Mechanisms of cell death in acute liver failure

Abstract

Acute liver failure (ALF) can be the consequence of various etiologies, that might vary between different geographic regions. Most frequent are intoxications with acetaminophen, viral hepatitis, or liver damage of unknown origin. ALF occurs when the extent of hepatocyte death exceeds the regenerative capacity of the liver. The mode of liver cell death that is predominantly induced in ALF, i.e., apoptosis or necrosis, is still controversial and presumably determined by the etiology, duration, and magnitude of liver injury. Severe liver damage involves oxidative stress and depletion of ATP resulting in necrosis. In contrast, maintenance of ATP stores is required for the execution of apoptosis. Recent data suggest that necrosis resulting from severe liver damage is associated with poor outcome of ALF patients. Discrimination between apoptosis and necrosis might be therefore useful for the identification of ALF patients requiring liver transplantation. Identification of the molecular cell death mechanisms remains an important issue not only for early prediction of ALF outcome, but also for therapeutic interventions. In view of the pleiotropic functions of critical mediators of cell death and tissue regeneration, a particular challenge will be to reduce hepatocellular death without inhibiting the regenerative capacity of the liver. Here, we review the molecular mechanisms of hepatocyte injury and the pathways leading to apoptosis and necrosis, which might represent potential diagnostic and therapeutic targets in ALF.

Keywords: ATP; acute liver failure; apoptosis; caspases; death receptors; necrosis; oxidative stress; tumor necrosis factor.

Figure 1

Simplified scheme of cell death and survival pathways involved in ALF. Activation of TNF receptor-1 can mediate NF-κB activation, apoptosis, or necroptosis. The different outcomes are determined by distinct TNF receptor-associated signaling complexes. Activation of NF-κB is mediated by TRAF-2, RIP-1, and other signaling molecules that lead to activation of IκB kinase and subsequent activation of NF-κB target genes. FADD and caspase-8 are the essential adapter proteins involved in apoptosis, which in hepatocytes requires a mitochondrial amplification loop through caspase-8-mediated cleavage of Bid. The subsequent translocation of Bax and Bak results in mitochondrial outer membrane permeabilization, cytochrome c release, and effector caspase-3 activation. Under conditions of impaired apoptosis, TNF receptor-1 can induce necroptosis, which involves RIP-1 and RIP-3 kinases. Among other effects, RIP-3 can increase the production of reactive oxygen species (ROS) due to increased oxidative phosphorylation, resulting in intracellular calcium overload, mitochondrial membrane permeability transition (MPT), depletion of ATP, and necrosis. APAP-induced necrosis is essentially mediated by a toxic metabolite, which depletes glutathione and forms APAP protein adducts, triggering oxidative stress, compromised respiratory function, and ATP depletion. Although APAP treatment can instigate the mitochondrial pathway of apoptosis, high doses of APAP will ultimately mediate liver cell death by necrosis.