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Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, hepatocellular injury, and progressive liver fibrosis. Resmetirom (MGL-3196) is a liver-directed, orally active, selective thyroid hormone receptor-β agonist designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity. We aimed to assess the safety and efficacy of resmetirom in patients with NASH. MGL-3196-05 was a 36-week randomised, double-blind, placebo-controlled study at 25 centres in the USA. Adults with biopsy confirmed NASH (fibrosis stages 1–3) and hepatic fat fraction of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned 2:1 by a computer-based system to receive resmetirom 80 mg or matching placebo, orally once a day. Serial hepatic fat measurements were obtained at weeks 12 and 36, and a second liver biopsy was obtained at week 36. The primary endpoint was relative change in MRI-PDFF assessed hepatic fat compared with placebo at week 12 in patients who had both a baseline and week 12 MRI-PDFF. This trial is registered with ClinicalTrials.gov, number NCT02912260. 348 patients were screened and 84 were randomly assigned to resmetirom and 41 to placebo at 18 sites in the USA. Resmetirom-treated patients (n=78) showed a relative reduction of hepatic fat compared with placebo (n=38) at week 12 (−32·9% resmetirom vs −10·4% placebo; least squares mean difference −22·5%, 95% CI −32·9 to −12·2; p<0·0001) and week 36 (−37·3% resmetirom [n=74] vs −8·5 placebo [n=34]; −28·8%, −42·0 to −15·7; p<0·0001). Adverse events were mostly mild or moderate and were balanced between groups, except for a higher incidence of transient mild diarrhoea and nausea with resmetirom. Resmetirom treatment resulted in significant reduction in hepatic fat after 12 weeks and 36 weeks of treatment in patients with NASH. Further studies of resmetirom will allow assessment of safety and effectiveness of resmetirom in a larger number of patients with NASH with the possibility of documenting associations between histological effects and changes in non-invasive markers and imaging. Madrigal Pharmaceuticals.

PurposeTo enhance clinician’s decision-making by diagnosing hepatocellular carcinoma (HCC) in cirrhotic patients with indeterminate liver nodules using quantitative imaging features extracted from triphasic CT scans.Material and methodsWe retrospectively analyzed 178 cirrhotic patients from 27 institutions, with biopsy-proven liver nodules classified as indeterminate using the European Association for the Study of the Liver (EASL) guidelines. Patients were randomly assigned to a discovery cohort (142 patients (pts.)) and a validation cohort (36 pts.). Each liver nodule was segmented on each phase of triphasic CT scans, and 13,920 quantitative imaging features (12 sets of 1160 features each reflecting the phenotype at one single phase or its change between two phases) were extracted. Using machine-learning techniques, the signature was trained and calibrated (discovery cohort), and validated (validation cohort) to classify liver nodules as HCC vs. non-HCC. Effects of segmentation and contrast enhancement quality were also evaluated.ResultsPatients were predominantly male (88%) and CHILD A (65%). Biopsy was positive for HCC in 77% of patients. LI-RADS scores were not different between HCC and non-HCC patients. The signature included a single radiomics feature quantifying changes between arterial and portal venous phases: DeltaV-A_DWT1_LL_Variance-2D and reached area under the receiver operating characteristic curve (AUC) of 0.70 (95%CI 0.61–0.80) and 0.66 (95%CI 0.64–0.84) in discovery and validation cohorts, respectively. The signature was influenced neither by segmentation nor by contrast enhancement.ConclusionA signature using a single feature was validated in a multicenter retrospective cohort to diagnose HCC in cirrhotic patients with indeterminate liver nodules. Artificial intelligence could enhance clinicians’ decision by identifying a subgroup of patients with high HCC risk.Key Points• In cirrhotic patients with visually indeterminate liver nodules, expert visual assessment using current guidelines cannot accurately differentiate HCC from differential diagnoses. Current clinical protocols do not entail biopsy due to procedural risks. Radiomics can be used to non-invasively diagnose HCC in cirrhotic patients with indeterminate liver nodules, which could be leveraged to optimize patient management.• Radiomics features contributing the most to a better characterization of visually indeterminate liver nodules include changes in nodule phenotype between arterial and portal venous phases: the “washout” pattern appraised visually using EASL and EASL guidelines.• A clinical decision algorithm using radiomics could be applied to reduce the rate of cirrhotic patients requiring liver biopsy (EASL guidelines) or wait-and-see strategy (AASLD guidelines) and therefore improve their management and outcome.

ObjectivesThe 8th International Forum for Liver Magnetic Resonance Imaging (MRI), held in Basel, Switzerland, in October 2017, brought together clinical and academic radiologists from around the world to discuss developments in and reach consensus on key issues in the field of gadoxetic acid–enhanced liver MRI since the previous Forum held in 2013.MethodsTwo main themes in liver MRI were considered in detail at the Forum: the use of gadoxetic acid for contrast-enhanced MRI in patients with liver cirrhosis and the technical performance of gadoxetic acid–enhanced liver MRI, both opportunities and challenges. This article summarises the expert presentations and the delegate voting on consensus statements discussed at the Forum.Results and conclusionsIt was concluded that gadoxetic acid–enhanced MRI has higher sensitivity for the diagnosis of hepatocellular carcinoma (HCC), when compared with multidetector CT, by utilising features of hyperenhancement in the arterial phase and hypointensity in the hepatobiliary phase (HBP). Recent HCC management guidelines recognise an increasing role for gadoxetic acid–enhanced MRI in early diagnosis and monitoring post-resection. Additional research is needed to define the role of HBP in predicting microvascular invasion, to better define washout during the transitional phase in gadoxetic acid–enhanced MRI for HCC diagnosis, and to reduce the artefacts encountered in the arterial phase. Technical developments are being directed to shortening the MRI protocol for reducing time and patient discomfort and toward utilising faster imaging and non-Cartesian free-breathing approaches that have the potential to improve multiphasic dynamic imaging.Key Points• Gadoxetic acid–enhanced MRI provides higher diagnostic sensitivity than CT for diagnosing HCC.• Gadoxetic acid–enhanced MRI has roles in early-HCC diagnosis and monitoring post-resection response.• Faster imaging and free-breathing approaches have potential to improve multiphasic dynamic imaging.

Given the worldwide prevalence of NAFLD and NASH, there is a need to develop treatments to slow or reverse disease progression. GR-MD-02 (galactoarabino-rhamnogalaturonate) has been shown to reduce hepatic fibrosis in animal studies, and lower serum biomarkers of NASH fibrogenesis in humans. The primary aim of this study was to determine the difference between four-months of treatment with GR-MD-02 or placebo in liver inflammation and fibrosis as measured by iron-corrected T1 (cT1) mapping, a non-invasive magnetic resonance imaging (MRI) biomarker that correlates with the extent of hepatic fibro-inflammatory disease. The secondary aims were to determine change in liver stiffness as measured by magnetic resonance elastography (MRE) and shear-wave ultrasonic elastography (LSM), and to explore test-retest repeatability of the three biomarkers. Thirty subjects (13 females, 46-71 years) with NASH and advanced fibrosis were recruited. Subjects were randomized to receive 8 mg.kg-1 GR-MD-02 (via IV infusion) or placebo, administered biweekly over a 16-week period. Therapeutic efficacy was examined using cT1, MRE, and LSM. Statistical analyses on group differences in the biomarkers were performed using robust ANCOVA models adjusting for baseline measurement and additional covariates. There was no significant difference in cT1 (p = 0.16) between GR-MD-02 and placebo groups following a 16-week intervention. There was also no significant difference in liver stiffness, measured by MRE (p = 0.80) or LSM (p = 0.63), between groups. Examination of repeatability of the cT1, MRE and LSM revealed coefficient of variations of 3.1%, 11% and 40% respectively. 8 mg.kg-1 of GR-MD-02 had no significant effect on non-invasive biomarkers of liver inflammation or fibrosis over a 4-month period. Histological confirmation was not available in this study. The high reproducibility of the primary outcome measure suggests that cT1 could be utilized for monitoring longitudinal change in patients with NASH.

A combined model was developed using contrast-enhanced CT-based radiomics features and clinical characteristics to predict liver fibrosis stages in patients with chronic liver disease (CLD). We retrospectively analyzed multiphase CT scans and biopsy-confirmed liver fibrosis. 160 CLD patients were randomly divided into 7:3 training/validation ratio. Clinical laboratory indicators associated with liver fibrosis were identified using Spearman's correlation and multivariate logistic regression correlation. Radiomic features were extracted after segmenting the entire liver from multiphase CT images. Feature dimensionality reduction was performed using RF-RFE, LASSO, and mRMR methods. Six radiomics-based models were developed in the training cohort of 112 patients. Internal validation was conducted on 48 randomly assigned patients. Receptor Operating Characteristic (ROC) curves and confusion matrices were constructed to evaluate model performance. The radiomics model exhibited robust performance, with AUC values of 0.810 to 1.000 for significant fibrosis, advanced fibrosis, and cirrhosis. The integrated clinical-radiomics model had superior diagnostic efficacy in the validation cohort, with AUC values of 0.836 to 0.997. Moreover, these models outperformed established biomarkers such as the aspartate aminotransferase to platelet ratio index (APRI) and the fibrosis 4 score (FIB-4), as well as the gamma glutamyl transpeptidase to platelet ratio (GPR), in predicting the fibrotic stages. The clinical-radiomics model holds considerable promise as a non-invasive diagnostic tool for the assessment and staging of liver fibrosis in the patients with CLD, potentially leading to better patient management and outcomes.

Objective To develop a novel logistic regression model based on liver/spleen volumes and portal vein diameter measured on magnetic resonance imaging (MRI) for predicting oesophagogastric variceal bleeding (OVB) secondary to HBV cirrhosis. Methods One hundred eighty-five consecutive cirrhotic patients with hepatitis B undergoing abdominal contrast-enhanced MRI were randomly divided into training cohort ( n = 130) and validation cohort ( n = 55). Spleen volume, total liver volume, four liver lobe volumes, and diameters of portal venous system were measured on MRI. Ratios of spleen volume to total liver and to individual liver lobe volumes were calculated. In training cohort, univariate analyses and binary logistic regression analyses were to determine independent predictors. Performance of the model for predicting OVB constructed based on independent predictors from training cohort was evaluated by receiver operating characteristic (ROC) analysis, and was validated by Kappa test in validation cohort. Results OVB occurred in 42 and 18 individuals in training and validation cohorts during the 2 years’ follow-up, respectively. An OVB prediction model was constructed based on the independent predictors including right liver lobe volume (RV), left gastric vein diameter (LGVD) and portal vein diameter (PVD) (odds ratio = 0.993, 2.202 and 1.613, respectively; p -values < 0.001 for all). The logistic regression model equation (−0.007 × RV + 0.79 × LGVD + 0.478 × PVD−6.73) for predicting OVB obtained excellent performance with an area under ROC curve of 0.907. The excellent performance was confirmed by Kappa test with K -value of 0.802 in validation cohort. Conclusion The novel logistic regression model can be reliable for predicting OVB. Key Points • Patients with oesophagogastric variceal bleeding are mainly characterized by decreased right lobe volume, and increased spleen volume and diameters of portal vein system. • The right liver lobe volume, left gastric vein diameter and portal vein diameter are the independent predictors of oesophagogastric variceal bleeding. • The novel model developed based on the independent predictors performed well in predicting oesophagogastric variceal bleeding with an area under the receiver operating characteristic curve of 0.907.

We prospectively investigated the changes of liver stiffness (LS) and the occurrence of hepatocellular carcinoma (HCC) after hepatitis C virus (HCV) eradication using direct antiviral agents (DAA) over three years. LS measurement using transient elastography and serum fibrosis surrogate markers before treatment and at 48, 96, 144 weeks after starting direct-acting antivirals (DAA) according to the protocol were evaluated. Patients were also compared with historical cohort treated with pegylated interferon (peg-IFN). Sustained viral response (SVR) was observed in 95.8%. LS value in the patients achieving SVR significantly decreased over time (19.4 ± 12.9 kPa [baseline], 13.9 ± 9.1 kPa [48 weeks], 11.7 ± 8.2 kPa [96 weeks], 10.09 ± 6.23 [144 weeks], all p  < 0.001). With matched analysis, the decrease in LS value was significantly larger in DAA group than peg-IFN group at both 48 weeks (29% vs. 9%) and 96 weeks (39% vs. 17%). The incidence of HCC was not significantly different between DAA and peg-IFN groups (5.5% vs. 5.4%) at 144 weeks. HCV eradication with DAA can lead to improvement of liver stiffness over time. The regression of fibrosis was greater in the group with DAA than peg-IFN. Clinical trials registration: ClinicalTrials.gov (NCT02865369).

Baveno-VI guidelines recommend that patients with compensated cirrhosis with liver stiffness by transient elastography (LSM-TE) <20 kPa and platelets >150,000/mm(3) do not need an esophagogastroduodenoscopy (EGD) to screen for varices, since the risk of having varices needing treatment (VNT) is <5%. It remains uncertain if this tool can be used in patients with cholestatic liver diseases (ChLDs): primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). These patients may have a pre-sinusoidal component of portal hypertension that could affect the performance of this rule. In this study we evaluated the performance of Baveno-VI, expanded Baveno-VI (LSM-TE <25 kPa and platelets >110,000/mm(3)), and other criteria in predicting the absence of VNT. This was a multicenter cross-sectional study in four referral hospitals. We retrospectively analyzed data from 227 patients with compensated advanced chronic liver disease (cACLD) due to PBC (n = 147) and PSC (n = 80) that had paired EGD and LSM-TE. We calculated false negative rate (FNR) and number of saved endoscopies for each prediction rule. Prevalence of VNT was 13%. Baveno-VI criteria had a 0% FNR in PBC and PSC, saving 39 and 30% of EGDs, respectively. In PBC the other LSM-TE-based criteria resulted in FNRs >5%. In PSC the expanded Baveno criteria had an adequate performance. In both conditions LSM-TE-independent criteria resulted in an acceptable FNR but saved less EGDs. Baveno-VI criteria can be applied in patients with cACLD due to ChLDs, which would result in saving 30-40% of EGDs. Expanded criteria in PBC would lead to FNRs >5%.

PurposeTo investigate the performance of spleen to non-cancerous liver volume ratio (STnLR) for diagnosing liver cirrhosis in patients with hepatocellular carcinoma (HCC) during preoperative evaluation.MethodsPatients were randomly divided into experiment group and validation group. Patients were grouped into cirrhosis group and non-cirrhosis group according to Scheuer staging. Patients’ routine image data were reconstructed using a three-dimensional system. STnLR, spleen to liver volume ratio (STLR), spleen volume, aspartate aminotransferase to platelet ratio index (APRI), and fibrosis index based on the four factors (FIB-4) were calculated. Correlations between indices and cirrhosis were measured by Spearman correlation analysis. Diagnostic performance was assessed and compared using receiver operating characteristic analysis. Accuracies of the models were analyzed in validation group.ResultsNo statistical difference in demographic and clinical characteristics was observed between groups. In experiment group, STnLR had the strongest correlation (r = 0.5399, P < 0.0001), and STLR, spleen volume, APRI, and FIB-4 had moderate correlations (r = 0.4583, 0.4123, 0.3648, and 0.3405, P < 0.0001, < 0.0001, < 0.0001, and = 0.0002) with liver cirrhosis stage. AUROC of STnLR (0.8326) was not statistically higher than that for spleen volume (0.7542, P = 0.09832) and STLR (0.8046, P = 0.3034), but was significantly higher than that for APRI (0.7099, P = 0.02046) and FIB-4 (0.7294, P = 0.03987). In validation group, STnLR showed the highest AUROC value (0.8538) and highest Youden index (0.5869) among all models.ConclusionSTnLR is an accurate and stable volumetric model to diagnose hepatic cirrhosis in the HCC population, which is superior to APRI and FIB-4.

IntroductionThe surveillance of hepatocellular carcinoma (HCC) using semi-annual liver ultrasound (US) is justified in patients with cirrhosis. In this context, US has a low sensitivity (<30%) for the detection of HCC at the very early stage (ie, Barcelona clinic liver cancer (BCLC) 0, uninodular tumour <2 cm). The sensitivity of abbreviated liver MRI (AMRI) is reported to exceed 80%, but its use is hampered by costs and availability. Our hypothesis is that AMRI used as a screening examination in patients at high risk of HCC (>3% per year) could increase the rates of patients with a tumour detected at an early stage accessible to curative-intent treatment, and demonstrate its cost-effectiveness in this population.Methods and analysisThe FASTRAK trial is a multicentre, randomised controlled trial with two parallel arms, aiming for superiority and conducted on patients at high risk for HCC (yearly HCC incidence >3%). Randomisation will be conducted on an individual basis with a centralised approach and stratification by centre. After inclusion in the trial, each patient will be randomly assigned to the experimental group (semi-annual US and AMRI) or the control group (semi-annual US alone). The main objective is to assess the cost/quality-adjusted life year and cost/patient detected with a BCLC 0 HCC in both arms. A total of 944 patients will be recruited in 37 tertiary French centres during a 36-month period and will be followed-up during 36 months.Ethics and disseminationThe FASTRAK trial received ethical approval on 4 April 2022. Results will be disseminated via publication in peer-reviewed journals as well as presentation at international conferences.Trial registration numberClinical trial number (ClinicaTrials.gov) NCT05095714.