Drug-Induced Liver Disease

From the New England Journal of Medicine, July 17, 2003
Books and articles entitled Drug-Induced Liver Disease have always held promise but ultimately disappointed, since they have never delivered a plausible account of the mechanisms involved. So why should this 700-page, beautifully presented book be any better? Our understanding of the mechanisms of how drugs cause liver disease has advanced enormously, and the past decade has seen an explosion of new information concerning the immunology, toxicology, and pharmacology of liver disease. Simultaneously, there has been a substantial increase in the number of drugs on the market, with the result that drugs are now the most common cause of acute liver failure, accounting for up to half of cases. Clinically, there are still diagnostic and therapeutic challenges, and diagnoses are more often based on "implication" than on certainty. It is therefore fitting that this book should appear now. It is authoritative, with contributions by experts in basic sciences as well as by clinical hepatologists. The first part of the book deals with mechanisms and the roles of cytochrome P-450, antioxidants, cytokines, and growth factors in hepatic regeneration, repair, and fibrosis. No book on liver disease can be complete without a discussion of the mechanisms of cell death, and here the current knowledge of apoptosis has provided much-needed insight into the induction of cell death by drugs. The roles of membrane transport and hepatotoxicity due to mitochondrial injury are also discussed. Although drugs and chemicals can cause hepatic damage directly, evidence is fast accumulating of an indirect effect by inflammatory mediators released by nonparenchymal cells, particularly macrophages, endothelial cells, stellate cells, and infiltrating leukocytes. Nevertheless, the mechanisms whereby a particular drug may cause a particular type of damage may not be obvious, and the book includes an axiomatic summary to serve as a guide for the generalist. Overall, hepatocellular injury has a much less favorable prognosis (particularly if there is jaundice) and is more likely to produce life-threatening illness than would be expected on the basis of a cholestatic picture. Diagnosis and management are discussed with particular attention to the spectrum of disease. There are helpful comments on the identification and diagnosis of problems caused by specific drugs, backed up by information about the histopathological features. Despite the expected overlap in the histologic pictures of these drug-specific problems, the reader comes away with a better understanding, albeit from the pathologist's point of view. The usual drugs associated with hepatotoxicity are discussed, but the authors also venture into alternative medicines, vitamins, natural hepatotoxins, and occupational and environmental causes -- all of which are now potential and important hazards. The science discussed in the early chapters is used to inform the reader about possibly damaging mechanisms -- an indication of a well-edited book. It was refreshing to see a whole chapter devoted to the regulatory perspective, which outlines the path a new drug takes from discovery to established use -- a process that may take many years. Extensive and rigorous testing of drugs in animals and premarketing trials are a frequent cause of the early termination of a drug's developmental program, particularly if hepatotoxicity is detected. Sadly, even these large testing programs, often involving several thousand patients, cannot always detect an idiosyncratic event that may occur in 1 of every 10,000 to 100,000 patients. The editors emphasize the importance of randomized, double-blind, prospective, multigroup clinical trials as the gold standard for reducing unwanted bias and confounding factors. Postmarketing data for the first two years after the release of a drug on the risk associated with it, its optimal use, and its administration over longer periods are absolutely crucial. In summary, this book provides an excellent and authoritative account of the whole subject, from basic science to the clinical manifestations of drug-induced disease. It will be used by gastroenterologists, liver specialists, and basic scientists as their regular reference but will also be dipped into by other clinicians when they are confronted with an unusual case of liver disease. I was definitely not disappointed. Parveen J. Kumar, M.D.
Copyright © 2003 Massachusetts Medical Society. All rights reserved. The New England Journal of Medicine is a registered trademark of the MMS.

Review

…brings together in one place excellent discussions of drug-induced liver diseases…well-referenced and well-written….
…a very worthy addition to the libraries of academic hepatologists, practicing hepatologists, and Ph.D. liver investigators interested in hepatotoxicity.
-Doody's Electronic Journal

…an up-to-date…authoritative tool.
It should find a home on the shelf of all medical libraries.
-Practical Gastroenterology

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