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The LAC Score Indicates Significant Fibrosis in Patients With Chronic Drug-Induced Liver Injury: A Large Biopsy-Based Study.

ABSTRACT: Currently, there are no satisfactory noninvasive methods for the diagnosis of fibrosis in patients with chronic drug-induced liver injury (DILI). Our goal was to develop an algorithm to improve the diagnostic accuracy of significant fibrosis in this population. In the present study, we retrospectively investigated the biochemical and pathological characteristics of consecutive patients with biopsy-proven chronic DILI, who presented at our hospital from January 2013 to December 2017. A noninvasive algorithm was developed by using multivariate logistic regression, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA) to diagnose significant fibrosis in the training cohort, and the algorithm was subsequently validated in the validation cohort. Totally, 1,130 patients were enrolled and randomly assigned into a training cohort (n = 848) and a validation cohort (n = 282). Based on the multivariate analysis, LSM, CHE, and APRI were independently associated with significant fibrosis. A novel algorithm, LAC, was identified with the AUROC of 0.81, which was significantly higher than LSM (AUROC 0.78), CHE (AUROC 0.73), and APRI (AUROC 0.68), alone. The best cutoff value of LAC in the training cohort was 5.4. When the LAC score was used to diagnose advanced fibrosis and cirrhosis stages, the optimal cutoff values were 6.2 and 6.7, respectively, and the AUROC values were 0.84 and 0.90 in the training cohort and 0.81 and 0.83 in the validation cohort. This study proved that the LAC score can contribute to the accurate assessment of high-risk disease progression and the establishment of optimal treatment strategies for patients with chronic DILI.

SUBMITTER: Li ZB

PROVIDER: S-EPMC8416439 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: The current diagnosis of early-stage liver fibrosis often relies on a serological or imaging-based evaluation of the stage of fibrosis, sometimes followed by an invasive liver biopsy procedure. Novel non-invasive experimental diagnostic tools are often based on markers of hepatocyte damage, or changes in liver stiffness and architecture, which are late-stage characteristics of fibrosis progression, making them unsuitable for the diagnosis of early-stage liver fibrosis. miRNAs control hepatic stellate cell (HSC) activation and are proposed as relevant diagnostic markers. Methods: We investigated the possibility of circulating miRNAs, which we found to be dysregulated upon HSC activation, to mark the presence of significant liver fibrosis (F ? 2) in patients with chronic alcohol abuse, chronic viral infection (HBV/HCV), and non-alcoholic fatty liver disease (NAFLD). Results: miRNA-profiling identified miRNA-451a, miRNA-142-5p, Let-7f-5p, and miRNA-378a-3p to be significantly dysregulated upon in vitro HSC activation, and to be highly enriched in their extracellular vesicles, suggesting their potential use as biomarkers. Analysis of the plasma of patients with significant liver fibrosis (F ? 2) and no or mild fibrosis (F = 0-1), using miRNA-122-5p and miRNA-29a-3p as positive control, found miRNA-451a, miRNA-142-5p, and Let-7f-5p, but not miRNA-378a-3p, able to distinguish between the two patient populations. Using logistic regression analysis, combining all five dysregulated circulating miRNAs, we created the miRFIB-score with a predictive value superior to the clinical scores Fibrosis-4 (Fib-4), aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio, and AST to platelet ratio index (APRI). The combination of the miRFIB-score with circulating PDGFR?-levels further increased the predictive capacity for the diagnosis of significant liver fibrosis. Conclusions: The miRFIB- and miRFIBp-scores are accurate tools for the diagnosis of significant liver fibrosis in a heterogeneous patient population.

Project description:AbstractPatients with metabolic syndrome are at a higher risk of nonalcoholic fatty liver disease (NAFLD) and liver fibrosis than the general population. Still, accessibility of screening method for NAFLD with significant fibrosis, such as transient elastography (FibroScan) are limited in some settings. This study aimed to develop a simple clinical predictive score for detecting NAFLD with significant fibrosis in patients with metabolic syndrome.A cross-sectional study was designed to obtain the data from medical records of all relevant patients who underwent transient elastography between January 2011 and December 2020 at Siriraj Hospital, Thailand. A liver stiffness cutoff value of 7.0 kilopascal was used to define the presence of significant liver fibrosis. To examine potential predictors, medical history and clinical data commonly assessed in routine practice were selected by following expert opinions and univariable statistical analysis. Backward and forward stepwise logistic regression was performed to acquire a final prediction model. To simplify the model, a weighted score was assigned for each categorized predictor. In addition, eligible cutoff values of the score and their predictive performances were determined.A total of 745 medical records were reviewed. The prevalence of NAFLD with significant fibrosis in patients with metabolic syndrome was 12.6%. Most clinical characteristics of patients with NAFLD with significant fibrosis and those non-NAFLD and NAFLD with no/mild fibrosis were quite disparate. The most practical model comprised globulin, aspartate transaminase, platelet count, and type 2 diabetes. It provided a good predictive performance with an area under the receiver operating characteristic curve of 0.828 (95% confidence interval [CI]: 0.782, 0.874). At the proper cutoff value, sensitivity and specificity were 76.6% (95% CI: 66.7%, 84.7%) and 72.4% (95% CI: 68.7%, 75.8%), respectively. The likelihood ratio of testing positive for NAFLD with significant fibrosis was 2.8 (95% CI: 2.34, 3.27) among patients with scores above the cutoff value.The first score for detecting of NAFLD with significant fibrosis in patients with metabolic syndrome was developed. This practical score, providing a good predictive performance, should be useful to help clinicians prioritize needs for further investigations among high-risk patients, especially in resource-limited settings.

Project description:UNLABELLED:Distinguishing drug-induced liver injury (DILI) from idiopathic autoimmune hepatitis (AIH) can be challenging. We performed a standardized histologic evaluation to explore potential hallmarks to differentiate AIH versus DILI. Biopsies from patients with clinically well-characterized DILI [n = 35, including 19 hepatocellular injury (HC) and 16 cholestatic/mixed injury (CS)] and AIH (n = 28) were evaluated for Ishak scores, prominent inflammatory cell types in portal and intra-acinar areas, the presence or absence of emperipolesis, rosette formation, and cholestasis in a blinded fashion by four experienced hepatopathologists. Histologic diagnosis was concordant with clinical diagnosis in 65% of cases; but agreement on final diagnosis among the four pathologists was complete in only 46% of cases. Interface hepatitis, focal necrosis, and portal inflammation were present in all evaluated cases, but were more severe in AIH (P < 0.05) than DILI (HC). Portal and intra-acinar plasma cells, rosette formation, and emperiopolesis were features that favored AIH (P < 0.02). A model combining portal inflammation, portal plasma cells, intra-acinar lymphocytes and eosinophils, rosette formation, and canalicular cholestasis yielded an area under the receiver operating characteristic curve (AUROC) of 0.90 in predicting DILI (HC) versus AIH. All Ishak inflammation scores were more severe in AIH than DILI (CS) (P ? 0.05). The four AIH-favoring features listed above were consistently more prevalent in AIH, whereas portal neutrophils and intracellular (hepatocellular) cholestasis were more prevalent in DILI (CS) (P < 0.02). The combination of portal inflammation, fibrosis, portal neutrophils and plasma cells, and intracellular (hepatocellular) cholestasis yielded an AUC of 0.91 in predicting DILI (CS) versus AIH. CONCLUSION:Although an overlap of histologic findings exists for AIH and DILI, sufficient differences exist so that pathologists can use the pattern of injury to suggest the correct diagnosis.

Project description:UNLABELLED: BACKGROUND:The possibility of extracting RNA and measuring RNA expression from paraffin sections can allow extensive investigations on stored paraffin samples obtained from diseased livers and could help with studies of the natural history of liver fibrosis and inflammation, and in particular, correlate basic mechanisms to clinical outcomes. RESULTS:To address this issue, a pilot study of multiplex gene expression using branched-chain DNA technology was conducted to directly measure mRNA expression in formalin-fixed paraffin-embedded needle biopsy samples of human liver. Twenty-five genes were selected for evaluation based on evidence obtained from human fibrotic liver, a rat BDL model and in vitro cultures of immortalized human hepatic stellate cells. The expression levels of these 25 genes were then correlated with liver fibrosis and inflammation activity scores. Statistical analysis revealed that three genes (COL3A1, KRT18, and TUBB) could separate fibrotic from non-fibrotic samples and that the expression of ten genes (ANXA2, TIMP1, CTGF, COL4A1, KRT18, COL1A1, COL3A1, ACTA2, TGFB1, LOXL2) were positively correlated with the level of liver inflammation activity. CONCLUSION:This is the first report describing this multiplex technique for liver fibrosis and has provided the proof of concept of the suitability of RNA extracted from paraffin sections for investigating the modulation of a panel of proinflammatory and profibrogenic genes. This pilot study suggests that this technique will allow extensive investigations on paraffin samples from diseased livers and possibly from any other tissue. Using identical or other genes, this multiplex expression technique could be applied to samples obtained from extensive patient cohorts with stored paraffin samples in order to correlate gene expression with valuable clinically relevant information. This method could be used to provide a better understanding of the mechanisms of liver fibrosis and inflammation, its progression, and help development of new therapeutic approaches for this indication.

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The LAC Score Indicates Significant Fibrosis in Patients With Chronic Drug-Induced Liver Injury: A Large Biopsy-Based Study.

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