1、概概 要要 人血白蛋白简介人血白蛋白简介 肝硬化概述 人血白蛋白在肝硬化并发症治疗中应用人血白蛋白制品人血白蛋白制品 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。白蛋白分子特性白蛋白分子特性 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，危重患者则仅9天。水溶性好，粘度低，25%的白蛋白粘度与全血相当。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
2、离子、激素、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。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）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）不良反应不良反应与血浆相比要低得多与血浆相比要低得多 偶有寒战、发热、头痛症状，需对症处理。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
3、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。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，如心衰或心功能低下、高血压患者、肺功能不全 严重贫血患者 肾功能不全者 脱水状态尚未补足液体小小 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。概概 要要 人血白蛋白简介 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肝硬化概念肝硬化概念 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
4、亡 残存肝细胞再生、结节 结缔组织增生形成纤维隔 正常小叶结构破坏 代之硬化结节或假小叶Normal liver histologyCirrhotic liver histology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、空回肠短路术后 营养不良。肝硬化病理生理与主要并发症肝硬化病理生理与主要并发症 门静脉高压症 侧支循环建立与扩大 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Slight
5、 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 oxidePRI
6、MARY 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 B
7、LOOD VOLUMERAA,renin-angiotensin-aldosterone;ADH,antidiuretic hormoneMarked decrease in effective arterial blood volume血容量明显下降Increased blood/plasma volume血容量增加Portal hypertension门脉高压CIRRHOSISCirculatory function in advanced cirrhosisAvid renal retention of sodium and water钠水潴留+Increased cardiac out
8、putRelease 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 fac
9、torsINADEQUATE MAINTENANCE OF EFFECTIVE BLOOD VOLUME有效循环血容量不能充分维护有效循环血容量不能充分维护Prognostic scoring of cirrhosis肝硬化预后评分肝硬化预后评分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;33:464470Prognost
10、ic 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,
11、B and C(good,moderate and poor operative risks,respectively)Class correlates with prognosis概概 要要 人血白蛋白简介 肝硬化概述 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 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 难治性腹水大容量穿刺后循环功能障碍的防治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 肝肾综合征治疗中血管收缩的辅助用药AscitesLVP,large-volume paracentesisGins&Arroyo.Eu
12、r 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%传统治疗方案传统治疗方案
13、 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-3.0RAA,renin-angiotensin aldosterone;ADH,antidiuretic hormoneDecrease in effective arterial blood volumeIncreased blood/plasma volumePortal hypertension CIRRHOSISPathophysiology of ascitesRenal retention of sodium and waterIncreased hydrostatic p
14、ressure 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 activ
15、ation of baroreceptors and RAA system,release of ADH and anti-natriuretic factorsASCITESGrading of ascites腹水分级腹水分级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 he
16、patorenal syndrome in cirrhosis.J Hepatol 2010;53:397417轻、中度腹水治疗轻、中度腹水治疗 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。补充白蛋白对利尿剂效果的影响补充白蛋白对利尿剂效果的影响(RCT)G
17、entilini et al.J Hepatol 1999;30:639645Hypothesis Intravascular volume expansion with human albumin exerts beneficial effects in patients with ascites receiving diuretics Albumin supplementation increases the rate of responders to diuretic therapyRegimen Patients received potassium canrenoate(200 mg
18、/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 1 63 patients received diuretics alone(Group A);63 patients received diuretics plus albumin(Group B)Protocol 2 Patients from Protocol 1 followed
19、after discharge from hospital after mobilisation of ascitesResults1:白蛋白增加了利尿剂的治疗效果！白蛋白增加了利尿剂的治疗效果！p0.05Group A Group BGentilini et al.J Hepatol 1999;30:639645 Further evidence for the effects of albumin on survival in patients with ascites was provided by an open-label randomised comparative study o
20、f 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 diur
21、etics 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.补充白蛋白对腹水患者生存率的影响补充白蛋白对腹水患者生存率的影响Results:长期的白蛋白补充显著提高腹水患者生存率！长期的白蛋白补充显著提高腹水患者生存率！Romanelli et al.World J Gastroenterol 2006;12:1403140701224
22、364860728496108120p6L的LVP，白蛋白组PPCD发生率显著低于高张盐水组！Incidence of PPCDEvidence 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 rem
23、oved 50%of dose within 2 hours of paracentesis 50%68 hours after5 L LVP，白蛋白组PPCD发生率明显低于右旋糖苷组！p=0.04p=0.02 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
24、 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 PPCD LVP 5 L:albumin must be used;other plasma expanders are less effective at preventing PPCD LVP 5 L ascitic fluid are removed albumin dose 8 g/L
25、of fluid removed The underlying cause of ascites should be addressed LVP should be followed by dietary restriction and diuretic therapy to reverse sodium retention and prevent fluid re-accumulationHome treatment of ascites with albumin Treatment of ascites with albumin can be prolonged A Delphi stud
26、y sought consensus on several issues surrounding the use of albumin,including its use at home following discharge from hospital It was agreed that benefits of domiciliary albumin could include reduced rate of ascites relapse improved response to diuretics enhanced quality of life decreased need for
27、hospitalisationGentilini et al.Dig Liver Dis 2004;36:539346小小 结结 腹水的形成提示预后不良。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。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 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内没有感染源（如腹
28、腔脓肿、急性胰腺炎、胆囊炎、肠穿内没有感染源（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。孔等）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。水的患者。自发性细菌性腹膜炎自发性细菌性腹膜炎(SBP)SBP 是肝硬化腹水常见而严重的并发症，发生率高达是肝硬化腹水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
29、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。自发性细菌性腹膜炎自发性细菌性腹膜炎(SBP)诊断主要依靠诊断性腹腔穿刺后腹水多形核细胞计数和腹诊断主要依靠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
30、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。SBP肾损害肾损害 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。因此扩容治疗可能获益。因此扩容治疗可能获益。1Follo et al.Hepatology 1994;20:14951501;2Navasa et al.Hepatology 1998;27:12271232;3Sort et al.N Engl J Med 1999;341:403409Effects of albumin infusi
31、on on renal impairment in SBPSort et al.N Engl J Med 1999;341:403409Hypothesis Plasma volume expansion with intravenous albumin prevents renal impairment and decreases mortality in patients with cirrhosis and SBPProtocol 1 n=63:intravenous cefotaxime at daily doses according to the serum creatinine
32、levelProtocol 2 n=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 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）有效预防了有效预防了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
33、Med 1999;341:403409Patients(%)p=0.002p=0.01p=0.0321/636/6318/636/6314/6326/63Albumin 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 d
34、esign Meta-analysis of RCTs Studies included 4 RCTs(N=228);albumin vs no albumin(3 trials),albumin vs artificial colloid(1 trial)Primary endpoints Incidence of renal impairment MortalityResults:Albumin infusion in SBPSBP,spontaneous bacterial peritonitis;RCT,randomised controlled trials;AASLD,Americ
35、an 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
36、 patients with SBPEuropean guidelines recommend all patients with SBP should receive albumin infusion until further evidence is available2 小小 结结 肝硬化腹水住院患者中，SBP发生率10%。肾损害是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。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 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 肝肾综合征治疗中血管
37、收缩的辅助用药肝肾综合征治疗中血管收缩的辅助用药肝肾综合征肝肾综合征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。一种功能性肾衰竭。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、预后凶险。病情顽固、预后凶险。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。肝肾综合征的病理生理机制肝肾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
38、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 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
39、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 vasodila
40、tors 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 an
41、d anti-natriuretic factorsPathogenesis 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 outp
42、utRelease 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-na
43、triuretic factorsCardiac dysfunctionImpaired activity of renal vasodilator systemsHEPATORENAL SYNDROMEHRS,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 dep
44、letionShockBiochemicalparametersAbnormalrenal ultrasonographySigns of infectionProteinuriaand/or haematuriaClinical signsRenalultrasonographyHRSPRERENAL FAILUREACUTE TUBULARNECROSISINFECTION-INDUCEDRENAL FAILURENEPHROTOXICITYPARENCHYMALNEPHROPATHYClassification of hepatorenal syndrome:Type 1SBP,spon
45、taneous 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;53:397417 Rapidly progressive acute renal failure急进性肾衰竭 Defined by doubling of initial
46、 serum creatinine to 226 mol/L(2.5 mg/dL)within 2 weeks Often develops following a precipitating event(e.g.SBP)but may occur spontaneously Associated with acute deterioration of circulatory function(arterial hypotension and activation of the endogenous vasoconstrictor systems)rapid impairment in liv
47、er function and encephalopathy Very poor prognosis mean survival approximately 1 month if untreatedClassification 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 asci
48、tes,spontaneous bacterial peritonitis,and hepatorenal syndrome in cirrhosis.J Hepatol 2010;53:397417 Slowly progressive moderate renal failure缓慢进展中度 Defined by serum creatinine 1.5 mg/dL or 133 mol/L Often develops spontaneously Usually associated with refractory ascites May progress to Type 1 HRS e
49、ither spontaneously or precipitated by an event(e.g.SBP)Decreased survival compared with ascitic patients without renal failure(median survival approximately 6 months)肝肾综合征对肝移植结局的影响肝肾综合征对肝移植结局的影响EventsHRSNo HRS p valueSurvival(5 years)60%68%0.03Days in intensive care unit post-transplantation18 236
50、110.001Days in hospital post-transplantation42 3427 180.001Dialysis post-transplantation35%5%0.001HRS,hepatorenal syndromeGonwa et al.Transplantation 1995;59:361365 HRS患者肝移植后结局更差患者肝移植后结局更差!肝肾综合征治疗史对移植后结局的影响肝肾综合征治疗史对移植后结局的影响EventsTreated HRSNo HRSp valueSurvival(3 years)(%)10083N.S.Days in intensive
