Clinical extracorporeal hybrid liver support – phase I study with primary porcine liver cells

Abstract: The objective of this study was to evaluate the feasibility and safety of a hybrid liver support system with extracorporeal plasma separation and bioreactor perfusion in patients with acute liver failure (ALF) who had already fulfilled the criteria for high urgency liver transplantation (LTx). Eight patients (one male, seven female) were treated in terms of bridging to transplantation. The mean age was 36.5 yr (range 20 to 58). Etiology of liver failure was drug‐related in two patients, hepatitis B infection in three patients, and unknown for three patients. The bioreactors were charged with primary liver cells from specific pathogen‐free pigs. Cell viability varied between 91 and 98%. Continuous liver support treatment over a period of 8 to 46 h (mean 27.3 h) was safely performed and well‐tolerated by all patients. No complications associated with the therapy were observed during the follow‐up period. Thrombocytopenia was considered to be an effect of the plasma separation. Subsequently, all patients were transplanted successfully and were observed over at least 3 yr with an organ and patient survival rate of 100%. Screening of patient's sera for antibodies specific for porcine endogenous retroviruses (PERVs) showed no reactivity – either prior to application of the system, or after extracorporeal treatment. The results encourage us to continue the development of the technology, and further studies appear to be justified. The bioreactor technology has been integrated into a modular extracorporeal liver support (MELS) system, combining biologic liver support with artificial detoxification technology.

[1]  D. Mutimer,et al.  Artificial liver support in acute liver failure. , 1999, European journal of gastroenterology & hepatology.

[2]  P. Neuhaus,et al.  Extracorporeal liver perfusion as hepatic assist in acute liver failure: a review of world experience , 2002, Xenotransplantation.

[3]  J. Denner.  Immunosuppression by Retroviruses: Implications for Xenotransplantation , 1998, Annals of the New York Academy of Sciences.

[4]  Igor M Sauer,et al.  Modular extracorporeal liver support. , 2002, Artificial organs.

[5]  R. Williams,et al.  Coagulopathy of Fulminant Hepatic Failure , 1986, Seminars in liver disease.

[6]  A. Demetriou.  Support of the acutely failing liver: state of the art. , 1998, Annals of surgery.

[7]  J. Encke,et al.  Bioreactor for a larger scale hepatocyte in vitro perfusion. , 1994, Transplantation.

[8]  X. M. Fernández-Suárez,et al.  Monitoring xenotransplant recipients for infection by PERV. , 2001, Clinical biochemistry.

[9]  N. Sussman,et al.  The Hepatix extracorporeal liver assist device: initial clinical experience. , 1994, Artificial organs.

[10]  High yield hepatocyte isolation from pig livers for investigation of hybrid liver support systems: influence of collagenase concentration and body weight. , 1996, The Journal of surgical research.

[11]  J. Denner,et al.  Productive infection of human primary cells and cell lines with porcine endogenous retroviruses. , 2001, Virology.

[12]  A. Demetriou,et al.  Clinical experience with a bioartificial liver in the treatment of severe liver failure. A phase I clinical trial. , 1997, Annals of surgery.

[13]  P Neuhaus,et al.  Improved hepatocyte in vitro maintenance in a culture model with woven multicompartment capillary systems: Electron microscopy studies , 1995, Hepatology.

[14]  I M Sauer,et al.  Experimental Evaluation of a Cell Module for Hybrid Liver Support , 2001, The International journal of artificial organs.

[15]  S. Nyberg,et al.  Characterization of the three-compartment gel-entrapment porcine hepatocyte bioartificial liver , 1997, Cell Biology and Toxicology.

[16]  Angelika Berg,et al.  Sensitive and specific immunological detection methods for porcine endogenous retroviruses applicable to experimental
and clinical xenotransplantation , 2001, Xenotransplantation.

[17]  R Williams,et al.  Extracorporeal support and hepatocyte transplantation in acute liver failure and cirrhosis , 1999, Journal of gastroenterology and hepatology.

[18]  Yasuhiro Takeuchi,et al.  Infection of human cells by an endogenous retrovirus of pigs , 1997, Nature Medicine.

[19]  P. Newsome,et al.  Which hepatocyte will it be? Hepatocyte choice for bioartificial liver support systems , 2001, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.