Saich, R.; (2012) Toxic molecules in liver failure plasma. Doctoral thesis , UCL (University College London).

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Abstract

Liver failure remains a disease with a high mortality and with the exception of transplantation therapeutic options are limited. The liver however has regenerative potential, and strategies based not only at supporting the failing liver, but promoting its recovery would be a significant evolution. Plasma from patients with liver failure contains toxic molecules that have many effects on the liver including loss of cell viability. These factors represent a significant barrier to stem cell transplantation, bioreactor function and autologous liver recovery, suggesting removal or antagonism of these factors may be appropriate therapeutic strategies. Since apoptosis has been implicated in the pathogenesis of a number of liver diseases including liver failure we proposed that it may be one of the mechanisms by which plasma is toxic to hepatocytes. We developed and validated a model using primary human hepatocytes to investigate if plasma from patients with acute and acute-on-chronic liver disease was pro-apoptotic. Compared with normal plasma, acute liver failure plasma induced apoptosis whereas plasma from patients with acutely-decompensated chronic liver disease did not. Having identified that acute-liver failure plasma was pro-apoptotic we investigated the pathway via which the apoptosis was mediated by using specific inhibitors of caspases, key components of the death receptor and mitochondrial pathways. We found that apoptosis was induced via a pathway involving caspase 8 and caspase 3, suggesting involvement of the death-receptor pathway. We investigated the effects of Caspase inhibition as a therapeutic option in acute liver failure by using an established animal model but did not find an improved outcome in treated animals. We also investigated the effects of treatment with molecular adsorbent dialysis (MARS) on the pro-apoptotic effects of plasma and found MARS dialysis improved biochemical parameters, indicating effective removal of albumin-bound molecules, but the apoptotic effects of the patients' plasma were unchanged.

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