CELL DEATH AT THE MILLENNIUM: Implications for Liver Diseases

The past 5 years or so have witnessed an explosion of interest and information concerning the processes that participate in the demise of cells. For many years, in the field of hepatology, two morphological patterns of lethal injury have been recognized: zonal coagulative necrosis and spotty shrinkage necrosis (Councilman bodies). Little significance was attributed to this morphological distinction until the work of Kerr in the early 1970s. Kerr recognized that hepatic atrophy following ligation of the portal vein was accompanied by loss of cells through a process of condensation and fragmentation of cells, 50 followed by their separation from neighbors and phagocytosis. Kerr and his associates subsequently referred to this process as apoptosis, 51 a Greek word referring to the dropping of petals from flowers or leaves from trees. Recently, the mechanisms and regulation of the process became accessible through the tools of modern molecular and cellular biology. Now the study of cell death has become one of the most rapidly advancing fields of biology, and translational applications in all fields of medicine are likely by the beginning of the next millenium. Two fundamental types of cell death have been distinguished: necrosis and apoptosis. Necrosis involves loss of ATP, swelling of cells, lysis, and secondary inflammation. Apoptosis involves preservation of ATP (at least initially), shrinkage, cytoplasmic and nuclear condensation and fragmentation, and rapid phagocytic removal by macrophages and epithelial cells, with little inflammation. In the liver, necrosis tends to be zonal, whereas apoptosis tends to be spotty. The question arises as to whether these two types of cell death are as distinct as their morphology would suggest. Although this issue will be discussed in detail later, the short answer is that the manner of cell death appears to represent a spectrum of responses to the same stimuli, such as cytokines and toxins. Although apoptosis is a fundamental and specific mode of cell death in certain normal biologic processes, such as development and tissue turnover (so-called programmed cell death ), in disease processes it is less certain that the manner of cell death is as important as its cause. Undoubtedly there exist certain noxious events (mild hypoxia or oxidative stress) that are relatively mild but that activate the quiescent components of the cell-death program. In contrast, there are more massive assaults (e.g., marked oxidative stress or anoxia) that kill the cells quickly by necrosis. There are also, however, intermediate situations which appear to induce apoptosis preferentially, but that lead to necrosis when the apoptosis execution program is blocked, thus demonstrating the inevitability of cell death. Indeed, both apoptosis and necrosis may be seen in different cells in the liver at the same time. This observation is further complicated because massive apoptosis can overwhelm the phagocytic removal of fragmented cells, which then may remain in situ and undergo morphological changes indistinguishable from coagulative necrosis (i.e., secondary necrosis), making it difficult for the pathologist to determine which type of cell death had occurred originally. In summary, apoptosis occurs physiologically in development and tissue turnover, and mild to moderate exposure to reactive oxygen metabolites, hypoxia, or toxins can activate the built-in death program. Severer exposures may be directly lethal, causing necrosis while inhibiting the apoptosis death program. Intermediate situations can occur in which the cell is committed to death whether the apoptosis machinery is active or inhibited.