Browsing by Subject "Drug-induced liver injury"

Now showing 1 - 10 of 16
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    A 68-Year-Old Woman With Unexplained Liver Enzyme Elevation and Active Chronic Hepatitis: Beware of Drug-Induced Autoimmune-Like Hepatitis
    (Elsevier, 2023-10-04) Dara, Lily; Ghabril, Marwan; Phillips, Elizabeth; Kleiner, David; Chalasani, Naga; Medicine, School of Medicine
    This patient’s case history (void of protected health information) was discussed in a multidisciplinary meeting including hepatologists (LD, MG), a pathologist (DK), an immunologist (EP) with NC as moderator. We summarize the case history and discussion in the following article.
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    A state-of-the-art update on hepatotoxicity: Introduction to the special series on drug-induced liver injury
    (Wolters Kluwer, 2024-07-03) Dara, Lily; Ghabril, Marwan; Medicine, School of Medicine
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    Amoxicillin-Clavulanate-Induced Liver Injury
    (Springer, 2016-08) deLomos, Andrew S.; Ghabril, Marwan; Rockey, Don C.; Gu, Jiezhun; Barnhart, Huiman X.; Fontana, Robert J.; Kleiner, David E.; Bonkovsky, Herbert L.; Department of Medicine, IU School of Medicine
    Background and Aims Amoxicillin–clavulanate (AC) is the most frequent cause of idiosyncratic drug-induced injury (DILI) in the US DILI Network (DILIN) registry. Here, we examined a large cohort of AC-DILI cases and compared features of AC-DILI to those of other drugs. Methods Subjects with suspected DILI were enrolled prospectively, and cases were adjudicated as previously described. Clinical variables and outcomes of patients with AC-DILI were compared to the overall DILIN cohort and to DILI caused by other antimicrobials. Results One hundred and seventeen subjects with AC-DILI were identified from the cohort (n = 1038) representing 11 % of all cases and 24 % of those due to antimicrobial agents (n = 479). Those with AC-DILI were older (60 vs. 48 years, P < 0.001). AC-DILI was more frequent in men than women (62 vs. 39 %) compared to the overall cohort (40 vs. 60 %, P < 0.001). The mean time to symptom onset was 31 days. The Tb, ALT, and ALP were 7 mg/dL, 478, and 325 U/L at onset. Nearly all liver biopsies showed prominent cholestatic features. Resolution of AC-DILI, defined by return of Tb to <2.5 mg/dL, occurred on average 55 days after the peak value. Three female subjects required liver transplantation, and none died due to DILI. Conclusion AC-DILI causes a moderately severe, mixed hepatocellular–cholestatic injury, particularly in older men, unlike DILI in general, which predominates in women. Although often protracted, eventual apparent recovery is typical, particularly for men and usually in women, but three women required liver transplantation.
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    Clinical Characteristics and HLA Associations of Azithromycin-Induced Liver Injury
    (Wiley, 2024) Conlon, Caroline; Li, Yi-Ju; Ahmad, Jawad; Barnhart, Huiman; Fontana, Robert J.; Ghabril, Marwan; Hayashi, Paul H.; Kleiner, David E.; Lee, William M.; Navarro, Victor; Odin, Joseph A.; Phillips, Elizabeth J.; Stolz, Andrew; Vuppalanchi, Raj; Halegoua-DeMarzio, Dina; Drug-Induced Liver Injury Network (DILIN); Medicine, School of Medicine
    Background: Azithromycin (AZ) is a widely used antibiotic. The aim of this study was to characterise the clinical features, outcomes, and HLA association in patients with drug-induced liver injury (DILI) due to AZ. Methods: The clinical characteristics of individuals with definite, highly likely, or probable AZ-DILI enrolled in the US Drug-Induced Liver Injury Network (DILIN) were reviewed. HLA typing was performed using an Illumina MiSeq platform. The allele frequency (AF) of AZ-DILI cases was compared to population controls, other DILI cases, and other antibiotic-associated DILI cases. Results: Thirty cases (4 definite, 14 highly likely, 12 probable) of AZ-DILI were enrolled between 2004 and 2022 with a median age of 46 years, 83% white, and 60% female. Median duration of AZ treatment was 5 days. Latency was 18.5 days. 73% were jaundiced at presentation. The injury pattern was hepatocellular in 60%, cholestatic in 27%, and mixed in 3%. Ten cases (33%) were severe or fatal; 90% of these were hepatocellular. Two patients required liver transplantation. One patient with chronic liver disease died of hepatic failure. Chronic liver injury developed in 17%, of which 80% had hepatocellular injury at onset. HLA-DQA1*03:01 was significantly more common in AZ-DILI versus population controls and amoxicillin-clavulanate DILI cases (AF: 0.29 vs. 0.11, p = 0.001 and 0.002, respectively). Conclusion: Azithromycin therapy can lead to rapid onset of severe hepatic morbidity and mortality in adult and paediatric populations. Hepatocellular injury and younger age were associated with worse outcomes. HLA-DQA1*03:01 was significantly more common in AZ cases compared to controls.
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    Consensus: guidelines: best practices for detection, assessment and management of suspected acute drug-induced liver injury during clinical trials in patients with nonalcoholic steatohepatitis
    (Wiley, 2019-03) Regev, Arie; Palmer, Melissa; Avigan, Mark I.; Dimick‐Santos, Lara; Treem, William R.; Marcinak, John F.; Seekins, Daniel; Krishna, Gopal; Anania, Frank A.; Freston, James W.; Lewis, James H.; Sanyal, Arun J.; Chalasani, Naga; Gastroenterology, IU School of Medicine
    BACKGROUND: The last decade has seen a rapid growth in the number of clinical trials enrolling patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). Due to the underlying chronic liver disease, patients with NASH often require different approaches to the assessment and management of suspected drug-induced liver injury (DILI) compared to patients with healthy livers. However, currently no regulatory guidelines or position papers systematically address best practices pertaining to DILI in NASH clinical trials. AIMS: This publication focuses on best practices concerning the detection, monitoring, diagnosis and management of suspected acute DILI during clinical trials in patients with NASH. METHODS: This is one of several papers developed by the IQ DILI Initiative, comprised of members from 15 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. This paper is based on extensive literature review, and discussions between industry members with expertise in drug safety and DILI experts from outside industry to achieve consensus on common questions related to this topic. RESULTS: Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, DILI detection, approach to a suspected DILI signal, causality assessment and hepatic discontinuation rules. CONCLUSIONS: This paper provides a framework for the approach to assessment and management of suspected acute DILI during clinical trials in patients with NASH.
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    Drug Hepatotoxicity: Environmental Factors
    (Elsevier, 2017-02) Stine, Jonathan G.; Chalasani, Naga; Medicine, School of Medicine
    Drug-induced liver injury presents as various forms of acute and chronic liver disease. There is wide geographic variation in the most commonly implicated agents. Smoking can induce cytochrome P450 enzymes but this does not necessarily translate into clinically relevant drug-induced liver injury. Excessive alcohol consumption is a clear risk factor for intrinsic hepatotoxicity from acetaminophen and may predispose to injury from antituberculosis medications. Understanding of the role of infection, proinflammatory states, disorders of coagulation, and the hepatic clock in predisposing patients to drug-induced liver injury is evolving. More study focusing specifically on environmental risk factors predisposing patients to drug-induced liver injury is needed.
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    Febuxostat-induced acute liver injury
    (Wiley, 2016-03) Bohm, Matt; Vuppalanchi, Raj; Chalasani, Naga; Department of Medicine, IU School of Medicine
    Febuxostat is a unique xanthine oxidase inhibitor that was approved for the prevention of gout in the United States in 2009. Unlike allopurinol, febuxostat is not a nucleoside analogue and has a higher specificity for xanthine oxidase. Although this drug has not been on the market for a long time, febuxostat may be safer than allopurinol. Importantly, febuxostat appears to be safer than allopurinol, which has been linked to many instances of severe hypersensitivity reactions, including skin rash with eosinophilia and systemic manifestations (DRESS syndrome), Stevens Johnson syndrome, acute nephritis, acute icteric hepatitis and acute liver failure. While febuxostat is not infrequently associated with serum enzyme elevations during treatment, it has yet to be linked to cases of clinically apparent acute liver injury. We report a case of acute liver injury with jaundice due to febuxostat and which was identified in a prospective study of drug-induced liver injury in the United States.
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    Levocarnitine for pegaspargase-induced hepatotoxicity in older children and young adults with acute lymphoblastic leukemia
    (Wiley, 2021-11) Schulte, Rachael; Hinson, Ashley; Huynh, Van; Breese, Erin H.; Pierro, Joanna; Rotz, Seth; Mixon, Benjamin A.; McNeer, Jennifer L.; Burke, Michael J.; Orgel, Etan; Pediatrics, School of Medicine
    Background: Pegaspargase (PEG-ASP) is an integral component of therapy for acute lymphoblastic leukemia (ALL) but is associated with hepatotoxicity that may delay or limit future therapy. Obese and adolescent and young adult (AYA) patients are at high risk. Levocarnitine has been described as potentially beneficial for the treatment or prevention of PEG-ASP-associated hepatotoxicity. Methods: We collected data for patients age ≥10 years who received levocarnitine during induction therapy for ALL, compared to a similar patient cohort who did not receive levocarnitine. The primary endpoint was conjugated bilirubin (c.bili) >3 mg/dl. Secondary endpoints were transaminases >10× the upper limit of normal and any Grade ≥3 hepatotoxicity. Results: Fifty-two patients received levocarnitine for prophylaxis (n = 29) or rescue (n = 32) of hepatotoxicity. Compared to 109 patients without levocarnitine, more patients receiving levocarnitine were obese and/or older and had significantly higher values for some hepatotoxicity markers at diagnosis and after PEG-ASP. Levocarnitine regimens varied widely; no adverse effects of levocarnitine were identified. Obesity and AYA status were associated with an increased risk of conjugated hyperbilirubinemia and severe transaminitis. Multivariable analysis identified a protective effect of levocarnitine on the development of c.bili >3 mg/dl (OR 0.12, p = 0.029). There was no difference between groups in CTCAE Grade ≥3 hepatotoxicity. C.bili >3 mg/dl during induction was associated with lower event-free survival. Conclusions: This real-world data on levocarnitine supplementation during ALL induction highlights the risk of PEG-ASP-associated hepatotoxicity in obese and AYA patients, and hepatotoxicity's potential impact on survival. Levocarnitine supplementation may be protective, but prospective studies are needed to confirm these findings.
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    Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs
    (Wolters Kluwer, 2012) Urban, Thomas J.; Shen, Yufeng; Stolz, Andrew; Chalasani, Naga; Fontana, Robert J.; Rochon, James; Ge, Dongliang; Shianna, Kevin V.; Daly, Ann K.; Lucena, M. Isabel; Nelson, Matthew R.; Molokhia, Mariam; Aithal, Guruprasad P.; Floratos, Aris; Pe'er, Itsik; Serrano, Jose; Bonkovsky, Herbert; Davern, Timothy J.; Lee, William M.; Navarro, Victor J.; Talwalkar, Jayant A.; Goldstein, David B.; Watkins, Paul B.; Drug-Induced Liver Injury Network; DILIGEN; EUDRAGENE; Spanish DILI Registry; International Serious Adverse Events Consortium; Medicine, School of Medicine
    Background and aims: Drug-induced liver injury (DILI) is a serious adverse drug event that is suspected to have a heritable component. We carried out a genome-wide association study of 783 individuals of European ancestry who experienced DILI due to more than 200 implicated drugs. Methods: DILI patients from the US-based Drug-Induced Liver Injury Network (n=401) and three international registries (n=382) were genotyped with the Illumina 1Mduo BeadChip and compared with population controls (n=3001). Potential associations were tested in 307 independent Drug-Induced Liver Injury Network cases. Results: After accounting for known major histocompatibility complex risk alleles for flucloxacillin-DILI and amoxicillin/clavulanate-DILI, there were no genome-wide significant associations, including in the major histocompatibility complex region. Stratification of DILI cases according to clinical phenotypes (injury type, latency, age of onset) also did not show significant associations. An analysis of hepatocellular DILI (n=285) restricted to 193 single-nucleotide polymorphisms previously associated with autoimmune disease showed a trend association for rs7574865, in the vicinity of signal transducer and activator of transcription 4 (STAT4) (P=4.5×10(-4)). This association was replicated in an independent cohort of 168 hepatocellular DILI cases (P=0.011 and 1.5×10(-5) for combined cohorts). No significant associations were found with stratification by other clinical or demographic variables. Conclusion: Although not significant at the genome-wide level, the association between hepatocellular DILI and STAT4 is consistent with the emerging role of the immune system in DILI. However, the lack of genome-wide association study findings supports the idea that strong genetic determinants of DILI may be largely drug-specific or may reflect rare genetic variations, which were not assessed in our study.
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    Liver Injury Following Tinospora Cordifolia Consumption: Drug-Induced AIH, or de novo AIH?
    (Elsevier, 2022) Björnsson, Einar S.; Navarro, Victor J.; Chalasani, Naga; Medicine, School of Medicine