病毒性肝炎與NAFLD

1、Hepatic Steatosis and Viral Hepatitis co-factor or bystander?宓余強(qiáng)宓余強(qiáng) 天津市傳染病醫(yī)院天津市傳染病醫(yī)院 天津市肝病醫(yī)學(xué)研究所天津市肝病醫(yī)學(xué)研究所NAFLD流行情況Aliment Pharmacol Ther 2011; 34: 274285101020202020333310102929（10 years10 years）Science. 2011 June 24; 332(6037): 15191523.4 42727HBV流行情況2009年天津市肝病年會(huì)HCV流行情況2009年天津市肝病年會(huì)Liver Internation

2、al (2011)：61-80HCVHCV與NAFLDNAFLDHCV感染者感染者HS患病率及臨床特點(diǎn)患病率及臨床特點(diǎn)Angulo P. Archives of Medical Research 2007;38:621-7.HCVHCV基因分型與肝脂肪變基因分型與肝脂肪變3型1型/4型檢出率70%30%危險(xiǎn)因素HCV-RNA肥胖和IR加劇肝損傷是是降低SVR否是SVR后脂肪變消退有所減輕?減肥后脂肪變有所減輕？消退HCVHCV與與NAFLDNAFLDHCV病毒蛋白誘導(dǎo)的脂代謝紊亂的機(jī)制病毒蛋白誘導(dǎo)的脂代謝紊亂的機(jī)制固醇調(diào)節(jié)元件結(jié)合蛋白 微粒體三酰甘油轉(zhuǎn)移蛋白 過氧化體增殖劑激活的受體 蛋白酶體

3、激活劑PA28亞單位 HCV與IR Cancer 2009;115:565161. IRS-1 2、 TNF-a、 PI3-K、 Akt、 SREBPPI3K-AktPI3K-Akt信號(hào)通路信號(hào)通路HCV病毒蛋白誘導(dǎo)的病毒蛋白誘導(dǎo)的HE,IR,HCC的機(jī)制的機(jī)制 NAFLDNAFLD與與CHCCHC肝纖維化肝纖維化Author, yearAuthor, yearPatients Patients (n)(n)Characteristics associated with fibrosis (Characteristics associated with fibrosis (P P) )Cros

4、s 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)HOM

5、A-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),

7、cirrhosis (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 ther

8、apy in hepatitis C virusFactors associated with poor response to antiviral therapy in hepatitis C virusNAFLDNAFLD與與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與

9、與AFLDAFLDHost factors influencing HCV SVRHost factors influencing HCV SVR細(xì)胞激酶信號(hào)-3抑制劑 胰島素受體底物-1 信號(hào)轉(zhuǎn)導(dǎo)及轉(zhuǎn)錄活化因子 Virus-related mechanisms for decreased SVRVirus-related mechanisms for decreased SVRHCVHCV與與AFLDAFLDPioglitazone with Peg-IFN -2a and RBV in HCV Genotype 1 Patients (Placebo-controlled RCT)Viro

10、logic 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 Patie

11、nts with IR (TRIC-1)Virologic Response (%)p = 0.031Multicenter, 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 i

12、n patients 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

13、C co-factorHBVHBV與NAFLDNAFLD葡萄牙學(xué)者4100例例HBV感染者感染者薈萃分析：（1）HS患病率：29.6%（普通人群類似，低于HCV感染者）（2）高危因素：男性，BMI, 肥胖，糖尿病等（3）無關(guān)因素：轉(zhuǎn)氨酶，HBeAg,基因型，肝組織學(xué)等HBVHBV與與NAFLDNAFLDJournal of Gastroenterology and Hepatology 26 (2011) 13611367Journal of Gastroenterology and Hepatology 26 (2011) 13611367HBVHBV與與NAFLDNAFLDJournal

14、of Gastroenterology and Hepatology 26 (2011) 13611367HBVHBV與與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. 2009

15、Minakari et al. 2009Persico et al. 2009Wong GL et al. 2009NoNoNoNoNoNoNot mentionedNot mentionedNo NoNoNoNoNoNoYesHBVHBV與與NAFLDNAFLDo of f l li iv ve er r c ci ir rr rh ho os si is s i in n C CH HB B. .Metabolic syndrome is an independent risk factor Metabolic syndrome is an independent risk factor

16、of liver cirrhosis in CHBof liver cirrhosis in CHB HBVHBV與與NAFLDNAFLDBiochem. J. (2008) 416, e15e17肝脂肪變對(duì)CHB抗病毒治療SVR的影響 無肝細(xì)胞脂肪變性或僅發(fā)生局限性脂肪變性的無肝細(xì)胞脂肪變性或僅發(fā)生局限性脂肪變性的CHBCHB患者對(duì)聚乙二醇干患者對(duì)聚乙二醇干擾素治療的反應(yīng)較佳，能夠長(zhǎng)時(shí)間保持?jǐn)_素治療的反應(yīng)較佳，能夠長(zhǎng)時(shí)間保持HBVHBV的低復(fù)制狀態(tài)。的低復(fù)制狀態(tài)。Kau A,et al. J Hepatol. 2008 Oct;49(4):634-51Mehmet Cindoruk,J Cl

17、in Gastroenterol,2007,513-5170%10%20%30%HBeAg+HBeAg+40%肝脂肪變肝脂肪變無肝脂肪變無肝脂肪變P0.05P0.05P0.05P0.0539.639.633.333.336.236.231.531.5HBeAg -HBeAg - HBVHBV與與NAFLDNAFLD影響影響Peg-IFN抗抗HBV治療治療SVR的因素的因素Mehmet Cindoruk,MD,et al.J Clin Gastroenterol. 2007,41（ 5）:513-517影響影響Peg-IFN抗抗HBV治療治療SVR的因素的因素-98wksSHI JP, EASL

18、/NASH,2009我們的工作CHB患者合并脂肪變性發(fā)生率情況33.4%33.4%（422/1263422/1263）HBVHBV與與NAFLDNAFLD宓余強(qiáng)，劉勇鋼，徐亮等. 中華肝臟病雜志 2009;第11期HBVHBV與與NAFLDNAFLD組 別例數(shù)BMI (kg/m2)FPG (mmol/L)TG (mmol/L)TC (mmol/L)肝脂肪變組11425.133.355.391.241.581.044.591.26無肝脂肪變組11321.993.144.910.881.200.474.161.04t值6.8112.7333.0632.340P值 0.01 0.01 0.01 0.

19、05 0.05 0.05 0.05 0.05HBVHBV與與NAFLDNAFLD 肝脂肪變組與無脂肪變組肝脂肪變組與無脂肪變組CHBCHB患者血清患者血清HBV DNAHBV DNA滴度的比較（例，滴度的比較（例，%）宓余強(qiáng)，劉勇鋼，徐亮等. 中華肝臟病雜志 2009;第11期組 別例數(shù) 105 拷貝/ml肝脂肪變組10127（26.7%）15（14.9%）59（58.4%）無肝脂肪變組9512（12.6%）18（18.9%）65（68.4%）2值6.154P值 0.05HBV-DNA肝脂肪變組與無脂肪變組肝脂肪變組與無脂肪變組CHBCHB患者血清患者血清HBV DNAHBV DNA滴度的比較

20、滴度的比較HBVHBV與與NAFLDNAFLD宓余強(qiáng)，劉勇鋼，徐亮等. 中華肝臟病雜志 2009;第11期2=6.154， P 0.05HBVHBV與與NAFLDNAFLD 宓余強(qiáng)，劉勇鋼，徐亮等. 中華肝臟病雜志 2009;第11期不同程度肝脂肪變組不同程度肝脂肪變組CHBCHB患者患者HBV DNAHBV DNA滴度比較（例，滴度比較（例，%）組 別 105 拷貝/ml 105 拷貝/ml輕度肝脂肪變組29（35.4%）53（64.6%）中重度脂肪變組12（63.2%）7（36.8%）2值4.941P值0.05HBV-DNA不同程度肝脂肪變組不同程度肝脂肪變組CHBCHB患者患者HBV D

21、NAHBV DNA滴度分層比較（滴度分層比較（%）宓余強(qiáng)，劉勇鋼，徐亮等. 中華肝臟病雜志 2009;第11期2=4.941，P0.05HBVHBV與與NAFLDNAFLD結(jié)論慢性乙型肝炎合并肝脂肪變常見且不斷增多，主要與代謝紊亂有關(guān)；并存的肝脂肪變對(duì)乙型肝炎患者肝損傷可能無不良影響；HBV DNA滴度是否與肝脂肪變呈負(fù)相關(guān)有待進(jìn)一步驗(yàn)證。 肝脂肪變組與無脂肪變組患者部分肝臟病理指標(biāo)的比較（肝脂肪變組與無脂肪變組患者部分肝臟病理指標(biāo)的比較（% %）組 別例數(shù)中重度炎癥明顯肝纖維化 HBsAg染色強(qiáng)陽性 HBcAg染色強(qiáng)陽性無脂肪變組14745（30.6%）39（26.5%）34（23.1%）2

22、1（14.3%）肝脂肪變組14923（15.4%）19（12.8%）10（6.7%）16（10.7%）2值9.6318.91715.7610.851P值 0.01 0.01 0.05HBVHBV與與NAFLDNAFLD宓余強(qiáng)，劉勇鋼，徐亮等. 中華消化病雜志，2012年 CHB不伴有肝脂肪變（上）及CHB合并肝脂肪變（下）典型病例病理形態(tài)特征 G 3（HE染色）S 2-3S 2-3（網(wǎng)狀纖維染色）（網(wǎng)狀纖維染色） HBsAg HBsAg陽性表達(dá)陽性表達(dá) HBcAgHBcAg陽性表達(dá)陽性表達(dá) HBsAgHBsAg陽性表達(dá)陽性表達(dá) HBcAgHBcAg陽性表達(dá)陽性表達(dá)G 1G 1（HEHE染色）染色） S 1S 1（網(wǎng)狀纖維染色）（網(wǎng)狀纖維染色） 肝脂肪變影響了CHB患者肝組織內(nèi)HBsAg、HBcAg的表達(dá)，隨肝脂肪變的出現(xiàn)及加重，其表達(dá)呈下降趨勢(shì)；肝脂肪變與其肝組織學(xué)損傷程度較輕相一致。 結(jié)論研究對(duì)象：天津市傳染病醫(yī)院經(jīng)肝組織病理檢查確診