病毒性肝炎治疗之困惑如何评价抗炎保肝价值？

1、病毒性肝炎治疗病毒性肝炎治疗之之困惑困惑如何评价抗炎保肝价值如何评价抗炎保肝价值？肝脏肝脏炎症有何意义炎症有何意义？.肝脏免疫反应的独特性能肝脏免疫反应的独特性能 先天性免疫：先天性免疫： 大量独特的免疫细胞群：大量独特的免疫细胞群：KC、NK、NK-T 肠道肠道PAMPs的暴露的暴露 肝脏分泌肝脏分泌DAMPs的暴露的暴露 HSC和纤维化的活性限制和纤维化的活性限制 临床结局临床结局：Inflammation!Inflammation！ Inflammation！Inflammation！MetabolicSyndromeIschemia/ReperfusionNecroticlesionI

2、nflammationinallorgansNatural History of Chronic Hepatitis 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

3、patients have progressive diseaseCirrhosisHCC.Cumulative Incidence 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 .001403020100130123456789101112Ba

4、seline HBV DNA Level, copies/mL 1.0 x 1061.0 x 105 - 9.9 x 1051.0 x 104 - 9.9 x 104300-9.9 x 103 300.REVEAL: 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 patie

5、nt-yrs of follow-up and adjusted for sex, age, anti-HCV levels, smoking, and alcohol use. 1 IU/mL equals approximately 5.6 genomes/mL.P = NSHBeAg-Negative Patients 104(n = 2132)HBeAg-Positive PatientsP .01P .00 104 to 105 (n = 631) 105(n = 451) 104(n = 22) 105(n = 520) 104 to 105 (n = 18)B

6、L HBV DNA, c/mL:Adjusted RR* P .001P .0011.01.94.902.04.06.08.010.0Cases of Cirrhosis:10455 9623 135Chen 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

7、 1 million100,000-999,99910,000-99,999300-9999 300N = 3653 Taiwanese patientsYr of Follow-upChen CJ, et al. JAMA. 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 a

8、dvanced fibrosis or cirrhosis6 Pts With Disease Progression (%)P = .00125201510503018126036n = 198n = 173n = 417n = 385n = 43n = 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 car

9、cinoma (HCC) patients had serious inflammation and fibrosisit is often overlooked that 90% of HCC cases have a natural history of unresolved inflammation and severe fibrosis (or cirrhosis). 1HCV patients with cirrhosis of the liver survival rate is far lower than the patients without liver cirrhosis

10、21Samuele De Minicis. et al. Transl Gastrointest Cancer . 2012;1:88-94.2 Vishal Bhagat,et al. The American Journal of Gastroenterology 2009; 104: 117160. .抗病毒治疗是否能解决所有问题？抗病毒治疗是否能解决所有问题？.HBeAg阳性慢乙肝患者治疗一年阳性慢乙肝患者治疗一年ALT的复常率的复常率数据源于不同的研究数据源于不同的研究 (不同的人群不同的人群, 基线值基线值)，非直接对照，非直接对照66%48%68%77%39%20%30%40%5

11、0%60%70%80%拉米夫定阿德福韦酯恩替卡韦替比夫定PEG干扰素HEPATOLOGY 2007;45:1056-1075.HBsAg/HBeAg血清状态和血清状态和ALT校正校正HCC的风险比的风险比HBsAg/HBeAg/ALT校正相关风险校正相关风险阴性阴性/阴性阴性/正常正常阳性阳性/阴性阴性/正常正常阳性阳性/阳性阳性/正常正常阴性阴性/阴性阴性/升高升高阳性阳性/阴性阴性/升高升高阳性阳性/阳性阳性/升高升高1.010.3* 61.3* 5.4* 29.3*109.0*P 0.001 adjusted for age, anti-HCV, cigarette smoking an

12、d alcohol consumptionChen, et al. New Engl J Med 2002.ALT居高不下居高不下是是CHB严重不良预后的重要危险因素严重不良预后的重要危险因素之一之一N2780台湾台湾REVEAL-HBV试验显示：试验显示：入组时及随访期间，入组时及随访期间，ALT水平与肝癌和肝硬化发生率密切相关水平与肝癌和肝硬化发生率密切相关.CHB病人经抗病毒治疗后病人经抗病毒治疗后ALT复常率常不理想复常率常不理想-From AASLD CHB guideline 2007.15病毒耐药导致病毒耐药导致ALT显著增加显著增加2009年AASLDCHB防治指南指出：接受单

13、药抗病毒序贯治疗患者中出现多药物耐药变异；病毒耐药性的出现导致ALT显著增加（肝炎发作）病毒学反弹病毒学突破基因学突破肝炎发作生化学突破正常上限Lok ASF,McMahon BJ.Hepatology 2009;50:1-36抗病毒治疗抗病毒耐药性的表现15抗病毒治疗后病毒耐药导致肝脏炎症加重抗病毒治疗后病毒耐药导致肝脏炎症加重PretreatmentvsMedianFollow-upof3.5YearsDienstag J, et al. Gastroenterology. 2003;124:105-117.8070605040302010拉米夫定拉米夫定1,41,4阿德福韦酯阿德福韦酯2

14、,32,3恩替卡韦恩替卡韦4 4替比夫定替比夫定5 5炎症坏死改善率炎症坏死改善率纤维化改善率纤维化改善率1.1. NEJM 1998 339:61-68 2.NEJM 1998 339:61-68 2.阿德福韦酯阿德福韦酯437,438437,438研究研究 3.Gestroentology 2006:131:1743-1751 3.Gestroentology 2006:131:1743-1751 4.4.恩替卡韦恩替卡韦022,027,026022,027,026研究研究 5.5.替比夫定替比夫定007GLOBE007GLOBE研究研究49-66%49-66%53-64%53-64%35

15、-38%35-38%34-35%34-35%70-72%70-72%35-39%35-39%65-67%65-67%41-48%41-48%90炎性坏死炎性坏死改善率改善率纤维化改纤维化改善率善率NUCs治疗治疗1年炎症及纤维化改善现状年炎症及纤维化改善现状组织学改善率定义：组织学改善率定义：Knodell炎性坏死评分（共炎性坏死评分（共18分）下降分）下降 2分，分， 且纤维化评分（共且纤维化评分（共4分）无恶化分）无恶化纤维化改善率定义纤维化改善率定义： Ishak评分（共评分（共6分）下降分）下降1分分.延长延长NUCs抗病毒时间，肝纤维化改善率仍不理想抗病毒时间，肝纤维化改善率仍不理想

16、70706060505040403030202010105 5年年 LdTLdT 基线基线IshakIshak评分评分3 3分分7 7年年 ETV ETV 基线基线 IshakIshak评分评分3 3分分1010年年 LVD LVD 基线基线IshakIshak评分评分4 4分分3232% %2929% %4444% %0肝纤维化未改善率肝纤维化未改善率纤维化程度重的病人，延长抗病毒治疗至纤维化程度重的病人，延长抗病毒治疗至5-105-10年，肝纤维化未改善率仍高达年，肝纤维化未改善率仍高达3 35 5% %左右左右1. 2011AASLD 壁报壁报 2. EPATOLOGY, Vol. 52

17、, No. 3, 2010 2. 3. 许蓓，谢青等，中华传染病杂志许蓓，谢青等，中华传染病杂志 2010. vol.28, No. 11, 656-6616/197/247/19.不规范停药导致肝炎复发不规范停药导致肝炎复发138例慢乙肝患者接受例慢乙肝患者接受LAM治疗至少治疗至少12个月获得生化学应答后不同停药情况下个月获得生化学应答后不同停药情况下累积肝炎复发率累积肝炎复发率Jin et al. Virology Journal 2012, 9:23921.4%CHB患者患者由于由于费用问题而自行停药费用问题而自行停药.抗病毒治疗并不能解决所有问题抗病毒治疗并不能解决所有问题u 20-

18、50%的患者抗病毒治疗应答不佳u 肝细胞内HBV ccc DNA难以清除u 病毒变异出现耐药引起病情反复u 病毒抑制但炎症仍然会持续存在,部分患者肝纤维化改善不明显u 部分患者合并存在其他损肝因素（酒精、脂肪肝）u 并非所有患者均可接受抗病毒治疗 .No inflammation，no liver disease？www. miaoxh. com病毒性肝病毒性肝炎炎药物性肝药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遗传代谢性肝病？肝脏肝脏炎症如何发生炎症如何发生？.InflammasomeInflammasome activating activating

19、 p pathways athways G Szabo and T Csak.Inflammasomes in liver diseases.J Hepatol, Sep 2012; 57(3): 642-54. Fig. Inflammasome activating pathways.Secretion of DAMPS(HMGB1)PyroptosisCell repair via SREBPsRestriction of bacterialreplicase (caspase-7)Fig. Cell-specific inflammasome expression in the liv

20、er.Cell-specific inflammasome expression in the liverCell-specific inflammasome expression in the liverG Szabo and T Csak.Inflammasomes in liver 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.

21、朱鹏，王宇明. JH 中文版 ，Triggers of inflammasome activation in liver diseaseTriggers of inflammasome activation in liver disease.问题问题抗炎保抗炎保肝有何作用肝有何作用和地位？和地位？.肝脏炎症是各型慢性肝炎及肝硬化共同病理肝脏炎症是各型慢性肝炎及肝硬化共同病理基础基础肝脏炎症坏死及其所致的肝纤维化是疾病进展的主要病理学基础肝脏炎症坏死及其所致的肝纤维化是疾病进展的主要病理学基础1随着炎症加重，肝脏疾病最终可进展为肝硬化和肝癌随着炎症加重，肝脏疾病最终可进展为肝硬化和肝癌21. 王

22、宇明. 中华肝脏病杂志. 2011; 19(1):76-77.2. Adapted from EASL Consensus Statement. J Hepatol. 2003; 39(s1):s3-25.5年发生率12-25%5年发生率6-15%5年发生率20-30%肝癌肝癌正常肝脏正常肝脏肝衰竭肝衰竭肝硬化肝硬化肝脏炎症肝脏炎症肝纤维化肝纤维化肝病发展进程肝病发展进程.长期抗炎保肝可以降低肝硬化和肝癌的发生，延缓肝硬化长期抗炎保肝可以降低肝硬化和肝癌的发生，延缓肝硬化和肝癌发生和肝癌发生研究显示，采用长期抗炎保肝治疗研究显示，采用长期抗炎保肝治疗有效降低有效降低肝硬化和肝癌进展肝硬化和肝癌

23、进展在长期采用复方甘草酸苷治疗的178名患者中，与100名患者的对照组相比，肝硬化发生率频繁减少(28vs40%，在13年的时候 ， P 0.002)。长期使用甘草酸最显著的优点是减少肝癌发生率Kumada H. Oncology. 2002; 62 Suppl 1:94-100.肝癌发生率肝癌发生率(%)年年SNMC(+)SNMC().-甘草酸抗炎作用强，快速改善肝脏功能甘草酸抗炎作用强，快速改善肝脏功能天晴甘美治疗慢性乙型肝炎患者肝功能指标下降幅度更大中心，随机、双盲、多剂量，阳性药物平行对照的试验设计，480例患者随机进入异甘草酸镁100mg/d剂量组(A组，180例)、150mg/d剂

24、量组(B组，180例)和阳性药复方甘草酸苷对照组(C组，120例)。旨在观察异甘草酸镁注射液治疗ALT升高的慢性肝病的临床疗效和安全性茅益民, 等. 中华肝脏病杂志. 2009; 17(11):847-851.甘草酸治疗可协同增效抗病毒治疗效果甘草酸治疗可协同增效抗病毒治疗效果 共6项随机对照试验(RCT)704 例患者入选。异甘草酸镁联合核苷类似物治疗慢性乙型肝炎的疗效与单用核苷类似物相比，ALT,AST,TBIL的改善以及HBeAg转阴率，联用皆优于单用，且存在统计学差异，对HBV DNA 转阴率的比较无差异。晏泽辉 王宇明，等.,中华肝脏病杂志，2014，1(22):110-114.Ac

25、cumulationofETVinHepG2cells(ng/mgprotein)AccumulationofETVinLO2cells(ng/mgprotein)细胞试验证明：甘草酸二铵在HepG2和LO2肝细胞中，均能不同程度的增加恩替卡韦在细胞内的摄取量，统计学分析具有显著性差异，存在一定的药物相互作用。.抗炎保肝药物治疗增加抗炎保肝药物治疗增加CHB患者抗病毒治疗患者抗病毒治疗的疗的疗效及依从效及依从性性抗抗炎保肝药炎保肝药物治疗物治疗可以改善可以改善CHB患者的肝脏炎症患者的肝脏炎症和纤维化和纤维化抗抗病毒治疗联合抗炎保肝药物治疗能更好改善肝病毒治疗联合抗炎保肝药物治疗能更好改善肝脏

26、脏组织学组织学总总 结结.问题问题肝脏炎症及其防治专家共识肝脏炎症及其防治专家共识有无必要？有无必要？.背背 景景 肝脏肝脏炎症见于炎症见于几乎所有原因所致的几乎所有原因所致的肝病肝病 肝脏肝脏炎症常常贯穿肝病始终（肝炎炎症常常贯穿肝病始终（肝炎-肝硬化肝硬化-肝癌）肝癌） 有关防治研究特别是抗炎保肝方面进展不够理想有关防治研究特别是抗炎保肝方面进展不够理想 临床应用手段与方法临床应用手段与方法有限有限 存在诸多不同存在诸多不同意见意见 亟需规范亟需规范临床医疗思维和防治方法临床医疗思维和防治方法2012.11.23意向讨论会2013.3共识(草案)2013.3-9意见征询2013.9.14共

27、识讨论会2013.12.21共识发布会2014.2共识发表2014共识巡讲Prevention and Management of Liver Inflammation: an Expert Consensus in ChinaExpert committee for prevention and management of liver inflammation2013.1.A variety of evidences suggest that liver inflammation can be found in the liver diseases induced by almost all

28、 causes()2.In China，the number of patients with viral hepatitis are currently staying high, and the incidences of drug-induced hepatitis, alcoholic, nonalcoholic steatohepatitis and autoimmune liver diseases are increasing obviously. ()3.The main pathology and pathogenesis in liver disease progressi

29、on includes liver inflammation, fibrosis, cirrhosis and liver failure, etc.()4.All-round accessorial tests can be used to evaluate liver damage degree of inflammatory, with the elevated serum ALT as the most commonly used indicator. However, it is so far controversial on the ULN of the serum ALT, am

30、ong 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 replace of antiviral therapy on the etiologies, etc. Conversely, etiological treatment such as antiviral therapy cannot completely

31、replace the anti-inflammatory therapy. ()Recommendations.6.Regardless of whether there is an effective etiological treatment, it is necessary to implement the anti-inflammatory therapy in inflammation-induced liver disease, ()particularly in the liver disease that lacks effective etiological therapy

32、. ()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 the pharmacological effects of anti-inflammatory drugs or protectants have different features, the clinicians are su

33、ggested to choose proper drugs according to the characteristics of various liver inflammations and the drugs pharmacological effects. ()9.As various anti-inflammatory drugs have different functional features, and their combinations may obtain better efficacy, including the drugs of anti-inflammation

34、 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 protectants should be considered, particularly in elevated serum ALT or obvious inflammatory necrosis, eg. if serum

35、 ALT2ULN or pathological examination presents obvious inflammation in a patient with CHB or CHC. ()Recommendations.11. To determine whether a HBV infected patient with elevated ALT at the first time 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 obv