Warm and cold hepatic ischemia followed by reperfusion leads to necrotic cell death (oncosis), which often occurs within minutes of reperfusion. Recent studies also suggest a large component of apoptosis after ischemia/reperfusion. Here, we review the mechanisms underlying adenosine triphosphate depletion-dependent oncotic necrosis and caspase-dependent apoptosis, with emphasis on shared features and pathways. Although apoptosis causes internucleosomal DNA degradation that can be detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and related assays, DNA degradation also occurs after oncotic necrosis and leads to pervasive terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining far in excess of that for apoptosis. Similarly, although apoptosis can occur in a physiological setting without inflammation, in pathophysiological settings apoptosis frequently induces inflammation because of the onset of secondary necrosis and stimulation of cytokine and chemokine formation. In liver, the mitochondrial permeability transition represents a shared pathway that leads to both oncotic necrosis and apoptosis. When the mitochondrial permeability transition causes severe adenosine triphosphate depletion, plasma membrane failure and necrosis ensue. If adenosine triphosphate is preserved, at least in part, cytochrome c release after the mitochondrial permeability transition activates caspase-dependent apoptosis. Mitochondrial permeability transition-dependent cell death illustrates the concept of necrapoptosis, whereby common pathways lead to both necrosis and apoptosis. In conclusion, oncotic necrosis and apoptosis can share features and mechanisms, which sometimes makes discrimination between the 2 forms of cell death difficult. However, elucidation of critical cell death pathways under clinically relevant conditions will show potentially important therapeutic intervention strategies in hepatic ischemia/reperfusion injury.

This article summarizes strategies to protect the liver from injuries caused by ischemia and reperfusion. Three different sections (i.e., surgical and pharmacologic strategies and gene therapy) present approaches to enhance the survival and viability of the liver in various surgical procedures including liver transplantation. The first section reviews approaches using surgical interventions such as ischemic preconditioning and intermittent clamping. Their protective effects are discussed with respect to the mechanism of injury. In the second section, pharmacologic agents targeting microcirculation, oxidative stress, proteases, and inflammation are described. Mechanisms of injury and their suppression by a wide variety of drugs are discussed. The third section focuses on gene therapy. Potential target genes have been identified (e.g., superoxide dismutase or heme oxygenase). Animal experiments in which the liver injury is reduced successfully may pave the way to novel strategies applied to different liver diseases in humans.

Many drugs exhibit variable efficacy and toxicity. Pharmacogenetics explores the genetic underpinnings of variable drug response. Pharmacogenetic testing is beginning to enter the clinic and will have a significant impact on the practice of clinical gastroenterology. Thiopurine S-methyltransferase screening, which will likely become routine for thiopurine recipients, illustrates the promise and limitations of pharmacogenetics. Testing for variation in other drug metabolism pathways may also become important. Pharmacogenetics will complement but not replace traditional methods for choosing drugs and for selecting dosing regimens for narrow-therapeutic-index drugs.

Exocrine pancreas cancer has a dismal prognosis. The precise reasons accounting for its biological and clinical behavior are not known. A "catastrophe" takes place in the course of pancreas cancer development/progression so that, once it occurs, the evolution of the tumor is very rapid, leading to local invasion and metastasis. Up to now, such behavior cannot be conclusively ascribed to a single molecular event. If correct, this hypothesis has important implications regarding pancreas cancer research. Further work is warranted to examine this hypothesis and to identify the putative "catastrophic" elements participating in this tumor.

The transjugular intrahepatic portosystemic shunt (TIPS) was developed in the 1980s for treatment of complications of portal hypertension. Once it was shown that the shunt could be placed with relative ease, TIPS was rapidly applied to the treatment of many of the complications of portal hypertension. These complications include actively bleeding gastroesophageal varices, prevention of rebleeding from varices, control of refractory cirrhotic ascites and hepatic hydrothorax, and treatment of hepatorenal failure and hepatopulmonary syndrome. TIPS has also been used as therapy for Budd-Chiari syndrome and veno-occlusive disease. Despite these broad applications, TIPS has been compared with other forms of therapy in only 2 situations: prevention of rebleeding from varices and control of refractory cirrhotic ascites. In the trials, TIPS was shown to provide better control of these 2 complications of portal hypertension than standard forms of therapy. However, there was no improvement in survival and the incidence of encephalopathy was greater for patients receiving a TIPS. Thus, the use of TIPS for the control of ascites and prevention of rebleeding from varices should be limited to a select group of patients. There have been no controlled trials for the other indications listed. Despite the apparent efficacy of TIPS in many of these situations, its use should be limited to salvage therapy pending the publication of controlled trials showing it is a better treatment than other forms of therapy.