CRC DRUG-INDUC LIVER DIS PDF

Preface

With the ever-increasing exposure to pharmaceuticals, more and more examples of druginduced liver disease have been identified in recent years. At the same time, the basic science of hepatic pharmacology, toxicology, and immunology has exploded in the past decade, with exciting new developments and insights. At the beginning of the 21st century, we now have the opportunity to re-evaluate this important topic as we look to the promise of understanding, predicting, preventing, and healing a common problem that is of importance to all branches of clinical medicine and to anyone who prescribes pharmaceutical or alternative medications. Therefore, we believe that this authoritative, up-to-date volume— with contributions by experts in basic pathogenesis and clinical pathology, and coverage of various categories of agents—will be of great interest to a broad audience. In this regard we have drawn on worldwide expertise; one-third of the chapters were written by authors outside the United States.

Innovations in methodology have had a major impact on research in drug-induced liver injury, and this has led to a greater understanding of the mechanisms involved. A few examples should illustrate the progress that has been made and that is described in this book. The explosion of information on apoptosis has provided insight into the subtleties of drug-induced cell death (Chapter 2). The use of molecular biological techniques has permitted the cloning of numerous genes encoding for P450 isoenzymes. This has made possible the expression of recombinant P450 enzymes and specific P450 antibodies. The availability of recombinant enzymes and of specific inhibiting antibodies has facilitated studies to determine the contribution of individual P450 isoenzymes to the metabolism of specific drugs (Chapter 3). Until quite recently, cholestasis was thought to be due either to mechanical obstruction of bile flow or to cell toxicity which impeded the handling of bile. Improved techniques for isolating membrane vesicles and the cloning and characterization of hepatocyte membrane transporters have allowed the elucidation of a novel mechanism of cholestasis: drug-induced impairment of bile acid transporters in otherwise intact hepatocytes (Chapter 6). As more investigators have taken advantage of relatively new methods to isolate pure nonparenchymal cells, there have been rapid gains in information on the contribution of Kupffer cells, sinusoidal endothelial cells, and stellate cells to a variety of liver diseases, including drug- and toxin-induced liver injury (Chapter 10). The concept of the mitochondrion as a major target of drug-induced toxicity was raised only as recently as the early 1980s. Since then, toxicity of an ever-increasing number of drugs has been linked to selective toxicity in the mitochondrion (Chapter 4). Although reference is made in these examples to the chapters in Part I, on mechanisms in Section I, Part III will reiterate many of these processes in the context of individual drugs that have been linked to one of these modes of toxicity.

As noted, Part I examines hepatotoxicity from the perspective of the mechanisms, across categories of drugs, so that the principles involved can be explored in depth. Examples of drugs to which these mechanisms apply are provided, but the main focus is on the mechanism. Because the authors are experts who are writing about the state of the art in their own fields, this information will be useful both to clinicians who want to gain understanding of the fundamental principles as we understand them today and to knowledgeable clinicians and investigators who wish to read about the newest advances.

Part II provides a general outline of the clinical presentation and management of drug-induced hepatotoxicity. Chapter 11 systematically reviews the clinical presentation and pathological picture of the types of liver injury that can be induced by drugs and toxins. Chapter 12 reviews the factors that predispose an individual to drug toxicity, suggests strategies for monitoring patients at risk for toxicity, and provides information on preventive measures. The information provided in these chapters provide a basic framework for any clinician who might be confronted with xenobiotic-induced hepatotoxicity.

Part III systematically reviews specific toxins implicated in drug-induced hepatotoxicity. Each chapter examines the toxicity induced by drugs or toxins within a specific pharmacological class or by drugs used within a clinical specialty. The current understanding of the mechanism of toxicity, risk factors for developing toxicity, histological characteristics, clinical manifestations, and management are discussed for each category of drugs. This section will be of value to gastroenterologists and hepatologists who want a systematic review of drug-induced liver disease. It will also serve as a reference for clinicians in a variety of specialties who are confronted with a patient with liver disease that might be attributable to drug therapy.