Acute liver failure (ALF) is a disease with a mortality of 60–90% depending on the cause. Only high-urgency liver transplantation is able to increase survival compared to standard intensive care therapy. Liver transplantation is hampered by the increasing shortage of organ donors, resulting in a high incidence of patients with ALF dying on the transplantation waiting list. Amongst a variety of liver assist therapies, bioartificial liver (BAL) therapy is marked as the most promising solution to bridge ALF patients to liver transplantation or to liver regeneration, since several BAL systems showed significant improvement of survival time in experimental animals with irreversible ALF. One of these systems has been developed at the Academic Medical Center in Amsterdam, The Netherlands – the AMC-BAL. This overview describes the development of the AMC-BAL based on porcine hepatocytes which was started 10 years ago. Positive results of in vitrofunctionality and in vivo safety and efficacy led to a successful phase I study in 12 ALF patients in Italy. However, xenotransplantation legislation in many European countries prohibits the use of porcine hepatocytes in clinically applied BAL systems. The future of the BAL, therefore, resides in the development of a human-derived hepatocyte cell line as biocomponent of BAL systems.

1.
Sanyal AJ, Stravitz RT: Hepatology: A Textbook of Liver Disease; in Zakim D, Boyer TD (eds): Acute Liver Failure. Philadelphia, WB Saunders Comp 2003, ed 4, chap 16.
2.
Adam R, Cailliez V, Majno P, Karam V, McMaster P, Caine RY, O’Grady J, Pichlmayr R, Neuhaus P, Otte JB, Hoeckerstedt K, Bismuth H: Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry Study. Lancet 2000;356:621–627.
3.
Lidofsky SD, Bass NM, Prager MC, Washington DE, Read AE, Wright TL, Ascher NL, Roberts JP, Scharschmidt BF, Lake JR: Intracranial pressure monitoring and liver transplantation for fulminant hepatic failure. Hepatology 1992;16:1–7.
4.
De Rave S, Tilanus HW, van Der LJ, de Man RA, van Der BB, Hop WJ, Ijzermans JM, Zondervan PE, Metselaar HJ: The importance of orthotopic liver transplantation in acute hepatic failure. Transpl Int 2002;15:29–33.
5.
Wall WJ, Adams PC: Liver transplantation for fulminant hepatic failure: North American experience. Liver Transpl Surg 1995;1:178–182.
6.
Farmer DG, Anselmo DM, Ghobrial RM, Yersiz H, McDiarmid SV, Cao C, Weaver M, Figueroa J, Khan K, Vargas J, Saab S, Han S, Durazo F, Goldstein L, Holt C, Busuttil RW: Liver transplantation for fulminant hepatic failure: experience with more than 200 patients over a 17-year period. Ann Surg 2003;237:666–676.
7.
United Network for Organ Sharing: Liver transplantation data 2002; www.unos.org (Internet communication 2002).
8.
Rahman TM, Hodgson HJ: Review article: Liver support systems in acute hepatic failure. Aliment Pharmacol Ther 1999;13:1255–1272.
9.
Stockmann HB, Hiemstra CA, Marquet RL, Ijzermans JN: Extracorporeal perfusion for the treatment of acute liver failure. Ann Surg 2000;231:460–470.
10.
Davenport A: Artificial hepatic support. Where are we now? Blood Purif 2001;19:1–3.
11.
Mito M: Hepatic assist: present and future. Artif Organs 1986;10:214–218.
12.
Kjaergard LL, Liu J, Als-Nielsen B, Gluud C: Artificial and bioartificial support systems for acute and acute-on-chronic liver failure: A systematic review. JAMA 2003;289:217–222.
13.
Van de Kerkhove MP, Hoekstra R, Chamuleau RAFM, van Gulik TM: Clinical application of bioartificial liver support systems. Ann Surg 2004;240:216–230.
14.
Flendrig LM, la Soe JW, Jorning GG, Steenbeek A, Karlsen OT, Bovee WM, et al: In vitro evaluation of a novel bioreactor based on an integral oxygenator and a spirally wound nonwoven polyester matrix for hepatocyte culture as small aggregates. J Hepatol 1997;26:1379–1392.
15.
Flendrig LM, Sommeijer D, Ladiges NCJJ, te Velde AA, Maas MAW, Jorning GGA, Daalhuisen J, Chamuleau RAFM: Commercially available media for flushing extracorporeal bioartificial liver systems prior to connection to the patient’s circulation: an in vitro comparative study in two- and three-dimensional porcine hepatocyte cultures. Int J Artif Organs 1998;21:467–472.
16.
Seglen PO: Preparation of isolated rat liver cells. Methods Cell Biol 1975;29–83.
17.
Te Velde AA, Ladiges NC, Flendrig LM, Chamuleau RA: Functional activity of isolated pig hepatocytes attached to different extracellular matrix substrates. Implication for application of pig hepatocytes in a bioartificial liver. J Hepatol 1995;23:184–192.
18.
Van de Kerkhove MP, Poyck PPC, van Wijk ACWA, Galavotti D, Hoekstra R, van Gulik TM, et al: Assessment and improvements of liver specific function of the AMC-bioartificial liver. Int J Artif Organs 2005;28:617–630.
19.
Abrahamse SL, van de Kerkhove MP, Sosef MN, Hartman R, Chamuleau RA, van Gulik TM: Treatment of acute liver failure in pigs reduces hepatocyte function in a bioartificial liver support system. Int J Artif Organs 2002;25:966–974.
20.
Van de Kerkhove MP, Hoekstra R, van Gulik TM, Chamuleau RAFM: Large animal models of fulminant hepatic failure in liver support research. Biomaterials 2004;25:1613–1625.
21.
Flendrig LM, te Velde AA, Chamuleau RA: Semipermeable hollow-fiber membranes in hepatocyte bioreactors: A prerequisite for a successful bioartificial liver? Artif Organs 1997;21:1177–1181.
22.
Flendrig LM, Chamuleau RA, Maas MA, Daalhuisen J, Hasset B, Kilty CG, et al: Evaluation of a novel bioartificial liver in rats with complete liver ischemia: treatment efficacy and species-specific α-GST detection to monitor hepatocyte viability. J Hepatol 1999;30:311–320.
23.
Flendrig LM, Calise F, Di Florio E, Mancini A, Ceriello A, Santaniello W, et al: Significantly improved survival time in pigs with complete liver ischemia treated with a novel bioartificial liver. Int J Artif Organs 1999;22:701–709.
24.
Sosef MN, Abrahamse LS, van de Kerkhove MP, Hartman R, Chamuleau RA, van Gulik TM: Assessment of the AMC-bioartificial liver in the anhepatic pig. Transplantation 2002;73:204–209.
25.
Sosef MN, van de Kerkhove MP, Abrahamse LS, Levi M, Chamuleau RA, van Gulik TM: Blood coagulation in anhepatic pigs: Effects of treatment with the AMC bioartificial liver. J Thromb Haemost 2003;1:511–515.
26.
Watanabe FD, Mullon CJ, Hewitt WR, Arkadopoulos N, Kahaku E, Eguchi, Khalili T, Arnaout W, Shackleton CR, Rozga J, Solomon B, Demetriou AA: Clinical experience with a bioartificial liver in the treatment of severe liver failure. A phase I clinical trial. Ann Surg 1997;225:484–491.
27.
Demetriou AA, Brown RS Jr, Busuttil RW, Fair J, McGuire BM, et al: Prospective, randomised, multicenter controlled trial of a bioartificial liver in treating acute liver failure. Ann Surg 2004;239:660–667.
28.
Calise F, Mancini A, Amoroso P, Belli A, Bracco A, Ceriello A, et al: Functional evaluation of the AMC-BAL to be employed in a multicentric clinical trial for acute liver failure. Transplant Proc 2001;33:647–649.
29.
Van de Kerkhove MP, Di Florio E, Scuderi V, Mancini A, Belli A, Bracco A, et al: Phase I clinical trial with the AMC-bioartificial liver. Int J Artif Organs 2002;25:950–959.
30.
Van de Kerkhove MP, Di Florio E, Scuderi V, Mancini A, Belli A, Bracco A, et al: Bridging a patient with acute liver failure to liver transplantation by the AMC-bioartificial liver. Cell Transplant 2003;12:563–568.
31.
Koebe HG, Dahnhardt C, Muller-Hocker J, Wagner H, Schildberg FW: Cryopreservation of porcine hepatocyte cultures. Cryobiology 1996;33:127–144.
32.
Morsiani E, Pazzi P, Puviani AC, Brogli M, Valieri L, Gorini P, Scoletta P, Marangoni E, Ragazzi R, Azzena G, Frazzoli E, Di Luca D, Cassai E, Lombardi G, Cavallari A, Faenza S, Pasetto A, Girardis M, Jovine E, Pinna AD: Early experiences with a porcine hepatocyte-based bioartificial liver in acute hepatic failure patients. Int J Artif Organs 2002;25:192–202.
33.
Doorschodt BM, Bessems M, van Vliet AK, van Gulik TM: The first disposable perfusion preservation system for kidney and liver grafts. Ann Transplant 2004;9:40–41.
34.
Crepaldi G, Demetriou AA, Muraca M: Experience in design of controlled clinical trials in acute liver failure; in Riordan SM, Williams R (eds): Bioartificial Liver Support Systems. Rome, CIC Edizioni Internazionali, 1997, pp 104–115.
35.
O’Grady JG, Alexander GJ, Hayllar KM, Williams R: Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989;97:439–445.
36.
Bernuau J, Goudeau A, Poynard T, Dubois F, Lesage G, Yvonnet B, Degott C, Bezeaud A, Rueff B, Benhamou JP: Multivariate analysis of prognostic factors in fulminant hepatitis B. Hepatology 1986;6:648–651.
37.
Di Nicuolo G, van de Kerkhove MP, Hoekstra R, Amoroso P, Battisti S, Starace M, di Florio E, Scuderi V, Scala S, Bracco A, Mancini A, Chamuleau RAFM, Calise F: No evidence of in vitro and in vivo porcine endogenous retrovirus infection after plasmapheresis through the AMC-Bioartificial liver. Xenotransplantation 2005;12:286–292.
38.
Busch MP, Satten GA: Time course of viremia and antibody seroconversion following human immunodeficiency virus exposure. Am J Med 1997;102:117–124.
39.
Watson A, Ranchalis J, Travis B, McClure J, Sutton W, Johnson PR, et al: Plasma viremia in macaques infected with simian immunodeficiency virus: plasma viral load early in infection predicts survival. J Virol 1997;71:284–290.
40.
Dixon FJ, Vazquez JJ, Weigle WO, et al: Pathogenesis of serum sickness. Arch Pathol 1958;65:18–28.
41.
Te Velde AA, Flendrig LM, Ladiges NC, Chamuleau RA: Immunological consequences of the use of xenogeneic hepatocytes in a bioartificial liver for acute liver failure. Int J Artif Organs 1997;20:229–233.
42.
Nyberg SL, Remmel RP, Mann HJ, Peshwa MV, Hu WS, Cerra FB: Primary hepatocytes outperform HepG2 cells as the source of biotransformation functions in a bioartificial liver. Ann Surg 1994;220:59–67.
43.
Ellis AJ, Hughes RD, Wendon JA, Dunne J, Langley PG, Kelly JH, et al: Pilot-controlled trial of the extracorporeal liver assist device in acute liver failure. Hepatology 1996;24:1446–1451.
44.
Werner A, Duvar S, Muthing J, Buntemeyer H, Kahmann U, Lunsdorf H, et al: Cultivation and characterization of a new immortalized human hepatocyte cell line, HepZ, for use in an artificial liver support system. Ann NY Acad Sci 1999;875:364–368.
45.
Pfeifer AM, Cole KE, Smoot DT, Weston A, Groopman JD, Shields PG, et al: Simian virus 40 large tumor antigen-immortalized normal human liver epithelial cells express hepatocyte characteristics and metabolize chemical carcinogens. Proc Natl Acad Sci USA 1993;90:5123–5127.
46.
Schippers IJ, Moshage H, Roelofsen H, Muller M, Heymans HS, Ruiters M, et al: Immortalized human hepatocytes as a tool for the study of hepatocytic (de)differentiation. Cell Biol Toxicol 1997;13:375–386.
47.
Kobayashi N, Fujiwara T, Westerman KA, Inoue Y, Sakaguchi M, Noguchi H, et al: Prevention of acute liver failure in rats with reversibly immortalized human hepatocytes. Science 2000;287:1258–1262.
48.
Strick-Marchand H, Morosan S, Charneau P, Kremsdorf D, Weiss MC: Bipotential mouse embryonic liver stem cell lines contribute to liver regeneration and differentiate as bile ducts and hepatocytes. Proc Natl Acad Sci USA 2004;101:8360–8365.
49.
Hoekstra R, Chamuleau RAFM: Recent developments on human cell lines for the bioartificial liver. Int J Artif Organs 2002;25:182–191.
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