Effects of irsoglandine maleate in an experimentally-induced acute hepatic failure model using mice

When heat-killedPropionibacterium acnes was intravenously injected into mice followed by an intravenous injection of a small amount of Gram-negative lipopolysaccharide seven days later, most of the mice died of massive hepatic cell necrosis within 24 hours. However, when irsoglandine maleate, an antiulcer agent, was administered to mice during the period of experimental induction of acute hepatic failure, the survival rate, serum transaminase levels and histological changes of the liver remarkably improved. These results suggested that irsoglandine maleate may have protective effects on the liver in our experimentally-induced acute hepatic failure model using mice. Therefore, in the absence of a definitive therapy for fulminant hepatitis, irsoglandine maleate may be a promising therapeutic agent.     

An experimentally-induced acute hepatic failure model in various strains of mice

When BALB/cAJc1 mice are intravenously injected with heat-killed Propionibacterium acnes (P. acnes) followed by an intravenous injection of lipopolysaccharide (LPS) 7 days later, massive necrosis is induced in the liver tissue and most of the mice die within 24 hours of LPS injection. Using this experimental model, acute hepatic failure was induced in various strains of mice and the difference in the response was studied. As a result, as in BALB/cAJc1 mice, acute hepatic failure was also induced in BALB/cAJc1-nu, AKR/J, C3H/HeNJc1, C57BL/6NJc1 and DDy mice. However, as an exception, hepatic cell necrosis was hardly seen and the survival rate was remarkable high in C3H/HeJ mice, which genetically do not respond to LPS stimulation. These results indicate that for this experimental induction of acute hepatic failure, macrophages must be activated by the two-step stimulation of P. acnes and LPS.     

胎肝细胞培养上清液对小鼠急性肝衰竭的保护作用

为探讨胎肝细胞治疗重型肝炎的机制,将84只小鼠随机分为3组(每组28只),经D-氨基半乳糖/内毒素(D-galn/LPS)诱导急性肝衰竭后,分别给予生理盐水(NS)、RPMI1640培养液(RPMI)和人胎肝细胞培养上清液(FHCS)治疗,各组分别取14、8、6只小鼠进行存活率、血清谷丙酶(ALT)及肝脏病理观察。结果显示,NS组和RPMI组24小时存活率分别为14.3％和21.4％;ALT升高达207.2±41.3IU/L和188.4±52.6IU/L。FHCS组小鼠存活率为57.1％,ALT为92.5±28.7IU/L,与对照组相比差异显著(P<0.05,P<0.01)。此外,对照组分别有5(83.3％)只和4(66.7％)只动物肝组织病理改变在Ⅲ级以上,而FHCS组仅有2(33.3％)只。上述结果表明,FHCS对急性肝衰竭有保护作用,同时提示胎肝细胞分泌产物可能与保护肝细胞、治疗重型肝炎及肝衰竭的机制有关。     

Liver transplantation for acute hepatic failure

There are numerous causes of acute hepatic failure (AHF). Cerebral edema, coagulopathy, renal failure, metabolic disturbances and infection are the main clinical sequelae. Patients with AHF should be stabilized when first encountered and transferred to the nearest liver transplant center, as AHF progresses quickly and is often fatal. There are few adequate medical interventions and care of patients with AHF is supportive until spontaneous recovery ensues. If recovery does not appear to occur, most causes of AHF are well accepted indications for liver transplantation.     

A double-blinded,randomized trial of hydrocortisone in acute hepatic failure

The Acute Hepatic Failure Study Group (AHFSG) has conducted a double-blinded, randomized evaluation of hydrocortisone in patients with acute hepatic failure. From July 1975 through August 1978, a 38-month period, 18 medical centers in the United States and one in Canada participated in this trial. A total of 64 patients were accessed and found eligible to participate in the study; two of them were subsequently eliminated from our analysis. Eighteen patients received placebo; 23 received 400 mg hydrocortisone per day, and 21 patients were administered 800 mg hydrocortisone per day. We did not observe any therapeutic effect of hydrocortisone, and the survival rates for placebo versus 400 mg and versus 800 mg hydrocortisone per day were 22%, 9%, and 24%, respectively. Fulminant hepatitis associated with drug hepatotoxicity or non-A, non-B hepatitis seemed to have a worse prognosis than fulminant B, although these differences were not significant. Serum -fetoprotein had a modest prognostic value of survival and seemed to be limited to fulminant B. The AHFSG recommends, therefore, that corticosteroid use in acute hepatic failure with hepatic encephalopathy be discontinued.Supported in part by grants from the National Institute of Health (HL-23420 and CA-30209)     

急性肝功能哀竭动物模型的建立

目的建立与临床较相近的急性肝功能衰竭动物模型.方法应用中国实验小型猪7头,采用Β期门静脉-下腔静脉吻合、Ⅱ期(48 h后)供肝动脉暂时结扎4 h的方法建立缺血性急性肝功能衰竭动物模型;中国实验小型猪6头给于1.2 g/kg的D-氨基半乳糖诱导肝功能衰竭,建立药物性急性肝功能衰竭动物模型.观察比较每组动物一般状况、生存时间、生理生化指标、颅内压、组织病理等方面的变化.结果在缺血性模型中,1头猪死于术中大出血,1头猪的生存时间超过5 d,其余5头存活时间为18～30h[平均存活时间(22.5±5.6)h];反映肝功能的主要指标(AST,总胆红素、凝血酶原时间、血氨、血糖)均明显异常;组织病理显示肝脏大块坏死.在药物性模型中,动物在给药后12 h各项指标开始变化明显,给药后48 h损伤达高峰,平均存活时间为(67.9±9.4)h,最终死于严重肝功能衰竭.结论应用缺血方法与药物方法均能建立急性肝功能衰谒动物模型,其中D-氨基半乳糖1.2g/kg的给药剂量建立的模型稳定性好且能较好模拟临床急性肝功能衰竭发生发展的病理生理过程,可用于研究机制和评价疗效.     

Decreasing serum alpha-fetoprotein levels in predicting poor prognosis of acute hepatic failure in patients with chronic hepatitis B

Background: Background: We carried out a study to predict the prognosis of acute hepatic failure in patients with chronic hepatitis B. Methods: We studied 25 consecutive patients with severe acute hepatitis. Severe acute hepatitis was defined as the development of acute hepatitis with a total serum bilirubin level of more than 15 mg/dl, prolonged prothrombin time (PT) of more than 5 s, and hepatic encephalopathy (HE). All patients were assessed for King's criteria. Positivity for King's criteria was defined as PT more than 100 s, or any three of the following: (age < 10 years or >40 years; cryptogenic or drug-induced hepatitis; jaundice for more than 7 days before the onset of HE; PT > 50 s; and serum bilirubin > 17.5 mg/dl). All but 1 patient had serial serum alpha-fetoprotein (AFP) levels measured every 1–2 weeks. Results: Eleven of 17 patients who died during the study met the King's criteria, whereas none of the surviving patients met the criteria. The sensitivity was 64.7% and the specificity, 100% for King's criteria in predicting a poor prognosis. In 16 of the 17 deceased patients, the AFP levels were reduced while their jaundice increased (sensitivity, 94.1%; specificity, 87.5%). All 17 deceased patients met the King's criteria and/or had reduced AFP levels while their jaundice increased (sensitivity, 100%; specificity, 87.5%). Conclusions: Our observations suggest that the combined use of follow-up AFP levels and King's criteria is helpful in predicting the poor prognosis of severe acute hepatitis superimposed on chronic hepatitis B. Received: August 20, 2001 / Accepted: December 27, 2001     

Effects of irsoglandine maleate in an experimentally-induced acute hepatic failure model using mice

When heat-killed Propionibacterium acnes was intravenously injected into mice followed by an intravenous injection of a small amount of Gram-negative lipopolysaccharide seven days later, most of the mice died of massive hepatic cell necrosis within 24 hours. However, when irsoglandine maleate, an anti-ulcer agent, was administered to mice during the period of experimental induction of acute hepatic failure, the survival rate, serum transaminase levels and histological changes of the liver remarkably improved. These results suggested that irsoglandine maleate may have protective effects on the liver in our experimentally-induced acute hepatic failure model using mice. Therefore, in the absence of a definitive therapy for fulminant hepatitis, irsoglandine maleate may be a promising therapeutic agent.     

药物性急性肝衰竭动物模型的建立

目的建立用于人工肝实验研究的急性肝衰竭大动物模型。方法应用中国实验小型猪13头随机分为3组,低剂量组(n=3)给予1.0g/kg的D-氨基半乳糖;中剂量组(n=6)给予1.2g/kg的药物;大剂量组(n=4)给药剂量为1.5g/kg。观察比较每组动物的一般状况、生存时间、生理生化指标、颅内压、组织病理等方面的变化,从中得出建立急性肝衰竭动物模型的较稳定方法。结果低剂量组动物在给药后均出现一过性的肝功能损害,未出现肝昏迷表现,在给药后3～4d肝功能开始恢复,约1周后指标基本恢复正常,所有动物均存活;高剂量组的动物肝损害出现时间早,损伤剧烈,存活时间短(24.8±5.3h),均死于严重的肝衰竭。中等剂量组的动物在给药后12h各项指标开始变化明显,在给药48h时损伤达高峰,存活时间为67.9±9.4h,最终死于严重的肝衰竭。结论应用药物方法能建立急性肝衰竭动物模型,其中D-氨基半乳糖1.2g/kg的给药剂量建立的模型稳定性好,且能较好模拟临床急性肝衰竭发生、发展的病理、生理过程,可作为人工肝治疗的实验平台。     

对乙酰氨基酚诱导急性肝衰竭小鼠动物模型的建立

目的通过腹腔注射高剂量对乙酰氨基酚(APAP)构建稳定的用于研究药物导致急性肝衰竭的动物模型。方法本研究首先进行生存率实验,取60只C57BL/6小鼠随机分为4组,每组15只,分别腹腔注射0.9%氯化钠溶液及不同剂量(300 mg/kg、500 mg/kg、750 mg/kg)APAP后,观察不同组别72 h内小鼠的精神、活动状态和生存率。根据生存率分析结果,另选取180只C57BL/6小鼠,随机分为3组,分别腹腔注射0.9%氯化钠溶液、低剂量(300 mg/kg)和高剂量(750 mg/kg)APAP,每组分别在0、1、3、6、12 h等时间点随机选取12只小鼠,留取血清和肝组织,验证小鼠的生化和组织学是否符合急性肝衰竭的表现。结果生存率实验结果显示,0.9%氯化钠溶液组、300 mg/kg以及500 mg/kg组72 h内无小鼠死亡;750 mg/kg组72 h死亡率为100%,推测750 mg/kg组可能为急性肝衰竭导致的死亡。生化和组织学验证实验结果发现,对照组各时间点转氨酶均无明显升高;APAP处理的两组动物模型ALT3 h时开始升高,6 h时低剂量组ALT升高达到峰值[(6766.5±2001.27)IU/L],而高剂量组ALT于12 h达到(11707.58±1882.45)U/L(P0.01)。从HE病理染色来看,0.9%氯化钠溶液组各时间点肝脏形态结构正常。APAP处理的两组动物模型的肝组织学,主要表现为以中央静脉为中心的肝细胞变性坏死,并随时间延长,损伤范围逐渐扩大。低剂量组坏死周围界限清楚,汇管区肝细胞结构形态正常,12 h可见坏死区周围肝细胞增生表现。高剂量组表现为典型的急性大片状坏死特点,仅汇管区残存少量变性的肝细胞,细胞快速坏死后,留下空的网状纤维支架,肝窦淤积大量红细胞,未见肝细胞增生。HAI评分结果显示,高剂量组的HAI得分(7.33±1.5)显著高于低剂量组(5.25±2.26,P0.05)。结论 C57BL/6小鼠腹腔注射高剂量APAP(750 mg/kg)后,生化和组织学改变与急性肝衰竭相似,本研究构建的动物模型对于探索APAP导致的AHF的发病及进展机制研究具有潜在的应用价值。     

Flumazenil does not improve hepatic encephalopathy associated with acute ischemic liver failure in the rabbit

The effect of flumazenil, a benzodiazepine antagonist, on hepatic encephalopathy was studied in rabbits with acute hepatic failure induced by a two-stage liver devascularization procedure. The rabbits were randomized for treatment with 5 mg/kg of flumazenil or the placebo. The drug was administered at two easily recognizable time points in the course of the encephalopathy: first, when the righting reflex was disturbed, and second, when the animal could no longer achieve to the sitting position. The response after flumazenil did not differ from that after the placebo, as measured by clinical evaluation and automated EEG analysis. Furthermore, the progression of the encephalopathy, as measured by the survival time after the first injection, was not affected by flumazenil.     

Insulin and glucagon therapy of acute hepatic failure

When insulin and glucagon are administered to rats with severe liver injury, survival is enhanced with an attenuation of the liver injury compared to that of untreated controls. In rats with acute liver injury both hormones produce a rapid normalization of hepatic protein content following initiation of DNA synthesis. When rats receive both hormones after partial hepatectomy, the first burst of DNA synthesis reaches a maximum earlier than that seen in controls. Both hormones enhance the increment of hepatic putrescine essential for DNA synthesis through activation of ornithine decaroxylase and/or spermidine-N¹-acetyltransferase. The enhancement of putrescine content by each hormone is additive. Putrescine supplementation promotes hepatic DNA synthesis after hepatectomy. Based on these data, we conclude that a combination of insulin, and glucagon is effective in the therapy of acute hepatic failure in rats. The restoration of liver function as well as the stimulation of liver cell proliferation via putrescine production may contribute to this effect.Presented at the Proceedings of the International Meeting on Normal and Neoplastic Growth in Hepatology, Bari, Italy, June 1989.     

Acute hepatic failure in India: a perspective from the East

Acute hepatic failure (AHF) in India almost always presents with encephalopathy within 4 weeks of the onset of acute hepatitis. Further subclassification of AHF into hyperacute, acute and subacute forms may not be necessary in this geographical area, where the rapidity of onset of encephalopathy does not seem to influence survival. Viral hepatitis is the cause in approximately 95-100% of patients, who therefore constitute a more homogeneous population than AHF patients in the West. In India, hepatitis E (HEV) and hepatitis B (HBV) viruses are the most important causes of AHF; approximately 60% of cases are caused by to these viruses. Hepatitis B virus core mutants are very important agents in cases where hepatitis B results in AHF in this country. Half of the patients with AHF admitted to our centre are female, one-quarter of whom are pregnant. Therefore, pregnant females who contract viral hepatitis constitute a high-risk group for the development of AHF. However, the outcome of AHF in this group is similar to that in non-pregnant women and men. No association with any particular virus has been identified among sporadic cases of AHF. In our centre, approximately one-third of AHF patients survive with aggressive conservative therapy, whereas two-thirds of deaths occur within 72 h of hospitalization. Cerebral oedema and sepsis are the major fatal complications. Both fungal and gram-negative bacteria are major causes of sepsis. Among patients with AHF, despite the presence of sepsis, its overt clinical features (i.e. fever, leucocytosis) may be absent and objective documentation of the presence of sepsis in such patients is achieved by repeated culture of various body fluids. It should be possible to develop simple, clinical prognostic markers for AHF in this geographical region, in order to identify patients suitable for liver transplantation.     

急性肝衰竭肺部感染短帚霉的病原特征研究

目的探讨急性肝衰竭患者肺部感染短帚霉的实验诊断特征,为临床诊治该菌感染提供科学依据。方法 2017年1月收集1例药物性肝损伤导致急性肝衰竭并肺部感染短帚霉患者,对其标本进行痰真菌培养,通过观察菌落生长形态和光学显微镜下菌株形态,质谱仪检测及扩增ITS序列对其进行鉴定确诊;采用E-test方法进行真菌体外药物敏感性(药敏)试验。结果结合不同温度、不同培养基下真菌生长的形态学特征,质谱仪分析及r DNA-ITS序列分析确定为短帚霉,该株短帚霉对伏立康唑和两性霉素B有较好的敏感性,最小抑菌浓度值分别为≥0.50μg/ml和≤0.75μg/ml。结论本例为急性肝衰竭患者肺部感染短帚霉的首例报道,短帚霉有其形态特征和药敏特点,临床应正确选用抗菌药物。     

Hepatoprotective effect of nitric oxide in experimental model of acute hepatic failure

AIM: To evaluate the effect of nitric oxide (NO) on the development and degree of liver failure in an animal model of acute hepatic failure (AHF).METHODS: An experimental rat model of galactosamine-induced AHF was used. An inhibitor of NO synthase, nitroarginine methyl ester, or an NO donor, arginine, were administered at various doses prior to or after the induction of AHF.RESULTS: All tested groups developed AHF. Following inhibition of the endogenous NO pathway, most liver parameters improved, regardless of the inhibitor dose before the induction of liver damage, and depending on the inhibitor dose after liver damage. Prophylactic administration of the inhibitor was more effective in improving liver function parameters than administration of the inhibitor after liver damage. An attempt to activate the endogenous NO pathway prior to the induction of liver damage did not change the observed liver function parameters. Stimulation of the endogenous NO pathway after liver damage, regardless of the NO donor dose used, improved most liver function parameters.CONCLUSION: The endogenous NO pathway plays an important role in the development of experimental galactosamine-induced AHF.