Acute liver failure (ALF) is a devastating condition in which subjects with no previous history of liver disease can develop life-threatening multi-organ failure within weeks of the first symptoms. ALF is characterised by massive liver cell death leading to loss of essential metabolic and synthetic functions, a deranged inflammatory response and brain oedema. Consequently, jaundice, coagulopathy, hepatic encephalopathy, coma and multi-organ failure develop rapidly. Mortality from acute liver failure (ALF) is high despite maximal supportive intensive care treatment: 60-80 % depending on the cause. Orthotopic liver transplantation (OLT) is at present the best therapy with one-year survival rates ranging between 50 and 75 % (Bismuth 1996). However, the scarcity of donor livers is limiting this therapy; in the Eurotransplant zone there was a need for 2249 liver transplants in 2006, while only 1277 OLTs were carried out. In the US, probably ALF accounts for about 6% of the OLTs among adults (Seaberg , 1998). The low number of donor livers leads to long waiting times on the OLT waiting list and deaths in up to 20-30% patients waiting for a suitable donor organ to become available. As the liver has an enormous capacity for regeneration, recovery is possible even in patients who have severe liver injury or undergo substantial liver resection.
Bioartificial livers (BALs) have been developed to either prolong the waiting period for an adequate graft or to promote the regeneration capacity of the diseased liver, in the latter case rendering OLT superfluous. This liver support method is therefore promising as it may provide vital life support for ALF patients. Several different types of BALs are currently under investigation. Most of them are in experimental stages. A few of them have been tested clinically in a Phase 1 study, two of which have been tested in a controlled clinical trial in patients with ALF waiting for OLT (Strain and Neuberger 2002). Until now they appear to be safe.
The AMC-BAL has been successfully used in a Phase 1 study in Italy in 14 patients with ALF. The treatment appeared to be safe without important adverse effects. Thirteen of the fourteen patients were successfully bridged to OLT; one patient recovered during BAL treatment and did not need OLT (see publication of the first 8 patients in: Van de Kerkhove 2002). The use of the porcine liver cell loaded AMC-BAL is, however, not allowed in many European countries (including the Netherlands), because of xenotransplantation-related risks.
For these reasons our research group has started to apply human liver cell lines with sufficient functionality in the bioreactor. The human liver cell line HepaRG showed superior and all-round liver functionality in the AMC-BAL. Proof of principle has been shown in rats with ALF (Nibourg, 2012); HepaRG-BAL treatment reduced the development of kidney failure, coma and increased the survival time. This has paved the road to prepare a new clinical trial. Due to a large grant of the EU the expectation is that the first 10 patients with ALF will be treated with the HepaRG-BAL in the beginning of 2015.
Bismuth H, Samuel D, Castaing D, Williams R, Pereira SP, Liver transplantation in Europe for patients with acute liver failure. Seminars in liver disease 1996, 16 (4); 415-425.
Strain AJ, Neuberger JM. A bioartificial liver-State of the art. Science 2002;295:1005-1009.
Van de Kerkhove, Di Florio E, Scuderi V et al . Phase 1 clinical trial with the AMC-bioartificial liver. Int J. Artif Organs 2002; 25:950-959.
Hoekstra R, Chamuleau RAFM. Recent developments on human cell lines for the bioartificial liver. Int J Artif Organs 2002;25/3:182-191
Di Nicuolo, G. Van de Kerkhove, M.P., Hoekstra, R., Amoroso, P., Battisti, S., Starace, M., Di Florio, E., Scuderi, V., Scala, S., Bracco, A., Manzini, A., Chamuleau, R.A.F.M. and Calise, F. No evidence of in vitro and in vivo porcine endogenous retrovirus infection after plasmapheresis through the AMC-Bioartificial liver. Xenotransplantation 2005;12: 286-92
Giuseppe Di Nicuolo, Alba D’Alessandro, Barbara Andria, Vincenzo Scuderi, Michele Scognamiglio, Angela Tammaro, Antonio Mancini, Ernesto Di Florio, Adele Bracco, Fulvio Calise, Robert A.F.M. Chamuleau. Long-term absence of PERV infection in chronically immunosuppressed patients after treatment with the porcine cell based AMC-bioartificial liver and in healthcare workers exposed to porcine materials during its preparation and application. Xenotransplantation, 2010; 17: 431-439.
Geert A.A. Nibourg, Robert A.F.M. Chamuleau, Tessa V. van der Hoeven, Martinus A.W. Maas, Mariette T Ackermans, Ronald P.J. Oude Elferink, Thomas M. van Gulik, Ruurdtje Hoekstra. Human hepatoma cell line HepaRG based bioartificial liver therapy increases survival time in rats with acute liver failure. PlosOne 2012; 7(6):e38778