病毒性肝炎治療之困惑如何評(píng)價(jià)抗炎保肝價(jià)值

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！,Inflammati

2、on！,Metabolic Syndrome,Ischemia/Reperfusion,Necrotic lesion,Inflammation in all organs,Natural History of Chronic Hepatitis B,Cumulative Incidence of Cirrhosis by Serum HBV DNA Level at Study Entry,Iloeje UH, et al.

3、 Gastroenterology. 2006;130:678-686.,N = 3582 Taiwanese patients,Yr of Follow-up,REVEAL: Relationship Between Baseline HBV DNA and Cirrhosis,Baseline HBV DNA predicted progression to cirrhosis Relationship independent

4、of HBeAg status,Cases of Cirrhosis:10455 96,23 135,Chen CJ, et al. EASL 2005. Abstract 476.,Cumulative Incidence of HCC by Serum HBV DNA Level at Study Entry,N = 3653 Taiwanese patients,Yr of Follow-up,Chen CJ, et a

5、l. 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 cir

6、rhosis[6],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,i

7、t 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

8、 without liver cirrhosis[2],[1]Samuele De Minicis. et al. Transl Gastrointest Cancer . 2012;1:88-94.[2] Vishal Bhagat,et al. The American Journal of Gastroenterology 2009; 104: 117–160.,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

9、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,HEPATOLOGY 2007;45:1056-1075,HBsAg/HBeAg血清狀態(tài)和ALT校正HCC的風(fēng)險(xiǎn)比,*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

10、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,N＝2780,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 2007,15,病毒耐藥導(dǎo)致ALT顯著增加,2009年A

11、ASLD《CHB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,Pretreatment vs Median Follow-up of 3.5

12、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,NEJM 1998 339:61-68 2.阿德福韋酯437,438研究 3.Gestroentology 2006:131:1743

13、-1751 4.恩替卡韋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

14、惡化纖維化改善率定義： Ishak評(píng)分（共6分）下降≥1分,延長NUCs抗病毒時(shí)間，肝纖維化改善率仍不理想,70,60,50,40,30,20,10,,5年 LdT 基線Ishak評(píng)分≥3分,7年 ETV 基線 Ishak評(píng)分≥3分,10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，延長抗病毒治療至5-10年，肝纖維化未改善率仍高達(dá)35%左右,2011AA

15、SLD 壁報(bào) 2. EPATOLOGY, Vol. 52, No. 3, 2010 3. 許蓓，謝青等，中華傳染病雜志 2010. vol.28, No. 11, 656-661,6/19,7/24,7/19,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. Virology Journal 2012, 9:239,21.4%C

16、HB患者由于費(fèi)用問題而自行停藥,抗病毒治療并不能解決所有問題,20-50%的患者抗病毒治療應(yīng)答不佳 肝細(xì)胞內(nèi)HBV ccc DNA難以清除 病毒變異出現(xiàn)耐藥引起病情反復(fù) 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 部分患者合并存在其他損肝因素（酒精、脂肪肝） 并非所有患者均可接受抗病毒治療,No inflammation，no liver disease？,www. miaoxh. com,,自身免疫性

17、肝炎,,脂肪性肝炎,遺傳代謝性肝??？,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),Pyro

18、ptosisCell repair via SREBPs,Restriction of bacterialreplicase (caspase-7),,,,Fig. Cell-specific inflammasome expression in the liver.,Cell-specific inflammasome expression in the liver,G Szabo and T Csak.Inflammasomes

19、 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. JH 中文版 ，,Triggers of inflammasome activation i

20、n 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,王宇明. 中華肝臟病雜志. 2011; 19(1):76-77.Adapted from EASL Consensus Statement. J Hepatol. 2003; 39(s1):s3-25.,長期抗炎保肝可以

21、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(jìn)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.,α-甘草酸抗炎作用強(qiáng)，快速改善肝臟功能,天晴

22、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，隨機(jī)、雙盲、多劑量，陽性藥物平行對(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. 2009; 17(11):847-851.,甘草酸治療可協(xié)同增效抗病毒治療效果,共

23、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)計(jì)學(xué)差異，對(duì)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.,Accumulation of ETV in HepG2 cells(ng / mg protein),Accumula

24、tion of ETV in LO2 cells(ng / mg protein),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組織學(xué),總 結(jié),問題,《肝臟炎癥及其防治專家共識(shí)

25、》有無必要？,背 景,肝臟炎癥見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亟需規(guī)范臨床醫(yī)療思維和防治方法,《肝臟炎癥及其防治專家共識(shí)》推動(dòng),Prevention and Management of Liver Inflammation: an Expert Consensus in China,Expert comm

26、ittee for prevention and management of liver inflammation2013,A variety of evidences suggest that liver inflammation can be found in the liver diseases induced by almost all causes(Ⅰ)In China，the number of patients wit

27、h viral hepatitis are currently staying high, and the incidences of drug-induced hepatitis, alcoholic, nonalcoholic steatohepatitis and autoimmune liver diseases are increasing obviously. (Ⅰ)The main pathology and patho

28、genesis in liver disease progression includes liver inflammation, fibrosis, cirrhosis and liver failure, etc.(Ⅰ)All-round accessorial tests can be used to evaluate liver damage degree of inflammatory, with the elevated

29、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. (Ⅰ)Although anti-inflammatory therapy is a part

30、 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-inflammat

31、ory therapy. (Ⅰ),Recommendations,,,Regardless of whether there is an effective etiological treatment, it is necessary to implement the anti-inflammatory therapy in inflammation-induced liver disease, (Ⅲ)particularly in t

32、he liver disease that lacks effective etiological therapy. (Ⅰ)As anti-HBV or HCV therapy cannot control liver inflammation rapidly and directly, including elevated serum ALT, anti-inflammatory therapy should be given s

33、imultaneously. (Ⅰ)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

34、inflammations and the drug’s pharmacological effects. (Ⅱ)As various anti-inflammatory drugs have different functional features, and their combinations may obtain better efficacy, including the drugs of anti-inflammation

35、 and liver protectant, including glycyrrhizic acid)and liver protectants. (Ⅲ)When patients with CHB and CHC are using anti-viral therapy, treatments using anti-inflammation or liver protectants should be considered, pa

36、rticularly in elevated serum ALT or obvious inflammatory necrosis, eg. if serum ALT≥2×ULN or pathological examination presents obvious inflammation in a patient with CHB or CHC. (Ⅰ),Recommendations,To determine whet

37、her 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. (Ⅲ)CH

38、C patients elevated serum ALT or obvious inflammation should be considered anti-inflammation and liver protectants treatments. (Ⅲ)Anti-inflammation and liver protectants treatments are recommended to be used preventativ

39、ely used in DILI, including anti-tubercular drugs and chemotherapy of tumor. (Ⅰ)Duration of anti-inflammation and liver protectants treatments is depend on various etiologies and conditions, among which attention should

40、 be paid on the gradual reduction of drugs, maintenance treatment, and slow drug withdrawal to avoid relapse.(Ⅲ)Patients with liver inflammation are suggested to have proper rest, rational diet and well living habits, t

41、o avoid precipitation factors of liver damages, and to have appropriate physical excises.(Ⅲ)To avoid increasing burden of the liver, the combination therapy should be limited to two or three drugs, and usually the combi

42、nation same category of drugs is not recommended, and meanwhile regular following-up and regulation is recommended. (Ⅲ),Recommendations,十余年來肝病學(xué)界的幾個(gè)重要爭議性的問題,一生一世（試）還是一世（試）一生？To stop or not to stop?To treat or not to tre