病毒性肝炎治療之困惑如何評(píng)價(jià)抗炎保肝價(jià)值.pptx

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1、病毒性肝炎治療之困惑如何評(píng)價(jià)抗炎保肝價(jià)值？ 肝臟炎癥有何意義？ 肝臟免疫反應(yīng)的獨(dú)特性能 先天性免疫： 大量獨(dú)特的免疫細(xì)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！ MetabolicSyndrome Ischemia/Reperfusion NecroticlesionInflammationinallorgans Natural History of Chronic Hepatitis BNormal liver C

2、hronichepatitis B ESLDNo 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 transplantation Not all patients have progressive diseaseCirrhosis HCC Cumulative Incidence of Cirrhosis by Serum HBV DNA Level at St

3、udy Entry Iloeje UH, et al. Gastroenterology. 2006;130:678-686. N = 3582 Taiwanese patientsYr of Follow-upCumulative Incidence of Liver Cirrhosis (%) Log-rank P .001403020100 130 1 2 3 4 5 6 7 8 9 10 11 12Baseline 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

4、103 300 REVEAL: Relationship Between Baseline HBV DNA and Cirrhosis Baseline HBV DNA predicted progression to cirrhosis Relationship independent of HBeAg status Adjusted 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 alcohol use. 1

5、 IU/mL equals approximately 5.6 genomes/mL. P = NSHBeAg-Negative Patients 104(n = 2132) HBeAg-Positive PatientsP .01 P .0012.6 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 .0011.0 1.9 4.902.04.06.08.010.0Cases of Cirrhos

6、is: 104 55 96 2 3 135Chen CJ, et al. EASL 2005. Abstract 476. Cumulative Incidence of HCC by Serum HBV DNA Level at Study Entry Cumulative Incidence of HCC (%) 02468101214 0 1 2 3 4 5 6 7 8 9 10 11 12 13Baseline HBV DNA Level, copies/mL 1 million100,000-999,99910,000-99,999300-9999 300 N = 3653 Taiw

7、anese patientsYr 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

8、(%) P = .0012520151050 30181260 36n = 198 n = 173n = 417 n = 385 n = 43n = 12224 LamivudinePlaceboKaplan-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 fi

9、brosis it 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 cirrhosis2 1Samuele De Minicis. et al. Transl Gastrointest Ca

10、ncer . 2012;1:88-94.2 Vishal Bhagat,et al. The American Journal of Gastroenterology 2009; 104: 117160. 抗病毒治療是否能解決所有問(wèn)題？ HBeAg陽(yáng)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(duì)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;45:1056-1075 HBsAg/HBeAg血清狀態(tài)和ALT校正HCC的風(fēng)險(xiǎn)比HBsA

11、g/HBeAg/ALT 校正相關(guān)風(fēng)險(xiǎn)陰性/陰性/正常陽(yáng)性/陰性/正常陽(yáng)性/陽(yáng)性/正常陰性/陰性/升高 陽(yáng)性/陰性/升高陽(yáng)性/陽(yáng)性/升高 1.010.3* 61.3* 5.4* 29.3*109.0*P 0.001 adjusted for age, anti-HCV, cigarette smoking and alcohol consumptionChen, et al. New Engl J Med 2002 ALT居高不下是CHB嚴(yán)重不良預(yù)后的重要危險(xiǎn)因素之一 Chen CJ et al. J Gastroenterol Hepatol. 2011;10.1111/j.1440-1746

12、 N2780 臺(tái)灣REVEAL-HBV試驗(yàn)顯示：入組時(shí)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 2007 1 5 病毒耐藥導(dǎo)致ALT顯著增加 2009年AASLDCHB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 學(xué) 突 破 肝 炎 發(fā) 作生 化 學(xué) 突 破正 常 上 限Lok ASF,McMahon BJ.Hepatology 2 0 0 9 ;5 0 :1 -3 6抗病毒治療抗

13、 病 毒 耐 藥 性 的 表 現(xiàn) 1 5 抗病毒治療后病毒耐藥導(dǎo)致肝臟炎癥加重PretreatmentvsMedianFollow-upof3 .5 Years Dienstag J, et al. Gastroenterology. 2003;124:105-117. 80706050403020 10 拉 米 夫 定 1,4 阿 德 福 韋 酯 2,3 恩 替 卡 韋 4 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 437,438研 究 3.Gestroentology 2006:131:1743-1751 4.恩 替

14、 卡 韋 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 壞 死改 善 率纖 維 化 改善 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(píng)分（共18分）下降 2分， 且纖維化評(píng)分（共4分）無(wú)惡化纖維化改善率定義： Ishak評(píng)分（共6分）下降1分 延長(zhǎng)NUCs抗病毒時(shí)間，肝纖維化改善率仍不理想706050 40302010 5年 LdT 基 線 Ishak評(píng) 分 3分 7年 ETV 基 線 Ishak評(píng) 分 3分 10

15、年 LVD 基 線 Ishak評(píng) 分 4分32% 29% 44%0肝纖維化未改善率 纖 維 化 程 度 重 的 病 人 ， 延 長(zhǎng) 抗 病 毒 治 療 至5-10年 ， 肝 纖 維 化 未 改 善 率 仍 高 達(dá) 35%左 右 1. 2011AASLD 壁報(bào) 2. EPATOLOGY, Vol. 52, No. 3, 2010 2. 3. 許蓓，謝青等，中華傳染病雜志 2010. vol.28, No. 11, 656-6616/19 7/24 7/19 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(gè)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. Vir

16、ology Journal 2012, 9:239 21.4%CHB患者由于費(fèi)用問(wèn)題而自行停藥 抗病毒治療并不能解決所有問(wèn)題u 20-50%的患者抗病毒治療應(yīng)答不佳u 肝細(xì)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(huì)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 并非所有患者均可接受抗病毒治療 No inflammation， no liver disease？ www. miaoxh. com病 毒 性 肝 炎藥 物 性 肝 炎 酒 精 性 肝 炎自 身 免 疫 性 肝 炎 脂 肪 性 肝 炎遺 傳 代 謝

17、 性 肝 病 ？ 肝臟炎癥如何發(fā)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 )PyroptosisCell repair via SREBPsRestriction of bacterialreplicase (caspase-7 ) Fig. Cell-specifi

18、c 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 鵬 ， 王 宇 明

19、. JH 中 文 版 ， Triggers of inflammasome activation in liver disease 問(wèn)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理基礎(chǔ) 肝臟炎癥壞死及其所致的肝纖維化是疾病進(jìn)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(jìn)展為肝硬化和肝癌2 1. 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

20、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(jìn)程 長(zhǎng)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(zhǎng)期抗炎保肝治療有效降低肝硬化和肝癌進(jìn)展 在長(zhǎng)期采用復(fù)方甘草酸苷治療的178名患者中，與100名患者的對(duì)照組相比，肝硬化發(fā)生率頻繁減少(28vs40%，在13年的時(shí)候 ， P 0.002)。長(zhǎng)期使用甘草酸最顯著的優(yōu)點(diǎn)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(qiáng)，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(biāo)下降幅度更大 中心，隨

21、機(jī)、雙盲、多劑量，陽(yáng)性藥物平行對(duì)照的試驗(yàn)設(shè)計(jì)，480例患者隨機(jī)進(jìn)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(yáng)性藥復(fù)方甘草酸苷對(duì)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床療效和安全性茅益民, 等. 中華肝臟病雜志. 2 0 0 9 ; 1 7 (1 1 ):8 4 7 -8 5 1 . 甘草酸治療可協(xié)同增效抗病毒治療效果 共6項(xiàng)隨機(jī)對(duì)照試驗(yàn)(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)

22、計(jì)學(xué)差異，對(duì)HBV DNA 轉(zhuǎn)陰率的比較無(wú)差異。晏澤輝 王宇明，等.,中華肝臟病雜志，2014，1(22):110-114.Accumulationof ETVinHepG2cells (ng/mgprotein) AccumulationofETVinLO2cells (ng/mgprotein)細(xì)胞試驗(yàn)證明：甘草酸二銨在HepG2和LO2肝細(xì)胞中，均能不同程度的增加恩替卡韋在細(xì)胞內(nèi)的攝取量，統(tǒng)計(jì)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

23、組織學(xué)總 結(jié) 問(wèn)題肝臟炎癥及其防治專家共識(shí)有無(wú)必要？ 背 景 肝 臟 炎 癥 見(jiàn) 于 幾 乎 所 有 原 因 所 致 的 肝 病 肝 臟 炎 癥 常 常 貫 穿 肝 病 始 終 （ 肝 炎 -肝 硬 化 -肝 癌 ） 有 關(guān) 防 治 研 究 特 別 是 抗 炎 保 肝 方 面 進(jìn) 展 不 夠 理 想 臨 床 應(yīng) 用 手 段 與 方 法 有 限 存 在 諸 多 不 同 意 見(jiàn) 亟 需 規(guī) 范 臨 床 醫(yī) 療 思 維 和 防 治 方 法 2012.11.23意 向 討 論 會(huì) 2013.3 共識(shí) (草 案 ) 2013.3-9意見(jiàn) 征 詢 2013.9.14 共 識(shí) 討論 會(huì) 2013.12.21

24、 共 識(shí) 發(fā)布 會(huì) 2014.2 共識(shí) 發(fā) 表 2014 共 識(shí) 巡 講 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 al

25、l 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 pro

26、gression 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

27、 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 c

28、ompletely 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 etiol

29、ogical 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

30、 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

31、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

32、necrosis, eg. if serum ALT2 ULN 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 , th

33、e 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-inflammation and liver protectants treatments are recommended to be used preve

34、ntatively 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 paid on the gradual reduction of drugs, maintenance treatment, and

35、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.( )16. To avoid increasing burden of the liver, the combina

36、tion 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(lái)肝病學(xué)界的幾個(gè)重要爭(zhēng)議性的問(wèn)題一生一世（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 it！