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Nonalcoholic fatty liver disease (NAFLD) includes simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and eventually cirrhosis and hepatocellular carcinoma (HCC). The diagnosis of NAFLD is based on the detection of excess fat disposition in the liver, which is the first step to trigger further evaluation of NAFLD, including necroinflammation and fibrosis. In this review, we discuss non‐invasive biomarkers and imaging tools that are currently and potentially available for different features (steatosis, necroinflammation and fibrosis) and disease severity assessment of NAFLD. In the past 2 decades, advances in non‐invasive tests of fibrosis have transformed the management of NAFLD. Blood and imaging biomarkers have already been evaluated in multiple studies for the diagnosis of fibrosis and cirrhosis. Among the various histological features of NAFLD, the degree of fibrosis has the strongest correlation with liver‐related morbidity and mortality. Non‐invasive tests of fibrosis have been shown to predict liver‐related outcomes, both in the general population and among patients with NAFLD. What is lacking, however, is good data to support the use of non‐invasive tests as monitoring and response biomarkers. With the conclusion of several large phase 3 studies in the next few years, the availability of paired liver biopsy, non‐invasive test and clinical outcome data will likely advance the field and shed light on new biomarkers and the way to use various non‐invasive tests in a longitudinal manner.

Unlike for advanced liver fibrosis, the practical rules for the early non-invasive diagnosis of cirrhosis in NAFLD remain not well defined. Here, we report the derivation and validation of a stepwise diagnostic algorithm in 1568 patients with NAFLD and liver biopsy coming from four independent cohorts. The study algorithm, using first the elastography-based tests Agile3+ and Agile4 and then the specialized blood tests FibroMeter V3G and CirrhoMeter V3G , provides stratification in four groups, the last of which is enriched in cirrhosis (71% prevalence in the validation set). A risk prediction chart is also derived to allow estimation of the individual probability of cirrhosis. The predicted risk shows excellent calibration in the validation set, and mean difference with perfect prediction is only −2.9%. These tools improve the personalized non-invasive diagnosis of cirrhosis in NAFLD. The practical rules for the early non-invasive diagnosis of cirrhosis in NAFLD are not well defined. Here, the authors develop and validate two diagnostic tools: a stepwise stratification algorithm including a cirrhosis group, and a risk prediction chart providing a personalized assessment of the individual probability of cirrhosis.

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. A total of 3308 participants with biopsy‐proven MASLD from 34 centers were enrolled in the study. We collected liver biopsy pathological scores and clinical parameters and conducted correlation analysis. We finally found that eGFR levels are inversely associated with liver fibrosis in Asians, even after adjusting for traditional renal risk factors.

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 StatementJFB: Bayer, ESAI, IPSEN, ROCHE, ASTRA-ZENECA, BMS MD: Roche, Servier