Drug-Induced Liver Injury: New Perspectives on an Old Disease

Abstract

Liver injury due to chemicals and drugs is an ancient disease. Since the industrial era, hepatotoxicity caused by phosphorus and carbon tetrachloride, among other toxicants, has been commonly reported. With the advent of modern pharmacotherapy, adverse drug reactions became an important and sometimes limiting issue in its clinical application. Liver injury caused by isoniazid and other antituberculosis drugs was probably the first drug-induced liver injury (DILI) that physicians had to deal with, having an important impact on tuberculosis management. Subsequently, DILI emerged as a potential threat to the significant benefits of numerous drugs, making it a subject of paramount interest to the pharmaceutical industry, basic researchers, clinicians, pharmacoepidemiologists and regulators.

Overall, DILI is a rarely diagnosed liver condition and one of the most challenging situations clinicians face, due to the difficulty of obtaining an accurate diagnosis and the risk of severe outcomes, including liver failure and death [1]. In addition, DILI is a cross-cutting issue in health care. It's foreseeable that almost every medical and surgical prescriber will encounter one or more DILI cases during their long career. DILI is also a major cause of drugs being stopped from further development or removed from the market, and as such, it is in the spotlight for regulators and experts in the pharmaceutical industry. This monographic issue is a collection of review articles written by experts in different aspects of DILI and addresses a number of hot topics in the fast-moving field of DILI, which has experienced huge growth in recent years.

Despite being the best-known model of intrinsic hepatotoxicity, one article provides a comprehensive review of new insights into the mechanisms driving acetaminophen hepatotoxicity, paving the way for innovative therapeutic strategies [2]. Specific articles are dedicated to the epidemiology and risk factors of idiosyncratic drug-induced liver injury (DILI) [3], including genetic and genomic approaches to studying DILI [4]. Genetic risk factors have been identified over the last two decades, thanks to the availability of bioinformatics platforms for genome-wide association studies. While these findings provide valuable insights into the role of the adaptive immune system in idiosyncratic drug-induced liver injury (DILI), they cannot yet effectively predict DILI occurrence in a given individual. However, new approaches that include polygenic risk scores show promise in better identifying subjects at risk of DILI when taking certain drugs [4].

Another tool that is sometimes overlooked is the liver biopsy. In the hands of an experienced pathologist, histological findings can help with the differential diagnosis of DILI and the prediction of severe outcomes. Dedicated articles review the value of histological findings in cases of suspected DILI [5] and the natural history of hepatotoxicity as well as the development of scores for predicting fulminant liver failure and chronic DILI [6]. Both histological findings and clinical scores can be used to stratify DILI patients for closer follow-up and specific therapeutic measures [5, 6].

Hepatotoxicity associated with immunotherapeutic agents used in cancer treatment is an emerging concern in oncology and hepatology. This comprehensive review covers recent advances in our understanding of the mechanisms underlying liver injury caused by immune checkpoint inhibitors and the clinical management of this new form of hepatotoxicity. This article also discusses cases that do not respond to steroids and the possibility of rechallenge in specific circumstances [7]. Additionally, a separate manuscript provides a detailed discussion of the new phenotype of sclerosing cholangitis, which is particularly, albeit not exclusively, associated with immunotherapeutic agents [8]. Likewise, the challenge regarding liver safety that emerging cancer therapies pose is discussed in detail in another comprehensive overview [9].

A dedicated review also addresses the growing issue of liver injury caused by herbal and dietary supplements. Despite advances in identifying at-risk genetic phenotypes, it emphasises that there are still unmet needs in the regulation of quality standards, marketing and distribution of these products to protect public health [10].

The article addressing the topic of patients with various underlying chronic liver diseases, their risk of developing drug-induced liver injury (DILI), their phenotypes, and the outcome of hepatotoxicity will help clinicians prescribe to these patients and interpret abnormal liver test results when they are receiving potentially hepatotoxic medicines. This overview pays particular attention to the worst-case scenario of acute-on-chronic liver disease [11].

One of the most controversial topics in recent years in the field of DILI is liver injury following SARS-CoV2 vaccination. The pathogenic basis of this association, which may represent a unique form of drug-induced, autoimmune-like hepatitis, as well as its clinical presentation and the management of affected patients, is discussed in depth [12].

For disorders such as DILI, which lack specific biomarkers, it is essential to properly assess causality in order to accurately identify patients. Although far from perfect, causality assessment scales are an easy-to-use and accessible tool in clinical and regulatory settings, as well as in clinical research. The article focuses on the most widely used RUCAM method and its updated electronic tool, RECAM, highlighting that the structured expert opinion is better suited to cases occurring during drug development and those with atypical phenotypes [13].

In the era of artificial intelligence, no disorder could potentially benefit more from it than DILI. This monographic issue includes a comprehensive review that discusses how artificial intelligence-driven models can advance DILI research, improve risk stratification and prognostic evaluation, and enhance causality assessment. It also covers the adoption of natural language processing and large language models in clinical settings [14].

We are confident that this monographic issue provides exciting, in-depth information on various aspects of DILI, covering perspectives that will interest hepatologists, gastroenterologists, internists, oncologists, pathologists, toxicologists, government regulators and pharmaceutical industry members involved in hepatotoxicity.

The author declares no conflicts of interest.