BACKGROUND:Individuals with chronic hepatitis B (CHB) may harbor occult yet significant liver pathology despite normal alanine aminotransferase (ALT) levels, representing a major diagnostic challenge. We aimed to identify and validate noninvasive biomarkers for detecting significant liver pathology among this population. METHODS:This multicenter study screened 3258 CHB cases from 2013 to 2023, enrolling 137 treatment-naive hepatitis B e antigen (HBeAg)-positive (HBeAg+) and 253 HBeAg-negative patients with CHB with normal ALT levels (≤40 U/L). All participants underwent liver biopsy (reference standard) and measurement of liver function and novel biomarkers (including cytokeratin 18 [CK18]-M30, CK18-M65, Golgi protein (GP73), interleukin 10, and interleukin 2 receptor). Significant liver pathology was defined as inflammation grade and/or fibrosis stage ≥2. Sixteen CK18-M65-centered biomarker combinations were evaluated using 8 machine learning algorithms with multicenter stratified validation. RESULTS:Significant liver pathology was observed in 45.2% of patients with HBeAg+ infection. CK18-M65, CK18-M30, and GP73 were strongly correlated with the severity of pathology (correlation with inflammation grade, r = 0.757, r = 0.688, and r = 0.453, respectively; P < .001), independent of ALT levels. CK18-M65 demonstrated optimal diagnostic performance (area under the curve, 0.934 [95% confidence interval, .896-.973]) with 85.5% sensitivity and 88% specificity, especially in those with low-normal ALT. High CK18-M65 levels conferred >40-fold increased risk of severe liver injury (adjusted odds ratio, 40.64). The optimal biomarker combination (CK18-M65 + CK18-M30 + GP73) achieved an area under the receiver operating characteristic curve of 0.942, significantly outperforming liver stiffness measurement (0.824), aspartate aminotransferase-to-platelet ratio index (0.783), and Fibrosis-4 score (0.745) (all P < .01), with enhanced clinical utility. HBeAg-negative patients with CHB showed significant pathology in 46%, but exhibited weaker diagnostic performance. CONCLUSIONS:CK18-M65-centered biomarker models suggest promising noninvasive tools for detecting occult liver pathology and risk stratification of ALT-normal HBeAg+ CHB infection, potentially avoiding unnecessary biopsies while identifying candidates for early intervention, nonetheless requiring validation in larger cohorts.

Accurate, non-invasive liver fibrosis detection is essential for chronic liver disease management, particularly with rising metabolic dysfunction-associated liver disease (MASLD) and chronic hepatitis B (CHB). While the Fibrosis-4 (FIB-4) index is widely used, its performance for advanced fibrosis is limited. We develop Met-FIB using metabolomics and machine learning, integrating FIB-4 parameters (age, aspartate aminotransferase, alanine aminotransferase, and platelet count) with tyrosine and taurocholic acid identified in a CHB discovery cohort (n = 3,251). Validation includes one CHB cohort (n = 729) and two MASLD cohorts (n = 149, n = 155). Met-FIB outperforms FIB-4, FibroScan, and other serum markers across all fibrosis stages. In CHB, Met-FIB achieves 96.3% rule-out sensitivity and 85.4% rule-in specificity for significant fibrosis, with rule-in specificity reaching 98.6% and 98.8% for advanced fibrosis and cirrhosis. In MASLD, corresponding values are 93.9% and 90.2% for significant fibrosis, with >97.9% specificity for late-stage disease. Met-FIB demonstrates clinical utility for non-invasive fibrosis staging across diverse etiologies.

INTRODUCTION:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disease, and liver biopsy remains the gold standard for diagnosis. However, a subset of patients diagnosed with MASLD by imaging paradoxically exhibit steatosis grade S0 on liver biopsy, posing a diagnostic challenge. This study investigated the outcomes and causes of steatosis 0. METHODS:Steatosis 0 was defined as imaging-detected MASLD with a biopsy-defined steatosis grade S0. We used global cohorts to evaluate outcomes, histologic progression by paired biopsies, and possible causes. The cause analysis included MRI-proton density fat fraction (MRI-PDFF) for fat distribution, pathologist consistency testing, and comparison of serial biopsy sections. RESULTS:In a follow-up cohort of 3,273 biopsy individuals from 16 centers, 123 (3.8%) exhibited steatosis 0. Of these, 29.3% of them had advanced fibrosis (burnt-out MASLD) and demonstrated a risk of liver-related events, whereas those without advanced fibrosis had no such events. In the paired-biopsy cohort of 1,865 patients, 74 (4.0%) individuals initially showed steatosis grade S0; among them, 93.2% retained no or mild steatosis on follow-up biopsy. MRI-PDFF assessments in 42 MASLD patients revealed heterogeneous hepatic fat distribution, with some segments showing steatosis grade S0 despite elevated average liver fat. Interpathologist variability and discrepancies across consecutive biopsy sections contributed to misclassification of steatosis grade. DISCUSSION:Steatosis 0 represents a potential diagnostic gray zone in MASLD. It may be caused by burnt-out MASLD, uneven liver fat distribution, or variability in pathological assessment. Understanding the causes and implications of steatosis 0 is critical for diagnosis and management.

The conventional biomarker discovery approach in metabolomics treats metabolites as isolated features, failing to capture their interdependencies. We applied a network-based method using Tabular Prior-Data Fitted Networks (TabPFN) integrated with SHapley Additive exPlanations (SHAP) to derive stage-specific metabolic networks capturing statistical metabolite co-contribution patterns and identify key metabolites. We analyzed 1312 participants across five stages (control, hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC)), quantitatively profiling 160 metabolites, and externally validated the results in 721 samples. We compared three approaches: (1) TabPFN-SHAP, (2) conventional statistics with machine learning, and (3) TabPFN-SHAP integrated with literature-validated biomarkers. TabPFN-SHAP–based approaches outperformed the conventional pipeline, revealing distinct stage-specific metabolic signatures with overlapping metabolites between consecutive networks, marking consistently prioritized features. A five-metabolite HCC-screening panel (sebacic acid, alpha-linolenic acid, phenylalanyl-tryptophan, arachidonic acid, and glycocholic acid) was identified. At the screening-oriented cutoff, the panel achieved an AUROC of 0.979 (95% CI: 0.966–0.991) for Control vs HCC and 0.955 (95% CI: 0.936–0.977) for Fibrosis/Cirrhosis vs HCC, with sensitivity of 0.937, specificity ≥0.855, accuracy ≥0.897, and negative predictive value ≥ 0.981 across both clinical scenarios, outperforming all comparative approaches. TabPFN-SHAP provides an interpretable computational framework for metabolite-panel discovery, with demonstrated utility for HCC screening.

Background Metabolic dysfunction-associated steatotic liver disease (MASLD) often coexists with chronic hepatitis B (CHB), yet early diagnosis remains challenging, particularly in non-obese patients or those with subclinical features. This study aimed to identify metabolic signatures of CHB-related MASLD and construct a predictive model using untargeted metabolomics integrated with machine learning. Methods Serum metabolomics was performed on 160 subjects (80 CHB + MASLD and 80 healthy controls). Differential metabolites were identified and analyzed using KEGG enrichment and 4 machine learning algorithms (Random Forest, XGBoost, SVM, and LASSO). Metabolite-clinical correlations and diagnostic model performance were evaluated. Results A total of 924 differential metabolites were identified, with significant enrichment in pathways related to the TCA cycle, sphingolipid metabolism, and amino acid turnover. Machine learning prioritized six robust and biologically relevant metabolites: L-aspartic acid, succinic acid, caproic acid, sebacic acid, monomenthyl succinate, and glycolaldehyde, which consistently distinguished CHB + MASLD patients from controls (AUC > 0.75). These metabolites reflect key disruptions in mitochondrial function, lipid oxidation, and redox homeostasis. Integrated models combining metabolomics with clinical indices achieved perfect classification (AUC = 1.000). Conclusion CHB-associated MASLD is driven by systemic metabolic remodeling centered on mitochondrial overload, oxidative stress, and impaired amino acid metabolism. The identified metabolites provide mechanistic insights and hold promise for non-invasive MASLD screening in CHB patients. This study underscores the potential of multi-algorithmic metabolomics in advancing early diagnosis and personalized management of complex liver comorbidities.

BACKGROUND & AIMS:Fibrosis-4 Index (FIB-4) is a noninvasive tool for assessing liver fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD). However, its role of dynamic FIB-4 for assessing fibrosis progression and predicting clinical outcomes remains unclear. The aim of this study was to examine the association between changes in FIB-4 and changes in liver stiffness, fibrosis progression, and outcomes in MASLD. METHODS:Three cohorts were analyzed: VCTE-Prognosis cohort (n = 10,203) for stiffness progression, Paired Liver Biopsy cohort (n = 1,145) for fibrosis progression, and Wenzhou Real-World (WRW) cohort (n = 41,105) for clinical outcomes. Stiffness progression was defined as an increase in liver stiffness measurement, and fibrosis progression by a 1-stage increase. Outcomes included all-cause mortality, cardiovascular events, and liver-related events (LREs). FIB-4 was dichotomized into low (<1.3) and high (≥1.3). Increases were defined as ≥20% rise and to ≥1.3 in the low FIB-4 group, and ≥20% rise in the high FIB-4 group. RESULTS:In the VCTE-Prognosis cohort, stiffness progression was more likely with increasing vs stable FIB-4 (adjusted odds ratio [OR], 2.36; P < .001) in those with low baseline FIB-4. In the high FIB-4 group, stiffness progression rates increased from stable to increasing FIB-4 (adjusted OR, 3.42; P < .001). In the Paired Liver Biopsy cohort, fibrosis progression was more frequent with increasing FIB-4 (adjusted OR, 2.20; P = .004 in low FIB-4; adjusted OR, 3.68; P < .001 in high FIB-4). In the WRW cohort, an increase in dynamic FIB-4 was linked to higher risks for all-cause mortality, cardiovascular events, and LREs (all P < .001). CONCLUSIONS:Dynamic FIB-4 monitoring tracks fibrosis and stiffness progression and predicts clinical outcomes in MASLD.

BACKGROUND:Non-invasive assessment of improvement in fibrotic metabolic dysfunction-associated steatohepatitis (MASH) is an important clinical problem. We aimed to develop and validate the fibrotic MASH resolutionVCTE index, a non-invasive tool for identifying fibrotic MASH resolution and predicting liver-related events (LREs). METHODS:We collected data from 2,017 individuals who had two liver biopsies, separated in time, across 40 centers in the first dataset. This dataset included two independent cohorts, which were used to develop and externally validate the tool (including the baseline and change in acFibroMASH index plus change in serum alanine aminotransferase levels). The second independent dataset, comprising 17,949 patients who underwent vibration-controlled transient elastography (VCTE) at 16 centers, was used to examine associations between the developed index and the risk of incident LREs. FINDINGS:After application of the inclusion and exclusion criteria, 252 and 8,752 patients were included in the first and second datasets, respectively. The fibrotic MASH resolutionVCTE index accurately identified fibrotic MASH resolution with an area under the receiver operating curve (AUROC) of 0.82 (95% CI 0.74-0.90) in the derivation cohort and 0.80 (95% CI 0.72-0.88) in the validation cohort. Patients with a fibrotic MASH resolutionVCTE index >0.61 had a substantially lower risk of incident LREs than those with an index <0.24 (adjusted-hazard ratio 0.043). The index achieved AUROCs of 0.86 and 0.87, respectively, for predicting the 5- and 10-year probability of not developing LREs. CONCLUSIONS:This global multicenter study suggests that the fibrotic MASH resolutionVCTE index may offer a non-invasive approach to estimate fibrotic MASH resolution and stratify long-term risk of LREs. FUNDING:National Natural Science Foundation.

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.

Early identification of significant liver pathology is crucial for timely antiviral intervention in individuals with chronic hepatitis B (CHB) infection. Current non-invasive methods show limited accuracy in detecting occult liver damage, particularly in those with normal ALT. This study evaluated serum N-glycan profiles for diagnosing significant liver pathology in treatment-naïve CHB patients across clinical phases. This cross-sectional study analyzed 626 treatment-naïve CHB patients confirmed by liver biopsy, classified according to 2025 EASL guidelines. Serum N-glycan profiles were determined using DNA sequencer-assisted fluorophore-assisted carbohydrate electrophoresis. Significant liver pathology was defined as inflammation grade ≥ G2 and/or fibrosis stage ≥ S2 (per Scheuer scoring system). Multivariate logistic regression models were developed and compared with traditional non-invasive markers. Among 626 CHB patients, 66.0

The efficacy and safety of a lower dose of vitamin E for metabolic dysfunction-associated steatohepatitis (MASH) treatment are unclear. This multi-center, randomized, double-blind, placebo-controlled study includes 124 non-diabetic participants with biopsy-proven MASH. Participants are randomly assigned to receive oral vitamin E 300 mg or the placebo in a 1:1 ratio. The primary outcome is improvement in hepatic histology. In the modified intention-to-treat population, 29.3% of participants in the vitamin E group achieve the primary outcome compared with 14.1% in the placebo group. Significant improvement in steatosis, lobular inflammation, and fibrosis stages is observed in the vitamin E group. 12 serious adverse events are reported in this trial but are not considered to be related to the treatment. Vitamin E 300 mg daily achieves sound improvements in liver histology in the Chinese population with MASH. This study is registered at ClinicalTrials.gov (NCT02962297).

BACKGROUND:Inhibition of liver fibrosis plays a crucial role in curbing the advancement of chronic disease to cirrhosis and even liver cancer. However, modern medicine currently lacks direct anti-fibrotic drugs. He-He-Shu-Yang formula (HHSY) is a renowned Chinese medicine for the treatment of liver fibrosis. However, its mechanism of action has not been fully unraveled. AIM:To explore the efficacy and mechanism of action of HHSY through in vitro and in vivo experiments. METHODS:A liver fibrosis rat model (carbon tetrachloride-induced) was treated with low- or high-dose HHSY (10.42 g/kg or 20.84 g/kg) or with colchicine (1 mg/kg) for 9 weeks. In vitro, LX-2 human hepatic stellate cells (HSCs) were activated using transforming growth factor-β1 and subsequently treated with HHSY-containing serum or a nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) inhibitor. Through high-performance liquid chromatography, histopathology (hematoxylin and eosin, Masson), immunohistochemistry, western blot, and quantitative reverse transcription polymerase chain reaction analyses, we demonstrated that HHSY inhibited HSC activation and suppressed the NOX4/reactive oxygen species (ROS)/nucleotide binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) pathway. RESULTS:In vivo, HHSY improved liver function and alleviated liver pathology, including reducing inflammatory cell infiltration, and liver fibrosis in carbon tetrachloride rats. with more significant effects at higher doses. Immunohistochemistry revealed that HHSY could decrease alpha-smooth muscle actin, NOX4, and NLRP3 expression, as well as serum ROS levels (O2 - and H2O2, P < 0.05). Western blot analysis confirmed HHSY also reduced NLRP3 protein levels (P < 0.05). In vitro, HHSY at 1.25% or 2.5% reduced the levels of ACTA2 mRNA, NOX4 protein and NOX4 mRNA, ROS production, and NLRP3 and IL-1β mRNA in activated LX-2 cells (P < 0.05). CONCLUSION:HHSY effectively treats liver fibrosis, likely by inhibiting HSC activation through the NOX4/ROS/NLRP3 pathway. This underscores HHSY's clinical relevance as a potential therapeutic option for liver fibrosis.

BACKGROUND & AIMS:Hypertension is common in metabolic dysfunction-associated steatotic liver disease (MASLD), but its impact on long-term clinical outcomes and disease progression remains unclear. This study investigated the association of hypertension with the risk of adverse clinical outcomes and progression of liver stiffness/fibrosis in MASLD. METHODS:Three multicenter large cohorts were analyzed: the UK Biobank (UKBB) cohort to assess the risk of adverse clinical outcomes, the VCTE-Prognosis cohort to assess liver stiffness/fibrosis progression, and the Paired Liver Biopsy cohort to assess histologic liver fibrosis progression. Adverse clinical outcomes were defined as all-cause mortality, cardiovascular events, and/or liver-related events. Liver stiffness progression was defined as an increase in liver stiffness measurement from <10 kPa to ≥10 kPa or an increase of ≥20% for baseline liver stiffness measurement ≥10 kPa. Liver fibrosis progression was defined as a 1-stage fibrosis stage increase. Cox regression and Kaplan-Meier analyses were used to evaluate the impact of baseline hypertension on outcomes. RESULTS:A total of 107,316 adults from the UKBB cohort, 8,169 from the VCTE-Prognosis cohort, and 1,670 from the Paired Liver Biopsy cohort were included. The prevalence of hypertension was 37.1%, 33.4%, and 48.9%, respectively. In the UKBB cohort, hypertension was associated with long-term adverse clinical outcomes (adjusted hazard ratio [HR] 1.30, 95% CI 1.26-1.33, p <0.001). In the VCTE-Prognosis cohort, hypertension was associated with a higher risk of liver stiffness progression (adjusted HR 1.57, 95% CI 1.30-1.90, p <0.001), while in the Paired Liver Biopsy cohort, hypertension was associated with a greater risk of histologic liver fibrosis progression (adjusted HR 1.41, 95% CI 1.12-1.78, p = 0.004). Subgroup and sensitivity analyses supported these findings. CONCLUSIONS:Hypertension is a modifiable risk factor that increases the risk of adverse clinical outcomes and progression of liver stiffness and fibrosis in MASLD. IMPACT AND IMPLICATIONS:This study provides robust evidence from three large multicenter cohorts demonstrating that hypertension is independently associated with increased risks of adverse clinical outcomes and liver fibrosis progression in individuals with MASLD. These findings reveal that hypertension, traditionally managed from a cardiovascular perspective, also plays a critical and underrecognized role in liver disease progression, making them highly relevant for hepatologists, cardiologists, and primary care providers. Incorporating non-invasive fibrosis assessments into routine care for patients with MASLD and hypertension may facilitate early risk stratification and support targeted interventions to reduce both hepatic and cardiovascular complications.

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: The aim of this study was to evaluate the accuracy of LiveBoost™, a gradient boosting (GB)-based prediction system based on standard biochemical values (AST, ALT, platelet count) and age, in Chinese patients with chronic hepatitis B (CHB) and compare its performance with FIB-4 (fibrosis-4 score) and APRI (the aspartate transaminase to platelet ratio index). Methods: This retrospective trial enrolled 454 participants, including 279 CHB patients who underwent liver biopsy and 175 normal controls from 3 centers in China. All participants underwent laboratory blood testing. LiveBoost was constructed using GB and FIB-4 and APRI were calculated from laboratory data. Results: LiveBoost outperformed APRI and FIB-4 in predicting hepatic fibrosis and cirrhosis. The GB model had an AUROC of 0.977 for CHB diagnosis, 0.804 for early and advanced fibrosis, and 0.836 for non-cirrhosis and cirrhosis, compared to AUROC of 0.554, 0.673 and 0.720 for FIB-4, AUROC of 0.977, 0.652 and 0.654 for APRI. Conclusions: LiveBoost is a more reliable and cost-effective method than APRI and FIB-4 for assessing liver fibrosis in Chinese patients with CHB.

Background: The combined effect of hepatitis B virus infection and metabolic dysfunction-associated steatotic liver disease (MASLD) on hepatocellular carcinoma (HCC) risk remains unclear. The current study sought to elucidate the impact of MASLD on HCC progression in chronic hepatitis B (CHB) patients.Method: This retrospective cohort study included CHB patients who had undergone liver biopsy and abdominal imaging at the Guangdong Provincial Hospital of Chinese Medicine between 2013 and 2019. We investigated the correlation between MASLD and HCC risk, and inverse probability treatment weighting (IPTW) was used to adjust for patient characteristics.Results: A total of 1,613 patients were included, and 483 (29.9%) were diagnosed with MASLD. Over a median follow-up period of 5.02 years, 36 (2.2%) developed HCC, comprising 4.8% (23/483) of those with MASLD and 1.2% (13/1,130) of those without. Those with MASLD had a significantly higher cumulative incidence of HCC than those without (p < 0.001). The presence of MASLD was associated with a higher risk of HCC (adjusted hazard ratio [HR], 3.996; 95% confidence interval [CI], 2.007–7.959; p < 0.001). After adjustment using IPTW, the patients with MASLD retained a higher cumulative incidence of HCC (p < 0.001). Moreover, MASLD was found to be an independent risk factor for the development of HCC (adjusted HR, 10.191; 95% CI, 4.327–24.002; p < 0.001). However, among patients with MASLD, there were no significant differences in the cumulative risk of HCC between patients with and without overweight, between those with <2 and ≥2 cardiometabolic risk factors (CMRFs), between those with <3 and ≥3 CMRFs, or between those with <4 and ≥4 CMRFs (p = 0.110, p = 0.087, p = 0.066, and p = 0.490, respectively).Conclusion: The presence of MASLD is associated with a higher risk of HCC in patients with CHB. Notably, this higher risk is present in patients with MASLD, irrespective of the presence or absence of overweight or the number of CMRFs they have.

Background:Obesity often coincides with non-alcoholic fatty liver disease (NAFLD), yet a significant portion of NAFLD patients exhibit normal body mass index (BMI) but have abdominal obesity. Recognizing this discrepancy, we aimed to delve deeper into this phenomenon through observational studies coupled with two-sample Mendelian randomization (MR) analysis, with waist-to-hip ratio (WHR) serving as the indicator for abdominal obesity. Our objective was to ascertain whether WHR correlates with an increased risk of NAFLD development. Methods:This study utilized data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 to examine the association between WHR and NAFLD through weighted multivariate logistic regression models. On this basis, subgroup analyses were performed to further explore the correlation between WHR and NAFLD. Subsequently, a two-sample MR analysis was conducted using genome-wide association studies (GWAS) data to investigate the potential causal relationship between WHR and NAFLD. Sensitivity analyses were also employed to ensure the robustness of our findings. Results:A total of 3,732 eligible participants were included in the analysis. Weighted multivariable-adjusted logistic regression models revealed a positive association between WHR and the risk of NAFLD (Q2vsQ1: OR = 1.94 [95% CI: 1.55-2.44]; Q3vsQ1: OR = 2.08 [95% CI: 1.51-2.85]; Q4vsQ1: OR = 3.70 [95% CI: 2.13-6.43], p < 0.05). The results of the subgroup analysis suggested that there was an interaction in the correlation between WHR and NAFLD in normal weight, overweight, and obese populations (p < 0.05). The RCS curves indicated that there was a nonlinear relationship between WHR and NAFLD in populations with BMI in the normal versus obese categories. Furthermore, MR analysis provided additional support for the causal relationship between WHR and NAFLD. Using inverse variance weighting (IVW), the MR analysis yielded an OR of 2.062 (95% CI: 1.680-2.531, p<0.05). Consistent results were obtained with the other four MR methods, all supporting the same direction of causality. Sensitivity analyses were performed to assess the robustness of the findings (p > 0.5), further reinforcing the reliability of the observed associations. Conclusion:WHR elevation heightens the susceptibility to NAFLD.

Number connection test A (NCT-A) and digit symbol test (DST), the preferential neuropsychological tests to detect minimal hepatic encephalopathy (MHE) in China, haven’t been standardized in Chinese population. We aimed to establish the norms based on a multi-center cross-sectional study and to detect MHE in cirrhotic patients. NCT-A and DST were administered to 648 healthy controls and 1665 cirrhotic patients. The regression-based procedure was applied to develop demographically adjusted norms for NCT-A and DST based on healthy controls. Age, gender, education, and age by education interaction were all predictors of DST, while age, gender, and education by gender interaction were predictors of log10 NCT-A. The predictive equations for expected scores of NCT-A and DST were established, and Z-scores were calculated. The norm for NCT-A was set as Z ≤ 1.64, while the norm for DST was set as Z ≥ − 1.64. Cirrhotic patients with concurrent abnormal NCT-A and DST results were diagnosed with MHE. The prevalence of MHE was 8.89% in cirrhotic patients, and only worse Child–Pugh classification (P = 0.002, OR = 2.389) was demonstrated to be the risk factor for MHE. The regression-based normative data of NCT-A and DST have been developed to detect MHE in China. A significant proportion of Chinese cirrhotic patients suffered from MHE, especially those with worse Child–Pugh classification.