Liver Support Devices Research Articles

Alcoholic Hepatitis.

Alcoholic hepatitis is a multisystem disease seen in individuals who chronically abuse alcohol. When severe, it is associated with a very high mortality rate, with nearly 50% of severely affected persons dying within 1 month of hospitalization. Primary therapy is complete alcohol abstinence and supportive care. Corticosteroids have been shown to be beneficial in a subset of severely ill patients with alcoholic hepatitis and concomitant hepatic encephalopathy. Pentoxifylline has been shown to improve short-term survival rates. Other pharmacologic interventions, including colchicine, propylthiouracil, calcium channel antagonists, and insulin with glucagon infusions, have not been proven to be beneficial. Nutritional supplementation with high-calorie, high-protein diets does not improve mortality rates. Orthotopic liver transplantation is highly controversial in this population of patients and currently is not indicated as definitive treatment. Extracorporeal liver support devices are still in their developmental stage and are only experimental.

Animal models of fulminant hepatic failure: need to test liver support devices.

Fulminant hepatic failure is one of the most dramatic entities in clinical medicine, but experimental studies of its pathogenesis, evolution and treatment have, so far been limited by the lack of satisfactory animal models for testing new supportive treatment options. The variable aetiology, complex pathogenetic mechanisms and inconstant clinical evolution of human fulminant hepatic failure make it particularly difficult to establish an "ideal fulminant hepatic failure animal model" suitable for all studies: it is no longer mandatory to develop one single model serving all possible scientific needs, but the use of a specific model for a specific issue is more advisable. The currently available animal models of fulminant hepatic failure are the hepatotoxic, surgical and combined hepatotoxic and surgical models. From a general point of view, surgical models may be particularly appropriate for studying the consequences of hepatic necrosis on cerebral oedema. The anhepatic model is very useful for validating new supportive measures to bridge the period between the onset of fulminant hepatic failure and the time at which a suitable organ becomes available and, despite the many difficulties involved in their development, hepatotoxic models may still be useful for mimicking an acetaminophen overdose. The efficacy and reproducibility of a liver support system can be demonstrated by means of preclinical experimental models that mimic the specific application required in humans as closely as possible.

Results of a phase I trial evaluating a liver support device utilizing albumin dialysis

Background. We have previously reported the clearance of protein-bound and water-soluble hepatic toxins, in vitro and in an animal model, using albumin dialysis as an extracorporeal hepatic support (ECHS) device. Objective. The objective of this study was to evaluate albumin dialysis through a phase I clinical trial. We hypothesized that albumin dialysis would (1) decrease elevated levels of hepatic toxins, (2) increase the Fischer ratio, and (3) decrease hepatic encephalopathy (HES) and intracranial pressure (ICP), while (4) maintaining stable hemodynamics. Methods. Patients with acute liver failure were treated with an ECHS device utilizing continuous hemodiafiltration with continuous albumin dialysis. Mean arterial blood pressure (MAP), heart rate (HR), systemic venous oxygen saturation (Svo2), ICP, and HES were recorded. Blood samples were evaluated for hepatic toxins and factor VII levels. Results. Nine patients were enrolled (status I, n = 5; status IIA, n = 4). There was no significant change in MAP, HR, or Svo2 (MAP: Pre = 81 ± 5.6 mm Hg, Post = 79 ± 5.9 mm Hg, P =.70; HR: Pre = 104 ± 5.2 bpm, Post = 107 ± 6.2 bpm, P =.62; Svo2: Pre = 72 ± 3.5, Post = 71 ± 1.7, P =.77). There was a decrease in the ammonia and total bilirubin levels (NH3: Pre = 129.8 ± 23.8 mg/dL, Post = 63.9 ± 16.1 mg/dL, P =.01; total bilirubin: Pre = 20.3 ± 2.5 mg/dL, Post = 17.6 ± 2.7 mg/dL, P =.4). There was a significant increase of the Fischer ratio and factor VII levels (Fischer ratio: Pre = 0.98 ± 0.2, Post = 2.17 ± 0.5, P =.038; factor VII: Pre = 13.9 ± 4.9, Post = 23.2 ± 4.8, P =.015). There was a significant decrease in the HES and ICP (HES: Pre = 3.8 ± 0.1, Post = 2 ± 0.7, P =.02; ICP: Pre = 37 ± 3.9, Post = 13.3 ± 2.8, P =.048). Of 5 status I patients, 1 recovered native hepatic function and 3 were bridged to transplantation. Conclusions. This phase I study suggests that albumin dialysis as a liver support device is safe and effective in clearing hepatic toxins, with an associated decrease in the HES and ICP. This encouraging efficacy data warrant further investigation with a phase II/III trial. (Surgery 2001;130:354-62.)

Functional metabolic characteristics of intact pig livers during prolonged extracorporeal perfusion: potential for a unique biological liver-assist device.

The clinical development of liver-support devices based on perfusion of either pig hepatocytes cartridges or whole pig livers has been hampered by the ability to use sufficient liver cell mass to provide adequate metabolic support, limited perfusion times, and the potential for patient exposure to pig zoonotic diseases. We designed an original system in which an isolated intact pig liver was perfused extracorporeally under physiological conditions in a closed loop circuit with allogeneic pig blood and constant monitoring of major physiological and functional parameters. The perfusion circuit further included an interface membrane to provide for separation of patient and liver perfusion circulation. Prolonged (6-21 hr) liver perfusion did not produce significant liver damage as reflected by modest rises in the levels of the serum transaminases, stability of main biochemical parameters (including potassium), and the maintenance of normal cellular morphology. Optimal liver function was documented as measured by lactate consumption, control of glycemia, and the results of clotting studies and functional assays. The perfused liver cleared 82% and 79% of peak bilirubin and ammonia concentrations with clearing kinetics identical throughout perfusion. Indocyanine green clearance was identical to that observed in the living donor before explant surgery. In conclusion, the extracorporeal pig liver perfusion apparatus described here allows optimal pig liver function for prolonged periods of time. The microporous membrane to provide separation of donor organ and recipient and the high level of functional activity suggest that this form of liver metabolic support may have important clinical applications.

Evaluation of a Non-Cell Based Extracorporeal Liver Support Device in an Animal Model of Hepatic Failure

Background: Clearance of toxins, that have been implicated as a cause of hepatic encephalopathy and cerebral edema, has been proven effective in vitro, using a non-cell based extracorporeal liver support device (ECHS), which utilizes hemodiafiltration with an albumin dialysate.

Comparison of Pig, Human and Rat Hepatocytes as a Source of Liver Specific Metabolic Functions in Culture Systems - Implications for Use in Bioartificial Liver Devices

The limited availability of human hepatocytes results in the use of animal cells in most bioartificial liver support devices. In the present work, clinically relevant liver specific metabolic activities were compared in rat, pig and human hepatocytes cultured on liver-derived biomatrix to optimize the expression of differentiated functions. Pig hepatocytes showed higher rates of diazepam metabolism (2.549+/-0.821 microg/h/million cells vs. 0.474+/-0.079 microg/h/million cells rats, p<0.005, and vs. 0.704+/-0.171 microg/h/million cells in man, p<0.005) and of bilirubin conjugation (21.60116+/-8.433237 micromoles/l/24 h vs. 6.786809+/-2.983758 in man, p<0.001 and vs. 9.956538+/-1.781016 micromoles/l/24 h in rats, p<0.005). Urea synthesis was similar in pig and in human hepatocytes (150+/-46.3 vs. 144.8+/-21.46 nmoles/h/million cells) and it was lower in rats (84.38+/-35.2; p<0.001 vs. man, p<0.02 vs. pig). High liver specific metabolic activities in cultured pig hepatocytes further support their use as a substitue for human cells in bioartificial liver devices.

ARTIFICIAL LIVER SUPPORT DEVICES FOR FULMINANT LIVER FAILURE

Artificial liver-support devices attempt to bridge patients with fulminant hepatic failure until either a suitable liver allograft is obtained for transplantation or the patient's own liver regenerates sufficiently to resume normal function. It is thought that toxins contribute to the clinical picture of fulminant hepatic failure. The earliest reports of successful toxin removal were blood- and plasma-exchange transfusions. Given these successful case reports, mechanical liver-support devices were designed to filter toxins. These mechanical devices used hemodialysis, charcoal hemoperfusion, hemoperfusion through cation-exchange resins, hemodiabsorption, and combinations of all of these techniques as in the MARS liver-support device. Despite promising case reports and small series, no controlled studies of mechanical devices have ever showed a long-term survival benefit. Thus, the removal of presumed toxins seems to be insufficient to support patients with fulminant hepatic failure, and the biologic function of the liver must also be replaced. Attempts at replacing the biologic function have included extracorporeal liver perfusion, cross-circulation, and hepatocyte transplantation. Current technologies have combined mechanical and biologic support systems in hybrid liver-support devices. The mechanical component of these hybrid devices serves both to remove toxins and to create a barrier between the patient's serum and the biologic component of the liver-support device. The biologic component of these hybrid liver support devices may consist of liver slices, granulated liver, or hepatocytes from low-grade tumor cells or porcine hepatocytes. These biologic components are housed within bioreactors. Currently the most clinically studied bioreactors are those that use capillary hollow-fiber systems. Both the bioartificial liver by Demetrious and the extracorporeal liver-assist device by Sussman and Kelly are in clinical trials. Although the trials seemed to have yielded good survival data when the devices are used as a bridge to transplantation, the type and degree of liver support provided by these devices remains uncertain. Thus, despite decades of great progress in the field of artificial liver support, no one technique alone yet provides sufficient liver support. A hybrid system seems to be the best option at present. Still to be determined is the best tissue to use, how much liver tissue should be used, and the optimal design of the bioreactor.

Acute liver failure

Worldwide, viral hepatitis is the leading cause of acute liver failure, whereas acetaminophen hepatotoxicity is the most commonly identified cause in Western countries. Restricting the quantity of acetaminophen tablets dispensed has been shown to reduce morbidity and mortality in countries with a high incidence of acetaminophen overdose. Troglitazone and bromfenac are two recently approved medications that were withdrawn from the market due to an unacceptably high incidence of severe hepatotoxicity. In addition, trovafloxacin, nefazodone, and ritonavir were reported to be associated with severe hepatitis and acute liver failure. Moderate hypothermia is a simple and potentially effective means of reducing intracranial pressure in patients with acute liver failure and cerebral edema. However, controlled clinical trials are needed to determine proper patient selection and optimize treatment. Extracorporeal bioartificial liver support devices remain an exciting but as yet unproven means of supporting acute liver failure patients with advanced encephalopathy. Living donor liver transplantation has recently been reported for adults and children with acute liver failure. However, ethical concerns regarding donor safety and the ability to obtain informed consent without coercion have been raised. Lastly, advances in the identification and isolation of pluripotent liver stem cells in human bone marrow provides hope for a simple and effective means of enhancing native liver regeneration.

Morphology and metabolism of hepatocytes cultured in Petri dishes on films and in non-woven fabrics of hyaluronic acid esters

Polymers of hyaluronic acid (Hyal) esters exhibit good tissue compatibility and are available in various geometrical configurations. These properties can be exploited for the design of innovative bioartificial liver support devices (BALSDs) using primary hepatocytes. In this paper, we report a preliminary investigation of the polymer feasibility of the ethyl and the benzyl Hyal ester in the form of films and non-woven fabrics for the in vitro culture of primary rat hepatocytes. Cell function was evaluated daily in Petri dishes with respect to the rate of ammonia elimination (AER) and urea synthesis (USR). Cells cultured in non-woven fabrics of the ethyl ester of Hyal (HYAFF7 nw) exhibited an initial AER about 32% lower and synthesised urea 33% faster than that of cells on collagen films. After a week in culture, cells on collagen films retained only a minor fraction of their initial rates. Cells cultured in non-woven fabrics of HYAFF7 nw retained about 62 and 44% of their initial AER and USR, respectively, and exhibited an AER approximately equal to and a USR 3.6 times greater than those of cells adherent to collagen. These results suggest that non-woven fabrics of HYAFF7 nw are promising substrata for hepatocyte culture in BALSDs.

Characterization of the Distribution of Matter in Hybrid Liver Support Devices where Cells are Cultured in a 3-D Membrane Network or on Flat Substrata

Bioreactors for liver assist tested on small animal models are generally scaled-up to treat humans by increasing their size to host a given liver cell mass. In this process, liver cell function in different culture devices is often established based on the metabolite concentration difference between the bioreactor inlet and outlet irrespective of how matter distributes in the bioreactor. In this paper, we report our investigation aimed at establishing whether bioreactor design and operating conditions influence the distribution of matter in two bioreactors proposed for liver assist. We investigated a clinical-scale bioreactor where liver cells are cultured around a three-dimensional network of hollow fiber membranes and a laboratory-scale bioreactor with cells adherent on collagen-coated flat substrata. The distribution of matter was characterized under different operating modes and conditions in terms of the bioreactor residence time distribution evaluated by means of tracer experiments and modeled as a cascade of N stirred tanks with the same volume. Under conditions recommended by the manufacturers, matter distributed uniformly in the clinical-scale bioreactor as a result of the intense backmixing (N=1) whereas axial mixing was negligible in the laboratory-scale bioreactor (N=8). Switching from recycle to single-pass operation definitely reduced axial mixing in the clinical-scale bioreactor (N=2). Increasing feed flow rate significantly enhanced axial mixing in the laboratory-scale bioreactor (N=4). The effects of design, operating mode and conditions on matter distribution in bioreactors for liver cell culture suggest that characterization of the distribution of matter is a necessary step in the scale-up of bioreactors for liver assist and when function of liver cells cultured in different bioreactors is evaluated and compared.

Development and characterization of a hybrid bioartificial liver using primary hepatocytes entrapped in a basement membrane matrix.

For the development of a bioartificial liver (BAL) support device, it is most important to establish highly differentiated liver cells cultured at high density. When rat hepatocytes were cultured on a basement membrane matrix, Engelbreth-Holm-Swarm (EHS) gel, their rates of albumin secretion were very high, as measured by ELISA, and these high rates were maintained for more than three weeks of culturing. This level of activity greatly exceeded that of hepatocytes cultured on a plastic substratum, poly-N-p-vinylbenzyl-D-lactonamide (PVLA), on a single layer of collagen, or in a collagen sandwich culture. In an in vitro perfusion experiment, rat hepatocytes rapidly and completely removed ammonia from Eagle's MEM supplemented with 0.2 mM NH4Cl, although ammonia levels of the medium serially increased in modules containing HepG2 cells. A hybrid liver support system was developed and consisted of plasma perfusion through porous hollow fiber modules inoculated with 10 billion porcine hepatocytes entrapped in EHS gel. This system was applied to pigs with ischemic liver failure 8 hr after creation of a portocaval shunt and hepatic devascularization. In animals treated with the BAL support system, blood bicarbonate levels were increased immediately after treatment, and hemodynamic stability was improved. In control pigs, on the other hand, blood bicarbonate levels and blood pressure remained low. Plasma levels of ammonia and lactate decreased in pigs treated with the BAL device, but not in control animals. These results indicate that primary hepatocytes outperform HepG2 cells as a source of biotransformation functions in a BAL system and that the use of a BAL support device in combination with a hollow fiber module and hepatocytes entrapped in EHS gel has potential advantages for clinical use in patients with fulminant hepatic failure.

Microstructuring ceramic scaffolds for hepatocyte cell culture.

Both extracorporeal liver support devices and tissue engineering of liver for transplantation require the maintenance of functionality of liver cells (hepatocytes) in cell culture for a long time. One approach to achieve this is to optimize hepatocyte in vitro environment by using a scaffold with topographic structure at sub-millimeter scale which controls cell distribution. Therefore, a set of new type of titania ceramic scaffolds, containing cavities of several sizes, has been produced for deducing the best choice of cavity dimensions for culturing hepatocytes. The aim of this paper is to describe in detail the production methods and characterization of such ceramic scaffolds. Experimental production of the scaffolds consists of microfabrication of silicon templates as well as preparation and molding of titania ceramics. The templates, containing arrays of conical protrusions arranged in close-packed hexagonal order, have been achieved using microfabrication methods of photolithography and anisotropic etching in KOH at 50 degrees C. Protrusion dimensions and overall quality of the templates has been evaluated by scanning electron microscopy. The microfabricated templates have resulted in well-defined and reproducible cavities of corresponding dimensions on the titania ceramic surface after injection-molding. Alternatively, simple embossing of the plastified green ceramics with the silicon templates attached to a metal plate also creates cavities on the ceramic surface. While both methods yield good results, they have different advantages: the injection-molding provides a higher quality of imprints while embossing is quicker and less complicated, and is not limited by dimensions of specific molding equipment.

Glutathione Content during the Rinsing and Rewarming Process of Rat Hepatocytes Preserved in University of Wisconsin Solution

The addition of glutathione (GSH) to University of Wisconsin (UW) solution increases the intracellular content of GSH and decreases the release of lactate dehydrogenase used here as a measure of cell viability. However, we found a depletion of GSH when the cells were transferred from UW solution to the rewarming solution. This could sensitize the cells to various forms of oxidative injury. In this study we examined how different compositions of rinsing and rewarming solutions affected the GSH content and the viability of hepatocytes after 72 h of cold storage. For both the rinsing and the rewarming steps we used a Krebs–Henseleit solution with the addition of GSH, methionine, or both GSH and methionine. We found no loss of GSH when the hepatocytes were rinsed in the presence of 3 mM GSH. During the rewarming step we observed a loss of GSH in all of the study groups, but the cells that were incubated with 1 mM methionine showed a lesser depletion of GSH and improved viability. This finding may have valuable applications in hepatocellular transplantation and in the development of bioartificial liver support devices.

Animal models of acute hepatic failure.

The understanding and treatment of acute hepatic failure has developed rapidly over the last 40 years reducing morbidity and mortality from this syndrome. Progress has been made by the study of animal models that reflect the clinical, biochemical and histological pattern of the syndrome seen in man. This is of increasing importance with the use of therapeutic intervention, liver transplantation and the use of extra-corporeal liver support devices. This review examines and critically appraises the various approaches to the study of acute hepatic failure in animal models, including both surgical and pharmacological approaches.

A novel full-scale flat membrane bioreactor utilizing porcine hepatocytes: cell viability and tissue-specific functions.

When designing an extracorporeal hybrid liver support device, special attention should be paid to providing the architectural basis for reconstructing a proper cellular microenvironment that ensures highest and prolonged functional activity of the liver cells. The common goal is to achieve high cell density culture and to design the bioreactor for full-scale primary liver cell cultures under adequate mass transfer conditions. An important aim of this study was to evaluate the biochemical performance of a flat membrane bioreactor that permits high-density hepatocyte culture and simultaneously to culture cells under sufficient oxygenation availability conditions comparable to the in vivo-like microenvironment. In such a bioreactor pig liver cells were cultured within an extracellular matrix between oxygen-permeable flat-sheet membranes. In this investigation we used a novel scaled-up prototype consisting of up to 20 modules in a parallel mode. Each module was seeded with 2 x 10(8) cells. Microscopic examination of the hepatocytes revealed morphological characteristics as found in vivo. Cell concentration increased in the first days of culture, as indicated by DNA measurements. The performance of the bioreactor was monitored for 18 days in terms of albumin synthesis, urea synthesis, ammonia elimination, and diazepam metabolism. The ability of the hepatocytes to synthesize albumin and urea increased during the first days of culture. Higher rates of albumin synthesis were obtained at day 9 and remained at a value of 1.41 pg/h/cell until day 18 of culture. The rate of urea synthesis increased from 23 ng/h/cell to 28 ng/h/cell and then remained constant. Cells eliminated ammonia at a rate of about 56 pg/h/cell, which was constant over the experimental period. Hepatocytes in the bioreactor metabolized diazepam and generated three different metabolites: nordiazepam, temazepam, and oxazepam. The production of such metabolites was sustained until 18 days of culture. These results demonstrated that the scale-up of the bioreactor was assessed, and it could be demonstrated that the device design aimed at the reconstruction of the liver-specific tissue architecture supported the expression of liver-specific functions of primary pig liver cells.

Liver Bridging Techniques in the Treatment of Acute Liver Failure

The introduction of orthotopic liver transplantation in the management of acute liver failure has dramatically increased the survival rates of patients at the cost of removing the patient's native liver and life-long dependence on immunosuppression. However, it is well known that in many patients with acute liver failure the diseased liver has the potential to recover. Death in these patients is often due to increased intra-cranial pressure or infection. Liver bridging techniques are assigned to temporarily provide liver function and enable the native liver to recover in patients with acute liver failure. They represent an attractive alternative to conventional liver transplantation in the management of acute liver failure, since after recovery of the native liver the patient is freed from immuno-suppression with all associated side-effects and risks. Auxiliary liver transplantation, artificial liver support devices and hepatocyte transplantation represent different ways of bridging liver function in acute liver failure. The aim of this review is to present the ideas and principles of these three different liver bridging techniques. We will discuss the relative importance and the future potential of theses bridging techniques in the treatment of acute liver failure by comparing the experimental and clinical results.

CHARACTERIZATION OF INDUCED IgG AND IgM XENOANTIBODY RESPONSES TO PIG ENDOTHELIUM IN HUMANS

446 The severe shortage of allogeneic organs available for human transplantation has led to the consideration of the use of pigs as organ donors. Human preformed and induced antibody responses to pig xenografts, however, present a major barrier to the successful use of pig organs for human transplantation. We have recently identified the IgVH genes responsible for encoding IgM xenoantibody responses in humans exposed to pig tissues in a bioartificial liver support device. These responses are encoded by Ig genes that are members of the VH3 family and are restricted to genes encoded by the IgHV3-11 and IGHV3-74 germline progenitors. Induced xenoantibody responses in human patients at 10 days post BAL exposure demonstrate a clonal expansion of a VH gene with a unique VDJ gene configuration. We have recently demonstrated that this clonally expanded gene encodes a functional antibody that reacts with the α-gal epitope. In this report we have extended our analysis of the host response to the Ig genes used to encode IgG xenoantibodies. We have generated IgG gene libraries established from lymphocytes of patients at days 0 and 22 following treatment with a bioartificial liver containing pig hepatocytes and endothelial cells. cDNA libraries representing the VH3 family were screened by colony filter hybridization to identify increases in the frequency of expression of specific VH genes encoding α-gal antibodies. Immunoglobulin genes derived from the IGHV3-11 germline progenitor demonstrate an increase in frequency of expression from 2.9% at day 0 to 20% at day 22. A CDR3 specific probe was used to identify an IgM to IgG isotype switch during the maturation of the antibody response. A unique, clonally expanded IGHV3-11 gene identified in IgM clones at day 10 represent the majority of IgG clones expressed at high levels at day 22. The identify of this clone was confirmed by DNA sequencing. IgVH genes encoded by the IGHV3-74 family demonstrate an increase in expression from 0.8% at day 0 to 5.5% at day 22. Genes related to V3-7 germline progenitors do not contribute to the xenoantibody response. These results demonstrate that the xenoantibody response in humans is encoded by IgVH genes restricted to IGHV3-11 and IGHV3-74 germline families. A specific xenoantibody reactive with the α-gal epitope undergoes a clonal expansion and an isotype switch during the maturation of the xenoantibody response. The restricted nature of the humoral response to pig tissues is of potential importance for the development of therapeutic strategies to prevent xenograft rejection.

A new technique for total hepatectomy in the pig for testing liver support devices

Background: A large animal model of total hepatectomy is suitable to test the efficacy of any system designed to support patients in hepatic coma. The models previously described in the pig entail a significant degree of surgical trauma, which might alter the evolution of the ensuing hepatic failure and compromise the reproducibility of the model. Methods: Twenty-eight pigs underwent a total hepatectomy according to a new technique. A model was considered satisfactory when it required no blood transfusions and when hematologic and hemodynamic parameters determined before, during, and until 4 hours after hepatectomy showed no significant variations. Moreover, to revive the pattern of hepatic coma produced in the anhepatic model, 7 pigs were monitored until brain death occurred. Results: Twenty-five pigs (89%) underwent a smooth total hepatectomy with minimal variations of the selected parameters. They constituted a highly homogeneous group. Survival of the 7 pigs, followed up until brain death occurred, ranged from 625 to 1595 minutes (mean 1013.57 minutes). The animals remained stable until a few hours before brain death, an event heralded by a final sharp increase of the serum ammonia level and by a well-evident decline of both arterial pressure and liver-dependent clotting factors. Conclusions: This technique of total hepatectomy allows the construction of a reproducible model of anhepaty suitable to test the efficacy of any system conceived to temporarily replace hepatic functions. (Surgery 1999;125:448-55.)

A new technique for total hepatectomy in the pig for testing liver support devices

A new technique for total hepatectomy in the pig for testing liver support devices

FULMINANT HEPATIC FAILURE

Fulminant hepatic failure is a disease of varied causes and a high mortality rate. A sudden onset, jaundice, hepatic encephalopathy, and multiorgan failure are the hallmarks of this syndrome. The management of patients with FHF requires a multidisciplinary approach and intense monitoring. The availability of liver transplantation has provided the means to rescue such patients from near-certain death. Early prognostication and timely availability of donor livers are requirements for a successful outcome. The development of effective artificial liver support devices may greatly prolong the window of opportunity to provide a donor liver, or alternatively, to allow the native liver to regenerate.