病毒性肝炎合并脂肪肝的治療策略

1、病毒性肝炎合并脂肪肝的治療策略,NP-ESS-20170118-3,目 錄,病毒性肝炎合并脂肪肝的流行病學(xué)慢性乙型肝炎合并脂肪肝的危害和治療策略慢性丙型肝炎合并脂肪肝的危害和治療策略,全球和中國肝病的病因分布,Wang FS, et al. Hepatology. 2014 ;60(6):2099-108,,,HBV感染和脂肪肝是我國最主要的肝病病因。,14%-71%的慢乙肝患者合并脂肪肝,Raluca Pais, et al.

2、Clin Liver Dis 18 (2014) 165–178,歐洲和中東地區(qū),亞太地區(qū),40-86%的慢性丙型肝炎患者合并脂肪肝,,T Asselah, et al. Gut 2006;55:123–130,中國慢性乙型肝炎和慢性丙型肝炎患者脂肪肝的流行情況,,,Raluca Pais, et al. Clin Liver Dis 18 (2014) 165–178,合并脂肪肝對慢性病毒性肝炎患者臨床預(yù)后的影響,,肝硬化風(fēng)險,

3、,肝細(xì)胞癌風(fēng)險,范建高. 中華肝臟病雜志; 2009;17(11):801-805,問 題,如何正確理解病毒肝與脂肪肝之間的關(guān)系？如何治療病毒肝合并脂肪肝的患者？,病毒性肝炎（乙型、丙型）→ 脂肪肝 ？,病毒性肝炎（乙型、丙型） + 脂肪肝 ？,以治療脂肪肝為主？,以治療病毒肝為主？,雙管齊下？,目 錄,病毒性肝炎合并脂肪肝的流行病學(xué)慢性乙型肝炎合并脂肪肝的危害和治療策略慢性丙型肝炎合并脂肪肝的危害和治療策略,

4、肝臟在肥胖相關(guān)并發(fā)癥發(fā)病機(jī)制中的關(guān)鍵角色,Thomas Karlas, et al. Best Practice & Research Clinical Endocrinology & Metabolism 2013; 27:195–208,HBV 感染與代謝綜合征：事實還是虛構(gòu)？,Chia-Chi Wang, et al. J Gastroenterol Hepatol. 2014 Aug 5. doi: 10.11

5、11/jgh.12700. [Epub ahead of print],HBV感染與代謝綜合征的相互關(guān)系：臨床研究匯總,Chia-Chi Wang, et al. J Gastroenterol Hepatol. 2014 Aug 5. doi: 10.1111/jgh.12700. [Epub ahead of print],慢性HBV感染與代謝綜合征相關(guān)性的薈萃分析,Chia-Chi Wang, et al. J Gastroen

6、terol Hepatol. 2014 Aug 5. doi: 10.1111/jgh.12700. [Epub ahead of print],,OR= 0.82,合并代謝綜合征(包括脂肪肝)對HBV肝病進(jìn)展的影響,肝纖維化肝硬化,,風(fēng)險,HBV攜帶者合并超聲下脂肪肝對肝臟損傷具有協(xié)同作用,,Yu-Cheng Lin, et al. World J Gastroenterol 2007 ; 13(12): 1805-1810,A

7、 cross-sectional retrospective analysis of health records including medical history, physical examination, abdominal sonogram, blood biochemistry and hepatic virological tests. We utilized the Student’s t-test, chi-squar

8、e, multivariate logistic regression and synergy index to assess risks for LD.,合并NAFLD的CHB患者肝酶和肝組織學(xué)分期比不合并NAFLD的CHB升高,Arezoo Estakhri, et al. Open Journal of Gastroenterology, 2012, 2:18-21,,,,retrospectively evaluated 94

9、“eAg” negative CHB patients (with NAFLD: 44, without NAFLD: 50). In the NAFLD group, increase in AST, ALT, stage (P = 0.002), grade, and total score of liver biopsy were independently related to non-alcoholic fatty liv

10、er disease, while HBV-DNA viral load did not correlate with the presence of a fatty liver.,慢性病毒性肝炎合并脂肪肝的治療策略,整體治療的前提：脂肪肝的基礎(chǔ)治療,最根本的治療：抗病毒治療,重要組成部分：保肝藥物,改變生活方式治療原發(fā)病和去除相關(guān)危險因素：肥胖、2型糖尿病,抗病毒藥物,保肝藥物一般可選用多烯磷酯酰膽堿、水飛薊素等1-2種，治療

11、半年至1年以上。,施軍平, 等. 實用肝臟病雜志, 2008; 11(4):278-280,改變生活方式,通過健康宣教以及心理和行為修正治療，做到“合理膳食、增加運動、節(jié)制飲酒、慎用肝毒藥物以及避免接觸肝毒物質(zhì)”。,施軍平, 等. 實用肝臟病雜志, 2008; 11(4):278-280,抗炎保肝類藥物治療病毒性肝炎合并脂肪肝,應(yīng)用IFN-α類抗病毒治療時，ALT＞10×ULN，TBIL＞50μmol/L的患者；或使用過程中

12、ALT或AST繼續(xù)上升＞10×ULN應(yīng)用NUCs過程中少數(shù)ALT持久波動或ALT復(fù)升（除外耐藥因素）者（必要時尋找其他病因，相應(yīng)處置）使用抗病毒藥物正規(guī)治療中，ALT、AST仍異常者（必要時尋找其他病因，相應(yīng)處置）ALT、AST異常，但暫不宜應(yīng)用IFN-α及NUCs治療的CHB、CHC、肝硬化代償或失代償患者。,中華醫(yī)學(xué)會感染病學(xué)分會，肝臟炎癥及其防治專家共識專家委員會. 中國實用內(nèi)科雜志, 2014;34(2): 15

13、2-162,,針對病毒感染合并脂肪肝的患者，是否適用？,抗炎保肝藥物顯著改善乙肝合并脂肪肝患者的肝生化指標(biāo),選擇病毒性肝炎合并脂肪肝136例，慢性乙肝112例，慢性丙肝22例，急性乙肝2例對照組:一般治療+肝炎治療；治療組:一般治療+肝炎治療+多烯磷脂酰膽堿膠囊 2片/次 3次/日；療 程:3個月,姜寧華.易善復(fù)治療病毒性肝炎合并脂肪肝臨床療效評估. 中國現(xiàn)代應(yīng)用藥學(xué).2004;21(3):235-7,抗炎保肝藥物治療顯著改善

14、乙肝合并脂肪肝患者的影像學(xué),選擇病毒性肝炎合并脂肪肝136例，慢性乙肝112例，慢性丙肝22例，急性乙肝2例對照組:一般治療+肝炎治療；治療組:一般治療+肝炎治療+多烯磷脂酰膽堿膠囊 2片/次 3次/日；療 程:3個月,組間比較，p<0.05,姜寧華.易善復(fù)治療病毒性肝炎合并脂肪肝臨床療效評估. 中國現(xiàn)代應(yīng)用藥學(xué).2004;21(3):235-7,小結(jié)：慢性乙型肝炎合并脂肪肝的治療策略,合并代謝綜合征對HBV肝病進(jìn)展有影響(

15、如可能增加肝纖維化、肝硬化風(fēng)險)；HBV感染合并NAFLD對肝細(xì)胞損傷有協(xié)同作用，患者肝酶和肝組織學(xué)分期比不合并NAFLD的CHB高；對于慢乙肝合并脂肪肝的患者，脂肪肝的基礎(chǔ)治療是前提，抗病毒治療是根本、保肝藥物治療是重要組成部分；抗炎保肝類藥物能有效改善乙肝合并脂肪肝的患者肝功能和影像學(xué)。,目 錄,病毒性肝炎合并脂肪肝的流行病學(xué)慢性乙型肝炎合并脂肪肝的危害和治療策略慢性丙型肝炎合并脂肪肝的危害和治療策略,HCV在脂肪肝發(fā)生

16、過程中的作用,Anish Patel, and Stephen A. Harrison. Gastroenterology & Hepatology Volume 8, Issue 5 May 2012: 305-312,HCV感染患者促炎性細(xì)胞因子分泌顯著增多,A total of 28 consecutive nondiabetic patients with chronic hepatitis C were inclu

17、ded in the study (anti-HCV). Fourteen patients with chronic hepatitis other than HCV infection served as the control group (anti-HCV). Both groups were closely matched by the main clinical variables associated with insul

18、in resistance and the degree of liver fibrosis.,,ALBERT LECUBE, et al. Diabetes Care 2006; 29:1096–1101,促炎因子與胰島素抵抗發(fā)生有關(guān),A total of 28 consecutive nondiabetic patients with chronic hepatitis C were included in the study (a

19、nti-HCV). Fourteen patients with chronic hepatitis other than HCV infection served as the control group (anti-HCV). Both groups were closely matched by the main clinical variables associated with insulin resistance and t

20、he degree of liver fibrosis.,ALBERT LECUBE, et al. Diabetes Care 2006; 29:1096–1101,穩(wěn)態(tài)胰島素評價指數(shù)：HOMA-IR,代謝組學(xué)分析：丙肝患者和對照組存在差別,Classification of urine samples based on P function scores obtained through the metabonomics anal

21、ysis of the 1H NMR spectra model of 66 individuals,M. M. G. Godoy, et al. Journal of Viral Hepatitis, 2010, 17, 854–858,丙肝患者的核磁共振代謝組學(xué),FFA促進(jìn)HCV在肝細(xì)胞復(fù)制,Immunohistochemical staining for HCV core antigen in the infected Huh 7

22、.5 cells in the presence of different concentrations of FAA after 15 days,HCV infected Huh-7.5 cells were cultured with a mixture of saturated (palmitate) and unsaturated (oleate) long-chain free fatty acids (FFA). Intra

23、cytoplasmic fat accumulation in these cells was visualized by Nile red staining and electron microscopy then quantified by microfluorometry. The effect of FFA treatment on HCV replication and IFN-α antiviral response was

24、 measured by flow cytometric analysis, Renilla luciferase activity, and real-time RT-PCR,Feyza Gunduz, et al. Virology Journal 2012, 9:143,游離脂肪酸降低IFN對HCV的治療作用,HCV infected Huh-7.5 cells were cultured with a mixture of sa

25、turated (palmitate) and unsaturated (oleate) long-chain free fatty acids (FFA). Intracytoplasmic fat accumulation in these cells was visualized by Nile red staining and electron microscopy then quantified by microfluorom

26、etry. The effect of FFA treatment on HCV replication and IFN-α antiviral response was measured by flow cytometric analysis, Renilla luciferase activity, and real-time RT-PCR,Feyza Gunduz, et al. Virology Journal 2012, 9:

27、143,IR降低抗病毒治療病毒學(xué)應(yīng)答率：EVR,HOMA：穩(wěn)態(tài)模式評估法，Homeostasis Model Assessment，用于評估胰島素抵抗。,J . J . BLONSKY & S. A. HARRISON. Aliment Pharmacol Ther 27, 855–865,To conduct a systematic, evidence-based review of the epidemiology, pa

28、thophysiology and potential treatments of coexistent NAFLD and CHC. The terms such as hepatitis C, fatty liver, NAFLD, nonalcoholic steatohepatitis and steatosis were searched on PubMed up to January 2008. References fro

29、m selected articles and pertinent abstracts were also included.,IR降低抗病毒治療病毒學(xué)應(yīng)答率：SVR,HOMA：穩(wěn)態(tài)模式評估法，Homeostasis Model Assessment，用于評估胰島素抵抗。,J . J . BLONSKY & S. A. HARRISON. Aliment Pharmacol Ther 27, 855–865,To conduct

30、 a systematic, evidence-based review of the epidemiology, pathophysiology and potential treatments of coexistent NAFLD and CHC. The terms such as hepatitis C, fatty liver, NAFLD, nonalcoholic steatohepatitis and steatosi

31、s were searched on PubMed up to January 2008. References from selected articles and pertinent abstracts were also included.,脂肪肝分級不同，肝細(xì)胞癌累積發(fā)生率差異顯著,P = 0.0002 between grade 2 and grade 1 or grade 0).,Atsushi Tanaka, et al

32、. World J Gastroenterol 2007 October 21; 13(39): 5180-5187,獲得持久病毒學(xué)應(yīng)答的CHC患者的HCC累積發(fā)生率,Grade 2，Grade 1，Grade 0 指肝脂肪變分級,小結(jié)：與NAFLD的相互關(guān)系,,胰島素抵抗相關(guān)IR影響抗病毒療效,脂肪肝分級與CHC患者肝細(xì)胞癌風(fēng)險相關(guān),慢性病毒性肝炎合并脂肪肝的治療現(xiàn)狀,改變生活方式，包括運動和減重：但在HCV合并脂肪肝人群中尚缺乏正

33、規(guī)的臨床研究數(shù)據(jù)。1抗病毒治療。2抗炎保肝類藥物：保護(hù)肝細(xì)胞、拮抗氧應(yīng)激脂質(zhì)過氧化、抗炎、抗凋亡、抗纖維化，還避免使用減肥和調(diào)脂藥物誘發(fā)的肝膽損傷。2胰島素增敏劑：改善胰島素抵抗；提高持久病毒學(xué)應(yīng)答率？需要進(jìn)一步臨床研究的證明。1他汀類藥物：用于CHC合并脂肪肝的治療需要更大型、前瞻性、隨機(jī)研究數(shù)據(jù)評估。1,Anish Patel, and Stephen A. Harrison. Gastroenterology &

34、Hepatology, 2012;8(5):305-312施軍平, 等. 實用肝臟病雜志, 2008; 11(4):278-280,多項研究提示改變生活方式有效改善脂肪肝,Valerio Nobili, et al. BMC Medicine 2011, 9:70,通過生活方式干預(yù)代謝綜合征對抗病毒療效的影響,Tarantino G, et al. Gut. 2006;55:585,病毒學(xué)應(yīng)答率，HCV-RNA >2 lo

35、g 10,n=17,n=15,All patients were offered standard combined antiviral therapy Peg-interferon alpha 2b 1.5 mg/kg body weight/weekly and ribavirin 1000–1200 mg/daily) for at least three months for non-responders (same virol

36、ogical load before and after) and for 12 months if responders or partial responders (decrease in HCV-RNA >2 log 10),P=0.035 X2,有效的抗病毒治療顯著改善基因3型丙肝患者脂肪肝情況,L Castera, et al. Gut 2004;53:420–424,A total of 151 patients (

37、37 with HCV genotype 3; 114 with HCV non-3 genotypes) were selected to study the relationship between steatosis evolution and HCV clearance after antiviral treatment in patients with chronic hepatitis C and paired liver

38、biopsies,,Improvement was defined as a decrease of at least one grade between the two biopsies; stability was defined as identical grades between the two biopsies; worsening of steatosis was defined as an increase of a

39、t least one grade between the two biopsies,抗病毒治療后與脂肪肝改善相關(guān)的獨立影響因素,L Castera, et al. Gut 2004;53:420–424,A total of 151 patients (37 with HCV genotype 3; 114 with HCV non-3 genotypes) were selected to study the relationsh

40、ip between steatosis evolution and HCV clearance after antiviral treatment in patients with chronic hepatitis C and paired liver biopsies,,服用胰島素增敏劑二甲雙胍有效改善基因1型丙肝患者胰島素抵抗,Peg 干擾素-α+利巴韋林+二甲雙胍Peg 干擾素-α+利巴韋林,Jian-Wu Yu, et

41、al. International Journal of Infectious Diseases 2012;16 :e436–e441,P<0.01,胰島素增敏劑能否提高抗病毒治療應(yīng)答率？,Kathrin Overbeck, et al. Journal of Hepatology 2008;49 :295–298,胰島素增敏劑吡格列酮對抗病毒療效的影響與丙肝基因型的關(guān)系,Mahmoud Khattab, et al. Li

42、ver Int. 2010 Mar;30(3):447-54,Ninety-seven previously untreated patients with CHC and IR were randomly assigned into two arms; (arm A; n = 48) were given pioglitazone 30 mg/day combined with peginterferon (Peg-IFN)-a-2b

43、/ ribavirin (RBV) for 48 weeks, and (arm B; n = 49) were given standard of care (Peg-IFN-a-2b/RBV for 48 weeks); HOMA index and hepatitis C virus RNA (HCV RNA) levels were measured at baseline, during therapy and follow-

44、up,胰島素增敏劑二甲雙胍對基因1型丙肝患者抗病毒治療療效的影響,prospective, multicentered, randomized, double-blinded, placebo-controlled trial in 19 Spanish hospitals, including 123 consecutive patients with genotype 1 chronic hepatitis C and insul

45、in resistance. Patients were randomized to receive either metformin (arm A; n =59) or placebo (arm B; n =64) in addition to peginterferon alfa-2a (180 g/week) and ribavirin (1000-1200 mg/day). The primary end point was S

46、VR,Manuel Romero-G ′ omez, et al. HEPATOLOGY 2009;50:1702-1708,他汀對丙肝抗病毒治療療效的影響,Ben Verpaalen, et al. Antiviral Research 2014;105: 92–99,保肝藥物的治療作用,保護(hù)肝細(xì)胞,拮抗氧化應(yīng)激/脂質(zhì)過氧化,抗纖維化,抗凋亡,避免使用減肥和調(diào)脂藥物誘發(fā)的肝膽損傷,施軍平, 等. 實用肝臟病雜志, 2008; 11(4

47、):278-280,抗炎保肝藥物的用藥原則,應(yīng)按照循證醫(yī)學(xué)的原則選用，以提高療效。不宜同時應(yīng)用過多特別是同類抗炎保肝藥物，以免加重肝臟負(fù)擔(dān)及藥物間相互作用。大多數(shù)藥物以口服給入。但肝衰竭時多以靜脈給藥為主，對肝炎突發(fā)患者常見靜脈滴注后改用口服的序貫療法。用藥期間應(yīng)定期觀察患者的癥狀、體征和肝功能變化，必要時及時調(diào)整用藥方案。部分藥物有一定不良反應(yīng)。用于肝衰竭時尤應(yīng)謹(jǐn)慎并注意鑒別，以免誤判誤診。,中華醫(yī)學(xué)會感染病學(xué)分會，肝臟炎癥及

48、其防治專家共識專家委員會.中國實用內(nèi)科雜志, 2014; 34(2):152-162,多烯磷脂酰膽堿聯(lián)合干擾素有效提高慢性丙肝患者生化應(yīng)答率(24w),Niederau C et al: Hepato Gastroenterology 1998;45:797-804,ALT降低>50%有效P=0.016,治療24周時，慢性丙肝患者的生化（ALT）應(yīng)答率,ALT降低>50%的病人比例,試驗發(fā)現(xiàn)， IFN+PPC組比 IFN

49、+安慰劑組可實現(xiàn)更好的ALT治療反應(yīng)率。在 24周時，ALT降低>50%的病人比例IFN+PPC組顯著多于IFN+安慰劑組。表明，多烯磷脂酰膽堿膠囊可以改善病毒性肝炎患者的肝功能水平，有效治療病毒性肝炎。,基礎(chǔ)治療: a-干擾素Hep.B: 5 mio I.U. s.c. 3x 每周，24周，Hep.C: 3 mio I.U. s.c. 3x 每周，24周。試驗藥物:3 x 2 膠囊， PPC 每日使用 (1.8 g/天)或 3

50、x 2 膠囊，安慰劑每日使用24周，有效者（ALT 下降 > 50％）繼續(xù)治療24周，176 病人完成試驗: Hep.B. 22/25（47）， Hep.C 70/59（129）,多烯磷脂酰膽堿聯(lián)合干擾素48周時慢性丙肝患者ALT復(fù)常率,Niederau C et al: Hepato Gastroenterology 1998;45:797-804,P=0.06,治療24周時ALT降低>50％的病人，停用IFN，繼續(xù)

51、使用PPC（每日3次，每次2粒）或安慰劑治療，第48周時的ALT復(fù)常率,ALT正常的病人比例,基礎(chǔ)治療: a-干擾素Hep.B: 5 mio I.U. s.c. 3x 每周，24周，Hep.C: 3 mio I.U. s.c. 3x 每周，24周。試驗藥物:3 x 2 膠囊， PPC 每日使用 (1.8 g/天)或 3x 2 膠囊，安慰劑每日使用24周，有效者（ALT 下降 > 50％）繼續(xù)治療24周，176 病人完成試驗:

52、Hep.B. 22/25（47）， Hep.C 70/59（129）,小結(jié)：丙肝合并脂肪肝的危害和治療策略,HCV與脂肪肝在發(fā)病機(jī)理上相互促進(jìn)；NAFLD合并HCV和IR降低抗病毒治療的病毒學(xué)應(yīng)答率；治療策略包括針對脂肪肝的基礎(chǔ)治療、抗病毒治療和保肝治療等；胰島素增敏劑和他汀類對抗病毒治療效果的影響尚需進(jìn)一步的研究；抗炎保肝藥物如多烯磷脂酰膽堿，聯(lián)合干擾素能提高干擾素治療丙肝的療效。,總 結(jié),病毒性肝炎合并脂肪肝非常常見。