Slow but Steady Progress in a Field with Many Knowledge Gaps

Drug-induced liver injury (DILI) continues to command attention across the spectrum of health care from the lay public, patients, and clinicians, to the basic scientists, pharmaceutical industry, and regulatory agencies. Drug-induced liver injury reports are increasing overall, and severe cases sporadically make headlines in the lay press. It remains a leading cause of acute liver failure in the United States and around the world. It continues to challenge pharmaceutical companies and regulatory agencies to find better ways to prevent and monitor at a time when trimming health care costs is a widespread mandate. At the clinical level, DILI can be a devastating iatrogenic event for the individual patient and an unforgettable challenge to the clinician. Basic research into mechanisms of injury and markers of risk is the best hope for curtailing this disease that is rare in incidence, yet vast in its effects that go well beyond the individual patient. Indeed, DILI is a concern for all of us who are both prescribers of medications and consumers of health care.

“Making the world a safer place” to take medications was the theme of the last Seminars issue devoted to DILI. In the 5 years since, steady progress has been made toward that goal, but much remains poorly understood. In this issue, we provide updates on major scientific and clinical findings, as well as highlight areas of ongoing challenges. We also include new topics including perspectives from industry and government.

Dr. Björnsson starts this issue with a review of DILI epidemiology that is so critical in guiding downstream research, both basic science and clinical. He broadly covers current data on DILI incidence, including his own important contribution, an elegant population-based study that suggests DILI may not be as rare as previously thought. Our increased understanding of risk factors is also covered to aid the clinician. Drs. Urban, Daly, and Aithal cover genetic advancements including important links between genetic susceptibility and immune-mediated mechanisms of liver injury. Human leukocyte antigen associations with DILI provide convincing evidence for the importance of T-cell reactions to metabolites and antigen presentation. Such findings suggest new opportunities for research into markers of DILI diagnosis and targets for therapy.

Thereafter, several clinical topics are covered. Drs. Hayashi and Fontana emphasize the importance of meticulous clinical evaluation, basic knowledge of DILI presentations, and clinical course including a new concern over chronic DILI that may linger long after the initial hepatotoxic event has passed. They delineate the recently published critical elements of an evaluation and discuss the role of the most popular diagnostic algorithm known as the RUCAM. They also highlight the newly launched, online DILI resource, LiverTox that is proving remarkably popular and invaluable to the clinician. Drs. Andrade and Devarbhavi then review three classes of medications commonly reported to cause DILI: antibiotics, central nervous medications, (antiepileptics), and nonsteroidal anti-inflammatory drugs (NSAIDs). The first two classes are the most frequently reported in DILI registries, and the possibility of NSAID hepatotoxicity is commonplace because so many patients take them. Familiarity with these three classes of agents covers a large proportion, if not lion's share, of agents implicated in DILI.

Chemotherapy-induced hepatotoxicity represents one of the more challenging DILIs. The complexity of these cases leads to difficulties in firmly attributing elevated liver biochemistries to their chemotherapy, which probably leads to less prominence in DILI registries that favor clear-cut cases of DILI. Nevertheless, abnormal liver biochemistries in the oncology patient is a frequent consultation for the gastroenterologist, and Drs. Reddy and Bahirwani review the more commonly used chemotherapy agents and their hepatotoxicity profiles.

With roughly 50% of the U.S. population using herbal and dietary supplements (HDS), there are legitimate concerns over a rising risk of liver injury and underreporting. Drs. Navarro and Lucena cover the burgeoning use of HDS and their risk of hepatotoxicity. A useful reference table of the many HDS products causing hepatotoxicity is provided. Key points include variation in HDS ingredients between purchases and adulteration. They also cover the heterogeneous and less-stringent regulatory environment in the United States and abroad. Such knowledge is critical to clinicians as they must not only diagnose such liver injuries, but also take the lead in educating patients on the risks associated with HDS.

As mentioned, the role of the immune system in DILI is a growing field of interest. In DILI with an autoimmune hepatitis phenotype, the immune system takes on a central role in the injury mechanism. Other DILI cases have prominent nonhepatic immunoallergic features such as rash, bone marrow suppression, and fever. Dr. de Lemos and colleagues cover the broad range of immune-associated features of DILI including the typical agents, presentations, and pathophysiology. The authors review management issues including data on the use of immunosuppressants, which remains controversial.

A rare but important subset of DILI includes those causing steatosis. Drs. Amacher and Chalasani review advances in our understanding of this unusual injury pattern. They cover the more familiar macro- and microvesicular patterns of fat deposition as well as the less well-known phospholipidosis. Monitoring for such injuries can be a challenge because liver biochemistry abnormalities may be mild. Instructive examples of medications causing such injuries are given including the newly approved Apo-B inhibitors.

The diagnostic challenge section covers drug-induced noncirrhotic portal hypertension, another unusual DILI. Drs. Ghabril and Vuppalanchi provide a concise review of this injury that often presents late into therapy with signs and symptoms of portal hypertension. The presentation can take the clinician off guard as they initially assume a cirrhotic liver is at fault. Sadly, the diagnosis is easily missed and the inciting agent continued. The authors provide useful tips on the diagnostic evaluation and cover the most commonly reported culprit medications.

In these times of health care cost containment, the need for efficiency in bringing new and safe pharmaceuticals to the public has never been greater. Loss of a marketed agent due to unrecognized hepatotoxicity has large financial ramifications for the health care system. Dr. Avigan of the U.S. Food and Drug Administration (FDA) gives a very instructive review of the FDA's challenges as well as their progressive work on pre- and postmarketing monitoring strategies. In addition, he covers FDA measures to enhance the development of biomarkers for DILI. Dr. Regev offers the perspective from the pharmaceutical industry. As the prediction for a compound's liability for DILI during the preclinical phases is quite difficult, he points out that milder forms of liver injury occurring during clinical development, when assessed appropriately, may significantly enhance the ability to predict a medication's potential severe DILI postmarketing.

We hope this issue of Seminars provides an updated, broad, and practical review of idiosyncratic drug-induced liver injury. The issue contains tables and summaries that are useful references for the clinician. It also provides the researcher with updates on our current understanding of DILI pathophysiology and new avenues for inquiry. Views from government regulatory agencies and private industry round out the issue and give the reader a broader perspective on DILI.