The cirrhotic hepatocyte: navigating between Scylla and Charybdis

Abstract

See Article, pages 942–951In the chronically injured and cholestatic liver, thevarious hepatic cell types are exposed to a vicious cocktailof toxic and potentially lethal ingredients, such as cytokines,reactive oxygen species (ROS), bile acids, endotoxin andFas-Ligand expressed on immune cells. Some liver cellsthrive in this hostile environment, e.g. stellate cells, whichstart to proliferate and produce excessive amounts ofextracellular matrix and inflammatory and immune cells,which infiltrate the liver and produce cytokines. Others,e.g. hepatocytes, perish in this environment. It is still amatter of debate what the predominant mechanism ofhepatocyte cell death is in chronic liver injury: necrosis orapoptosis. This debate is not trivial, because any interven-tion aimed to protect hepatocytes in the injured liver must bebased on a correct understanding of the mechanism of celldeath, e.g. apoptosis is a highly regulated process involvingnumerous steps and components with ample opportunity tointervene and inhibit apoptosis. Prevention of necrosisrequires a fundamentally different approach aimed atreducing the necrosis-causing agent. In the chronicallyinjured liver, liver enzymes in serum are elevated. Althoughincreased AST and ALT levels are considered as markers ofnecrotic cell death, it may result from necrosis secondary toapoptosis (necro-apoptosis) [1]. With the introduction ofmethods to detect apoptosis, e.g the TUNEL assay,apoptosis was proposed as the major mechanism of celldeath in chronic cholestatic liver injury [2]. However, theTUNEL assay appeared to be prone to artifacts. Therefore,more specific methods have been applied, e.g. activecaspase-3 staining and morphological criteria. Based onthese latter methods, apoptosis as the predominant mode ofcell death was questioned and necrosis has been proposed asthe major mode of cell death in the cirrhotic liver [3–5].Bile acids, Fas-Ligand, reactive oxygen species (ROS)and cytokines like TNFaare all potent inducers of apoptoticcell death in normal primary cultures of hepatocytes. Thisraises the question why in vivo in the chronically injured orcirrhotic liver, apoptosis is not the prevailing mode ofhepatocyte cell death. It appears that the hepatocyte in thechronically injured liver is somehow resistant againstapoptotic cell death. Several mechanisms have been pro-posed which contribute to this resistant phenotype [4,6–9].First of all, the expression of the bile acid importer NTCP(Na