A state-of-the-art update on hepatotoxicity: Introduction to the special series on drug-induced liver injury
Year: 2024
Type: article
Abstract: This Clinical Liver Disease special series highlights the ever-growing, fascinating, and challenging field of hepatotoxicity. Since Zimmerman’s1 initial characterization and classification of hepatotoxicity in the 1970s established DILI as a clinical discipline, DILI remains a diagnostic and therapeutic challenge for clinicians, researchers, and drug development. Specifically, Idiosyncratic DILI (IDILI), which is by definition rare and unpredictable, lacks a gold standard biomarker, is notoriously difficult to diagnose, and can mimic various forms of liver disease. There are no targeted therapies for DILI, and the mainstay of therapy remains early recognition and withdrawal of the offending agent, which results in improvement of liver injury in the majority of cases. DILI can mimic all forms of liver disease, but the majority of cases present with a hepatocellular, mixed, or cholestatic phenotype of injury. Hepatocellular DILI with jaundice can result in severe liver injury and acute liver failure, leading to transplantation and death. These “Hy law” cases are at the extreme end of a spectrum of manifestations,2,3 which can range from sinusoidal obstruction syndrome to cholestatic hepatitis, steatohepatitis, vanishing bile duct syndrome, liver fibrosis, and everything in between depending on the agent. Despite these challenges, the past 3 decades have significantly advanced our understanding of DILI. Thanks to multiple prospective and retrospective patient registries that have compiled data on thousands of patients with this rare disease, we now have a better understanding of presentation, patterns of injury, latency, outcomes, and genetic associations for DILI.4–12 In addition, while there is no treatment for IDILI, we have seen that certain types of hepatotoxicity with immune features, such as drug-induced autoimmune-like hepatitis and immune-mediated liver injury from checkpoint inhibitors, do respond to steroids and immunosuppression.13,14 With this, we are pleased to introduce this state-of-the-art special series providing an update on the field. We have asked a diverse group of thought leaders in DILI from around the world to succinctly update readers about emerging topics in this space, emphasizing their translational research relevance, key clinical themes, and significant practical applications. Excluding competing etiologies of liver injury remains the backbone of DILI diagnosis. Currently, in many patients, polypharmacy and the increasingly widespread use of herbal and dietary supplements (HDSs) that contain complex formulations make identifying a single hepatotoxic agent difficult, even when the diagnosis of DILI is near certain. One notable resource that facilitates the recognition and diagnosis of DILI is LiverTox, a peer-reviewed online resource pioneered by Dr. Jay Hoofnagle and sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which is available on the NCBI Bookshelf. LiverTox offers up-to-date, unbiased, and easily accessed information on the diagnosis, cause, frequency, clinical patterns, and management of liver injury attributable to prescription and nonprescription medications and selected HDS.15 Causality assessment tools such as the Roussel Uclaf Causality Assessment Method for the diagnosis of DILI remain hindered by poor reliability, and expert opinion remains the Gold Standard. Recently, an updated and computerized causality assessment tool called the revised electronic causality assessment method was developed by Dr. Hayashi et al16, to aid clinicians in the systematic evaluation of agent-specific DILI. In this series, Drs. Hoofnagle and Hayashi17 discuss the role of revised electronic causality assessment method, and the major challenges in the diagnosis of DILI, and potential future directions for research in this area. The most ground-breaking development in the past 20 years in hepatotoxicity was the identification of associations between single nucleotide polymorphisms, notably in human leukocyte antigen genes, with IDILI from certain drugs.18 The literature now abounds with human leukocyte antigen associations for a variety of allopathic-drug and HDS-related hepatotoxicity. These data hold promise for the future as precision medicine evolves, but are they ready for prime-time use in clinical practice? Dr. Elizabeth Phillips, a leading world expert in personalized medicine and drug hypersensitivity, and her colleagues19 provide an overview on the hypotheses behind these genetic associations and address the clinical application of genetic testing for predicting DILI risk. Currently, a clinically relevant diagnostic challenge in DILI is differentiating drug-induced autoimmune-like hepatitis from idiopathic autoimmune hepatitis. This distinction not only impacts the diagnosis of DILI but also treatment duration and choice of immunosuppression.13,20 Drs. Andrade and Lucena,21 global experts in drug-induced autoimmune-like hepatitis from the Spanish Drug-Induced Liver Injury Network, summarize the diagnostic and management approach to this important clinical entity. Another increasingly recognized clinical challenge in DILI is hepatotoxicity in patients with underlying chronic liver disease such as metabolic dysfunction–associated steatotic liver disease and cirrhosis. Underlying liver disease is associated with more severe liver injury and worse outcomes from hepatotoxicity,10,22 however, are patients with chronic liver disease and metabolic dysfunction–associated steatotic liver disease more prone to liver injury? Does DILI promote acute on chronic liver failure?23 In this series, Dr. Devarbhavi and colleagues24 address these important and unresolved everyday clinical questions in the framework of the current evidence. Indeed, beyond underlying liver disease, the risk of DILI may be impacted by other patient factors such as age, sex, and polypharmacy. A classic example is the increased risk of INH DILI with increasing age.25 Extrahepatic injuries include severe skin reactions, which are described in 1% of patients with DILI. These represent an intriguing area of research and can provide clues to the diagnosis of a drug-related injury.10 Drug reaction with eosinophilia and systemic symptoms stands out as an example of a unique syndromic drug reaction that can accompany potentially severe DILI and is associated with certain drug classes, such as antiepileptics, as recently described by Dr. Chalasani et al.26,27 Recognizing such reactions in patients with DILI is of the utmost importance, given their prognostic and therapeutic implications. To that end, Dr. Chalasani and Dr. Rahnama-Moghadam28 describe the severe cutaneous adverse reactions that can present along with DILI, their clinical phenotypes, and common offending agents. This expert review includes examples of common skin rashes seen in DILI, which the readers will find very helpful. While we cannot cover every agent class in these short reviews, we have focused on agents and classes of topical significance as IDILI culprits in the United States and across the world. HDS stands out as an important and rising cause of liver injury, accounting for 20% of all cases of DILI in the US Drug-Induced Liver Injury Network.29 Therefore, all clinicians should be aware of HDS-associated DILI (HILI) and obtain a thorough history of over-the-counter, alternative, and herbal medications and dietary supplements from patients with liver injury. There is an ever-evolving cast of agents in HILI, where new compounds are regularly recognized as culprits in hepatotoxicity. As an example, turmeric supplement use is on the rise, and turmeric-induced liver toxicity was recently described by the Drug-Induced Liver Injury Network.30 In this series, Drs Halegoua-DeMarzio and Navarro31 provide a concise update on trends, diagnostic challenges, and prognostic implications in HILI for the practicing hepatologist and gastroenterologist. In a related article, the topic of anabolic steroid DILI, a uniquely cholestatic DILI, is covered by Dr. Andrew Stolz and colleagues.32 This has been described as a unique phenotype in young men taking dietary supplements often containing anabolic steroids and associated with protracted bland jaundice and pruritus.33 Although the most commonly implicated agents in IDILI are long-established medications such as antibiotics,10 DILI from more recently developed therapies such as biologic agents and immune checkpoint inhibitors is on the rise.34 Among biologic agents, the most common type associated with DILI is the anti-TNF agents. Data from Iceland shows the risk of DILI with these agents may be substantially higher than what is generally expected for idiosyncratic liver injury.35 Anti-TNF agents remain a mainstay of therapy in IBD, and the associated risks should be well known by gastroenterologists and hepatologists. Dr. Bjornsson discusses these risks, diagnostic and treatment considerations and the safety of considering alternate anti-TNF agents in affected patients.36 With the widespread use of immunotherapy for various cancers, immune-mediated liver injury from checkpoint inhibitors has become a rising cause of hepatotoxicity.14 This newer category of DILI often termed “indirect DILI” is the result of aberrant immune activation against the liver in the context of alteration in the patient’s capacity for immune tolerance. The mainstay of therapy for this disease remains stopping the immunotherapy and immunosuppression with corticosteroids, although a significant minority require second line agents.37 The manifestations of immune-mediated liver injury from checkpoint inhibitors the challenges associated with its diagnosis and treatment will be covered by Dr. Fontana and colleagues in this special series.38 It is with great enthusiasm that we dedicate this special series of Clinical Liver Disease to Hepatotoxicity as one of the final series published by the journal before it sunsets. Clinical Liver Disease has served as a valuable tool for clinicians, providing state-of-the-art research updates, evidence-based expert analyses, and topical reviews to help physicians navigate the diagnosis and treatment of liver disease. We are honored to pen this introduction and hope that you enjoy this special series on hepatotoxicity.
Source: Clinical Liver Disease
Authors: Lily Dara, Marwan Ghabril
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4400281535