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.
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