肠道菌群和内毒素易位及其防治

在创伤、烧伤、休克、严重感染、急危重症、多器官功能障碍综合征和大手术后,尤其是在应用抗菌药物的过程中,常会发生肠道微生态失调,以致病情加重甚至不治,因而受到临床界和微生物学者的极大关注。肠道微生态失调是指正常菌群和宿主两     

调整肠道菌群对肝硬化患者血浆内毒素及肝功能的影响

目的 观察肝硬化患者口服益生菌制剂前后肠道菌群、血浆内毒素及肝功能指标的变化.方法 选择肠道菌群中具有代表性的细菌共5种进行培养和计数.56例肝硬化失代偿期患者随机分成2组,益生菌组(治疗组)28例,对照组28例,对照组给予常规治疗,治疗组在常规治疗的基础上给予益生菌治疗,疗程14 d.测定治疗前后肠道菌群菌落计数、血浆内毒素水平及肝功能指标.另选择30例正常人为正常对照组.结果与正常对照组相比,肝硬化组患者存在不同程度的肠道菌群失调, 主要表现为双歧杆菌减少(10.19±0.72 vs 9.13±1.01,P<0.05),治疗后治疗组双歧杆菌、乳杆菌、肠球菌[(12.28±1.02)lg CFU/g、(11.17±1.18)lg CFU/g、(11.56±1.27)lg CFU/g]较治疗前 [(9.39±1.23)lg CFU/g、(9.26±1.13)lg CFU/g、(8.57±1.45)lg CFU/g]明显增加(P＜0.05),血浆内毒素则明显低于对照组[(0.082±0.031) EU/mL vs (0.145±0.047) EU/mL,P<0.05],肝功能指标明显好于对照组(P<0.05).结论 肝硬化患者存在肠道菌群失调.益生菌制剂可有效改善肝硬化患者肠道菌群失调,并降低血浆内毒素水平,改善患者的肝功能,可作为肝硬化患者的辅助用药.     

生脉散对急性肝衰竭大鼠内毒素诱导细胞因子的影响

[目的]探讨生脉散对急性肝衰竭大鼠内毒素（LPS）诱导细胞因子水平的影响。[方法]采用胁氨基半乳糖腹腔注射法制作急性肝衰竭大鼠模型。予生脉散灌胃2h及8h后,检测血清LPS与细胞因子水平。[结果]D-氨基半乳糖能明显增加大鼠血清白细胞介素6（IL-6）、细胞间黏附分子1（ICAM-1）和IL-1β水平（P〈0．01）,随着D-氨基半乳糖作用时间延长的趋势明显减弱,但对血清LPS、肿瘤坏死因子α（TNF-α）水平无明显影响（P〉0．05）;生脉散能显著降低D氨基半乳糖肝衰竭大鼠血清IL-6、ICAM-1和IL-1β水平（P〈0．01,〈O．05）。LPS攻击2h和8h后,能明显诱导D-氨基半乳糖大鼠血清LPS、TNF-α、IL-6、ICAM-1和IL-1β水平增加（P〈0．01）;除在8h对TNF-α无影响外,生脉散能明显减轻LPS攻击D-氨基半乳糖大鼠后对血清LPS、TNF-α、IL-6、ICAM-1和IL-1β水平的影响（P〈0．01,〈O．05）。[结论]SD大鼠在急性肝衰竭状态下,存在严重LPS血症,并引起细胞因子水平变化的炎症级联反应,生脉散可通过调节细胞及炎症因子水平起到治疗作用。     

温阳解毒化瘀方对HBV相关肝衰竭患者肠道菌群的影响

目的：观察温阳解毒化瘀方对HBV相关肝衰竭患者肠道菌群、血浆内毒素的影响。方法：将60例中医辨证为＂脾虚瘀黄＂的HBV相关慢加亚急性肝衰竭患者随机分为两组,治疗组（西医治疗＋温阳解毒化瘀方）30例,对照组（西医治疗）30例,疗程共4周。测定两组患者治疗前后肠道菌群的计数、血浆内毒素水平。结果：治疗组的有效率（92.8%）优于对照组（71.4%）;治疗组患者治疗后较治疗前双歧杆菌的菌落数增加（P〈0.01）,肠杆菌数量下降（P〈0.05）,血浆内毒素下降（P〈0.05）;治疗组患者治疗后比对照组患者双歧杆菌数量明显增加（P〈0.05）,血浆内毒素明显下降（P〈0.05）。结论：温阳解毒化瘀方治疗HBV相关肝衰竭可改善患者肠道菌群,降低血浆内毒素的水平,从而提高临床疗效。     

益生菌辅助治疗慢加急性肝衰竭后肠道菌群及预后观察

目的 分析慢加急性肝衰竭(ACLF)患者加用益生菌治疗后的预后情况。方法 选取我院84例ACLF患者，随机均分为两组。对照组常规治疗，观察组予以常规+肠道益生菌制剂治疗。观察治疗后患者菌群分布及生存情况。结果 观察组治疗前乳酸杆菌、双歧杆菌数量(6.9±0.8)log₁₀nCFU/g、(5.5±0.9)log₁₀nCFU/g,大肠埃希菌、大肠杆菌数量(9.2±1.4)log₁₀nCFU/g、(8.8±0.4)log₁₀nCFU/g;治疗后乳酸杆菌、双歧杆菌数量分别为(8.4±0.6)log₁₀nCFU/g、(9.7±0.8)log₁₀nCFU/g,大肠埃希菌、大肠杆菌数量分别为(5.9±0.5)log₁₀nCFU/g、(6.1±0.4)log₁₀nCFU/g。对照组治疗前乳酸杆菌、双歧杆菌数量分别为(6.8±0.7)log₁₀nCFU/g、(5.4±0.8)log₁₀n...     

中药方剂赤白汤对D-氨基半乳糖诱导的急性肝衰竭小鼠肠道菌群的影响研究*

目的 探讨中药方剂赤白汤对急性肝衰竭小鼠肠道菌群的影响。方法 将48只小鼠随机分为正常组、模型组、大剂量中药组、中剂量中药组、小剂量中药组和丽珠肠乐组,每组8只。先给动物生理盐水、中药或丽珠肠乐灌胃8 d,采用D-氨基半乳糖/脂多糖腹腔注射诱导急性肝衰竭（ALF）。采用平板活菌计数法检测小鼠粪便肠道菌群。结果 模型组小鼠血清ALT水平为（1983.3±629.0） U/L,显著高于正常组[（36.9±7.5）U/L,P<0.001],肝脏指数为（6.7±0.6）%,显著高于正常组[（5.2±0.3）%,P<0.001],大肠杆菌为（8.7±0.5） lgCFU/粪便和肠球菌为（9.5±0.3） lgCFU/粪便,显著高于正常组[（7.6±0.9）lgCFU/粪便,P<0.01和（8.8±0.2） lgCFU/粪便,P<0.001],乳酸杆菌为（9.3±0.3） lgCFU/粪便和双歧杆菌为（10.1±0.4） lgCFU/粪便,显著低于正常组[（10.4±0.5） lgCFU/粪便,P<0.001和（11.2±0.5） lgCFU/粪便,P<0.001];与模型组比,大、中、小剂量中药和丽珠肠乐处理动物肝组织出血、坏死改善,肠道菌群部分恢复。结论 中药方剂赤白汤具有改善急性肝衰竭小鼠肝功能和肠道菌群紊乱的作用。     

天然蒙脱石对急性肝衰竭大鼠的肠道干预实验

目的建立大鼠急性肝衰竭模型,并给予天然蒙脱石进行肠道干预研究。方法随机将40只大鼠分为正常对照组、模型组、思密达预防组和思密达治疗组,采用腹腔注射半乳糖胺法建立大鼠急性肝衰竭模型,观察大鼠肝功能、内毒素（LPS）及肝脏和回肠组织的病理学变化。结果与正常对照组比,模型组、思密达预防组和治疗组大鼠血ALT、AST、TBiL和LPS升高,Alb下降（P〈0．05）;与模型组比,思密达预防组和治疗组大鼠血ATJT、AST、TBiL和LPS下降,Alb升高（P〈0．05）;思密达预防组比治疗组大鼠血ALT、AST、TBiL和LPS更低（P〈0．01）;模型组大鼠肝脏形态学发生严重的病变,而预防组和治疗组病变较轻。结论应用天然蒙脱石进行肠道干预急性肝衰竭大鼠可明显减轻肝脏病理学改变,改善肝功能,降低LPS水平。     

慢性乙型肝炎、肝硬化和肝衰竭患者肠道菌群变化研究*

目的 探讨慢性乙型肝炎（CHB）、肝硬化(LC)和肝衰竭(LF)患者肠道菌群的结构差异。方法 纳入CHB患者23例,失代偿期LC患者20例,LF患者6例和成年健康人9例,采用粪便细菌基因组DNA提取试剂盒提取粪便肠道菌群DNA,应用16SrDNA测序技术检测肠道菌群。应用相关生物学软件和统计学软件对测序结果进行分析。结果 肠道菌群门分类水平分析显示,每个样本均以拟杆菌门为主,其次为变形菌门;CHB组拟杆菌门丰度 （617.83）显著高于LC组（343.16）、LF组（182.15）和健康组（236.66）,差异有统计学意义（P<0.05）;LC组变形菌门丰度（183.16）多于CHB组（35.86）、LF组（18.87）和健康组（53.40,P<0.05）;属分类水平显示,CHB组、LC组和LF组均以拟杆菌属为主,其次为普氏菌属、梭菌属;CHB组普氏菌属丰度（345.28）较LC组（46.75）、LF组（5.63）和健康组（20.14）明显增多,LC组拟杆菌属丰度最少（150.28,P<0.05）。结论 CHB、LC和LF患者肠道菌群结构有显著性差异。拟杆菌为肠道优势菌群,在各样本中菌群丰度发生了变化,了解这些变化可能有助于对疾病发生和处理的认识。     

生脉散对急性肝衰竭大鼠内毒素诱导抑制性-κBα及细胞因子的影响

目的:探讨生脉散对急性肝衰竭大鼠内毒素(LPS,即大肠杆菌脂多糖)诱导细胞因子水平及大鼠肠道组织抑制性-κBα(I-κBα)蛋白表达的影响.方法:采用D-氨基半乳糖(D-Gal)腹腔注射复制急性肝衰竭大鼠模型,观察LPS诱导2小时及8小时后生脉散对血清内毒素、细胞因子水平及大鼠肠道组织I-κBα蛋白表达的影响.结果:D-Gal能明显增加大鼠血清白细胞介素6(IL-6)、细胞间黏附分子-1(ICAM-1)和白细胞介素1β(IL-1β)水平(P＜0.001),随着D-Gal作用时间延长,其增加的趋势明显减弱,但对血清LPS、肿瘤坏死因子(TNF-α)水平无明显影响(P＞0.05);生脉散能显著降低D-Gal肝衰竭大鼠血清IL-6、ICAM-1和IL-1β水平(P＜0.001,P＜0.05).LPS攻击2小时和8小时,能明显升高D-Gal大鼠血清LPS、TNF-α、IL-6、ICAM-1和IL-1β水平(P＜0.001);除在8小时对TNF-α无影响外(P＞0.05),生脉散能明显减轻LPS攻击D-Gal大鼠后对血清LPS、TNF-α、IL-6、ICAM-1和IL-1β水平的影响(P＜0.001,P＜0.05);采用Western blot方法,检测大鼠肠道组织胞浆蛋白I-κBα表达发现,LPS可调节肠道组织I-κBα蛋白表达,诱导NF-κB激活,生脉散可抑制NF-κB激活.结论:在急性肝衰竭模型中,LPS能增加TNF-α、IL-1β、IL-6和ICAM-1等炎症因子水平,诱导I-κBα表达;生脉散可降低LPS水平,并抑制LPS诱导的炎症因子水平和I-κBα在胞浆内的表达,阻断了炎性介质及LPS本身对机体的损伤.     

肝硬化患者肠道菌群的研究

目的研究肝硬化患者肠道菌群的变化，并分析血浆内毒素水平与肠道细菌的关系。方法对３７例肝硬化患者和１８例健康者粪便中８种常见的厌氧菌及需氧菌进行定量研究，以偶氮基质显色法测外周血内毒素。结果（１）肝硬化患者双歧杆菌、拟杆菌、真杆菌量明显低于正常组，而大肠杆菌、产气荚膜杆菌量高于正常组（Ｐ＜０．０５）：（２）肠菌失调程度与肝功能Ｃｈｉｌｄ－Ｐｕｇｈ分级有关；（３）内毒素水平与大肠杆菌量存在相关性。结论肝硬化患者存在肠道菌群失调，具有代表性的厌氧菌减少，需氧菌增多。需氧革兰氏阴性杆菌大量繁殖可能是引起肝硬化肠源性内毒素血症的一个重要因素。     

Striking variability of hepatic copper levels in fulminant hepatic failure

Two cases of acute hepatic failure are reported in which the diagnosis of Wilson's disease was considered because of low serum ceruloplasmin, low serum copper levels and high 24 h urinary copper. Case 1 had Kayser-Fleischer rings, haemolysis and a high 24 h urinary copper, and so Wilson's disease was confidently diagnosed. Case 2 had high urinary copper excretion, but [64Cu] study indicated a 24:2 h ratio of 0.7 and made the diagnosis of Wilson's disease uncertain. Both patients underwent orthotopic hepatic transplantation, and multiple biopsies were taken from the resected specimen in order to estimate hepatic copper levels. In both cases, hepatic copper levels revealed considerable variation: 0.8-5.2 mumol/g dry wt (case 1) vs 0.02-12.65 mumol/g dry wt (case 2). In case 1, only two of 14 levels were within the diagnostic range for Wilson's disease (greater than 4 mumol/g dry wt), whereas hepatic copper levels in case 2 were in the Wilsonian disease range in three of 16 specimens. These results were in contrast to uniformly high hepatic copper levels in one patient with established cirrhosis secondary to Wilson's disease and two cases of primary biliary cirrhosis. This report indicates that hepatic copper levels vary greatly in acute liver failure, and that estimates from a single biopsy specimen may be misleading as to the cause of the underlying liver disease.     

拉克替醇对慢性病毒性肝炎患者肠道菌群及内毒素血症的影响

目的 观察拉克替醇对慢性病毒性肝炎患者肠道菌群及血内毒素水平的影响。方法60例慢性病毒性肝炎伴血内毒素升高的患者随机分为两组，对照组30例采用常规保肝降酶治疗，治疗组30例在常规治疗的基础上加用拉克替醇，观察两组患者治疗前及治疗3周后肠道菌群、血内毒素水平的变化。结果治疗组患者肠道内乳杆菌和双歧杆菌数量明显增加（P〈0．01），产气荚膜梭菌显著降低（P〈O．01），血内毒素水平显著降低（P〈O．01）。结论拉克替醇能通过调节慢性病毒性肝炎患者肠道菌群，更有效降低血内毒素水平。     

Changes of neurotensin and endotoxin in rats with intestinal ischemia

AIM: To investigate the changes of neurotensin (NT) and endotoxin in rats with segmental intestinal ischemia. METHODS: The distal ileal mesenteric arteries in rats were ligated to make segmental intestinal ischemia models. At the 2^nd, 6^th and 12^th hours after intestinal ischemia, endotoxin levels in portal blood were tested by limulus lysate test and NT levels in plasma from the heart and in intestine tissues (ischemia and peri-ischemia areas) were assayed by radioimmunoassay. Histological changes of the mucosa were examined under light and electron microscopes. RESULTS: NT levels decreased significantly in intestinal ischemia and peri-ischemia areas (34.07 ± 5.93 vs 40.14 ± 5.38, P < 0.05; 7.47 ± 1.38 vs 40.14 ± 5.38, P < 0.01), especially lower in ischemia area (34.07 ± 5.93 vs 7.47 ± 1.38, P < 0.05. However, NT level increased obviously in plasma (0.76 ± 0.16 vs 0.47 ± 0.10, P < 0.05). Levels of endotoxin elevated obviously in portal blood (389.0 ± 105.0 vs 55.1 ± 6.7, P < 0.01), and the mucosa was injured both in ischemia and peri-ischemia areas. CONCLUSION: Intestinal ischemia injures intestinal mucosa and leads to decrease of intestinal NT level, which is accelerated by endotoxemia and increase of blood NT level.     

Evidence against a role for endotoxin in the hepatic encephalopathy of rats with thioacetamide-induced fulminant hepatic failure

BACKGROUND AND AIMS: Endotoxin has been proposed to participate in the development of hepatic encephalopathy. However, there is no published data concerning the effects of endotoxin neutralization on the degree of hepatic encephalopathy. The present study investigated the effect of chronic intraperitoneal injection of polymyxin B, a neutralizing antagonist of endotoxin, on hepatic encephalopathy in rats with thioacetamide (TAA)-induced fulminant hepatic failure. METHODS: Male Sprague-Dawley rats weighing 300-350 g were used. Fulminant hepatic failure was induced by intraperitoneal injection of TAA (350 mg/kg/day) for 3 days. Two series of rats were designed to compare the effects of low dose (0.1 mg) or high dose (0.2 mg) intraperitoneal polymyxin B administration versus normal saline (NS) on hepatic encephalopathy. The injection was twice daily started from 2 days prior to TAA administration and lasted for 5 days. Severity of encephalopathy was assessed by the counts of motor activity in an Opto-Varimex animal activity meter. Plasma levels of endotoxin and tumor necrosis factor-alpha (an index of liver injury) were measured by Limulus assay and the ELISA method, respectively. RESULTS: Neutralization of endotoxin by either low dose or high dose polymyxin B administration did not significantly alleviate the degree of hepatic encephalopathy, as represented by the counts of motor activities (P > 0.05). Plasma levels of endotoxin and tumor necrosis factor-alpha were comparable between rats treated with polymyxin B or NS (P > 0.05). CONCLUSION: Our findings do not support the notion that endotoxin plays a major role in the pathogenesis of hepatic encephalopathy in rats with TAA-induced fulminant hepatic failure.     

乳果糖降低非酒精性脂肪性肝炎患者肠道通透性及血清内毒素水平

目的探讨乳果糖对非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH)患者肠道通透性的干预作用。方法选择健康正常成人30例作为正常对照组(A组),非酒精性脂肪性肝炎共60例,随机分为NASH对照组(B组)和乳果糖干预组(C组)各30例,其中C组给予乳果糖(10 mL/d)进行干预。检测所有被研究者的血清内毒素、二胺氧化酶(diamine oxidase,DAO)、D-乳酸及ALT的浓度。干预4周后,再次检测B、C两组的血清内毒素、二胺氧化酶(DAO)、D-乳酸及ALT的浓度。结果与A组比较,治疗前B、C两组内毒素、DAO、D-乳酸水平显著增高(P<0.01),B组干预前后比较,内毒素、DAO、D-乳酸及ALT水平无显著改变(P>0.05),而C组干预前后比较,内毒素、DAO、D-乳酸及ALT水平显著降低(P<0.01)。结论 NASH患者血清内毒素水平及肠道通透性增高,乳果糖可降低NASH患者肠道的通透性及血浆内毒素水平。     

暴发性肝衰竭中Toll样受体2表达的实验研究

目的 分析D-氨基半乳糖(D-Gal)/脂多糖(LPS)诱导的暴发性肝衰竭模型中肝组织Toll样受体2(TLR2)的表达变化及与细胞因子白细胞介素-18(IL-18)、肿瘤坏死因子α(TNF-α)、γ干扰素(IFN-γ)表达的关系,探讨TLR2在启动炎性应答而致肝损伤中的作用。 方法 BALB/C小鼠腹内联合注射D-Gal 900 mg/kg与LPS 10μg/kg后观察其存活率,并检测不同时间点血清转氨酶和血浆IL-18、TNF-α和IFN-γ含量。用半定量逆转录-聚合酶链反应和Tanon Gis2.0软件分析各时间点肝组织中TLR2 mRNA表达,并与血浆IL-18、TNF-α、IFN-γ含量进行相关分析;免疫组织化学观察肝组织TLR2蛋白的表达。 结果 给药后4 h,血清转氨酶明显升高(与0 h比较,P<0.05);10 h小鼠死亡率达80％。血浆IL-1 8、TNF一α和IFN-γ含量逐步上升,IL-18在1 h即显著升高,之后持续高表达;TNF-α在2 h、5 h有两个分泌高峰;IFN-γ在2 h前增加不明显(F=2.5 7,P=0.1 3),但3 h及以后则显著升高(与0 h比较,P<0.01)。正常小鼠肝组织少量表达TLR2 mRNA,给药后1 h表达即显著增强(与0 h比较,P<0.05);免疫组织化学也显示TLR2蛋白有类似的变化,尤其肝窦内皮细胞、库普弗细胞表达更为显著;且部分肝细胞凋亡、坏死后,残存肝组织仍有较高TLR2表达。相关分析表明,肝组织TLR2 mRNA表达与     

大白兔肝缺血再灌注损伤时血浆内毒素的变化及对肝肾功能的影响

目的探讨肝缺血再灌注损伤过程中,肠源性内毒素的动态变化和继发性肝肾功能损害。方法取27只健康成年新西兰大白兔,体重1.4~2.3?,随机分为对照组7只,另外20只作为实验组。以缺血10min(I10min)、缺血20min(I20min)、缺血30min(I30min)和分别再灌注30min(R30min)随机分为3组。对照组取门、腔静脉血测肝肾功能及血浆内毒素,实验组阻断第一肝门造成不同的缺血时段,松开血管夹再灌注30min,其余实验同对照组。结果实验组中血浆谷草转氨酶、谷丙转氨酶、尿素氮、肌苷含量及内毒素浓度均有升高,在I10min/R30min组即有升高,但与对照组相比差异无显著性(P>0.05);而后随着缺血时间的延长这些指标继续明显升高,至I30min/R30min组达最高值,与对照组比差异有显著性(P<0.05~0.01)。肾组织电镜观察发现I10min/R30min组肾脏超微结构无明显改变,而I20min/R30min组和I30min/R30min组肾脏超微结构损害明显。结论肝门阻断后门静脉系统淤血,致肠源性内毒素产生和移位;肝门再开放造成肝缺血再灌注损伤,且随着缺血时间的延长,门、腔静脉血中内毒素水平进行性升高,肝功能进一步损害,最终引起肝肾综合征。     

内毒素在酒精性肝病肠损伤中的作用

目的探讨内毒素在酒精性肝病肠损伤中的作用。方法选择酒精性肝病患者15例和健康不饮酒者15例。采用ELISA法测定血清内毒素;采用分光光度法测定血清丙二醛。另将20只小鼠随机分为对照组和模型组,每组10只,分别喂饲Lieber-Decarli无酒精和含酒精液体饲料。10周后处死小鼠,检测血清内毒素,并进行肝脏和肠组织形态学观察。结果酒精性肝病组和对照组血清内毒素水平分别为0.52±0.54 Eu/L和0.47±0.34 Eu/L（P〈0.05）;酒精性肝病组和对照组血清丙二醛水平分别为5.6±5.0nmol/ml和3.7±3.4nmol/m（lP〉0.05）;模型组和对照组小鼠血清内毒素水平分别为0.38±0.05 Eu/L和0.13±0.02 Eu/L（P〈0.01）;模型组肝细胞明显脂肪变,结肠组织损伤病理学评分为10.3±1.3分,较对照组明显升高（4.8±1.2分,P=0.01）。结论酒精性肝病伴发了肠粘膜损伤,内毒素可能参与了发病过程。     

Bacteraemia in patients with fulminant hepatic failure

ABSTRACT— Among 103 patients with fulminant hepatic failure due to viral hepatitis, paracetamol overdose, or halothane anaesthesia, treated over a 2-year period, 23 had bacteraemia. Gram-positive organisms, mainly streptococci and Staphylococcus aureus, were isolated from 61% of patients. Escherichia coli, the main type of gram-negative organism isolated, was found in 26% of patients and was associated with a fatal outcome more often than gram-positive bacteria. The type of organism isolated was not related to the aetiology of the hepatic necrosis, the presence of renal failure, or the clinical outcome. In the 23 patients with bacteraemia the same organism was isolated from other sites of infection, including sputum in four, urine in two, and the central venous catheter and arteriovenous shunt in one. Bacteraemia usually occurred 3 days after admission or on average 2 days after clinical deterioration to grade IV encephalopathy had begun. In 11 patients, the infection had an adverse effect on their clinical course, in three patients being implicated as a cause of the encephalopathy. Although in four patients the development of infection after all signs of encephalopathy had cleared may have been a major factor in their death, two of these patients had evidence of severe sepsis, pneumococcal peritonitis, and renal abscesses from which Candida albicans was cultured. An awareness of infection as a complication both of the acute stage of the illness and during recovery is essential if early detection and treatment are to be effective.     

Increased intracranial pressure in a porcine model of fulminant hepatic failure using amatoxin and endotoxin

BACKGROUND/AIMS: The purpose of this study was to develop a clinically relevant porcine model of fulminant hepatic failure (FHF) by means of administration of amatoxin and endotoxin. METHODS: Pigs were intraportally administered only saline in group 1 (n = 3), 1 microg/kg of lipopolysaccharide (LPS) in group 2 (n = 4), 0.1 mg/kg of alpha-amanitin in group 3 (n = 5), and amanitin plus LPS in group 4 (n = 9). RESULTS: All the pigs in groups 1 and 2 survived with minimal changes in liver function tests. In contrast to the 60% mortality in group 3, all the pigs in group 4 died within 96 h, with a significant increase in aspartate transaminase at 24 h (9,757 +/- 2,167 IU/I). In addition, they demonstrated severe metabolic disorders, such as serum lactate accumulation, hypoglycemia, coagulopathy, plasma amino acid imbalance, and hyperammonemia. The intracranial pressure significantly increased to 17.8 +/- 2.5 mmHg immediately before death. Reversal of FHF in these pigs following orthotopic liver transplantation confirmed that the toxicity is liver-specific and that the graft liver is unaffected. CONCLUSIONS: This porcine model of FHF induced by a combination of amanitin and LPS will be of much use in the development of new therapies for human FHF.