Sabine Weber

Drug-induced liver injury (DILI) is associated with high mortality risk. However, no biomarker can reliably predict outcome. In order to identify baseline parameters that are associated with mortality the data of 268 prospectively collected DILI patients were analyzed. Multivariate logistic regression and receiver operating characteristic curves were used to identify the parameters being most predictive for a fatal outcome, as defined by orthotopic liver transplantation (OLT) or death. 10.4% of patients had a fatal outcome, which was associated with higher levels of transaminases, total bilirubin, INR and model for end-stage liver disease (MELD) scores (25 vs. 12, p < 0.001). Multivariate analysis revealed that only MELD and aspartate aminotransferase (AST) were independently associated with a poor outcome, the MELD score in particular had an extraordinarily high c-statistic of 0.93 (95% CI: 0.87–0.97). At a cut-off of ≥ 20, MELD could predict a fatal outcome with a sensitivity and specificity of 88% and 81%. The predictive performance of the MELD score could even be enhanced by combing it with AST elevation: At a cut-off of ≥ 20 and ≥ 29.6xULN, respectively, positive and negative predictive values of 44% and 96% were observed, which were higher than for any other baseline parameter.

Differentiating drug-induced liver injury (DILI) and autoimmune hepatitis (AIH) is a diagnostic challenge. Liver biopsy is recommended in unclear cases, however, clear distinguishing patterns are unknown. We therefore aimed to further identify histopathological features that can discriminate DILI from AIH. The clinical and histological data of well-characterised 136 DILI and 43 AIH patients from our prospective cohort on patients with acute liver injury and potential drug-related cause were analysed. Logistic binary regression was performed to identify models that could differentiate both two entities. Histopathological findings showed high overlaps between DILI and AIH, and overall concordance between histological and clinical diagnosis was low (48.9%). While interface hepatitis, plasma cell infiltration, and portal-intralobular infiltration were favouring AIH, relevant proportions of DILI patients also presented with those features (44.1%, 46.3% and 29.2%, respectively). Interestingly, on multivariate analysis, lipofuscinosis was the only independent predictor of DILI diagnosis, showing a strong association with DILI diagnosis (odds ratio [OR] 10.8; positive predictive value [PPV] 96.2%). Moreover, logistic regression analysis showed that a model combining different histopathological features (lack of interface hepatitis, fibrosis and eosinophils together with presence of cholestasis, steatosis and lipofuscinosis) could differentiate DILI from AIH with an accuracy of 76.5% and a strikingly high sensitivity of 94.9%. DILI and AIH showed similar histological patterns, however lipofuscinosis was identified as a novel distinctive feature for DILI with an extraordinarily high PPV. Moreover, a model combining a variety of histological features could differentiate both entities with high sensitivity.

Background and Aims: Drug‐induced liver injury (DILI) due to metamizole has gained increasing attention. Causality assessment remains a challenge, especially in patients with co‐medications. We therefore aimed to further characterise metamizole DILI cases. Methods: The data of patients with metamizole intake from our prospective study on acute liver injury with potential drug‐related causes were analysed. Diagnosis and causality assessment were based on a thorough work‐up and long‐term follow‐up. Results: DILI was associated with metamizole in 61 of 324 DILI patients (prevalence 18.8%). A highly characteristic clinical pattern was observed in 43 of the 61 patients, characterised by marked elevation of transaminases peaking at the time of DILI recognition and a more pronounced increase of bilirubin within the first 3 days of clinical presentation. Patients fitting this picture had higher rates of jaundice, coagulopathy, and acute liver failure, however outcomes did not differ significantly when compared to non‐metamizole DILI and autoimmune hepatitis (AIH) patients. Overall, fatal adverse outcomes defined by death or liver transplantation were observed in 13.1% of metamizole DILI patients. On multivariate analysis, only aspartate aminotransferase (AST) and INR were independently associated with a fatal adverse outcome. INR, in particular, performed better than Hy's law, bilirubin, transaminases, and the model for end‐stage liver disease (MELD), with a c ‐statistic of 0.85 (95% CI: 0.70–1.0). At a cut‐off of ≥ 2.1, sensitivity and specificity for a fatal adverse outcome were 75% and 96%, respectively. Conclusions: Metamizole DILI can present with a characteristic pattern that can help clinicians to identify metamizole as the causative agent. Outcome, however, is not associated with this clinical picture and should rather be predicted by INR at onset. Trial Registration: ClinicalTrials.gov identifier: NCT 02353455

Background Molecular changes in HCC development are largely unknown. As the liver plays a fundamental role in the body’s metabolism, metabolic changes are to be expected. Aims We aimed to identify metabolomic changes in HCC in comparison to liver cirrhosis (LC) patients, which could potentially serve as novel biomarkers for HCC diagnosis and prognosis. Methods Metabolite expression from 38 HCC from the SORAMIC trial and 32 LC patients were analyzed by mass spectrometry. Metabolites with significant differences between LC and HCC at baseline were analyzed regarding expression over follow-up. In addition, association with overall survival was tested using univariate Cox proportional-hazard analysis. Results 41 metabolites showed differential expression between LC and HCC patients. 14 metabolites demonstrated significant changes in HCC patients during follow-up. Campesterol, lysophosphatidylcholine, octadecenoic and octadecadienoic acid, and furoylglycine showed a differential expression in the local ablation vs. palliative care group. High expression of eight metabolites (octadecenoic acid, 2-hydroxybutyrate, myo-inositol, isocitrate, erythronic acid, creatinine, pseudouridine, and erythrol) were associated with poor overall survival. The association between poor OS and octadecenoic acid and creatinine remained statistically significant even after adjusting for tumor burden and LC severity. Conclusion Our findings give promising insides into the metabolic changes during HCC carcinogenesis and provide candidate biomarkers for future studies. Campesterol and furoylglycine in particular were identified as possible biomarkers for HCC progression. Moreover, eight metabolites were detected as predictors for poor overall survival. Graphical Abstract

Zusammenfassung Medikamentös-toxische Leberschädigungen („drug-induced liver injury“ [DILI]) sind seltene, aber teils lebensbedrohliche Ereignisse. Abzugrenzen von der intrinsischen Leberschädigung, die vorhersagbar und reproduzierbar nach einer Überdosis Paracetamol auftritt, ist die idiosynkratische DILI – eine Leberentzündung, die meist mit einer Latenz von Wochen bis Monaten, dosisunabhängig und nicht vorhersagbar als Reaktion auf die Einnahme vieler verschiedener Präparate auftritt. Die Ursache dafür, dass bestimmte Medikamente bei einzelnen Personen einen Leberschaden hervorrufen, ist bisher nicht gänzlich geklärt. Allerdings ist mittlerweile bekannt, dass das Immunsystem eine zentrale Rolle spielt, was durch die Assoziation bestimmter Polymorphismen humaner Leukozytenantigene (HLA) mit DILI durch spezifische Medikamentenklassen unterstrichen wird. Aufgrund der immunologischen Vorgänge, die zur Leberschädigung führen, zeigen sich laborchemisch und histologisch viele Überschneidungen insbesondere zur Autoimmunhepatitis (AIH), was eine diagnostische Abgrenzung oft schwierig macht. Neben der konventionellen DILI gibt es weitere Phänotypen, die als autoimmunähnlich gewertet werden. So wurde erst kürzlich ein Konsensusreport zur Definition und Charakterisierung einer neuen DILI-Entität, der „drug-induced autoimmune-like hepatitis“ (DI-ALH), publiziert. Die DI-ALH zeigt große Überschneidungen zur idiopathischen AIH, spricht ebenfalls gut auf Kortikosteroide an, zeichnet sich aber durch ein meist fehlendes Rezidiv nach Absetzen der Immunsuppression aus. Ebenfalls zu den immunologischen Leberschädigungen werden die Reaktionen auf Checkpointinhibitoren und Impfungen gezählt, wobei sich histopathologisch ein anderes Schädigungsmuster mit Überwiegen zytotoxischer T‑Zellen zeigt.

Update on herbal and dietary supplement-induced liver injury: current gaps and future directions