学术讨论—白蛋白与肝硬化-刘文徽7-10-PPT文档.pptx

概概 要要人血白蛋白简介人血白蛋白简介肝硬化概述(i sh)人血白蛋白在肝硬化并发症治疗中应用第一页，共六十九页。人血白蛋白制品人血白蛋白制品(zhpn)是从健康人血浆中提纯的一类特殊药品。目前国内外临床需求量最大、使用最多、最安全(nqun)的一种血浆蛋白制品。与血浆相比，最大优势是经过病毒灭活处理，无传播病毒性传染病可能。第二页，共六十九页。白蛋白分子白蛋白分子(fnz)特性特性白蛋白含量最多，占52-58%。610个AA组成的多肽，不含糖，仅少量脂肪酸。分子量小，67KD。健康人血浆半衰期17-21天，危重患者(hunzh)则仅9天。水溶性好，粘度低，25%的白蛋白粘度与全血相当。第三页，共六十九页。白蛋白的生理功能白蛋白的生理功能维持和调节胶体渗透压 占血浆总胶体渗透压80%。运输 转运各种离子、激素(j s)、胆红素、药物等。解毒 如汞中毒。营养供给 合成组织蛋白、氧化供能、氮源为组织提供营养。促进肝细胞修复和再生。第四页，共六十九页。适应症适应症低蛋白血症（营养不良、合成障碍、丢失过多）大面积烧伤（补晶体液、补蛋白、维持血容量）血浆置换（丢失蛋白要及时补充，尤其有肝肾疾患者(hunzh)）扩容、维持胶体渗透压体外循环（用白蛋白和晶体液做底液，比血液安全，减少肾衰危险）新生儿溶血病（结合游离胆红素，避免胆红素脑病）脑水肿（提高胶渗压，减轻脑水肿）第五页，共六十九页。不良反应不良反应与血浆与血浆(xujing)相比要低得多相比要低得多偶有寒战、发热、头痛症状，需对症处理(chl)。快速输注可引起循环超负荷导致肺水肿。极少发生低血压、呼吸困难、甚至休克等严重过敏性变态反应。输注被污染的白蛋白，会出现菌血症、休克甚至败血症。第六页，共六十九页。禁忌症禁忌症对白蛋白有严重过敏者病情难以承受血容量迅速增加，如心衰或心功能(gngnng)低下、高血压患者、肺功能(gngnng)不全严重贫血患者肾功能不全者脱水状态尚未补足液体第七页，共六十九页。小小 结结适应症广泛、副反应极少。提高胶体渗透压功能更强，时间更持久。制品纯度高，副作用小，无需考虑(kol)血型相合问题。浓缩制品体积小，最高浓度可达25%，质量稳定。使用和储存方便，便于运输。第八页，共六十九页。概概 要要人血白蛋白简介(jin ji)肝硬化概述肝硬化概述人血白蛋白在肝硬化并发症治疗中应用第九页，共六十九页。肝硬化概念肝硬化概念(ginin)是一个病理解剖学概念多种原因引起的慢性、进行性、弥漫性肝病肝细胞弥漫性变性、坏死、凋亡残存肝细胞再生、结节结缔组织增生形成纤维隔正常小叶(xioy)结构破坏代之硬化结节或假小叶Normal liver histologyCirrhotic liver histology第十页，共六十九页。病病 因因病毒感染 乙、丙肝最常见、丁型、日本血吸虫病。药物与毒物 酒精、甲氨蝶呤、CCl4。代谢性 肝豆状核变性、血色病。心血管疾病 慢性右心衰竭、布-加综合征等等。其他可能原因 自身免疫性肝炎、空回肠(huchng)短路术后 营养不良。第十一页，共六十九页。肝硬化病理肝硬化病理(bngl)生理与主要并发症生理与主要并发症门静脉高压症侧支循环建立与扩大(kud)腹水形成腹水形成肝肾综合征自发性细菌性腹膜炎肝性脑病肝肺综合征原发性肝癌严重感染第十二页，共六十九页。Slight decrease in effective arterial blood volumeIncreased blood/plasma volumePortal hypertensionCIRRHOSISCirculatory function in early cirrhosisRAA,renin-angiotensin-aldosterone;ADH,antidiuretic hormoneRenal retention of sodium and waterIncreased cardiac outputRelease of vasodilators e.g.nitric oxidePRIMARY PATHOPHYSIOLOGICAL EVENTDecreased systemic vascular resistance;pooling of intravascular volume at splanchnic levelTransient activation of low and high pressure baroreceptors and RAAS,release of ADH and anti-natriuretic factorsModerate splanchnic arterial vasodilatationMAINTENANCE OF EFFECTIVE BLOOD VOLUME第十三页，共六十九页。RAA,renin-angiotensin-aldosterone;ADH,antidiuretic hormoneMarked decrease in effective arterial blood volume血容量(rngling)明显下降Increased blood/plasma volume血容量(rngling)增加Portal hypertension门脉高压(goy)CIRRHOSISCirculatory function in advanced cirrhosisAvid renal retention of sodium and water钠水潴留+Increased cardiac outputRelease of vasodilators e.g.nitric oxidePRIMARY PATHOPHYSIOLOGICAL EVENTDecreased systemic vascular resistance;pooling of intravascular volume at splanchnic levelPronounced splanchnic arterial vasodilatationChronic activation of baroreceptors and RAA system,release of ADH and anti-natriuretic factorsINADEQUATE MAINTENANCE OF EFFECTIVE BLOOD VOLUME有效循有效循环血容量不能充分血容量不能充分维护第十四页，共六十九页。Prognostic scoring of cirrhosis肝硬化预后肝硬化预后(yhu)评分评分PT,prothrombin time;MELD,Model for End-stage Liver Disease;INR,international normalised ratio1Pugh et al.Br J Surg 1973;60:646649;2Kamath et al.Hepatology 2001;33:464470Prognostic scoring systemBiochemical parameters生化指生化指标标Clinical factors临床因素临床因素Scoring method评分方法评分方法Child-Pugh-Turcotte1总胆红素血清白蛋白凝血酶原时间延长Extent of ascites腹水Grade of hepatic encephalopathy肝性脑病分级Value of biochemical parameters and level of clinical factors used to stratify patients into three classes:A,B and C(good,moderate and poor operative risks,respectively)Class correlates with prognosis第十五页，共六十九页。概概 要要人血白蛋白简介肝硬化概述(i sh)人血白蛋白在肝硬化并发症治疗中应用人血白蛋白在肝硬化并发症治疗中应用第十六页，共六十九页。白蛋白在肝硬化并发症的治疗白蛋白在肝硬化并发症的治疗(zhlio)难治性腹水大容量穿刺难治性腹水大容量穿刺(chunc)后循环功能障碍的防治后循环功能障碍的防治自发性细菌性腹膜炎治疗中肾损伤的预防肝肾综合征治疗中血管收缩的辅助用药第十七页，共六十九页。AscitesLVP,large-volume paracentesisGins&Arroyo.Eur J Gastroenterol Hepatol 1991;91:730734;EASL clinical practice guidelines on the management of ascites,spontaneous bacterial peritonitis,and hepatorenal syndrome in cirrhosis.J Hepatol 2010;53:397417腹水指过多的液体在腹腔内积聚腹水指过多的液体在腹腔内积聚是是肝硬化最常见的并发症肝硬化最常见的并发症病史病史10年以上肝硬化患者腹水发生近年以上肝硬化患者腹水发生近50%传统治疗传统治疗(zhlio)方案方案低钠饮食低钠饮食利尿剂应用利尿剂应用LVP穿刺穿刺James Heilman,MD/CC-BY-SA-3.0第十八页，共六十九页。RAA,renin-angiotensin aldosterone;ADH,antidiuretic hormoneDecrease in effective arterial blood volumeIncreased blood/plasma volumePortal hypertension CIRRHOSISPathophysiology of ascitesRenal retention of sodium and waterIncreased hydrostatic pressure in liver sinusoidsIncreased hepatic lymph production and transudation in peritoneumPRIMARY PATHOPHYSIOLOGICAL EVENTRelease of vasodilators e.g.nitric oxideDecreased systemic vascular resistance;pooling of intravascular volume at splanchnic levelSplanchnic arterial vasodilatationChronic activation of baroreceptors and RAA system,release of ADH and anti-natriuretic factorsASCITES第十九页，共六十九页。Grading of ascites腹水腹水(fshu)分级分级GradeDefinitionDetection1Mild仅能通过超声测出2Moderate中度对称性腹胀（蛙状腹）3Large or gross腹部膨隆（张力增高）EASL clinical practice guidelines on the management of ascites,spontaneous bacterial peritonitis,and hepatorenal syndrome in cirrhosis.J Hepatol 2010;53:397417第二十页，共六十九页。轻、中度腹水轻、中度腹水(fshu)治疗治疗轻度(grade 1)不需治疗，根据欧洲肝病研究学会指南，尚无轻度腹水进展到中、重度腹水的相关资料。中度腹水(grade 2):诱导负钠平衡，抵消肾钠潴留。限钠 4-6g/d，10%-20%患者有效。利尿首选醛固酮拮抗剂初始100mg/d，无效，增加100mg/7d直至(zhzh)400mg/d。最大剂量仍无效，加用呋塞米40mg/d，最大160mg/d。联合治疗是复发性腹水最合适的治疗方案。第二十一页，共六十九页。补充补充(bchng)白蛋白对利尿剂效果的影响白蛋白对利尿剂效果的影响(RCT)Gentilini et al.J Hepatol 1999;30:639645HypothesisIntravascular volume expansion with human albumin exerts beneficial effects in patients with ascites receiving diureticsAlbumin supplementation increases the rate of responders to diuretic therapyRegimenPatients received potassium canrenoate(200 mg/day)for a week;non-responders also received furosemide(25 mg/day),followed by increased doses of both diuretics in case of continued non-responseProtocol 163 patients received diuretics alone(Group A);63 patients received diuretics plus albumin(Group B)Protocol 2Patients from Protocol 1 followed after discharge from hospital after mobilisation of ascites第二十二页，共六十九页。Results1:白蛋白增加白蛋白增加(zngji)了利尿剂的治疗效果了利尿剂的治疗效果！p0.05Group A Group BGentilini et al.J Hepatol 1999;30:639645第二十三页，共六十九页。Further evidence for the effects of albumin on survival in patients with ascites was provided by an open-label randomised comparative study of 100 patients.The aim of this study was to determine the effects of albumin administration on the survival of patients,recurrence of ascites and incidence of further complications.Patients admitted to hospital with first-onset ascites were randomised to receive either diuretics plus albumin or diuretics alone.Albumin was administered at a dose of 25 g per week for the first year of the study,progressing to 25 g every 2 weeks for the remaining study period.补充白蛋白对腹水补充白蛋白对腹水(fshu)患者生存率的影响患者生存率的影响第二十四页，共六十九页。Results:长期的白蛋白补充长期的白蛋白补充(bchng)显著提高腹水患者生存率显著提高腹水患者生存率！Romanelli et al.World J Gastroenterol 2006;12:1403140701224364860728496108120p6L的LVP，白蛋白组PPCD发生率显著(xinzh)低于高张盐水组！Incidence of PPCD第三十二页，共六十九页。Evidence comparing albumin and dextran 70 and gelatin in large-volume paracentesisGins et al.Gastroenterology 1996;111:10021010Patients randomised to receive either albumin（n=97）,dextran 70（n=93）or gelatin(n=polygeline)（99）8 g per L removed50%of dose within 2 hours of paracentesis 50%68 hours after5 L LVP，白蛋白组PPCD发生率明显(mngxin)低于右旋糖苷组！p=0.04p=0.02 第三十三页，共六十九页。European guidelines for LVPEASL clinical practice guidelines on the management of ascites,spontaneous bacterial peritonitis,and hepatorenal syndrome in cirrhosis.Hepatol 2010;53:397417LVP is the first-line therapy for grade 3 ascitesLVP should be completed in a single sessionAlbumin(8 g/L ascitic fluid removed)should be administered to prevent PPCDLVP 5 L:albumin must be used;other plasma expanders are less effective at preventing PPCDLVP 5 L ascitic fluid are removed albumin dose 8 g/L of fluid removed The underlying cause of ascites should be addressedLVP should be followed by dietary restriction and diuretic therapy to reverse sodium retention and prevent fluid re-accumulation第三十五页，共六十九页。Home treatment of ascites with albuminTreatment of ascites with albumin can be prolongedA Delphi study sought consensus on several issues surrounding the use of albumin,including its use at home following discharge from hospitalIt was agreed that benefits of domiciliary albumin could includereduced rate of ascites relapseimproved response to diureticsenhanced quality of lifedecreased need for hospitalisationGentilini et al.Dig Liver Dis 2004;36:539346第三十六页，共六十九页。小小 结结腹水的形成提示预后不良(bling)。LVP是3级腹水的一线治疗。LVP后同时应用血浆扩容剂对预防PPCD至关重要。第三十七页，共六十九页。白蛋白在肝硬化并发症的治疗白蛋白在肝硬化并发症的治疗(zhlio)难治性腹水大容量穿刺后循环功能障碍的防治自发性细菌性腹膜炎治疗中肾损伤自发性细菌性腹膜炎治疗中肾损伤(snshng)的预防的预防肝肾综合征治疗中血管收缩的辅助用药第三十八页，共六十九页。自发性细菌性腹膜炎自发性细菌性腹膜炎(SBP)SBP 又称原发性或特发性腹膜炎，指在腹腔内或邻近组织又称原发性或特发性腹膜炎，指在腹腔内或邻近组织(zzh)内没有感染源（如腹腔脓肿、急性胰腺炎、胆囊炎、肠穿孔等）内没有感染源（如腹腔脓肿、急性胰腺炎、胆囊炎、肠穿孔等）情况下发生的腹膜急性弥漫性细菌感染。情况下发生的腹膜急性弥漫性细菌感染。肝硬化是发生肝硬化是发生SBP最常见的基础疾病。最常见的基础疾病。也可发生于急性肝衰竭及肾病综合征或晚期肿瘤伴大量腹水也可发生于急性肝衰竭及肾病综合征或晚期肿瘤伴大量腹水的患者。的患者。第三十九页，共六十九页。自发性细菌性腹膜炎自发性细菌性腹膜炎(SBP)SBP 是肝硬化腹水是肝硬化腹水(fshu)常见而严重的并发症，发生率高达常见而严重的并发症，发生率高达10%-25%，国际腹水俱乐部的统计资料是，国际腹水俱乐部的统计资料是10%-30%。重型肝炎重型肝炎SBP发生率发生率17.7%-47%，预后较肝硬化，预后较肝硬化SBP更差。更差。临床表现可为典型的腹膜炎，也可完全无症状。临床表现可为典型的腹膜炎，也可完全无症状。易漏诊，预后差，病死率高。易漏诊，预后差，病死率高。第四十页，共六十九页。自发性细菌性腹膜炎自发性细菌性腹膜炎(SBP)诊断主要依靠诊断主要依靠(yko)诊断性腹腔穿刺后腹水多形核细胞计数和腹诊断性腹腔穿刺后腹水多形核细胞计数和腹水培养。水培养。腹水培养阳性率低，国外报道腹水培养阳性率低，国外报道40%，国内更低，国内更低腹水腹水PMN计数最敏感的临界值计数最敏感的临界值 (0.25x109/L)最特异的临界值最特异的临界值0.5x109/L推荐对肝硬化腹水患者进行诊断性腹腔穿刺进行筛查。推荐对肝硬化腹水患者进行诊断性腹腔穿刺进行筛查。第四十一页，共六十九页。SBP肾损害肾损害(snhi)1/3的的SBP患者发生肾功能损害。患者发生肾功能损害。肾功能的恶化与肾功能的恶化与RAAS激活，肾脏血管收缩，有效灌激活，肾脏血管收缩，有效灌注不足有关。注不足有关。因此扩容治疗因此扩容治疗(zhlio)可能获益。可能获益。1Follo et al.Hepatology 1994;20:14951501;2Navasa et al.Hepatology 1998;27:12271232;3Sort et al.N Engl J Med 1999;341:403409第四十二页，共六十九页。Effects of albumin infusion on renal impairment in SBPSort et al.N Engl J Med 1999;341:403409HypothesisPlasma volume expansion with intravenous albumin prevents renal impairment and decreases mortality in patients with cirrhosis and SBPProtocol 1n=63:intravenous cefotaxime at daily doses according to the serum creatinine levelProtocol 2n=63:intravenous cefotaxime at daily doses according to the serum creatinine level plus intravenous albumin at 1.5 g/kg body weight at diagnosis(Day 1),followed by 1 g/kg on Day 3 第四十三页，共六十九页。Results:白蛋白联合抗生素（头孢噻肟）白蛋白联合抗生素（头孢噻肟）有效预防有效预防(yfng)了了SBP肾损害！降低了在院以及肾损害！降低了在院以及3个月死亡率！个月死亡率！Sort et al.N Engl J Med 1999;341:403409Patients(%)p=0.002p=0.01p=0.0321/636/6318/636/6314/6326/63第四十四页，共六十九页。Albumin infusion in SBPSBP,spontaneous bacterial peritonitis;RCTs,randomised controlled trialsSalerno et al.Clin Gastroenterol Hepatol 2013;11:123130AimTo evaluate the effect of albumin infusion on patients with SBP Study designMeta-analysis of RCTs Studies included4 RCTs(N=228);albumin vs no albumin(3 trials),albumin vs artificial colloid(1 trial)Primary endpointsIncidence of renal impairmentMortality第四十五页，共六十九页。Results:Albumin infusion in SBPSBP,spontaneous bacterial peritonitis;RCT,randomised controlled trials;AASLD,American Association for the Study of Liver Diseases Salerno et al.Clin Gastroenterol Hepatol 2013;11:123130This meta-analysis provides the basis for a Level A recommendation that patients with SBP should be treated with albumin Albumin infusion decreased the incidence of renal impairment and mortality in patients with SBPEuropean guidelines recommend all patients with SBP should receive albumin infusion until further evidence is available2 第四十六页，共六十九页。小小 结结肝硬化腹水住院患者中，SBP发生率10%。肾损害(snhi)是SBP的常见并发症。白蛋白输注预防SBP患者肾衰竭的发生。推荐白蛋白作为SBP治疗中广谱抗生素的辅助用药。第四十七页，共六十九页。白蛋白在肝硬化并发症的治疗白蛋白在肝硬化并发症的治疗(zhlio)难治性腹水大容量穿刺后循环功能障碍的防治自发性细菌性腹膜炎治疗中肾损伤的预防肝肾肝肾(n shn)综合征治疗中血管收缩的辅助用药综合征治疗中血管收缩的辅助用药第四十八页，共六十九页。肝肾肝肾(n shn)综合征综合征Hepatorenal syndrome是严重肝脏病变时发生的无肾脏器质性病变的一种功是严重肝脏病变时发生的无肾脏器质性病变的一种功能性肾衰竭。能性肾衰竭。是终末期肝病的严重并发症。是终末期肝病的严重并发症。腹水患者中，腹水患者中，1 year:18%;at 5 years:39%2病情顽固、预后病情顽固、预后(yhu)凶险。凶险。平均中位生存期平均中位生存期3月月功能性肾衰持续可导致急性肾衰。功能性肾衰持续可导致急性肾衰。第四十九页，共六十九页。肝肾肝肾(n shn)综合征的病理生理机制综合征的病理生理机制门脉高压时内脏血管扩张导致有效循环血量减少、平均动脉压的下降。为了恢复有效循环血量和动脉压，血管收缩机制启动。RAAS激活以及其他血管收缩介质释放(shfng)SNA激活 结果肾血管收缩，肾灌注不足，肾功能损害。RAA,renin-angiotensin-aldosterone Gins et al.Lancet 2003;362:18191827;EASL clinical practice guidelines on the management of ascites,spontaneous bacterial peritonitis,and hepatorenal syndrome in cirrhosis.J Hepatol 2010;53:397417第五十页，共六十九页。Marked decrease in effective arterial blood volumeIncreased blood/plasma volumePortal hypertensionCIRRHOSISCirculatory and renal function in advanced cirrhosisAvid renal retention of sodium and waterIncreased cardiac outputRAA,renin-aldosterone-angiotensin;ADH,antidiuretic hormoneRelease of vasodilators e.g.nitric oxidePRIMARY PATHOPHYSIOLOGICAL EVENTDecreased systemic vascular resistance;pooling of intravascular volume at splanchnic levelPronounced splanchnic arterial vasodilatationMAINTENANCE OF RENAL PERFUSIONActivation of low and high pressure baroreceptors and RAA system,release of ADH and anti-natriuretic factors第五十一页，共六十九页。Pathogenesis of hepatorenal syndromeMarked decrease in effective arterial blood volumeIncreased blood/plasma volumePortal hypertension CIRRHOSISRAA,renin aldosterone angiotensin;ADH,antidiuretic hormoneRenal retention of sodium and waterInsufficient increase in cardiac outputRelease of vasodilators e.g.nitric oxidePRIMARY PATHOPHYSIOLOGICAL EVENTDecreased systemic vascular resistance;pooling of intravascular volume at splanchnic levelPronounced splanchnic arterial vasodilatationActivation of low and high pressure baroreceptors and RAA system,release of ADH and anti-natriuretic factorsCardiac dysfunctionImpaired activity of renal vasodilator systemsHEPATORENAL SYNDROME第五十二页，共六十九页。HRS,hepatorenal syndromeGins et al.Lancet 2003;362:18191827;Lameire et al.Lancet 2005;385:417430 Diagnosis of hepatorenal syndromeRENAL FAILURE(Serum creatinine 1.5 mg/dL)Nephrotoxic drugsVolume depletionShockBiochemicalparametersAbnormalrenal ultrasonographySigns of infectionProteinuriaand/or haematuriaClinical signsRenalultrasonographyHRSPRERENAL FAILUREACUTE TUBULARNECROSISINFECTION-INDUCEDRENAL FAILURENEPHROTOXICITYPARENCHYMALNEPHROPATHY第五十三页，共六十九页。Classification of hepatorenal syndrome:Type 1SBP,spontaneous bacterial peritonitisSalerno et al.Gut 2007;56:13101318;EASL clinical practice guidelines on the management of ascites,spontaneous bacterial peritonitis,and hepatorenal syndrome in cirrhosis.J Hepatol 2010;53:397417Rapidly progressive acute renal failure急进(jjn)性肾衰竭Defined by doubling of initial serum creatinine to 226 mol/L(2.5 mg/dL)within 2 weeksOften develops following a precipitating event(e.g.SBP)but may occur spontaneouslyAssociated withacute deterioration of circulatory function(arterial hypotension and activation of the endogenous vasoconstrictor systems)rapid impairment in liver function and encephalopathyVery poor prognosismean survival approximately 1 month if untreated第五十四页，共六十九页。Classification of hepatorenal syndrome:Type 2HRS,hepatorenal syndrome;SBP,spontaneous bacterial peritonitisSalerno et al.Gut 2007;56:13101318;EASL clinical practice guidelines on the management of ascites,spontaneous bacterial peritonitis,and hepatorenal syndrome in cirrhosis.J Hepatol 2010;53:397417Slowly progressive moderate renal failure缓慢(hunmn