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Drug-induced liver disease
Book Reviews RAYMOND S. KOFF, BOOK EDITOR Department of Medicine MetroWest Medical Center Framingham Union Campus 115 Lincoln St Framingham, MA 01701
HEPATOLOGY welcomes books for review and invites its readers both to identify books ofhepatological interest and to serve as book reviewers. Books of note should be called to the attention of the Book Editor, and potential reviewers should indicate their areas of interest. The Book Editor nonetheless reserves the right to select appropriate reviews for publication on these pages.
Drug-Induced Liver Disease. By Geoffrey C. Farrell, 673 pp. Edinburgh: Churchill Livingstone, 1994.
$115. Adverse reactions affecting the liver as a consequence of the consumption of therapeutic drugs taken in accepted doses for appropriate indications are relatively uncommon events; hospitalizations for drug-induced liver injury are infrequent and serious hepatotoxicity leading to the withdrawal of drugs from clinical use is also a relatively rare occurrence. Of course, druginduced liver injury may be mild or subclinical and the economic and individual importance of this adverse effect may be grossly underestimated if only hospitalization data are evaluated. Adverse hepatic reactions may delay or impede therapy, thereby increasing the morbidity of the underlying condition, may result in use of expensive additional diagnostic resources in an attempt to understand the nature of the liver injury, and, occasionally, may result in progression to chronic liver disease, with its own set of complications and costs to society and the individual. There are hundreds of therapeutic drugs capable of inducing hepatic injury, and for a small number of affected persons, particularly individuals older than 50 years of age, the reaction may have serious or even fatal consequences. In fact, in some analyses, drug-induced liver disease may be responsible for as many as 25% of patients with fulminant hepatic failure. It should be emphasized that patients of all ages may be affected by drug-induced liver injury and, for some drugs, attack rates may be highest in children. Why so many drugs seem to preferentially cause adverse hepatic reactions in women, even correcting for higher frequencies of drug use by women compared with men, remains unclear. Dr Geoffrey Farrell's volume on drug-induced liver disease, with contributions from Drs Michael Murray, Ian Mackay, and Pauline Hall, is a welcome attempt to gather together current knowledge of the subject in a nonencyclopedic but explanatory and readily accessible format. In the 3 months I have had this book, I have used it regularly. I find it to be the most up-to-date text dealing with this subject. One innovation that is
particularly noteworthy is the availability of the listing of reported associations between drugs and liver injury, found in Chapter 9, on a diskette that is available, without charge, from the publishers. I have sent for this but have not yet received it. I am enthusiastic about the notion of an updatable compendium that could be easily accessed from the personal computer in my office or at home without the need to undertake additional electronic searches of the published literature. Although one of the take-home messages from this volume is that the mechanisms underlying the development of drug-induced liver disease still remain incompletely understood, considerable progress has been made in recent years. This is described in the first three chapters of this volume under the heading of"Underlying Concepts." The first chapter, by Dr Murray, reviews the importance of the liver in drug metabolism and drug-induced modification of drug metabolism. The second chapter is an outstanding synthesis of information on the biochemical mechanisms of drug-induced liver damage. It brilliantly defines current concepts of the nature ofhepatotoxic chemicals, the hepatocyte's cellular defense mechanisms against attack by reactive metabolites, the ultrastructural and macromolecular targets of liver injury, and the processes that may lead to death of the affected hepatocyte. The final chapter in this section, by Dr Mackay, describes, in considerable detail but in lucid, comprehensible language that a nonimmunologist might understand, immunologically mediated adverse drug reactions in the liver. I found the sections on the drug-induced autoantigen concept as it relates to the identification of LKM antigens as cytochrome P450 isoforms and the development and role of LKM antibodies in drug-induced immune-mediated disease particularly clarifying. The second section of the book, comprising five chapters, details some general aspects of adverse hepatic reactions to drugs. In the first chapter in this section, discussions of the definitions of drug-induced hepatic injury and the many terms used to describe this phenomenon and the epidemiology of drug-induced liver disease are presented. The next chapter describes the clinicopathological spectrum of hepatic drug reactions and is followed by Dr Hall's extensive review of the histopathological spectrum of drug-induced liver injury. This superb chapter is liberally sprinkled with black and white and color photomicrographs and photographs of gross liver specimens. A color photograph of excoriations of the skin of the legs in a patient with estrogen-induced cholestasis and another of an exfoliative dermatitis of the feet caused by allopurinol seem
1200
I~IEPATOLOGYVo]. 21, No. 4, 1995
BOOK REVIEWS
out of place in a chapter on histopathology but this is a trivial criticism. The final two chapters in this section deal with diagnosis and management. With regard to treatment of drug-induced liver disease, Dr Farrell notes that treatment remains unsatisfactory (with the exception of the use of N-acetylcysteine for acetaminophen overdose). He points out that the use of putative hepatic cytoprotective agents that might serve to ameliorate the severity of drug-induced liver injury is an area worthy of investigation. The third section is the largest of the three and represents almost two thirds of the text. It is focused on specific causative agents and forms of drug-induced liver injury. This section will, in all likelihood, prove to be the most useful to the busy clinician seeking a succinct but critical review of current knowledge of the hepatotoxicity of currently prescribed therapeutic drugs. After the compendium, mentioned above, and a chapter dealing with acetaminophen hepatic injury, individual chapters describe cytotoxic lesions, drug-induced acute hepatitis, granulomatous hepatitis, cholestasis, chronic hepatitis, steatohepatitis, hepatic fibrosis and cirrhosis, vascular diseases, and hepatic tumors. Within each chapter, clinical and histopathological information about the specific drugs that have been linked with these disorders is clearly presented. Other chapters describe the liver disease linked to anesthetic agents, nonsteroidal anti-inflammatory drugs, and drugs used in oncology. The final chapter, "Liver Disease Due to Environmental Toxins," reviews current knowledge of the hepatotoxicity of herbal remedies, plant toxins, aflatoxins, and a broad array of industrial toxins. Dr Farrell and his contributors are to be congratulated for this superb effort. Drug-Induced Liver Disease will be the book of choice in this area for some time to come; in my view it leaps ahead of the other recently published books on drug hepatotoxicity. I believe it will become an essential component of the hepatologist's library and that the very modest cost of this investment in knowledge will pay off very quickly. RAYMOND S. KOFF, MD MetroWest Medical Center Framingham, MA
Liver Transplantation & The Alcoholic Patient: Medical, Surgical and Psychosocial Issues. By Michael R. Lucey, Robert M. Merion, and Thomas P. Bereford, 134 pp. Cambridge: Cambridge University Press, 1994. $49.95. Given that donor shortages currently limit United States liver transplantation to 3,000 per year, should carefully selected alcoholic and nonalcoholic patients have equally unrestricted access to those transplantations? Drs Lucey, Merion, and Bereford (an internist, a surgeon, and a psychiatrist, respectively) say yes. These authors report on the transplantation of 90
1201
alcoholic patients among their 311 transplant recipients over an 8-year period (1985 to 1992). They find 1and 5-year survival rates of approximately 70% in both alcoholic and nonalcoholic populations. This compact little book is divided into seven clinically helpful chapters describing assessments of the alcoholic candidate for transplantation, outcome data, and follow-up care. The final chapter, contributed by Dr Martin Benjamin (a philosopher) and Dr Jeremiah Turcotte (a surgeon), provides a review of the complex ethical dialogue between the personal responsibility and equal access atguments in the selection of alcoholic patients for liver transplantation. There are some weaknesses in the presentation. 300 alcoholic patients were screened to select 90 alcoholic transplant recipients. But how many nonalcoholic patients were screened to select the 221 nonalcoholic recipients? What selection criteria were used and what were their outcomes? Regarding the patients who are discussed, different populations are reviewed in different chapters. Thus, Chapter 3 on psychiatric assessment reports on 233 patients (1987 to 1992), Chapter 6 on psychiatric follow-up reports on 61 patients, Chapter 4 on medical assessment reports on 99 patients (1985 to 1989), and Chapter 5 on outcome of transplantation reports on all 311 patients. One learns for instance about the posttransplantation drinking behavior of only 61 of the roughly 210, 2- to 5-year survivors in both groups. One wishes for more updated information on the whole population, regarding the proportion of patients who return to drinking after transplantation, the quantities of alcohol consumed, and the impact of the behavior on survival, quality of life, and cost of continuing medical care. The authors refer to studies on the natural course of alcoholic cirrhosis, which reveal widely varying outcomes, with 5-year survival rates of roughly 40% with continued heavy drinking, improving to roughly 60% when the drinking diminishes to minimal to moderate levels. In this context their patients are clearly quite ill, with actuarial survival as follows: 2-year survival rate of 59% of patients assessed to be "too well" for transplantation; 20-month survival rate of 0% of patients assessed to be "too psychiatrically unstable"; and l-year survival rate of 0% of patients assessed to be too "medically ill." All of these figures are from 99 patients studied between 1985 and 1989; updating them from the experience with the whole population would be useful. Despite these caveats, the authors provide excellent chapters with stimulating and lucid analyses of an important issue. For clinicians involved in liver transplantation and the care of the alcoholic patient, this text is a thought-provoking contribution. GEORGE A. ELLSWORTH, MD Department of Psychiatry Metro West Medical Center Framingham, MA
HEPATOLOGY welcomes books for review and invites its readers both to identify books ofhepatological interest and to serve as book reviewers. Books of note should be called to the attention of the Book Editor, and potential reviewers should indicate their areas of interest. The Book Editor nonetheless reserves the right to select appropriate reviews for publication on these pages.
Drug-Induced Liver Disease. By Geoffrey C. Farrell, 673 pp. Edinburgh: Churchill Livingstone, 1994.
$115. Adverse reactions affecting the liver as a consequence of the consumption of therapeutic drugs taken in accepted doses for appropriate indications are relatively uncommon events; hospitalizations for drug-induced liver injury are infrequent and serious hepatotoxicity leading to the withdrawal of drugs from clinical use is also a relatively rare occurrence. Of course, druginduced liver injury may be mild or subclinical and the economic and individual importance of this adverse effect may be grossly underestimated if only hospitalization data are evaluated. Adverse hepatic reactions may delay or impede therapy, thereby increasing the morbidity of the underlying condition, may result in use of expensive additional diagnostic resources in an attempt to understand the nature of the liver injury, and, occasionally, may result in progression to chronic liver disease, with its own set of complications and costs to society and the individual. There are hundreds of therapeutic drugs capable of inducing hepatic injury, and for a small number of affected persons, particularly individuals older than 50 years of age, the reaction may have serious or even fatal consequences. In fact, in some analyses, drug-induced liver disease may be responsible for as many as 25% of patients with fulminant hepatic failure. It should be emphasized that patients of all ages may be affected by drug-induced liver injury and, for some drugs, attack rates may be highest in children. Why so many drugs seem to preferentially cause adverse hepatic reactions in women, even correcting for higher frequencies of drug use by women compared with men, remains unclear. Dr Geoffrey Farrell's volume on drug-induced liver disease, with contributions from Drs Michael Murray, Ian Mackay, and Pauline Hall, is a welcome attempt to gather together current knowledge of the subject in a nonencyclopedic but explanatory and readily accessible format. In the 3 months I have had this book, I have used it regularly. I find it to be the most up-to-date text dealing with this subject. One innovation that is
particularly noteworthy is the availability of the listing of reported associations between drugs and liver injury, found in Chapter 9, on a diskette that is available, without charge, from the publishers. I have sent for this but have not yet received it. I am enthusiastic about the notion of an updatable compendium that could be easily accessed from the personal computer in my office or at home without the need to undertake additional electronic searches of the published literature. Although one of the take-home messages from this volume is that the mechanisms underlying the development of drug-induced liver disease still remain incompletely understood, considerable progress has been made in recent years. This is described in the first three chapters of this volume under the heading of"Underlying Concepts." The first chapter, by Dr Murray, reviews the importance of the liver in drug metabolism and drug-induced modification of drug metabolism. The second chapter is an outstanding synthesis of information on the biochemical mechanisms of drug-induced liver damage. It brilliantly defines current concepts of the nature ofhepatotoxic chemicals, the hepatocyte's cellular defense mechanisms against attack by reactive metabolites, the ultrastructural and macromolecular targets of liver injury, and the processes that may lead to death of the affected hepatocyte. The final chapter in this section, by Dr Mackay, describes, in considerable detail but in lucid, comprehensible language that a nonimmunologist might understand, immunologically mediated adverse drug reactions in the liver. I found the sections on the drug-induced autoantigen concept as it relates to the identification of LKM antigens as cytochrome P450 isoforms and the development and role of LKM antibodies in drug-induced immune-mediated disease particularly clarifying. The second section of the book, comprising five chapters, details some general aspects of adverse hepatic reactions to drugs. In the first chapter in this section, discussions of the definitions of drug-induced hepatic injury and the many terms used to describe this phenomenon and the epidemiology of drug-induced liver disease are presented. The next chapter describes the clinicopathological spectrum of hepatic drug reactions and is followed by Dr Hall's extensive review of the histopathological spectrum of drug-induced liver injury. This superb chapter is liberally sprinkled with black and white and color photomicrographs and photographs of gross liver specimens. A color photograph of excoriations of the skin of the legs in a patient with estrogen-induced cholestasis and another of an exfoliative dermatitis of the feet caused by allopurinol seem
1200
I~IEPATOLOGYVo]. 21, No. 4, 1995
BOOK REVIEWS
out of place in a chapter on histopathology but this is a trivial criticism. The final two chapters in this section deal with diagnosis and management. With regard to treatment of drug-induced liver disease, Dr Farrell notes that treatment remains unsatisfactory (with the exception of the use of N-acetylcysteine for acetaminophen overdose). He points out that the use of putative hepatic cytoprotective agents that might serve to ameliorate the severity of drug-induced liver injury is an area worthy of investigation. The third section is the largest of the three and represents almost two thirds of the text. It is focused on specific causative agents and forms of drug-induced liver injury. This section will, in all likelihood, prove to be the most useful to the busy clinician seeking a succinct but critical review of current knowledge of the hepatotoxicity of currently prescribed therapeutic drugs. After the compendium, mentioned above, and a chapter dealing with acetaminophen hepatic injury, individual chapters describe cytotoxic lesions, drug-induced acute hepatitis, granulomatous hepatitis, cholestasis, chronic hepatitis, steatohepatitis, hepatic fibrosis and cirrhosis, vascular diseases, and hepatic tumors. Within each chapter, clinical and histopathological information about the specific drugs that have been linked with these disorders is clearly presented. Other chapters describe the liver disease linked to anesthetic agents, nonsteroidal anti-inflammatory drugs, and drugs used in oncology. The final chapter, "Liver Disease Due to Environmental Toxins," reviews current knowledge of the hepatotoxicity of herbal remedies, plant toxins, aflatoxins, and a broad array of industrial toxins. Dr Farrell and his contributors are to be congratulated for this superb effort. Drug-Induced Liver Disease will be the book of choice in this area for some time to come; in my view it leaps ahead of the other recently published books on drug hepatotoxicity. I believe it will become an essential component of the hepatologist's library and that the very modest cost of this investment in knowledge will pay off very quickly. RAYMOND S. KOFF, MD MetroWest Medical Center Framingham, MA
Liver Transplantation & The Alcoholic Patient: Medical, Surgical and Psychosocial Issues. By Michael R. Lucey, Robert M. Merion, and Thomas P. Bereford, 134 pp. Cambridge: Cambridge University Press, 1994. $49.95. Given that donor shortages currently limit United States liver transplantation to 3,000 per year, should carefully selected alcoholic and nonalcoholic patients have equally unrestricted access to those transplantations? Drs Lucey, Merion, and Bereford (an internist, a surgeon, and a psychiatrist, respectively) say yes. These authors report on the transplantation of 90
1201
alcoholic patients among their 311 transplant recipients over an 8-year period (1985 to 1992). They find 1and 5-year survival rates of approximately 70% in both alcoholic and nonalcoholic populations. This compact little book is divided into seven clinically helpful chapters describing assessments of the alcoholic candidate for transplantation, outcome data, and follow-up care. The final chapter, contributed by Dr Martin Benjamin (a philosopher) and Dr Jeremiah Turcotte (a surgeon), provides a review of the complex ethical dialogue between the personal responsibility and equal access atguments in the selection of alcoholic patients for liver transplantation. There are some weaknesses in the presentation. 300 alcoholic patients were screened to select 90 alcoholic transplant recipients. But how many nonalcoholic patients were screened to select the 221 nonalcoholic recipients? What selection criteria were used and what were their outcomes? Regarding the patients who are discussed, different populations are reviewed in different chapters. Thus, Chapter 3 on psychiatric assessment reports on 233 patients (1987 to 1992), Chapter 6 on psychiatric follow-up reports on 61 patients, Chapter 4 on medical assessment reports on 99 patients (1985 to 1989), and Chapter 5 on outcome of transplantation reports on all 311 patients. One learns for instance about the posttransplantation drinking behavior of only 61 of the roughly 210, 2- to 5-year survivors in both groups. One wishes for more updated information on the whole population, regarding the proportion of patients who return to drinking after transplantation, the quantities of alcohol consumed, and the impact of the behavior on survival, quality of life, and cost of continuing medical care. The authors refer to studies on the natural course of alcoholic cirrhosis, which reveal widely varying outcomes, with 5-year survival rates of roughly 40% with continued heavy drinking, improving to roughly 60% when the drinking diminishes to minimal to moderate levels. In this context their patients are clearly quite ill, with actuarial survival as follows: 2-year survival rate of 59% of patients assessed to be "too well" for transplantation; 20-month survival rate of 0% of patients assessed to be "too psychiatrically unstable"; and l-year survival rate of 0% of patients assessed to be too "medically ill." All of these figures are from 99 patients studied between 1985 and 1989; updating them from the experience with the whole population would be useful. Despite these caveats, the authors provide excellent chapters with stimulating and lucid analyses of an important issue. For clinicians involved in liver transplantation and the care of the alcoholic patient, this text is a thought-provoking contribution. GEORGE A. ELLSWORTH, MD Department of Psychiatry Metro West Medical Center Framingham, MA