Browsing by Subject "Liver toxicity"

Now showing 1 - 3 of 3
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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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    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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    Gene therapy – are we ready now?
    (Wiley, 2022) Kaczmarek, Radoslaw; Pediatrics, School of Medicine
    Introduction: Haemophilia therapy has evolved from rudimentary transfusion-based approaches to an unprecedented level of innovation with glimmers of functional cure brought by gene therapy. After decades of misfires, gene therapy has normalized factor (F)VIII and factor (F)IX levels in some individuals in the long term. Several clinical programmes testing adeno-associated viral (AAV) vector gene therapy are approaching completion with imminent regulatory approvals. Discussion: Phase 3 studies along with multiyear follow-up in earlier phase investigations raised questions about efficacy as well as short- and long-term safety, prompting a reappraisal of AAV vector gene therapy. Liver toxicities, albeit mostly low-grade, occur in the first year in at least some individuals in all haemophilia A and B trials and are poorly understood. Extreme variability and unpredictability of outcome, as well as a slow decline in factor expression (seemingly unique to FVIII gene therapy), are vexing because immune responses to AAV vectors preclude repeat dosing, which could increase suboptimal or restore declining expression, while overexpression may result in phenotoxicity. The long-term safety will need lifelong monitoring because AAV vectors, contrary to conventional wisdom, integrate into chromosomes at the rate that calls for vigilance. Conclusions: AAV transduction and transgene expression engage the host immune system, cellular DNA processing, transcription and translation machineries in ways that have been only cursorily studied in the clinic. Delineating those mechanisms will be key to finding mitigants and solutions to the remaining problems, and including individuals who cannot avail of gene therapy at this time.