Drug-Induced Liver Injury: Expanding Our Knowledge by Enlarging Population Analysis With Prospective and Scoring Causality Assessment
2015; Elsevier BV; Volume: 148; Issue: 7 Linguagem: Inglês
10.1053/j.gastro.2015.04.027
ISSN1528-0012
AutoresRolf Teschke, Raúl J. Andrade,
Tópico(s)Liver Disease Diagnosis and Treatment
ResumoSee "Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study," by Chalasani N, Bonkovsky HL, Fontana R, et al, on page 1340; and "Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system," by Goldberg DS, Forde KA, Carbonari DM, et al, on page 1353. See "Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study," by Chalasani N, Bonkovsky HL, Fontana R, et al, on page 1340; and "Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system," by Goldberg DS, Forde KA, Carbonari DM, et al, on page 1353. Drug-induced liver injury (DILI) is a fascinating yet challenging and complex disease, concerning mostly patients but also clinicians, the pharmaceutical industry, and regulatory authorities. In the absence of a valid diagnostic biomarker, DILI diagnosis requires clinical expertise, intuition, commitment, and robust criteria. The necessity of concerted efforts to obtain reliable information on DILI causal agents, phenotypes, and risk factors has stimulated groups in the United States and Europe to develop large DILI prospective registries.1Andrade R.J. Lucena M.I. Fernández M.C. et al.Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period.Gastroenterology. 2005; 129: 512-521Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar, 2Chalasani N. Fontana R.J. Bonkovsky H.L. et al.Drug-Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.Gastroenterology. 2008; 35: 1924-1934Abstract Full Text Full Text PDF Scopus (713) Google Scholar In this issue of Gastroenterology, 2 studies provide new details on DILI epidemiology and outcome using different approaches.3Chalasani N. Bonkovsky H.L. Fontana R. et al.Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study.Gastroenterology. 2015; 148: 1340-1352Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar, 4Goldberg D.S. Forde K.A. Carbonari D.M. et al.Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.Gastroenterology. 2015; 148: 1353-1361Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar In the first study,3Chalasani N. Bonkovsky H.L. Fontana R. et al.Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study.Gastroenterology. 2015; 148: 1340-1352Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar the Drug-induced Liver Injury Network (DILIN) presents an updated and subgroup analysis of 889 DILI patients. Their results are in line with an earlier study,2Chalasani N. Fontana R.J. Bonkovsky H.L. et al.Drug-Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.Gastroenterology. 2008; 35: 1924-1934Abstract Full Text Full Text PDF Scopus (713) Google Scholar confirming a previous study of 461 DILI cases from Spain1Andrade R.J. Lucena M.I. Fernández M.C. et al.Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period.Gastroenterology. 2005; 129: 512-521Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar and a prospective population-based study from Iceland.5Björnsson E.S. Bergmann O.M. Björnsson H.K. et al.Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland.Gastroenterology. 2013; 144: 1419-1425Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar The second study used the Kaiser Permanente Northern California database as a surrogate of a wide population sample in order to determine the incidence and outcome of drug-induced acute liver failure (ALF).4Goldberg D.S. Forde K.A. Carbonari D.M. et al.Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.Gastroenterology. 2015; 148: 1353-1361Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar In both studies, DILI was not confined to synthetic drugs, but also included herbs and herbal dietary supplements,3Chalasani N. Bonkovsky H.L. Fontana R. et al.Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study.Gastroenterology. 2015; 148: 1340-1352Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar, 4Goldberg D.S. Forde K.A. Carbonari D.M. et al.Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.Gastroenterology. 2015; 148: 1353-1361Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar which were the second most common causative group (17%) in the DILIN cohort and whose proportion has more than doubled since the initiation of the study in 2004 (7%).2Chalasani N. Fontana R.J. Bonkovsky H.L. et al.Drug-Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.Gastroenterology. 2008; 35: 1924-1934Abstract Full Text Full Text PDF Scopus (713) Google Scholar, 4Goldberg D.S. Forde K.A. Carbonari D.M. et al.Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.Gastroenterology. 2015; 148: 1353-1361Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Indeed, herbs and dietary supplements are a growing cause of liver injury (HILI) worlwide.6Seeff L.B. Bonkovsky H.L. Navarro V.J. et al.Herbal products and the liver: 1 review of adverse effects and mechanisms.Gastroenterology. 2015; 148: 517-532.e3Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 7Teschke R. Wolff A. Frenzel C. et al.Review article: herbal hepatotoxicity – an update on Traditional Chinese Medicine preparations.Aliment Pharmacol Ther. 2014; 40: 32-50Crossref PubMed Scopus (120) Google Scholar Whereas the first cohort was homogenous owing to specific inclusion of only cases with idiosyncratic liver injury,3Chalasani N. Bonkovsky H.L. Fontana R. et al.Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study.Gastroenterology. 2015; 148: 1340-1352Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar the second cohort also included acetaminophen cases that allowed separate assessments.4Goldberg D.S. Forde K.A. Carbonari D.M. et al.Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.Gastroenterology. 2015; 148: 1353-1361Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar The most important new finding of clinical relevance in the DILIN cohort is the observation in a subgroup that the mortality rate from DILI is significantly higher in patients with preexisting liver disease (16% vs 5.2%),3Chalasani N. Bonkovsky H.L. Fontana R. et al.Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study.Gastroenterology. 2015; 148: 1340-1352Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar which is a long-standing clinical assumption that never had been verified. However, this statement may be misleading because the frequency of liver-related mortality was similar among DILI patients with and without preexisting chronic liver disease, despite the fact that the clinical severity of the liver injury tended to be higher in individuals with underlying affected liver. This suggests that other comorbidities could have contributed to this worse outcome. Indeed, patients with preexisting chronic liver disease that included mainly hepatitis C and nonalcoholic fatty liver disease also had a higher prevalence of diabetes; therefore, the mechanisms by which DILI further deteriorates a previously affected liver to result in an excess of mortality remains open. Among the overall 899 patients considered as cases, 10% of the patients died or underwent liver transplantation, and 17% had chronic liver injury.3Chalasani N. Bonkovsky H.L. Fontana R. et al.Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study.Gastroenterology. 2015; 148: 1340-1352Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar The definition of chronicity in DILI remains a matter of debate. The 1-year persistence of liver test abnormalities after DILI onset as recently proposed might be more realistic8Aithal G.P. Watkins P.B. Andrade R.J. et al.Case definition and phenotype standardization in drug-induced liver injury.Clin Pharmacol Ther. 2011; 89: 806-815Crossref PubMed Scopus (727) Google Scholar than the 6 months used by the DILIN investigators because the additional time likely removes unrelated reversible etiologies.3Chalasani N. Bonkovsky H.L. Fontana R. et al.Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study.Gastroenterology. 2015; 148: 1340-1352Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar Furthermore, the extent to which the persistent alterations in liver biochemistry in this study3Chalasani N. Bonkovsky H.L. Fontana R. et al.Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study.Gastroenterology. 2015; 148: 1340-1352Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar are the result of true "chronic" DILI, underlying unrecognized liver disease such as nonalcoholic fatty liver disease, or simply slowly resolving liver injury is difficult to estimate; this needs further assessments and prolonged follow-up. Actually, the DILIN cohort substantiates that cholestatic injury has a slower resolution with a higher rate of chronicity (31%) than hepatocellular and mixed injury with 13% and 14%, respectively.3Chalasani N. Bonkovsky H.L. Fontana R. et al.Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study.Gastroenterology. 2015; 148: 1340-1352Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar This study also confirms the previous intriguing observation from the Spanish DILI Registry9Lucena M.I. Andrade R.J. Kaplowitz N. et al.Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex.Hepatology. 2009; 49: 2001-2009Crossref PubMed Scopus (275) Google Scholar that older male individuals more frequently have cholestatic damage, whereas in younger females hepatocellular damage predominates. A biological explanation for this association is not evident, but it is unlikely as the authors suggest that such difference could be a reflection of causative agents (ie, antimicrobials causing cholestatic injury more represented in older individuals), because the phenotype of amoxicillin-clavulanate hepatotoxicity in Spanish patients in an earlier study was influenced by age.10Lucena M.I. Andrade R.J. Fernandez M.C. et al.Determinants of the clinical expression of amoxicillin-clavulanate hepatotoxicity: a prospective series from Spain.Hepatology. 2006; 44: 850-856Crossref PubMed Scopus (144) Google Scholar Data on the incidence of drug-induced ALF—a neglected topic—were highlighted in the study of Goldberg et al.4Goldberg D.S. Forde K.A. Carbonari D.M. et al.Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.Gastroenterology. 2015; 148: 1353-1361Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar The incidence rate per million person-years of any drug-induced ALF and acetaminophen-induced ALF (definitive or possible causality) were 1.91 and 1.07,4Goldberg D.S. Forde K.A. Carbonari D.M. et al.Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.Gastroenterology. 2015; 148: 1353-1361Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar with a corresponding mortality rate of 21% among the patients who developed non–acetaminophen-induced ALF and 6% among individuals with acetaminophen-induced ALF.4Goldberg D.S. Forde K.A. Carbonari D.M. et al.Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.Gastroenterology. 2015; 148: 1353-1361Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Although this is an important addition to fill some of the existing gaps in severe DILI incidence, the limitations of this study are its retrospective nature and the use of ICD-9 codes, which have poor accuracy if used by billing staff, leading to low specificity and sensitivity for DILI recognition.11Jinjuvadia K. Kwan W. Fontana R.J. Searching for a needle in the haystack: use of ICD-9-CM codes in drug-induced liver injury.Am J Gastroenterol. 2007; 102: 2437-2443Crossref PubMed Scopus (60) Google Scholar Furthermore, although determination of the etiology of ALF was based on independent adjudication by ≥2 hepatologists, retrospective causality assessment can be quite difficult when there are incomplete records and laboratory follow-up data. In the face of these shortcomings, clinicians need a robust framework to establish prospectively the diagnosis of DILI in the early clinical course, when the diagnosis is suspected and the disease is unfolding, and not thereafter and retrospectively, when the disease has vanished. Therefore, a pragmatic, stepwise approach is recommended. As the first step, a careful clinical assessment is necessary, associated with the use of a prospective diagnostic algorithm such as the scoring CIOMS scale (Council for International Organizations of Medical Sciences), also called RUCAM (Roussel Uclaf Causality Assessment Method),12Bénichou C. Danan G. Flahault A. Causality assessment of adverse reactions to drugs – II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge.J Clin Epidemiol. 1993; 46: 1331-1336Abstract Full Text PDF PubMed Scopus (467) Google Scholar best to be applied as the updated CIOMS scale.13Teschke R. Wolff A. Frenzel C. et al.Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment.World J Hepatol. 2014; 6: 17-32Crossref PubMed Scopus (66) Google Scholar The CIOMS scale was developed with test results of positive reexposures as gold standard and considers all core elements of hepatotoxicity, giving an individual score for each patient with suspected DILI or HILI.12Bénichou C. Danan G. Flahault A. Causality assessment of adverse reactions to drugs – II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge.J Clin Epidemiol. 1993; 46: 1331-1336Abstract Full Text PDF PubMed Scopus (467) Google Scholar, 13Teschke R. Wolff A. Frenzel C. et al.Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment.World J Hepatol. 2014; 6: 17-32Crossref PubMed Scopus (66) Google Scholar In a second step, and if uncertainty remains, an optional expert opinion may follow, using the scored CIOMS items established before as basic tool. CIOMS may also have some limitations, as detailed previously,13Teschke R. Wolff A. Frenzel C. et al.Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment.World J Hepatol. 2014; 6: 17-32Crossref PubMed Scopus (66) Google Scholar, 14Teschke R. Eickhoff A. Herbal hepatotoxicity in traditional and modern medicine: actual key issues and new encouraging steps.Front Pharmacol. 2015; (in press)Crossref PubMed Scopus (120) Google Scholar, 15García-Cortés M. Stephens C. Lucena M.I. et al.Causality assessment methods in drug induced liver injury: Strengths and weaknesses.J Hepatol. 2011; 55: 683-691Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar in particular, shortcomings related to ambiguous questions in few domains (ie, alcohol use as risk factor lacking quantification limits, and missing details for excluding various hepatitis types) that may result in mediocre reproducibility among raters as noted by the original authors12Bénichou C. Danan G. Flahault A. Causality assessment of adverse reactions to drugs – II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge.J Clin Epidemiol. 1993; 46: 1331-1336Abstract Full Text PDF PubMed Scopus (467) Google Scholar and later by the DILIN investigators.16Rochon J. Protiva P. Seeff L.B. et al.Reliability of the Roussel Uclaf Causality Assessment Method for assessing causality in drug-induced liver injury.Hepatology. 2008; 48: 1175-1183Crossref PubMed Scopus (159) Google Scholar For these reasons, the DILIN group probably does not include the CIOMS method in its adjudication protocol. However, the emerging new data on DILI and the practical experience gained with the CIOMS method should allow redesigning a new consensus method for causality assessment.13Teschke R. Wolff A. Frenzel C. et al.Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment.World J Hepatol. 2014; 6: 17-32Crossref PubMed Scopus (66) Google Scholar, 14Teschke R. Eickhoff A. Herbal hepatotoxicity in traditional and modern medicine: actual key issues and new encouraging steps.Front Pharmacol. 2015; (in press)Crossref PubMed Scopus (120) Google Scholar, 15García-Cortés M. Stephens C. Lucena M.I. et al.Causality assessment methods in drug induced liver injury: Strengths and weaknesses.J Hepatol. 2011; 55: 683-691Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar In the meantime, most of the weaknesses have been considered appropriately in an updated CIOMS scale.13Teschke R. Wolff A. Frenzel C. et al.Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment.World J Hepatol. 2014; 6: 17-32Crossref PubMed Scopus (66) Google Scholar It would be helpful if uniformity of DILI criteria, including specific scoring, is established worldwide so that published data across registries can be harmonized and interpreted easily across populations. Clearly, ethnicity, race, gender, and age are likely major contributors to DILI. In the second report, the use of the CIOMS scale was refuted on various grounds.4Goldberg D.S. Forde K.A. Carbonari D.M. et al.Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.Gastroenterology. 2015; 148: 1353-1361Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar First, the authors stated that CIOMS has not been validated outside of clinical settings.4Goldberg D.S. Forde K.A. Carbonari D.M. et al.Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.Gastroenterology. 2015; 148: 1353-1361Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar However, the CIOMS scale in its original and updated form has been used extensively for hepatotoxicity assessments in regulatory analyses, genotyping reports, epidemiologic studies, case reports, case series, and clinical trials.13Teschke R. Wolff A. Frenzel C. et al.Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment.World J Hepatol. 2014; 6: 17-32Crossref PubMed Scopus (66) Google Scholar, 14Teschke R. Eickhoff A. Herbal hepatotoxicity in traditional and modern medicine: actual key issues and new encouraging steps.Front Pharmacol. 2015; (in press)Crossref PubMed Scopus (120) Google Scholar, 15García-Cortés M. Stephens C. Lucena M.I. et al.Causality assessment methods in drug induced liver injury: Strengths and weaknesses.J Hepatol. 2011; 55: 683-691Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar Second, CIOMS was also disqualified by the assumption of being unable to ascertain causality when ≥2 drugs may be implicated.4Goldberg D.S. Forde K.A. Carbonari D.M. et al.Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.Gastroenterology. 2015; 148: 1353-1361Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Actually, CIOMS is well-prepared to assess comedication, with a separate CIOMS scale to be applied individually to each comedicated product, and can also be used to identify dietary/herbal supplement-induced liver injury.13Teschke R. Wolff A. Frenzel C. et al.Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment.World J Hepatol. 2014; 6: 17-32Crossref PubMed Scopus (66) Google Scholar, 14Teschke R. Eickhoff A. Herbal hepatotoxicity in traditional and modern medicine: actual key issues and new encouraging steps.Front Pharmacol. 2015; (in press)Crossref PubMed Scopus (120) Google Scholar, 15García-Cortés M. Stephens C. Lucena M.I. et al.Causality assessment methods in drug induced liver injury: Strengths and weaknesses.J Hepatol. 2011; 55: 683-691Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar Data incompleteness is a major issue in DILI cases according to an analysis of the DILIN group,17Agarwal V.K. McHutchison J.G. Hoofnagle J.H. Drug-Induced Liver Injury Network (DILIN). Important elements for the diagnosis of drug-induced liver injury.Clin Gastroenterol Hepatol. 2010; 8: 463-470Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar considering that DILI is a diagnosis of exclusion. Poor data quality is also found in cases of assumed HILI.18Teschke R. Black cohosh and suspected hepatotoxicity - inconsistencies, confounding variables, and prospective use of a diagnostic causality algorithm: a critical review.Menopause. 2010; 17: 426-440Crossref PubMed Scopus (73) Google Scholar In DILI cases, many elements were underreported with unclear descriptions of how certain diagnoses were excluded, lacking details of tests for hepatitis A, B, and C.19Davern T.J. Chalasani N. Fontana R.J. et al.Acute hepatitis E infection accounts for some cases of suspected drug-induced liver injury.Gastroenterology. 2011; 141: 1665-1672Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar For instance, data of immunoglobulin (Ig)M anti-HAV were reported in 0%–71% of the cases, IgM anti-HBc in 0%–50%, HCV RNA in 0%–12%, and HEV was not assessed.17Agarwal V.K. McHutchison J.G. Hoofnagle J.H. Drug-Induced Liver Injury Network (DILIN). Important elements for the diagnosis of drug-induced liver injury.Clin Gastroenterol Hepatol. 2010; 8: 463-470Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar Of note, the updated CIOMS scale considers all relevant hepatitis parameters to safely exclude various hepatitis viruses in addition to hepatitis A, B, C, and E, and each item receives an individual weighted score reflecting also its presence or absence.14Teschke R. Eickhoff A. Herbal hepatotoxicity in traditional and modern medicine: actual key issues and new encouraging steps.Front Pharmacol. 2015; (in press)Crossref PubMed Scopus (120) Google Scholar It is unclear to what extent these various hepatitis types have been excluded in the DILIN study, which only mentions hepatitis C and E,3Chalasani N. Bonkovsky H.L. Fontana R. et al.Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study.Gastroenterology. 2015; 148: 1340-1352Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar or in the second report, in which hepatitis E and herpes simplex A virus testing were not available in all patients.4Goldberg D.S. Forde K.A. Carbonari D.M. et al.Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.Gastroenterology. 2015; 148: 1353-1361Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Whether hepatitis E infection was excluded in most cases of DILIN and the ALF study remained unclear.3Chalasani N. Bonkovsky H.L. Fontana R. et al.Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study.Gastroenterology. 2015; 148: 1340-1352Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar, 4Goldberg D.S. Forde K.A. Carbonari D.M. et al.Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.Gastroenterology. 2015; 148: 1353-1361Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar In the United States, assays for anti-HEV antibodies are not approved by the Food and Drug Administration, a clinical problem.19Davern T.J. Chalasani N. Fontana R.J. et al.Acute hepatitis E infection accounts for some cases of suspected drug-induced liver injury.Gastroenterology. 2011; 141: 1665-1672Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar Missed alternative diagnoses in primarily suspected DILI cases were mentioned in the 2 reports,3Chalasani N. Bonkovsky H.L. Fontana R. et al.Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study.Gastroenterology. 2015; 148: 1340-1352Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar, 4Goldberg D.S. Forde K.A. Carbonari D.M. et al.Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.Gastroenterology. 2015; 148: 1353-1361Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar which is a major clinical issue in published DILI case series, accounting for 417 of 2906 cases (14%) with 47% in a single case series, providing a wide range of other hepatic causes and extrahepatic disorders with liver involvement.20Teschke R. Frenzel C. Wolff A. et al.Drug induced liver injury: accuracy of diagnosis in published reports.Ann Hepatol. 2014; 13: 248-255Crossref PubMed Google Scholar The 2 studies remind physicians that commonly used drugs, herbs, and dietary supplements may be hepatotoxic and striking causes of liver failure, to be considered in a clinical setting of patients with liver disease of initially unknown etiology.3Chalasani N. Bonkovsky H.L. Fontana R. et al.Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study.Gastroenterology. 2015; 148: 1340-1352Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar, 4Goldberg D.S. Forde K.A. Carbonari D.M. et al.Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.Gastroenterology. 2015; 148: 1353-1361Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar These reports also strengthen the argument that results of future DILI cohort studies may have a stronger impact when prospectively planned, using key items of hepatotoxicity that are individually scored. There is an urgent need for specific biomarkers for DILI, but in the meantime, integrating information on drug physicochemical properties with high-quality clinical data emerging from large databases will enable updated scales with scored elements for prospective causality assessment. In DILI, enlarging well-phenotyped populations for analysis places us 1 step closer to understanding this multilayered and elusive disease. Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective StudyGastroenterologyVol. 148Issue 7PreviewThe Drug-Induced Liver Injury Network is conducting a prospective study of patients with DILI in the United States. We present characteristics and subgroup analyses from the first 1257 patients enrolled in the study. Full-Text PDF Population-Representative Incidence of Drug-Induced Acute Liver Failure Based on an Analysis of an Integrated Health Care SystemGastroenterologyVol. 148Issue 7PreviewMedications are a major cause of acute liver failure (ALF) in the United States, but no population-based studies have evaluated the incidence of ALF from drug-induced liver injury. We aimed to determine the incidence and outcomes of drug-induced ALF in an integrated health care system that approximates a population-based cohort. Full-Text PDF Covering the CoverGastroenterologyVol. 148Issue 7PreviewThe use of biological agents has been a major advance in the treatment of patients with inflammatory bowel disease. For example, weight-based dosing (5 mg/kg) of the chimeric immunoglobulin (Ig)G1 monoclonal anti-tumor necrosis factor antibody, infliximab, involving an induction phase followed by maintenance treatment has been shown to be effective in inducing and maintaining clinical remission in patients with Crohn's disease (CD) and ulcerative colitis (UC). However, over time, therapeutic benefit is lost in many patients, requiring a dose escalation or a switch to another biological agent. Full-Text PDF
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