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Acute liver failure (ALF) is a clinical syndrome with high mortality rate, resulting from widespread hepatocyte damage. Its pathophysiological background is still poorly understood and preclinical studies evaluating pathophysiology and new potential therapeutic measures are needed. The model of ALF induced by administration of thioacetamide (TAA) in Lewis rats is recommended as optimal; however, the limitation of previous studies was that they were performed predominantly in male rats. In view of the growing recognition that sex as a biological variable should be taken into consideration in preclinical research, we examined its role in the development of TAA-induced ALF in Lewis rats. We found that, first, intact male Lewis rats showed lower survival rate than their female counterparts, due to augmented liver injury documented by higher plasma ammonia, and bilirubin levels and alanine aminotransferase activity. Second, in female rats castration did not alter the course of TAA-induced ALF whereas in the male gonadectomy improved the survival rate and attenuated liver injury, reducing it to levels observed in their female counterparts. In conclusion, we found that Lewis rats show a remarkable sexual dimorphism with respect to TAA-induced ALF, and male rats display dramatically poorer prognosis as compared with the females. We showed that testosterone is responsible for the deterioration of the course of TAA-induced ALF in male rats. In most general terms, our findings indicate that in the preclinical studies of the pathophysiology and treatment of ALF (at least of the TAA-induced form) the sex-linked differences should be seriously considered.

Acute liver failure (ALF) is known for extremely high mortality rate, the result of widespread damage of hepatocytes. Orthotopic liver transplantation is the only effective therapy but its application is limited by the scarcity of donor organs. Given the importance in the liver biology of Wnt/beta-catenin signaling pathway, we hypothesized that its stimulation could enhance hepatocyte regeneration and attenuate the course of thioacetamide (TAA)-induced ALF in Lewis rats. Chronic treatment with Wnt agonist was started either immediately after hepatotoxic insult ("early treatment") or when signs of ALF had developed ("late treatment"). Only 23 % of untreated Lewis rats survived till the end of experiment. They showed marked increases in plasma alanine aminotransferase (ALT) activity and bilirubin and ammonia (NH3) levels; plasma albumin decreased significantly. "Early" and "late" Wnt agonist treatment raised the final survival rate to 69 % and 63 %, respectively, and normalized ALT, NH3, bilirubin and albumin levels. In conclusion, the results show that treatment with Wnt agonist attenuates the course of TAA-induced ALF in Lewis rats, both with treatment initiated immediately after hepatotoxic insult and in the phase when ALF has already developed. Thus, the pharmacological stimulation of Wnt/beta-catenin signaling pathway can present a new approach to ALF treatment.

Acute liver failure (ALF) is a clinical syndrome resulting from widespread damage of hepatocytes, with extremely high mortality rate. Urgent orthotopic liver transplantation was shown to be the most effective therapy for ALF but this treatment option is limited by scarcity of donor organs. Therefore, hepatocyte transplantation (Tx) has emerged as a new therapeutical measure for ALF, however, the first clinical applications proved unsatisfactory. Apparently, extensive preclinical studies are needed. Our aim was to examine if hepatocytes isolated from transgenic "firefly luciferase" Lewis rats into the recipient liver would attenuate the course of thioacetamide (TAA)-induced ALF in Lewis rats. Untreated Lewis rats after TAA administration showed a profound decrease in survival rate; no animal survived 54 h. The rats showed marked increases in plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, in plasma level of bilirubin and ammonia (NH(3)), and in a significant decrease in plasma albumin. Hepatocyte Tx attenuated the course of TAA-induced ALF Lewis rats which was reflected by improved survival rate and reduced degree of liver injury showing as lowering of elevated plasma ALT, AST, NH(3) and bilirubin levels and increasing plasma albumin. In addition, bioluminescence imaging analyses have shown that in the TAA-damaged livers the transplanted hepatocyte were fully viable throughout the experiment. In conclusion, the results show that hepatocyte Tx into the liver can attenuate the course of TAA-induced ALF in Lewis rats. This information should be considered in attempts to develop new therapeutic approaches to the treatment of ALF.

Objective: Acute liver failure (ALF) is a rare disease with a bad prognosis. Its start is accompanied by haemodynamic instability. The aim of our study was to evaluate the influence of fractionated plasmatic separation and adsorption (FPSA) on body haemodynamics using a large animal experimental model of ALF., Methods: ALF was induced by the devascularisation of 21 laboratory pigs. FPSA was applied in 14 animals and seven animals formed a control group. Values of systemic vascular resistance index (SVRI), heart rate (HR), pulmonary artery wedge pressure (PAWP) and cardiac index (CI) at hours 3, 6, 9 and 12 of the experiment were compared. The values from laboratory tests conducted with FPSA-treated vs. untreated ALF animals were compared using Student's t-test, paired or unpaired, as required, and Mann-Whitney U-test using EXCEL and QUATRO spreadsheet applications., Results: We found no significant differences in mean arterial pressure, SVRI, or plasma lactate (p>0.05) in the FPSA-treated group but there was a significant decrease(p<0.05) in intracranial pressure (ICP). Furthermore, we observed a significant decrease in HR at hour 3. A significant increase in CI at hour 9 and a significant decrease in pulmonary artery wedge pressure at hours 6 and 12 were also observed., Conclusion: Our study of FPSA application (Prometheus device) for treatment of experimental ALF in a large animal model did not confirm the earlier reported development of changes in body haemodynamics.

Acute liver failure (ALF) is a clinical condition with very high mortality rate. Its pathophysiological background is still poorly understood, which necessitates a search for optimal experimental ALF models with features resembling those of the human disorder. Taking into consideration reproducibility of induction of ALF, adequate animal size, cost of animals, the required time gap between insult and death of animals ("therapeutic window"), potential risk to investigator and other aspects, administration of thioacetamide (TAA) in rats is currently most recommended. However, the fundamental details of this ALF model have not yet been evaluated. This prompted us to investigate, first, the course of ALF as induced by intraperitoneal TAA at doses increasing from 175 to 700 mg/kg BW per day. The animals' survival rate, plasma alanine and aspartate aminotransferase activities, and bilirubin and ammonia levels were determined over the follow-up period. Second, we examined whether Wistar and Lewis rats exhibit any differences in the course of ALF induced by different TAA doses. We found that the optimal dose for ALF induction in rats is 350 mg.kg(-1) i.p., given as a single injection. Wistar rats proved more susceptible to the development of TAA-induced ALF compared with Lewis rats. Collectively, our present findings provide a sound methodological background for experimental studies aimed at evaluation of pathophysiology and development of new approaches in the therapy of ALF.

Background: Cerebral edema is a well-recognized and potentially fatal complication of acute liver failure (ALF). The effectiveness of treatments that address intracranial hypertension is generally assessed by measuring intracranial pressure (ICP). The aim of this study was to determine the role of cerebral microdialysis in monitoring the efficacy of fractionated plasma separation and adsorption (FPSA) treatment for ALF. We hypothesized that in ALF cerebral microdialysis reflects the benefits of FPSA treatment on cerebral edema before ICP., Methods: A surgical resection model of ALF was used in 21 pigs. We measured plasma ammonia concentration, brain concentrations of glucose, lactate, pyruvate, glutamate and glutamine, and ICP. Animals were randomized into three groups: in one group eight animals received 6 hours of FPSA treatment 2 hours after induction of ALF; in another group 10 animals received supportive treatment for ALF only; and in the final group three underwent sham surgery., Results: The ICP was significantly higher in the ALF group than in the FPSA group 9 hours after surgery. The lactate/pyruvate (L/P) ratio was significantly lower in the FPSA group than the ALF group 5 hours after surgery, before any significant difference in ICP was detected. Indeed, significant changes in the L/P ratio could be observed within 1 hour of treatment. Glutamine levels were significantly lower in the FPSA group than the ALF group between 6 hours and 10 hours after surgery., Conclusions: Brain lactate/pyruvate ratio and concentration of glutamine measured by cerebral microdialysis reflected the beneficial effects of FPSA treatment on cerebral metabolism more precisely and rapidly than ICP in pigs with fulminant ALF. The role of glutamine as a marker of the efficacy of FPSA treatment for ALF appears promising, but needs further evaluation.

Objectives: Extracorporeal liver support (ELS) may play a role in bridging therapy in patients with acute liver failure (ALF). The aim of this study was to compare the influence of nonbiological and biological methods on intracranial pressure (ICP) in an animal model of ALF., Methods: A surgical devascularization model of ALF in pigs (35-40 kg) was used. Elimination therapy started after the onset of hypoglycemia. Biochemical parameters (bilirubin, ammonia, lactate, etc.) as well as ICP and cerebral perfusion pressure (CPP) were monitored for 12 hours. Of the total 31 pigs with ALF, 14 animals were treated by fractionated plasma separation and absorption (FPSA), 10 were treated with a bioartificial liver (BAL), and 7 animals were used as a control group., Results: FPSA and BAL treatment started on average 3 hours 17 minutes and 2 hours 21 minutes, after devascularization and lasted for 5 hours 54 minutes and 5 hours 43 minutes, respectively. Ammonia levels were lower in the FPSA group, and bilirubin levels differed significantly in both the FPSA and BAL groups compared with controls. However, ICP values were reduced more effectively in pigs treated by FPSA: 19.1 vs. 27.0 mm Hg at 9 hours, 22.5 vs. 28.7 mm Hg at 11 hours, and 24.0 vs. 33.0 mm Hg at 12 hours (p<0.05)., Conclusions: The artificial liver support system FPSA reduced ICP values more effectively than the Performer O. Liver RanD BAL system. Compared with this BAL system, the nonbiological elimination method of FPSA is a simpler application with the advantage that it can be applied in a more continuous way.

Acute liver failure is a severe condition with a very unfavourable prognosis. One of the common complications and limiting factors for the outcome is the development of the intracranial hypertension. The etiology and the pathogenetic pathways leading to the development of this fatal complication of acute liver failure is still not completely understood. The aim of this review is to inform about the actual knowledge of pathogenesis of the intracranial hypertension in acute liver failure. Finally, a new method of tissue metabolism monitoring--microdialysis--is shortly discussed as a perspective method in monitoring and research on acute liver failure.

Background: The aim of the study was to determine the influence of fractionated plasma separation and absorption (FPSA) on intracranial pressure (ICP) in acute liver failure (ALF)., Methods: A surgical model of ALF in pigs (35-40 kg) was used. We compared laboratory data and haemodynamic parameters from the ALF control group to the ALF group treated by Prometheus using ANOVA with repeated measures and grouping factors, by calculating the area under the curve, and by the Mann-Whitney rank test., Results: Bilirubin levels differed significantly in favour of the FPSA treatment group: after 6 h 12.81 +/- 6.54 versus 29.84 +/- 9.99, after 9 h 11.94 +/- 4.14 versus 29.95 +/- 12.36 (p < 0.01) and after 12 h 13.88 +/- 6.31 versus 26.10 +/- 12.23 mmol/l (p < 0.05). ICP values differed significantly in favour of the FPSA treatment group: after 9 h 19.1 +/- 4.09 versus 24.1 +/- 2.85 (p < 0.01), after 10 h 21.9 +/- 3.63 versus 25.1 +/- 2.19, after 11 h 22.5 +/- 3.98 versus 26.3 +/- 3.50, and after 12 h 24.0 +/- 4.66 versus 29.8 +/- 5.88 mm Hg (p < 0.05)., Conclusion: The authors demonstrated that a significant decrease in ICP was found in pigs with ALF following treatment by FPSA., (Copyright 2009 S. Karger AG, Basel.)

Background: There was an active interest in development of liver assist device in the last two decades. Using these devices to bridge patients with acute hepatic failure (AHF) to ortotopic liver transplantation (OLTx) or to liver regeneration might decrease the mortality rate. Several liver support systems have been described in different stages of experimental or clinical examination., Methods: PubMed (1986-2008) was searched using the keywords "artifitial livers", "liver support", "bioartifitial liver" and "cell transplantation". The own experience presenting by authors are the conclusions of their publications., Results and Discussion: Biological liver support (BAL) uses hepatocytes can support theoretically both detoxification and biosynthesis. Experimental study confirmed significant decrease in some of AHF metabolites. Nevertheless, randomized study didn't show any improvement in patient's survival. Source of viable hepatocytes and sufficient bioreactor capacity are some of unsolved problems. Nonbiological liver support as a plasma exchange, hemodialysis, hemofiltration, albumin dialysis or adsorbent recycling systems eliminate some of toxins, but other specific liver functions can't replace. MARS and Prometheus devices have been used successfully in treatment of AHF by human. However, the absence of randomized study still lasts. These devices remove some of toxins and cytokines unselectively and are also limited by adsorber capacity. Selective plasma filtration therapy and hybrid liver support systems which combine both of management advances present the possible solution. Authors themselves confirmed by application of both methods a significant decrease of bilirubin level. Intracranial pressure declines only by use of non-biological device - Prometheus., Conclusion: Effective liver assist device that gains a survival approval hasn't been developed till now. In confrontation with other current used cure possibilities, BAL didn't propose the original expectations. On the other hand, the non-biological devices seem to be perspective and their contribution has been proved by prospective studies. The randomized study is still absent. Authors' experiences confirm this trend.

Background: Development of biological and non-biological artificial liver devices in the previous 20 years enabled effective treatment of acute liver failure (ALF) of patients waiting for liver transplantation or for spontaneous liver parenchyma regeneration. Aim of the study was the evaluation of the effectiveness of biological (BAL - bioartificial liver) and non-biological (FPSA - Fractionated plasma separation and adsorption) methods in the treatment of experimental ALF on large laboratory animal., Methods and Results: Surgical model of ALF with liver devascularization in pigs (weight 25-40 kg) was provided following monitoring of ALF markers (AST, ALT, bilirubin, ammoniac, glycaemia, INR) including intracranial pressure (ICP). Control group included animals without treatment of ALF. Results of both experimental groups were compared and statistically worked-out with that of controls by T-test and Mann-Whitney non-parametric test by EXCEL and QUATRO. BAL group: 10 pigs (weight 30 +/- 5 kg) with ALF were treated by BAL with isolated hepatocytes. When plasma bilirubin was compared, significant differences (p < 0.05) in 6 and 9 hours interval were found favouring BAL group (18.1 vs. 13.1, 22.9 vs. 13.2 mmol/l). The value of ICP in both groups was no significant. Prometheus group: 14 pigs weight 35 kg (35 +/- 5 kg) with the identical ALF were treated by Prometheus (FPSA). Level of serum bilirubin in experimental group when compared to control group was significantly lower (p < 0.01) at 6 hour interval 12.81 +/- 6.54 vs. 29.84 +/- 9.99 at 9 hour 11.94 +/- 4.14 vs. 29.95 +/- 12.36 and at 12 hour 13.88 +/- 6.31 vs. 26.10 +/- 12.23 mmol/l. No significant difference in serum ammonia level was found. ICP was significantly different from 9 hour to 12 hour interval in favour of FPSA group (p < 0.01): 9 hour 19.1 +/- 4.09 vs. 24.1 +/- 2.85, 10 hour 21.9 +/- 3.63 vs. 25.1 +/- 2.19, 11 hour 22.5 +/- 3.98 vs. 26.3 +/- 3.50 and 12 hour 24.0 +/- 4.66 vs. 29.8 +/- 5.88 mm Hg., Conclusions: Significant improvement of bilirubin and ICP levels resulting from the treatment with fractionated plasma separation and adsorption (Prometheus) were observed in the case of experimental ALE Except the bilirubin levels, bioartificial liver provided by O. liver Performer with isolated hepatocytes did not bring any significant improvement of laboratory markers, including ICP.

Animal models of fulminant hepatic failure (FHF) are important for studying the pathophysiology of this process and for evaluation of the efficacy of artificial and bioartificial liver support systems. In experiments, hemodynamic parameters were monitored in a group of minipigs with FHF induced by surgical devascularization, and compared with those in a control group. During the experiment, animals were analgosedated and were on mechanical lung ventilation. Crystalloid and colloidal solutions were administered and norepinephrine in continuous infusion was applied if mean arterial pressure (MAP) decreased below 60 mm Hg despite adequate intravascular volumes. An increase in heart rate, and decreases in MAP and systemic vascular resistance, compared with the baseline, occurred in the FHF group from 6 h after surgery. A comparison of FHF and control groups revealed no significant differences in systemic vascular resistance and MAP until after 12 h after surgery (systemic vascular resistance index: 953 FHF vs. 1658 controls; p < 0.05; MAP: 58.1 FHF vs. 76 controls; p < 0.05). No significant differences in CI were seen between the FHF group and controls. FHF animals survived for about 13 h after surgery, i.e. a period, which we consider long enough to test a support device. The parameters are believed to be quite adequate, as we were able to maintain satisfactory hemodynamic stability in all experimental animals with induced acute hepatic failure.

Aim: The aim of this study was to create an easily reproducible model of the acute hepatic failure (ASJ) in a minipig, which may allow to test supporting eliminating systems. The aim of this report was to describe the surgical technique with the anaesthesiological procedure and to demonstrate the experimental results on a group of the laboratory animals., Methodology: The ASJ was mocked using surgical devascularization of the liver: a ligature of the a. hepatica propria and v. portae, creating a portocaval anastomosis end-to-side. The animals were analgosedated during the experiment and were on a ventilatory support. Biochemical indicators of the hepatic failure, the ICP and the haemodynamics parameters were monitored. Hypoglycaemia with levels below 3.5 mmol and any increase of the intracranial pressure (ICP) were considered the onset of the hepatic failure., Material: 20 minipigs weighing 25-30 kg and divided in 3 groups, were included in the experiment: I--10 animals were assigned to the acute hepatic failure (ASJ) group, II--5 animals with the mock acute hepatic failure (ASJ), whose ICP was monitored in conjunction with the standard monitoring and III. 5 animals without the acute hepatic failure (ASJ)--a control group., Results: We proved significant differences in the AST levels (33.44 +/- 39.96 vs. 1.56 +/- 0.50 mmol/l), the lactate levels (2.97 +/- 1.16 vs. 1.18 +/- 0.61 mmol/l), and the ammonium levels (264.3 +/- 93.05 vs. 42.5 +/- 12.98 micromol/l) in the acute hepatic failure (ASJ) group compared with the control group (p < 0.01) 6 hours after the surgery and significant changes in the glycaemia levels and the intracranial pressure (ICP) measurements 4 hours after the surgical procedure. Increase in the pulse frequency, the blood pressure, decrease of the mean arterial pressure (MAP) and decrease in the systemic venous resistence index (SVRI) in the acute hepatic failure (ASJ) group was recorded 6 hours after the procedure compared with the initial findings, with significant differences between the acute hepatic failure (ASJ groups and the control group as late as during the 12th hour following the procedure (SVRI: 953 ASJ vs. 1658 control, p - 0.05, MAP: 58.1 ASJ vs. 76 control, p - 0.05). No statistically significant differences in the heart index between the acute hepatic failure (ASJ) group and the control group were recorded. The animals with the acute hepatic failure (ASJ) survived 13 hours following the surgical procedure, on average.

Aim: The study was designed to develop a readily reproducible model of acute liver failure (ALF) in the minipig, to gain an 8-hour therapeutic window to mimic, as closely as possible, acute liver failure in man., Method: We used reversible devascularization model of ALF in the minipig involving hepatic artery ligation and establish an end-to-side portocaval anastomosis. Standard laboratory monitoring was complemented with intracranial pressure (ICP) measurement., Material: Twenty minipigs (weight 25-30 kg) were used for the experiment. The animals were divided into 3 groups: I: 10 animals in an experimental group with ALF; II: 5 animals in an experimental group with ALF and ICP measurement, and III: 5 animals in a control group without ALF., Results: Laboratory testing has shown the significant changes in levels of AST (33.44 +/- 39.96 vs. 1.56 +/- 0.50 mmol/l), lactate (2.97 +/- 1.16 vs. 1.18 +/- 0.61 mmol/l), and ammonia (264.3 +/- 93.05 vs. 42.5 +/- 12.98 mmol/l) between ALF groups and controls (p < 001) 6 h after the operative procedure, and significant changes in hypoglycemia and intracranial pressure were found 4 h after the operative procedure. The difference in Quick values (67.4 +/- 17.03 vs. 75.2 +/- 2.68) was not significant. We assume that the therapeutic window starts 4 h after the beginning of the experiment., Conclusion: Our devascularization model of ALF is simple and readily reproducible. The therapeutic window occurring shortly after surgery and persisting for a mean 9 h is suitable to evaluate bioartificial liver devices., (Copyright 2004 S. Karger AG, Basel)