Background & Aims: Therapeutic trials in metabolic dysfunction-associated steatohepatitis (MASH) are hampered by a high 70-80% screen failure rate mostly because of the absence of fibrotic MASH on baseline liver biopsies, underscoring the need for better selection of candidates. We compared the performance of eight non-invasive tests, designed or not for the diagnosis of fibrotic MASH. Methods: A total of 1,005 patients with histologically proven MASLD were included in five tertiary care centers. Three noninvasive tests developed for fibrotic MASH were evaluated: the simple blood test Fibrotic NASH Index (FNI), the specialized blood test MACK-3, and the elastography-based test FAST. Five non-invasive tests recommended for advanced fibrosis were evaluated as well: the simple blood test FIB-4, the specialized blood tests FibroTest and Enhanced Liver Fibrosis test (ELFTM), and the elastography-based tests FibroScan and Agile3+. Fibrotic MASH was defined as MASH with MASLD activity score >-4 and fibrosis score F >-2. Results: Among simple blood tests (n = 1,005), FNI had a significantly higher area under the receiver operating characteristic (AUROC) for fibrotic MASH than FIB-4 (0.709 [0.677-0.741] vs. 0.662 [0.628-0.695], p = 0.019). Among elastography-based tests (n = 817), FAST had a significantly higher AUROC (0.774 [0.743-0.806]) than FibroScan (0.728 [0.694-0.763], p = 0.013) and Agile3+ (0.708 [0.672-0.744], p = 0.004). Among specialized blood tests (n = 545), MACK-3 had a significantly higher AUROC (0.772 [0.734-0.811]) than FibroTest (0.615 [0.568-0.663], p <0.001) and ELF (0.700 [0.656-0.744], p = 0.028). Sequential combination (FAST then Agile3+; MACK-3 then ELF) identified a subset including one-third of patients in whom the false-positive rate was only 30%. Conclusions: Sequential combinations using first-line tests designed for fibrotic MASH improves the identification of candidates for MASH therapeutic trials. (c) 2025 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Purpose Hepatoscope® is an ultraportable ultrasound system with 50 Hz two-dimensional transient elastography (2DTE) for liver stiffness measurement (LSM). It provides a quality index (QI) for individual stiffness values that is based on imaging features. This study evaluated the 2DTE intra- and inter-user repeatability in patients with chronic liver diseases (CLD) for novice and expert operators across various QI conditions. We compared the performances with other imaging and non-imaging elastography techniques. Methods This investigation was a prospective cross-sectional single-center study. One hundred CLD patients underwent LSMs with vibration-controlled transient elastography (VCTE™), two-dimensional shear wave elastography (2DSWE) and 2DTE. Expert and novice operators each performed two consecutive exams with 2DTE, blinded to any output. Intra-class correlation coefficient for intra-, and inter-user repeatability were calculated as well as applicability for various QI conditions, and Spearman's correlations against VCTE and 2DSWE were assessed. Results Computing LSM as the median of 10 stiffness values with a QI>85 % yielded the best compromise between reliability and applicability. In this setting, expert and inter-operator repeatability showed significant improvement over the condition with no QI threshold (ICC = 0.81 and 0.79, respectively) and 95 % applicability. Novice repeatability was excellent with a more restrictive QI (ICC = 0.80). LSM with 2DTE demonstrated strong and moderate correlation with VCTE and 2DSWE (r = 0.63 and 0.55, respectively). Conclusion Hepatoscope 2DTE provides a promising and reliable alternative for non-invasive liver stiffness assessment in patients with CLD. The application of the image-based QI enhances LSM reliability and consistency across novice and expert operators.

Purpose: Hepatocellular carcinoma (HCC) is the most common form of liver cancer with a bad prognosis in case of advanced HCC, only eligible for palliative systemic therapies. After a decade of exclusive sorafenib monotherapy, with a response rate of <10%, the advent of immunotherapies represents a revolution in HCC. The combination of atezolizumab/bevacizumab is recommended as the first-line systemic treatment, with a response rate around 30%. However, there are currently no predictive factors for response to these treatment options. Experimental Design: We profiled, by high-resolution mass spectrometry-based proteomics combined with machine learning analysis, a selected cohort of fixed biopsies of advanced HCC. We grouped subjects according to their objective response to treatments, corresponded to a tumor regression vs tumor progression at 4 months after treatment. Results: We generated a proteome database of 50 selected HCC samples. We compared the relative protein abundance between tumoral and non-tumoral liver tissues from advanced HCC patients treated. The clear distinction of these two groups for each treatment is based on deregulation for 141 protein or 87 for atezolizumab/bevacizumab and sorafenib treatment, respectively. These specific proteomic signatures were sufficient to predict the response to treatment, and revealed biological pathways involved in treatments resistance. Particularly, we validated a shift in tumor cell metabolism with an immunosuppressive environment involved in the resistance to atezolizumab/bevacizumab combination. Conclusions: We performed an in-depth analysis of quantitative proteomic data from HCC biopsies to predict the treatment response to advanced HCC giving the ability to optimize patient management. ### Competing Interest Statement JFB: Bayer, ESAI, IPSEN, ROCHE, ASTRA-ZENECA, BMS MD: Roche, Servier

BACKGROUND & AIMS:Both liver stiffness measurement (LSM) and biochemical response have prognostic significance in patients with primary biliary cholangitis (PBC). However, the frequency and clinical relevance of discordant biochemical and LSM changes remain unclear. We aim to determine the performance of the most recent or current LSM (LSMc) in predicting first hepatic decompensation (HD) in the setting of discordant biochemical and LSM responses. METHODS:In this international, multicenter study, we included patients with at least two reliable LSM performed at least 6 months apart. Patients with prior HD, liver transplantation or hepatocellular carcinoma were excluded. Biochemical response was based on the Paris-II criteria. LSM response was defined as stable or any reduction in LSM. The primary outcome was the occurrence of the first HD. Secondary outcomes were liver transplantation and liver-related death. The influence of LSM on HD was estimated using Cox regression analysis. RESULTS:A total of 1,793 patients with PBC were analyzed. Over a median follow-up of 22 (IQR 12-39) months, 3.3% developed HD. Up to 55% of patients with PBC exhibited discordance between LSM and biochemical response. Among patients with LSM response, achieving Paris-II criteria was associated with a lower risk of HD (hazard ratio [HR] 0.25, 95% CI 0.06-0.97, p <0.044). Among patients with biochemical response, LSM response did not influence the risk of developing HD (HR 0.64, 95% CI 0.21-1.96, p = 0.429). The LSMc >10 kPa strongly predicted HD (HR 14.5, 95% CI 6.9-30.6, p <0.001), irrespective of biochemical response and prior LSM trajectories. CONCLUSIONS:Discordance between LSM and biochemical response is frequent. Most recent or current LSM is the strongest predictor of first liver-related events in patients with PBC, irrespective of prior biochemical response or LSM trajectory. IMPACT AND IMPLICATIONS:Both liver stiffness measurement (LSM) and biochemical response have prognostic significance in patients with primary biliary cholangitis. However, the clinical relevance and how discordant biochemical and LSM changes should be best interpreted remain unclear. In this large international multicenter study, we demonstrated that once the current LSM is known, prior LSM trajectories and biochemical changes did not improve the prediction of liver-related events in patients with primary biliary cholangitis. Our finding addresses a common clinical dilemma in risk-stratifying PBC patients with discordant biochemical and LSM responses. Importantly, the use of the latest LSM value for risk prediction significantly simplifies the use of LSM in clinical decision-making for PBC patients with multiple LSM readings.

ABSTRACT Metabolic dysfunction‐associated steatotic liver disease (MASLD) has become the most prevalent chronic liver disease globally. Previous studies have shown that MASLD is an independent risk factor for chronic kidney disease (CKD), but the variations in estimated glomerular filtration rate (eGFR) levels across countries with different ethnic backgrounds have not been extensively reported. We enrolled 3308 participants with biopsy‐proven MASLD from 34 centers in this multinational study and analyzed the associations between eGFR and histological severity of liver fibrosis in different countries. European participants had lower eGFR levels (92.2 ± 20.7 vs. 104.7 ± 17.3 mL/min/1.73 m2) and significant liver fibrosis (61.4 vs. 32.4%) than Asian individuals. In Asia, Chinese participants had the highest mean eGFR level at 105.8 mL/min/1.73 m2, while Malaysian participants had the lowest at 87.3 mL/min/1.73 m2 (p < 0.001). In Europe, French participants had the highest mean eGFR level at 95.3 mL/min/1.73 m2, while Romanian individuals had the lowest at 81.1 mL/min/1.73 m2 (p < 0.001). eGFR levels were inversely associated with liver fibrosis in Asian individuals (OR: 0.793, 95%CI: 0.685–0.917, p = 0.002), even after adjusting for traditional renal risk factors, but not in Europeans. Our findings provide the basis for further investigation of the burden of MASLD on CKD risk in different countries.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) and fibrotic MASH are significant health challenges. This multi-national study aimed to validate the acMASH index (including serum creatinine and aspartate aminotransferase concentrations) for MASH diagnosis and develop a new index (acFibroMASH) for non-invasively identifying fibrotic MASH and exploring its predictive value for liver-related events (LREs). METHODS: We analyzed data from 3004 individuals with biopsy-proven metabolic dysfunction-associated steatotic liver disease (MASLD) across 29 Chinese and 9 international cohorts to validate the acMASH index and develop the acFibroMASH index. Additionally, we utilized the independent external data from a multi-national cohort of 9034 patients with MASLD to examine associations between the acFibroMASH index and the risk of LREs. RESULTS: In the pooled global cohort, the acMASH index identified MASH with an area under the receiver operating characteristic curve (AUROC) of 0.802 (95% confidence interval [CI], 0.786-0.818). The acFibroMASH index (including the acMASH index plus liver stiffness measurement) accurately identified fibrotic MASH with an AUROC of 0.808 in the derivation cohort and 0.800 in the validation cohort. Notably, the AUROC for the acFibroMASH index was 0.835 (95% CI, 0.786-0.882), superior to that of the FAST score at 0.750 (95% CI, 0.693-0.800; P < .01) in predicting the 5-year risk of LREs. Patients with acFibroMASH >0.39 had a higher risk of LREs than those with acFibroMASH <0.15 (adjusted hazard ratio, 11.23; 95% CI, 3.98-31.66). CONCLUSIONS: This multi-ethnic study validates the acMASH index as a reliable, noninvasive test for identifying MASH. The newly proposed acFibroMASH index is a reliable test for identifying fibrotic MASH and predicting the risk of LREs.

BACKGROUND & AIMS: The existing hepatocellular carcinoma (HCC) risk scores have modest accuracy, and most are specific to chronic hepatitis B infection. In this study, we developed and validated a liver stiffness-based machine learning algorithm (ML) for prediction and risk stratification of HCC in various chronic liver diseases (CLDs). METHODS: MLs were trained for prediction of HCC in 5155 adult patients with various CLDs in Korea and further tested in 2 prospective cohorts from Hong Kong (HK) (N = 2732) and Europe (N = 2384). Model performance was assessed according to Harrell's C -index and time -dependent receiver operating characteristic (ROC) curve. RESULTS: We developed the SMART-HCC score, a liver stiffness-based ML HCC risk score, with liver stiffness measurement ranked as the most important among 9 clinical features. The Harrell's Cindex of the SMART-HCC score in HK and Europe validation cohorts were 0.89 (95% confidence interval, 0.85-0.92) and 0.91 (95% confidence interval, 0.87-0.95), respectively. The area under ROC curves of the SMART-HCC score for HCC in 5 years was double dagger 0.89 in both validation cohorts. The performance of SMART-HCC score was significantly better than existing HCC risk scores including aMAP score, Toronto HCC risk index, and 7 hepatitis B-related risk scores. Using dual cutoffs of 0.043 and 0.080, the annual HCC incidence was 0.09%-0.11% for low -risk group and 2.54%-4.64% for high -risk group in the HK and Europe validation cohorts. CONCLUSIONS: The SMART-HCC score is a useful machine learning-based tool for clinicians to stratify HCC risk in patients with CLDs.

Quantitative ultrasound (QUS) is a well-suited modality to address large-scale screening and monitoring of liver steatosis as it is low-cost, non-invasive, and point-of-care. However, technical and biological confounders lead to difficulties in establishing universal cutoff values for diagnosis. Hepatoscope® remedies this issue as it integrates a unique QUS measurement technique enabling the simultaneous measurements of the backscattering coefficient, the attenuation coefficient and the speed of sound. Such measurements are performed in a large two-dimensional region of interest (ROI) and in a free breathing regime such that a relatively large portion of the liver is sampled. We studied the influence of the size of the ROI, its depth and the number of measurements on the QUS parameters with Hepatoscope® both in vitro on four calibrated phantoms and clinically on 60 participants referred to a hepatology consultation for chronic liver disease. We demonstrated that using large ROIs consistently improves the system reliability and the clinical applicability. We did not observe any systematic effect related to the depth of the ROI. We also showed that averaging consecutive measurements leads to better system reliability and better clinical applicability.

BACKGROUND & AIMS:In primary biliary cholangitis (PBC), static liver stiffness measurement (LSM) has proven prognostic value. However, the added prognostic value of LSM time course in this disease remains uncertain. METHODS:We conducted an international retrospective cohort study among patients with PBC treated with ursodeoxycholic acid and followed by vibration-controlled transient elastography between 2003 and 2022. Using joint modeling, the association of LSM trajectory and the incidence of serious clinical events (SCE), defined as cirrhosis complications, liver transplantation, or death, was quantified using the hazard ratio and its confidence interval. RESULTS:A total of 6362 LSMs were performed in 3078 patients (2007 on ursodeoxycholic acid alone; 13% with cirrhosis), in whom 316 SCE occurred over 14,445 person-years (median follow-up, 4.2 years; incidence rate, 21.9 per 1000 person-years). LSM progressed in 59% of patients (mean, 0.39 kPa/year). After adjusting for prognostic factors at baseline, including LSM, any relative change in LSM was associated with a significant variation in SCE risk (P < .001). For example, the adjusted hazard ratios (95% confidence interval) associated with a 20% annual variation in LSM were 2.13 (1.89-2.45) for the increase and 0.40 (0.33-0.46) for the decrease. The association between LSM trajectory and SCE risk persisted regardless of treatment response or duration, when patients with cirrhosis were excluded, and when only death or liver transplantation was considered. CONCLUSIONS:Tracking longitudinal changes in LSM using vibration-controlled transient elastography provides valuable insights into PBC prognosis, offering a robust predictive measure for the risk of SCE. LSM could be used as a clinically relevant surrogate end point in PBC clinical trials.