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1、病毒性肝炎治療之困惑如何評價抗炎保肝病毒性肝炎治療之困惑如何評價抗炎保肝價值價值肝臟炎癥有何意義？肝臟免疫反應(yīng)的獨特性能肝臟免疫反應(yīng)的獨特性能先天性免疫：大量獨特的免疫細胞群：KC、NK、NK-T 腸道PAMPs的暴露 肝臟分泌DAMPs的暴露 HSC和纖維化的活性限制臨床結(jié)局：Inflammation!Inflammation！Inflammation！Inflammation！MetabolicSyndromeIschemia/ReperfusionNecroticlesionInflammationinallorgansNatural History of Chronic Hepatit
2、is BNatural History of Chronic Hepatitis BNormal liverChronichepatitis BESLDNo furtherprogressionHBV-related ESLD or HCC are responsible for 0.5-1 million deaths per yr and currently represent 5%to 10%of cases of liver transplantationNot all patients have progressive diseaseCirrhosisHCCCumulative In
3、cidence of Cirrhosis by Serum HBV DNA Level at Study EntryIloeje UH,et al.Gastroenterology.2006;130:678-686.N=3582 Taiwanese patientsYr of Follow-upCumulative Incidence of Liver Cirrhosis(%)Log-rank P .001403020100130123456789101112Baseline HBV DNA Level,copies/mL 1.0 x 1061.0 x 105-9.9 x 1051.0 x 1
4、04-9.9 x 104300-9.9 x 103 300REVEAL:Relationship Between Baseline HBV DNA and CirrhosisBaseline HBV DNA predicted progression to cirrhosis Relationship independent of HBeAg statusAdjusted RR*02.04.06.08.010.0*With 42,115 patient-yrs of follow-up and adjusted for sex,age,anti-HCV levels,smoking,and a
5、lcohol use.1 IU/mL equals approximately 5.6 genomes/mL.P=NSHBeAg-Negative Patients 104(n=2132)HBeAg-Positive PatientsP .01P .0012.66.28.6 104 to 105(n=631)105(n=451)104(n=22)105(n=520)104 to 105(n=18)BL HBV DNA,c/mL:Adjusted RR*P .001P .0011.01.94.902.04.06.08.010.0Cases of Cirrhosis:10455 9623 135C
6、hen CJ,et al.EASL 2005.Abstract 476.Cumulative Incidence of HCC by Serum HBV DNA Level at Study EntryCumulative Incidence of HCC(%)02468101214012345678910111213Baseline HBV DNA Level,copies/mL 1 million100,000-999,99910,000-99,999300-9999 300N=3653 Taiwanese patientsYr of Follow-upChen CJ,et al.JAMA
7、.2006;295:65-73.Successful Hepatitis B Treatment Reduces Clinical EndpointsHBV suppression with nucleos(t)ide analogue therapy reduces risk of hepatic decompensation and HCC in pts with advanced fibrosis or cirrhosis6 Pts With Disease Progression(%)P=.00125201510503018126036n=198n=173n=417n=385n=43n
8、=12224LamivudinePlaceboKaplan-Meier Estimate of Time to Disease Progression in Asians With CHB(Mos)Liaw YF,et al.N Engl J Med.2004;351:1521-1531.90%Hepatocellular carcinoma(HCC)patients had serious inflammation and fibrosisit is often overlooked that 90%of HCC cases have a natural history of unresol
9、ved inflammation and severe fibrosis(or cirrhosis).1HCV patients with cirrhosis of the liver survival rate is far lower than the patients without liver cirrhosis21Samuele De Minicis.et al.Transl Gastrointest Cancer.2012;1:88-94.2 Vishal Bhagat,et al.The American Journal of Gastroenterology 2009;104:
10、117160.抗病毒治療是否能解決所有問題？HBeAg陽性慢乙肝患者治療一年ALT的復(fù)常率數(shù)據(jù)源于不同的研究(不同的人群,基線值)，非直接對照66%48%68%77%39%20%30%40%50%60%70%80%拉米夫定阿德福韋酯恩替卡韋替比夫定PEG干擾素HEPATOLOGY 2007;45:1056-1075HBsAg/HBeAg血清狀態(tài)和ALT校正HCC的風(fēng)險比HBsAg/HBeAg/ALT校正相關(guān)風(fēng)險陰性/陰性/正常陽性/陰性/正常陽性/陽性/正常陰性/陰性/升高陽性/陰性/升高陽性/陽性/升高1.010.3*61.3*5.4*29.3*109.0*P 0.001 adjusted
11、for age,anti-HCV,cigarette smoking and alcohol consumptionChen,et al.New Engl J Med 2002ALT居高不下是CHB嚴重不良預(yù)后的重要危險因素之一Chen CJ et al.J Gastroenterol Hepatol.2011;10.1111/j.1440-1746 N2780臺灣REVEAL-HBV試驗顯示：入組時及隨訪期間，ALT水平與肝癌和肝硬化發(fā)生率密切相關(guān)CHB病人經(jīng)抗病毒治療后ALT復(fù)常率常不理想-From AASLD CHB guideline 200715病毒耐藥導(dǎo)致ALT顯著增加2009年A
12、ASLDCHB防治指南指出：接受單藥抗病毒序貫治療患者中出現(xiàn)多藥物耐藥變異；病毒耐藥性的出現(xiàn)導(dǎo)致ALT顯著增加（肝炎發(fā)作）病毒學(xué)反彈病毒學(xué)突破基因?qū)W突破肝炎發(fā)作生化學(xué)突破正常上限Lok ASF,McMahon BJ.Hepatology 2009;50:1-36抗病毒治療抗病毒耐藥性的表現(xiàn)15抗病毒治療后病毒耐藥導(dǎo)致肝臟炎癥加重PretreatmentvsMedianFollow-upof3.5YearsDienstag J,et al.Gastroenterology.2003;124:105-117.8070605040302010拉米夫定拉米夫定1,4阿德福韋酯阿德福韋酯2,3恩替卡韋恩
13、替卡韋4替比夫定替比夫定5炎癥壞死改善率纖維化改善率1.NEJM 1998 339:61-68 2.阿德福韋酯阿德福韋酯437,438研究研究 3.Gestroentology 2006:131:1743-1751 4.恩替卡韋恩替卡韋022,027,026研究研究 5.替比夫定替比夫定007GLOBE研究研究49-66%53-64%35-38%34-35%70-72%35-39%65-67%41-48%90炎性壞死炎性壞死改善率改善率纖維化改纖維化改善率善率NUCs治療1年炎癥及纖維化改善現(xiàn)狀組織學(xué)改善率定義：Knodell炎性壞死評分（共18分）下降 2分，且纖維化評分（共4分）無惡化纖維
14、化改善率定義：Ishak評分（共6分）下降1分延長NUCs抗病毒時間，肝纖維化改善率仍不理想706050403020105年年 LdT 基線基線Ishak評分評分3分分7 7年年 ETV ETV 基線基線 Ishak評分評分3分分1010年年 LVD LVD 基線基線Ishak評分評分4分分3232%2929%4444%0肝肝纖纖維維化化未未改改善善率率纖維化程度重的病人，延長抗病毒治療至纖維化程度重的病人，延長抗病毒治療至5-10年，肝纖維化未改善率仍高達年，肝纖維化未改善率仍高達3 35%左右左右1.2011AASLD 壁報 2.EPATOLOGY,Vol.52,No.3,2010 2.3
15、.許蓓，謝青等，中華傳染病雜志 2010.vol.28,No.11,656-6616/197/247/19不規(guī)范停藥導(dǎo)致肝炎復(fù)發(fā)138例慢乙肝患者接受LAM治療至少12個月獲得生化學(xué)應(yīng)答后不同停藥情況下累積肝炎復(fù)發(fā)率Jin et al.Virology Journal 2012,9:23921.4%CHB患者由于費用問題而自行停藥抗病毒治療并不能解決所有問題u 20-50%的患者抗病毒治療應(yīng)答不佳u 肝細胞內(nèi)HBV ccc DNA難以清除u 病毒變異出現(xiàn)耐藥引起病情反復(fù)u 病毒抑制但炎癥仍然會持續(xù)存在,部分患者肝纖維化改善不明顯u 部分患者合并存在其他損肝因素（酒精、脂肪肝）u 并非所有患者均
16、可接受抗病毒治療 No inflammation，no liver disease？病毒性肝病毒性肝炎炎藥物性肝藥物性肝炎炎酒精性肝酒精性肝炎炎自身免疫性肝自身免疫性肝炎炎脂肪性肝脂肪性肝炎炎炎癥炎癥炎癥炎癥遺傳代謝性肝病？肝臟炎癥如何發(fā)生？InflammasomeInflammasome activating activating p pathways athways G Szabo and T Csak.Inflammasomes in liver diseases.J Hepatol,Sep 2012;57(3):642-54.Fig.Inflammasome activating pa
17、thways.Secretion of DAMPS(HMGB1)PyroptosisCell repair via SREBPsRestriction of bacterialreplicase(caspase-7)Fig.Cell-specific inflammasome expression in the liver.Cell-specific inflammasome expression in the liverCell-specific inflammasome expression in the liverG Szabo and T Csak.Inflammasomes in l
18、iver diseases.J Hepatol,Sep 2012;57(3):642-54.Fig.Triggers of inflammasome activation in liver diseases.G Szabo and T.J Hepatol,Sep 2012;57(3):642-54.朱鵬，王宇明.JH 中文版，Triggers of inflammasome activation in liver diseaseTriggers of inflammasome activation in liver disease問題抗炎保肝有何作用和地位？肝臟炎癥是各型慢性肝炎及肝硬化共同病
19、理基礎(chǔ)肝臟炎癥壞死及其所致的肝纖維化是疾病進展的主要病理學(xué)基礎(chǔ)1隨著炎癥加重，肝臟疾病最終可進展為肝硬化和肝癌21.王宇明.中華肝臟病雜志.2011;19(1):76-77.2.Adapted from EASL Consensus Statement.J Hepatol.2003;39(s1):s3-25.5年發(fā)生率12-25%5年發(fā)生率6-15%5年發(fā)生率20-30%肝癌正常肝臟肝衰竭肝硬化肝臟炎癥肝纖維化肝病發(fā)展進程長期抗炎保肝可以降低肝硬化和肝癌的發(fā)生，延緩肝硬化和肝癌發(fā)生研究顯示，采用長期抗炎保肝治療有效降低肝硬化和肝癌進展在長期采用復(fù)方甘草酸苷治療的178名患者中，與100名患者的
20、對照組相比，肝硬化發(fā)生率頻繁減少(28vs40%，在13年的時候 ，P 0.002)。長期使用甘草酸最顯著的優(yōu)點是減少肝癌發(fā)生率Kumada H.Oncology.2002;62 Suppl 1:94-100.肝癌發(fā)生率(%)年SNMC(+)SNMC()-甘草酸抗炎作用強，快速改善肝臟功能天晴甘美治療慢性乙型肝炎患者肝功能指標下降幅度更大中心，隨機、雙盲、多劑量，陽性藥物平行對照的試驗設(shè)計，480例患者隨機進入異甘草酸鎂100mg/d劑量組(A組，180例)、150mg/d劑量組(B組，180例)和陽性藥復(fù)方甘草酸苷對照組(C組，120例)。旨在觀察異甘草酸鎂注射液治療ALT升高的慢性肝病的臨
21、床療效和安全性茅益民,等.中華肝臟病雜志.2009;17(11):847-851.甘草酸治療可協(xié)同增效抗病毒治療效果 共6項隨機對照試驗(RCT)704 例患者入選。異甘草酸鎂聯(lián)合核苷類似物治療慢性乙型肝炎的療效與單用核苷類似物相比，ALT,AST,TBIL的改善以及HBeAg轉(zhuǎn)陰率，聯(lián)用皆優(yōu)于單用，且存在統(tǒng)計學(xué)差異，對HBV DNA 轉(zhuǎn)陰率的比較無差異。晏澤輝 王宇明，等.,中華肝臟病雜志，2014，1(22):110-114.AccumulationofETVinHepG2cells(ng/mgprotein)AccumulationofETVinLO2cells(ng/mgprotein
22、)細胞試驗證明：甘草酸二銨在HepG2和LO2肝細胞中，均能不同程度的增加恩替卡韋在細胞內(nèi)的攝取量，統(tǒng)計學(xué)分析具有顯著性差異，存在一定的藥物相互作用。抗炎保肝藥物治療增加CHB患者抗病毒治療的療效及依從性抗炎保肝藥物治療可以改善CHB患者的肝臟炎癥和纖維化抗病毒治療聯(lián)合抗炎保肝藥物治療能更好改善肝臟組織學(xué)總 結(jié)問題肝臟炎癥及其防治專家共識有無必要？背 景肝臟肝臟炎癥見于炎癥見于幾乎所有原因所致的幾乎所有原因所致的肝病肝病肝臟肝臟炎癥常常貫穿肝病始終（肝炎炎癥常常貫穿肝病始終（肝炎-肝硬化肝硬化-肝癌）肝癌）有關(guān)防治研究特別是抗炎保肝方面進展不夠理想有關(guān)防治研究特別是抗炎保肝方面進展不夠理想臨床
23、應(yīng)用手段與方法臨床應(yīng)用手段與方法有限有限存在諸多不同存在諸多不同意見意見亟需規(guī)范亟需規(guī)范臨床醫(yī)療思維和防治方法臨床醫(yī)療思維和防治方法肝臟炎癥及其防治專家共識肝臟炎癥及其防治專家共識推動推動2012.11.23意向討論會2013.3共識(草案)2013.3-9意見征詢2013.9.14共識討論會2013.12.21共識發(fā)布會2014.2共識發(fā)表2014共識巡講Prevention and Management of Liver Inflammation:an Expert Consensus in ChinaExpert committee for prevention and manageme
24、nt of liver inflammation20131.A variety of evidences suggest that liver inflammation can be found in the liver diseases induced by almost all causes()2.In China，the number of patients with viral hepatitis are currently staying high,and the incidences of drug-induced hepatitis,alcoholic,nonalcoholic
25、steatohepatitis and autoimmune liver diseases are increasing obviously.()3.The main pathology and pathogenesis in liver disease progression includes liver inflammation,fibrosis,cirrhosis and liver failure,etc.()4.All-round accessorial tests can be used to evaluate liver damage degree of inflammatory
26、,with the elevated serum ALT as the most commonly used indicator.However,it is so far controversial on the ULN of the serum ALT,among which ages might have biggest influence on its level.()5.Although anti-inflammatory therapy is a part of comprehensive treatments for liver inflammation,it cannot rep
27、lace of antiviral therapy on the etiologies,etc.Conversely,etiological treatment such as antiviral therapy cannot completely replace the anti-inflammatory therapy.()Recommendations6.Regardless of whether there is an effective etiological treatment,it is necessary to implement the anti-inflammatory t
28、herapy in inflammation-induced liver disease,()particularly in the liver disease that lacks effective etiological therapy.()7.As anti-HBV or HCV therapy cannot control liver inflammation rapidly and directly,including elevated serum ALT,anti-inflammatory therapy should be given simultaneously.()8.As
29、 the pharmacological effects of anti-inflammatory drugs or protectants have different features,the clinicians are suggested to choose proper drugs according to the characteristics of various liver inflammations and the drugs pharmacological effects.()9.As various anti-inflammatory drugs have differe
30、nt functional features,and their combinations may obtain better efficacy,including the drugs of anti-inflammation and liver protectant,including glycyrrhizic acid)and liver protectants.()10.When patients with CHB and CHC are using anti-viral therapy,treatments using anti-inflammation or liver protec
31、tants should be considered,particularly in elevated serum ALT or obvious inflammatory necrosis,eg.if serum ALT2ULN or pathological examination presents obvious inflammation in a patient with CHB or CHC.()Recommendations11.To determine whether a HBV infected patient with elevated ALT at the first tim
32、e in an immune clearance stage and whether antiviral therapy is indicated,the treatment of anti-inflammation and liver protectant is not recommended.()12.CHC patients elevated serum ALT or obvious inflammation should be considered anti-inflammation and liver protectants treatments.()13.Anti-inflamma
33、tion and liver protectants treatments are recommended to be used preventatively used in DILI,including anti-tubercular drugs and chemotherapy of tumor.()14.Duration of anti-inflammation and liver protectants treatments is depend on various etiologies and conditions,among which attention should be pa
34、id on the gradual reduction of drugs,maintenance treatment,and slow drug withdrawal to avoid relapse.()15.Patients with liver inflammation are suggested to have proper rest,rational diet and well living habits,to avoid precipitation factors of liver damages,and to have appropriate physical excises.(
35、)16.To avoid increasing burden of the liver,the combination therapy should be limited to two or three drugs,and usually the combination same category of drugs is not recommended,and meanwhile regular following-up and regulation is recommended.()Recommendations十余年來肝病學(xué)界的幾個重要爭議性的問題一生一世（試）還是一世（試）一生一生一世（試）還是一世（試）一生？To stop or not to stop?To treat or not to treat?Treat or wait?How to treat?Grip it and rip itGrip it and rip it！
病毒性肝炎治療之困惑如何評價抗炎保肝價值
