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.     

Hepatic stimulator substance administration ameliorates liver regeneration in an animal model of fulminant hepatic failure and encephalopathy

Abstract: Aims/Background: Hepatic stimulator substance (HSS) is a liver‐specific growth factor implicated in hepatocellular proliferation and hepatoprotection in models of acute liver injury. In the present study, we examined the effect of exogenous HSS administration on liver proliferating capacity and survival outcome in an experimental animal model of fulminant hepatic failure (FHF) and encephalopathy, induced by repeated injections of thioacetamide (TAA) in rats. Methods: Fulminant hepatic failure was induced in adult male Wistar rats by three consecutive intraperitoneal injections of TAA (400 mg/kg of body weight), at 24 h time intervals. The animals received intraperitoneally either a saline solution or HSS (50 mg protein/kg of body weight), 2 h after the second and third TAA injections. The animals were killed at 6, 12 and 18 h post the last injection of TAA. Results: Levels of liver enzymes and urea in serum, blood ammonia values, liver histology, stage of hepatic encephalopathy and survival were statistically significantly improved in TAA‐intoxicated and HSS‐treated rats compared to TAA‐intoxicated and saline‐treated ones. Furthermore, HSS ameliorated liver regenerative indices – DNA biosynthesis, thymidine kinase activity and hepatocyte mitotic activity – in a statistically significant manner. Conclusions: Our data suggest the beneficial effect of HSS administration in this animal model of FHF and encephalopathy, supporting evidence for a possible use of HSS as supportive therapy, by increasing hepatocellular proliferation, in management of FHF.     

Prognostic factors for fatal outcomes prior to receiving liver transplantation in patients with non-acetaminophen-related fulminant hepatic failure

BACKGROUND AND AIM: Many patients continue to die due to the rapid development of cerebral edema and/or multiple organ failure prior to receiving a liver transplantation. METHODS: We investigated the prognostic factors associated with 1-week fatal outcomes after the diagnosis of fulminant hepatic failure, which were associated with fatal outcomes prior to receiving liver transplantation, in 104 patients with non-acetaminophen-related fulminant hepatic failure. RESULTS: With a multivariate logistic regression analysis, age (>40 years), systemic inflammatory response syndrome (SIRS) and plasma prothrombin activities (40 years), cause of fulminant hepatic failure (viral hepatitis), plasma prothrombin activity (相似文献   

Lack of therapeutic effects of gabexate mesilate on the hepatic encephalopathy in rats with acute and chronic hepatic failure

Background and Aim: Inflammation plays a pivotal role in liver injury. Gabexate mesilate (GM, a protease inhibitor) inhibits inflammation by blocking various serine proteases. This study examined the effects of GM on hepatic encephalopathy in rats with acute and chronic liver failure. Methods: Acute and chronic liver failure (cirrhosis) were induced by intraperitoneal TAA administration (350 mg/kg/day for 3 days) and common bile duct ligation, respectively, in male Sprague‐Dawley rats. Rats were randomized to receive either GM (50 mg/10 mL/kg) or saline intraperitoneally for 5 days. Severity of encephalopathy was assessed by the Opto‐Varimex animal activity meter and hemodynamic parameters, mean arterial pressure and portal pressure, were measured (only in chronic liver failure rats). Plasma levels of liver biochemistry, ammonia, nitrate/nitrite, interleukins (IL) and tumor necrosis factor (TNF)‐α were determined. Results: In rats with acute liver failure, GM treatment significantly decreased the plasma levels of alanine aminotransferase (P = 0.02), but no significant difference of motor activity, plasma levels of ammonia, IL‐1β, IL‐6, IL‐10 and TNF‐α or survival was found. In chronic liver failure rats, GM significantly lowered the plasma TNF‐α levels (P = 0.04). However, there was no significant difference of motor activity, other biochemical tests or survival found. GM‐treated chronic liver failure rats had higher portal pressure (P = 0.04) but similar mean arterial pressure in comparison with saline‐treated rats. Conclusions: Chronic GM treatment does not have a major effect on hepatic encephalopathy in rats with TAA‐induced acute liver failure and rats with chronic liver failure induced by common bile duct ligation.     

Encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit. A clinical and biochemical study

Abstract: To study the molecular basis of ammonia toxicity, highly reproducible models of acute liver failure and acute hyperammonemia in the rabbit were developed. Acute liver failure was induced by two-stage liver devascularization, and acute hyperammonemia by prolonged ammonia infusion such that the plasma ammonia pattern found in acute liver failure was simulated. Clinical symptoms, spectral analysis of the EEG, biochemistry (blood gasses, renal function, electrolytes and markers of hepatic injury) and the presence of cerebral edema were studied. During acute liver failure severe encephalopathy developed after 10.2 ± 1.9 h (n = 6, mean ± SEM). Other liver-failure-associated abnormalities were cerebral edema, lactic acidosis, renal dysfunction, hypothermia and septicemia. During acute hyperammonemia, severe encephalopathy developed after 18.2 ± 0.4 h (n = 6, mean ± SEM). Other abnormalities found were cerebral edema and lactic acidosis. In both animal models comparable EEG changes were observed (a decrease in mean dominant frequency and theta-activity, and an increase in delta activity). However, these changes were not statistically significant, and non-specific as they also occurred in control rabbits despite their clinical wellbeing. This study demonstrates in the rabbit the similarity between encephalopathy due to acute ischemic liver failure and that due to hyperammonemia. An observed difference in hyperammonemia-induced encephalopathy was pronounced ataxia, which did not occur during acute liver failure, whereas hypothermia, sepsis and renal failure occurred exclusively in acute liver failure. Our models appear satisfactory for the study of hepatic encephalopathy and ammonia toxicity.     

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.     

Diagnosis and treatment of hepatic encephalopathy

Hepatic encephalopathy arises from the combination of hepatocellular dysfunction and portal-systemic shunting. Encephalopathy is more prominent in advanced stages of liver cirrhosis and signals the presence of fulminant hepatic failure in patients with acute liver injury. As important as the extent of shunting is the presence of large spontaneous collaterals. Ammonia continues to be a leading toxin influencing brain function. Endogenous benzodiazepines and cytokines may contribute to one of ammonia's key effects in the brain: astrocyte swelling. The diagnosis of hepatic encephalopathy is a diagnosis of exclusion; the search for a precipitating factor should be started immediately in all cases of encephalopathy. The treatment of hepatic encephalopathy has three aims: decrease the nitrogenous load from the gut, improve the extra-intestinal elimination of ammonia and counteract central abnormalities of neurotransmission. The mainstay of treatment is directed at the colon. Newer approaches targeting the brain, such as flumazenil, have become available.     

106例慢加急性肝衰竭合并肝性脑病患者预后影响因素的Logistic回归分析

目的对影响慢加急性肝衰竭(ACLF)伴肝性脑病(HE)患者预后的因素进行分析,探讨影响预后的危险因素。方法回顾性分析2010年1月-2013年7月在聊城市人民医院住院的106例ACLF伴HE患者的临床资料,分为好转组(n=15)和恶化组(n=91),将两组患者的单因素指标:年龄、性别、实验室指标[TBil、Alb、ALT、AST、凝血酶原活动度(PTA)]、HE分期及并发症[持续性低钠血症、消化道出血、肝肾综合征(HRS)、腹水、感染、自发性细菌性腹膜炎(SBP)]、血浆置换进行χ2检验或t检验,再将有意义的单因素进一步行Logistic回归分析。结果单因素分析显示,ALT、PTA、HE分期、HRS差异有统计学意义(P值分别为0.009、0.043、0.000、0.003);性别、年龄、持续低钠血症、消化道出血、感染、SBP、腹水、TBil、Alb、AST、血浆置换差异无统计学意义(P0.05)。经二元Logistic回归分析得出,PTA、HRS、HE分期对ACLF伴HE患者的预后有意义,回归系数分别为-0.097、2.279、1.873,P值分别为0.025、0.007、0.000,优势比(OR值)分别为0.908、6.510、9.764。结论 HE分期、HRS、PTA是ACLF伴HE预后的独立危险因素,PTA越低、HE分期越高,出现HRS时预后越差。     

Intensive liver care and management of acute hepatic failure

In describing acute liver failure, the term fulminant hepatic failure (FHF) is used to denote patients with the most rapid progression, normally defined as the onset of encephalopathy within eight weeks of the onset of symptoms. For patients with a slower onset of encephalopathy, ranging from eight weeks to six months after the onset of symptoms, late-onset hepatic failure is the term used to reflect the overlap in clinical features with some patients with FHF. The importance of accurately determining the type of acute liver failure results from increasing evidence of an inverse relationship between the tempo of disease progression and the chances of recovery. Prognosis is also dependent on the underlying etiology. Principles of management are as follows: (1) an accurate recognition of the tempo of the hepatic failure—fulminant, late onset, acute on chronic—and the establishment of a likely etiology; (2) early detection and treatment of complications, particularly metabolic acidosis (early), renal failure, cerebral edema, and infection (late); (3) optimization of conditions for regeneration by maintenance of a near normal metabolic milieu (with removal of toxins by various methods of artificial liver support if necessary); and (4) early consideration of an orthotopic liver transplant for those patients in the poor prognosis group. Variations in the natural history and clinical features of acute liver failure (ALF) have led to a number of different classifications and subgroupings. Knowledge of these is important in relation to the assessment of prognosis and is even more important now that transplantation is a therapeutic option. Fulminant hepatic failure (FHF) is the term used to denote the subgroup where the tempo is greatest and is variously defined as the onset of encephalopathy within four weeks (1), six weeks (EASL, 1979) and eight weeks [as described by Trey and Davidson (2)] of the onset of symptoms, or within two weeks of the onset of jaundice (3). The patients with a more protracted course are designated by the terms subacute or late-onset hepatic failure (LOHF) (4) or subfulminant hepatic failure (3). The etiology of the hepatic failure also has a major influence on the likely prognosis.Presented at the Proceedings of International Meeting on Normal and Neoplastic Growth in Hepatology, Bari, Italy, June 1989.     

Arterial steroid injection therapy can inhibit the progression of severe acute hepatic failure toward fulminant liver failure

INTRODUCTION Although it is accepted that severe acute hepatic failure is self-limiting in most patients, it progresses to fulminant liver failure with a high mortality rate in some patients[1]. Liver transplantation (LT) is the only effective treatment f…     

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     

Diagnostic criteria of acute liver failure: A report by the Intractable Hepato-Biliary Diseases Study Group of Japan

The diagnostic criteria of fulminant hepatitis in Japan are different from those of acute liver failure in Europe and the United States, both in regard to the histological features in the liver and the cutoff values of the prothrombin time. Thus, the Intractable Hepato‐Biliary Disease Study Group established novel diagnostic criteria for “acute liver failure” in Japan based on the demographic and clinical features of the patients. Patients showing prothrombin time values of 40% or less of the standardized values or international normalized ratios of 1.5 or more caused by severe liver damage within 8 weeks of onset of the symptoms are diagnosed as having “acute liver failure”, where the liver function prior to the current onset of liver damage is estimated to be normal. Acute liver failure is classified into “acute liver failure without hepatic coma” and “acute liver failure with hepatic coma,” depending on the severity of the hepatic encephalopathy; the latter is further classified into two types, the “acute type” and the “subacute type”, in which grade II or more severe hepatic coma develops within 10 days and between 11 and 56 days, respectively, after the onset of disease symptoms. Patients without histological findings of hepatitis, such as those with liver damage caused by drug toxicity, circulatory disturbance or metabolic disease, are also included in the disease entity of “acute liver failure”, while acute‐on‐chronic liver injuries, such as liver injury caused by alcohol, are excluded. A nationwide survey of “acute liver failure” in Japan based on the novel criteria is proposed.     

Mild hypothermia prevents cerebral edema in acute liver failure

Mild hypothermia prevents the development of brain edema in rats with acute liver failure resulting from hepatic devascularization. Mechanistic studies performed in this model suggest that the protective effect of hypothermia results from the inhibition of blood-brain transfer of ammonia, an action which could result (at least in part) from an effect on cerebral blood flow. Hypothermia-induced reductions of brain ammonia are associated with normalization of extracellular brain glutamate concentrations in rats with acute liver failure. Studies in humans suggest that mild hypothermia is beneficial in the management of severely raised intracranial pressure, both before and after liver transplantation in patients with acute liver failure due to acetaminophen overdose. Mild hypothermia offers a potentially useful bridge therapy in patients with acute liver failure who are awaiting liver transplantation.