂肪变组CHBCHB患者血清患者血清HBV DNAHBV DNA滴度的比较滴度的比较HBVHBV与与NAFLDNAFLD宓余强，刘勇钢，徐亮等. 中华肝脏病杂志 2009;第11期2=， PHBVHBV
20、与与NAFLDNAFLD 宓余强，刘勇钢，徐亮等. 中华肝脏病杂志 2009;第11期不同程度肝脂肪变组不同程度肝脂肪变组CHBCHB患者患者HBV DNAHBV DNA滴度比较（例，滴度比较（例，% %）组 别 105 拷贝/ml 105 拷贝/ml轻度肝脂肪变组29（35.4%）53（64.6%）中重度脂肪变组12（63.2%）7（36.8%）2值4.941P值0.05HBV-DNA不同程度肝脂肪变组不同程度肝脂肪变组CHBCHB患者患者HBV DNAHBV DNA滴度分层比较（滴度分层比较（% %）宓余强，刘勇钢，徐亮等. 中华肝脏病杂志 2009;第11期2=，PHBVHBV与与NAF
21、LDNAFLD结论慢性乙型肝炎合并肝脂肪变常见且不断增多，主要与代谢紊乱有关；并存的肝脂肪变对乙型肝炎患者肝损伤可能无不良影响；HBV DNA滴度是否与肝脂肪变呈负相关有待进一步验证。 肝脂肪变组与无脂肪变组患者部分肝脏病理指标的比较（肝脂肪变组与无脂肪变组患者部分肝脏病理指标的比较（% %）组 别例数中重度炎症明显肝纤维化 HBsAg染色强阳性 HBcAg染色强阳性无脂肪变组14745（30.6%）39（26.5%）34（23.1%）21（14.3%）肝脂肪变组14923（15.4%）19（12.8%）10（6.7%）16（10.7%）2值9.6318.91715.7610.851P值 0.
22、01 0.01 0.05HBVHBV与与NAFLDNAFLD宓余强，刘勇钢，徐亮等. 中华消化病杂志，2012年 CHB不伴有肝脂肪变（上）及CHB合并肝脂肪变（下）典型病例病理形态特征 G 3（HE染色）S 2-3S 2-3（网状纤维染色）（网状纤维染色） HBsAg HBsAg阳性表达阳性表达 HBcAgHBcAg阳性表达阳性表达 HBsAgHBsAg阳性表达阳性表达 HBcAgHBcAg阳性表达阳性表达G 1G 1（HEHE染色）染色） S 1S 1（网状纤维染色）（网状纤维染色） 肝脂肪变影响了CHB患者肝组织内HBsAg、HBcAg的表达，随肝脂肪变的出现及加重，其表达呈下降趋势；肝
23、脂肪变与其肝组织学损伤程度较轻相一致。 结论研究对象：天津市传染病医院经肝组织病理检查确诊为慢性乙型肝炎、且进行PEG-INF -2a抗病毒治疗的患者50例，其中男性40例，女性10例；无脂变组：28例；脂变组：22例，其中轻度脂肪变21例，中度脂肪变1例。CHBCHB合并肝脂肪变抗病毒治疗合并肝脂肪变抗病毒治疗两组应用PEG-INF -2a抗乙肝病毒疗效比较n（%）组别组别无应答无应答不全应答不全应答完全应答完全应答无脂变组（无脂变组（2828例）例）1212（42.942.9）5 5（17.917.9）1111（39.339.3）有脂变组（有脂变组（2222例）例）9 9（40.940.9
24、）4 4（18.218.2）9 9（40.940.9）两组应用PEG-INF-2a抗乙肝病毒疗效应答率比较（%）PEG-INF -2a抗乙肝病毒治疗48周与治疗前血脂变化比较CHOCHO（mmol/Lmmol/L）TGTG（mmol/Lmmol/L）治疗前治疗前治疗后治疗后治疗前治疗前治疗后治疗后无脂变组（无脂变组（2828例）例）4.220.634.220.634.661.764.661.761.110.501.110.501.330.571.330.57有脂变组（有脂变组（2222例）例）4.291.114.291.113.990.513.990.511.250.521.250.522.301.922.301.92较治疗前比较，较治疗前比较，；两组治疗前后的变化比较无显著统计学差异，；两组治疗前后的变化比较无显著统计学差异，。结论此次研究未发现轻度肝脂肪变对PEG-INF -2a抗HBV治疗的疗效有明显影响。 肝脂肪变组PEG-INF -2a抗HBV治疗中总胆固醇下降。Hepatic Steatosis and Hepatitis Bco-factor or bystander?
