病毒性肝炎治疗之困惑如何评价抗炎保肝价值？课件

病毒性肝炎治疗之困惑 如何评价抗炎保肝价值 ？ 肝脏炎症有何意义？ 肝脏免疫反应的独特性能 先天性免疫： 大量独特的免疫细胞群：KC、NK、NK-T 肠道PAMPs的暴露 肝脏分泌DAMPs的暴露 HSC和纤维化的活性限制 临床结局： Inflammation!Inflammation！ Inflammation！Inflammation！ Metabolic Syndrome Ischemia/Reperfusion Necrotic lesion Inflammation in all organs Natural History of Chronic Hepatitis B Normal liver Chronic hepatitis B ESLD No further progression HBV-related ESLD or HCC are responsible for 0.5-1 million deaths per yr and currently represent 5% to 10% of cases of liver transplantation Not all patients have progressive disease Cirrhosis HCC Cumulative Incidence of Cirrhosis by Serum HBV DNA Level at Study Entry Iloeje UH, et al. Gastroenterology. 2006;130:678-686. N = 3582 Taiwanese patients Yr of Follow-up Cumulative Incidence of Liver Cirrhosis (%) Log-rank P .001 40 30 20 10 0 130123456789101112 Baseline HBV DNA Level, copies/mL 1.0 x 106 1.0 x 105 - 9.9 x 105 1.0 x 104 - 9.9 x 104 300-9.9 x 103 300 REVEAL: Relationship Between Baseline HBV DNA and Cirrhosis Baseline HBV DNA predicted progression to cirrhosis Relationship independent of HBeAg status Adjusted RR* 0 2.0 4.0 6.0 8.0 10.0 *With 42,115 patient-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 = NS HBeAg-Negative Patients 104 (n = 2132) HBeAg-Positive Patients P .01 P .001 2.6 6.2 8.6 104 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 .001 P .001 1.0 1.9 4.9 0 2.0 4.0 6.0 8.0 10.0 Cases of Cirrhosis:10455 9623 135 Chen CJ, et al. EASL 2005. Abstract 476. Cumulative Incidence of HCC by Serum HBV DNA Level at Study Entry Cumulative Incidence of HCC (%) 0 2 4 6 8 10 12 14 012345678910111213 Baseline HBV DNA Level, copies/mL 1 million 100,000-999,999 10,000-99,999 300-9999 300 N = 3653 Taiwanese patients Yr of Follow-up Chen CJ, et al. JAMA. 2006;295:65-73. Successful Hepatitis B Treatment Reduces Clinical Endpoints HBV 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 = .001 25 20 15 10 5 0 3018126036 n = 198 n = 173 n = 417 n = 385 n = 43 n = 122 24 Lamivudine Placebo Kaplan-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 fibrosis it is often overlooked that 90% of HCC cases have a natural history of unresolved inflammation and severe fibrosis (or cirrhosis). 1 HCV patients with cirrhosis of the liver survival rate is far lower than the patients without liver cirrhosis2 1Samuele 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？ HBeAg阳性慢乙肝患者治疗一年ALT的复常率 数据源于不同的研究 (不同的人群, 基线值)，非直接对照 66% 48% 68% 77% 39% 20% 30% 40% 50% 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ALT校正HCC的风险比 HBsAg/HBeAg/ALT校正相关风险 阴性/阴性/正常 阳性/阴性/正常 阳性/阳性/正常 阴性/阴性/升高 阳性/阴性/升高 阳性/阳性/升高 1.0 10.3* 61.3* 5.4* 29.3* 109.0* *P 0.001 adjusted for age, anti-HCV, cigarette smoking and alcohol consumption Chen, et al. New Engl J Med 2002 ALT居高不下是CHB严重不良预后的重要危险因素之一 Chen CJ et al. J Gastroenterol Hepatol. 2011;10.1111/j.1440-1746 N2780 台湾REVEAL-HBV试验显示： 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 CHB病人经抗病毒治疗后ALT复常率常不理想 -From AASLD CHB guideline 2007 15 病毒耐药导致ALT显著增加 2009年AASLDCHB防治指南指出：接受单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 Pretreatment vs Median Follow-up of 3.5 Years Dienstag J, et al. Gastroenterology. 2003;124:105-117. 80 70 60 50 40 30 20 10 拉米夫定1,4阿德福韦酯2,3恩替卡韦4替比夫定5 炎症坏死改善率 纤维化改善率 1. NEJM 1998 339:61-68 2.阿德福韦酯437,438研究 3.Gestroentology 2006:131:1743-1751 4.恩替卡韦022,027,026研究 5.替比夫定007GLOBE研究 49-66%53-64% 35-38% 34-35% 70-72% 35-39% 65-67% 41-48% 90 炎性坏死 改善率 纤维化改 善率 NUCs治疗1年炎症及纤维化改善现状 组织学改善率定义：Knodell炎性坏死评分（共18分）下降 2分， 且纤维化评分（共4分）无恶化 纤维化改善率定义： Ishak评分（共6分）下降1分 延长NUCs抗病毒时间，肝纤维化改善率仍不理想 70 60 50 40 30 20 10 5年 LdT 基线Ishak评分3 分 7年 ETV 基线 Ishak评分3分 10年 LVD 基线Ishak评分4 分 32% 29% 44% 0 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 5-10年，肝纤维化未改善率仍高达35%左右 1. 2011AASLD 壁报 2. EPATOLOGY, Vol. 52, No. 3, 2010 2. 3. 许蓓，谢青等，中华传染病杂志 2010. vol.28, No. 11, 656-661 6/197/247/19 不规范停药导致肝炎复发 138例慢乙肝患者接受LAM治疗至少12个月获得生化学应答后不同停药情况下 累积肝炎复发率 Jin et al. Virology Journal 2012, 9:239 21.4%CHB患者由于 费用问题而自行停药 抗病毒治疗并不能解决所有问题 u 20-50%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 病毒性肝炎 药物性肝炎酒精性肝炎 自身免疫性肝炎 脂肪性肝炎 炎症炎症 遗传代谢性肝病？ 肝脏炎症如何发生？ Inflammasome activating pathways 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) Pyroptosis Cell repair via SREBPs Restriction of bacterial replicase (caspase-7) Fig. Cell-specific inflammasome expression in the liver. Cell-specific inflammasome expression in the liver G 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. 朱鹏，王宇明. JH 中文版 ， Triggers of inflammasome activation in liver disease 问题 抗炎保肝有何作用和地位？ 肝脏炎症是各型慢性肝炎及肝硬化共同病理基础 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2 1. 王宇明. 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 正常肝脏 肝衰竭 肝硬化 肝脏炎症 肝纤维化 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 和肝癌发生 研究显示，采用长期抗炎保肝治疗有效降低肝硬化和肝癌进展 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(%) 年 SNMC(+) SNMC() -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 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. Accumulation of ETV in HepG2 cells (ng / mg protein) Accumulation of ETV in LO2 cells (ng / mg protein) 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CHB患者抗病毒治疗的疗 效及依从性 抗炎保肝药物治疗可以改善CHB患者的肝脏炎症 和纤维化 抗病毒治疗联合抗炎保肝药物治疗能更好改善肝 脏组织学 总 结 问题 肝脏炎症及其防治专家共识有无必要？ 背 景 肝脏炎症见于几乎所有原因所致的肝病 肝脏炎症常常贯穿肝病始终（肝炎-肝硬化-肝癌 ） 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有限 存在诸多不同意见 亟需规范临床医疗思维和防治方法 肝脏炎症及其防治专家共识肝脏炎症及其防治专家共识推动推动 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 China Expert committee for prevention and management of liver inflammation 2013 1.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 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, 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 replace of antiviral therapy on the etiologies, etc. Conversely, etiological treatment such as antiviral therapy cannot completely 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. () 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 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 different 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 protectants 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. () 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 obvious inflammation should be considered anti-inflammat