We herein describe the clinical course of a consecutive series of fulminant hepatic failure patients treated with a molecular adsorbent recirculating system (MARS), a cell-free albumin dialysis technique. From November 2000 to September 2002, seven adult patients ages 22-61 (median, 41), one male (14.2%) and six females (85.7%), affected by fulminant hepatic failure underwent seven courses (one to five sessions each, 6 hr in duration) of extracorporeal support using the MARS technique. Pre- and posttreatment blood glucose, liver function tests, ammonia, arterial lactate, electrolytes, hemodynamic parameters, arterial blood gases, liver histology, Glasgow Coma Scale, and coagulation studies were reviewed. No adverse side effects such as generalized bleeding on noncardiogenic pulmonary edema, often seen during MARS treatment, occurred in the patients included in this study. Six patients (85.7%) are currently alive and well, and one (14.2%) died. Four patients (57%) were successfully bridged (two patients in 1 day and two other patients in 4 days) to liver transplantation, while two (5%) recovered fully without transplantation. All the measured variables stabilized after commencement of the MARS. No differences were noted between the pre- and the post-MARS histology. We conclude that the MARS is a safe, temporary life support mechanism for patients awaiting liver transplantation or recovering from fulminant hepatic failure.

Effective liver support is needed for a variety of indications. A large number of both biological (containing hepatocytes) and non-biological extracorporeal liver support systems have been described in the literature over the last 50 years. Despite this, there is a paucity of good quality randomized control data examining the effectiveness of these therapies in human liver failure. In this review article, we examine the available data, with particular emphasis on the current front runners, the MARS and HepatAssist systems. Other problems associated with the development of these liver support systems are also discussed. Although promising in animal studies, we conclude that the use of these technologies is not supported currently by a sufficient evidence base to recommend them for routine clinical use and that a lack of understanding about the critical functions required of a liver support system is retarding a more rational approach to the design of these systems.

Because acute liver cell failure is associated with an exceedingly high mortality, liver support has been proposed since the 1950s to improve patient outcome. Early devices, including hemodialysis, hemofiltration, exchange transfusion, plasmapheresis, hemoperfusion, plasma and cross-hemodialysis or cross-circulation, appeared inefficient. Meanwhile, documented results of extracorporeal liver perfusion (ECLP) suggested its superiority over conventional treatment. These devices were abandoned with the development of liver transplantation (LT), which allowed a better outcome and longer survival rate. In the present day, the fact that patients die while waiting for LT because of organ shortage led to a renewed interest in liver support as bridge to LT or regeneration. These devices can be classified according to the presence or lack of hepatocytes, whereas biologic devices refers to the presence of cells or other organic and biochemical component. The absence of individual success of early models led to the development of combined hepatocyte free devices, or artificial liver, which are based upon the hemodiabsorption principle (Biologic-DT) or on the "albumin bound toxin hypothesis" (Molecular Adsorbents Recirculating System) with encouraging results. Meanwhile, hepatocyte based bioartificial liver devices (BLD) were conceived for a global "metabolic support." BLD were developed with the use of human hepatoma cell line (C3A) or primary or cryopreserved porcine hepatocytes. Preliminary experience gave promising results bridging patients to LT. Based upon the same principle of global hepatocyte metabolic support, ECLP regained interest, particularly with the development of transgenic pigs. Several concerns were raised about these devices. Artificial livers lacked any metabolic synthetic activity, the use of human liver for ECLP seems hardly acceptable because of organ shortage, and the accepted use of borderline livers for transplantation is pending trials for the use of xenogenic livers. For BLD, the concerns were the low hepatocyte mass, the absence of accessory liver cells, and the potential risk of seeding tumor cells into patient with the use of human hepatoma cell line. The use of porcine hepatocytes (BLD or ECLP) raised physiologic and immunologic concerns and particularly the fear of a possible transfer of porcine viral material. Although recent studies clearly demonstrate clinical improvement of patients with the use of recently developed liver support devices, most of reported prospective, controlled, or randomized trials had a small number of patients. To give the deciding vote and avoid previous pitfalls, trials need to be developed with a larger number of patients based upon statistically significant models with the following characteristics: 1) comprehensive understanding of the acute liver cell failure mechanisms, 2) world wide classification of conditions that require liver support, and 3) a clear definition of treatment success pending patients to LT or recovery without transplantation. There has not yet been conclusive evidence to support the benefits of extracorporeal liver support. We are still waiting for the deciding vote.

Dysbalance between branched chain (BCAA) and aromatic amino acids (AAA), which can be quantified by a low Fischer's Index (SigmaBCAA/SigmaAAA), as well as elevated levels of free tryptophan in plasma are common in hepatic failure and may contribute to the development of hepatic encephalopathy.

To evaluate the influence of a new extracorporeal detoxification system for liver failure (Molecular Adsorbents Recirculating System, MARS(R), i.e. dialysis against a recirculating albumin solution cleaned online by charcoal and an anion exchange resin) on plasma tryptophan and Fischer's Index.

Plasma samples were taken before, during and after MARS treatments (n = 11, mean blood flow 135 ml/min, mean dialysate flow 120 ml/min, high flux polysulfone membrane). Simultaneous to blood sampling, aliquots of the albumin dialysate were taken between the elements of the dialysate circuit.

Fischer's Index in systemic blood increased during MARS by 24% (from 1.44 to 1.79, P < 0.001; mean treatment duration, 5.5 h). Systemic tryptophan level was significantly reduced at the same time (-25%, n = 8). Amino acid removal rates from plasma during a single dialyser passage ranged from 10 to 53%. In particular, AAA were preferentially removed (42-44% throughout treatment), while BCAA removal was 28-46% initially and later declined to 24-28%. A maximum concentration gradient between plasma and dialysate was maintained for the AAA throughout treatment through their apparently complete removal by the charcoal adsorber. Conversely, BCAA removal at both adsorbers was only minor. As a result, Fischer's Index showed a significant increase in the processed plasma, which became even more pronounced with increasing treatment duration.

MARS enables an elevation of a pathologically decreased Fischer's Index as well as a reduction of systemic tryptophan levels in patients with liver failure. The effects of MARS on plasma amino acid dysbalance may contribute to an improvement of hepatic encephalopathy.

Molecular Adsorbent Recirculating System (MARS) is a blood-filtering system designed to provide biological artificial liver support. We describe its use in a small child to illustrate its effectiveness and practicality in this age group. A 15-month-old male underwent split liver transplantation for acute liver failure following bone marrow transplantation. After development of graft dysfunction we instituted MARS-dialysis. MARS therapy led to a dramatic fall in serum bilirubin and transaminases. Liver synthetic function was not affected. This was accompanied by a stabilization of the patients clinical condition until repeat split liver transplantation was performed 2 weeks after the first graft. MARS-dialysis is practical in the small child. In this case, it did not provide definitive treatment but was an excellent bridging therapy before retransplantation.

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.

An efficient bioartificial liver-assisted device can sustain the lives of patients with acute liver failure. Among different configurations of the bioreactor design, hepatocyte encapsulation has important features that satisfy most requirements of the device. We have encapsulated rat hepatocytes in a two-layer polymeric membrane by complex coacervation using a simple setup and demonstrated enhanced cellular functions up to three times higher than those of the monolayer control. These microcapsules of the functioning hepatocytes have a 2- to 3-microm outer layer of synthetic polymer with 25% 2-hydroxyethyl methacrylate, 25% methacrylic acid, and 50% methyl methacrylate and an inner layer of positively charged modified collagen as a suitable substrate for the enhanced cellular functions. Permeable only to small molecules up to albumin, the microcapsules should allow unimpeded exchange of nutrients, oxygen, growth factors, and metabolites but prevent attack by immunoglobulins of the immune system, and no "skin effect" of the collagen has been observed. Mechanical properties of the microcapsules measured with a nano-indentation method suggest that the microcapsules should be suitable for use in a bioartificial liver-assisted device.

Xenotransplantation of the liver, in its broadest conception, might involve the transplantation of an intact organ or xenogeneic hepatocytes, or the use of an intact xenogeneic liver or cells as an ex vivo "device." The indications for xenotransplantation include not only hepatic failure but also, potentially, the treatment of metabolic diseases. The hurdles to xenotransplantation include immune, physiologic, and infectious complications. New information and progress in experimental systems are bringing xenotransplantation closer to clinical application.

Severe hepatitis A infection is an infrequent but well-recognized cause of acute liver failure that can now be effectively prevented with vaccination against hepatitis A virus. Bromfenac and troglitazone hepatotoxicity as well as various herbal remedies are some of the newly identified causes of acute liver failure. The recently identified transfusion-transmitted virus has been implicated in some cases of idiopathic acute liver failure whereas hepatitis G virus does not appear to be a causative agent. Recognizing, monitoring, and treating patients with life-threatening cerebral edema remain critically important but difficult aspects of the clinical care of acute liver failure. Hypothermia and N-acetylcysteine are promising experimental approaches to cerebral edema but emergency liver transplantation is the only proven means of improving patient survival. Although recent changes in organ allocation may reduce waiting time to transplantation, more reliable and validated markers of liver regeneration and prognosis are needed to triage patients. The potential application and limitations of novel technologies including bioartificial liver devices and auxiliary liver transplantation continue to evolve from pioneering work in animal models and human subjects.