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Background: The association between nonalcoholic fatty liver disease and cardiovascular disease is firmly established, yet the association between noninvasive liver fibrosis scores and cardiovascular events remains a topic of uncertainty. Our study aimed to explore the association between liver fibrosis and heart failure., Methods and Results: The data set was from the National Health and Nutrition Examination Survey 2011 to 2018. Advanced hepatic fibrosis risk was assessed through 3 noninvasive liver fibrosis scores: Fibrosis-4 score (FIB-4), the nonalcoholic fatty liver disease fibrosis score (NFS), and the aspartate aminotransferase to platelet ratio index (APRI). We included 19 695 eligible participants. The national prevalence of advanced liver fibrosis risk in the United States was 4.20%, 8.06%, and 0.35% as determined by FIB-4, NFS, and APRI scores, respectively. Weighted logistic regression analysis revealed significant associations between advanced liver fibrosis risk and the prevalence of heart failure (continuous variables, FIB-4: odds ratio [OR], 1.15 [95% CI, 1.07-1.23]; NFS: OR, 1.42 [95% CI, 1.23-1.64]; APRI: OR, 1.44 [95% CI, 1.15-1.81]). When the scores were assessed as categorical variables, the results were still significant (FIB-4 ≥2.67 versus FIB-4 <1.3: OR, 2.18 [95% CI, 1.47-3.24]; NFS ≥0.675 versus NFS <-1.455: OR, 2.53 [95% CI, 1.37-4.68]). Subgroup analysis found that the association between APRI and heart failure was stronger in female patients., Conclusions: In the general US population, the prevalence of advanced liver fibrosis risk varied between 0.35% and 8.06% as indicated by noninvasive liver fibrosis scores. FIB-4, NFS, and APRI scores were linked to an elevated prevalence of heart failure.

Mitochondrial dysfunction with oxidative stress contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) progression. We aimed to evaluate the fibrosis predictive efficacy of a novel non-invasive diagnostic panel using metabolic stress biomarkers. From a population-based general cohort, 144 subjects with MASLD were recruited in the development group and underwent magnetic resonance imaging-based liver examinations, anthropometric and laboratory tests. As an external validation group, 41 patients enrolled in a biopsy-evaluated MASLD cohort participated in this study. Liver fat content and stiffness were measured by magnetic resonance (MR) imaging-proton density fat fraction and MR elastography (MRE), respectively. Serologic stress biomarkers were quantitated by ELISA. Multivariate regression showed that waist-to-height ratio, growth differentiation factor-15 (GDF15), γ-glutamyltransferase, decorin, and alkaline-phosphatase were independent predictors of hepatic fibrosis (rank-ordered by Wald). The area under receiver-operator characteristics curve [AUROC (95% CI)) of the metabolic stress index for fibrosis (MSI-F) was 0.912 (0.85‒0.98) and 0.977 (0.92‒1.00) in development and validation groups, respectively. MSI-F also had better diagnostic accuracy (82.6‒92.4%) than other fibrosis indices in the both study cohorts. MSI-F consistently differentiated fibrosis severities across cohorts of MRE-evaluated general population and biopsy-proven patients with MASLD, while other indices showed no or less discrimination. MSI-F, as a novel non-invasive index based on a stress-stimulated protective hormone GDF15 and decorin, effectively predicted hepatic fibrosis. Furthermore, MSI-F may serve as pre-screening tool to increase the population that could be excluded from further evaluation, reducing unnecessary invasive investigations more effectively than other indices., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics statement All aspects of this study, including research methods were conducted in strict accordance with relevant guidelines and regulations. This study was conducted in compliance with the ethical principles outlined in the Declaration of Helsinki. All data were de-identified, and all study protocols and procedures were reviewed and approved by the Institutional Review Board of Wonju Severance Christian Hospital (approval No. CR317131). Informed consent Written informed consent was obtained from all participants, who have consented to the publication of any data included in the study., (© 2024. The Author(s).)

Background: Hepatocellular carcinoma (HCC) is plagued by failures across the cancer care continuum, leading to frequent late-stage diagnoses and high mortality. We evaluated the effectiveness of mailed outreach invitations plus patient navigation to promote HCC screening process completion in patients with cirrhosis., Methods: Between April 2018 and September 2021, we conducted a multicentre pragmatic randomised clinical trial comparing mailed outreach plus patient navigation for HCC screening (n=1436) versus usual care with visit-based screening (n=1436) among patients with cirrhosis at three US health systems. Our primary outcome was screening process completion over a 36-month period, and our secondary outcome was the proportion of time covered (PTC) by screening. All patients were included in intention-to-screen analyses., Results: All 2872 participants (median age 61.3 years; 32.3% women) were included in intention-to-screen analyses. Screening process completion was observed in 6.6% (95% CI: 5.3% to 7.9%) of patients randomised to outreach and 3.3% (95% CI: 2.4% to 4.3%) of those randomised to usual care (OR 2.05, 95% CI: 1.44 to 2.92). The intervention increased HCC screening process completion across most subgroups including age, sex, race and ethnicity, Child-Turcotte-Pugh class and health system. PTC was also significantly higher in the outreach arm than usual care (mean 37.5% vs 28.2%; RR 1.33, 95% CI: 1.31 to 1.35). Despite screening underuse, most HCC in both arms were detected at an early stage., Conclusion: Mailed outreach plus navigation significantly increased HCC screening process completion versus usual care in patients with cirrhosis, with a consistent effect across most examined subgroups. However, screening completion remained suboptimal in both arms, underscoring a need for more intensive interventions., Trial Registration Number: NCT02582918., Competing Interests: Competing interests: AGS has served as a consultant or on advisory boards for Bayer, FujiFilm Medical Sciences, Exact Sciences, Universal Dx, Glycotest, Roche, Freenome, DELFI, GRAIL, Genentech, AstraZeneca, Eisai, Exelixis, Merck, Boston Scientific, Sirtex and HistoSonics. CM has served as a consultant for Freenome. None of the other authors have any relevant conflicts of interest to disclose., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Hepatocellular carcinoma (HCC) is typically detected only at advanced stages when treatment options are limited. Most of the current HCC risk models focus on patients with viral hepatitis or diagnosed cirrhosis or require variables not routinely available in clinical care., Objective: To identify modifiable HCC risk factors in the general population and to develop a risk score to inform HCC screening and risk-factor modification interventions for high-risk individuals without viral hepatitis or decompensated cirrhosis., Design, Setting, and Participants: This cohort study analyzed demographic, clinical, laboratory, and diagnostic data from the US Department of Veterans Affairs (VA) electronic health records. Data were divided into development and validation samples. Veterans aged 30 to 95 years were included, and those with hepatitis B or C virus infection, hepatic decompensation, or prevalent HCC were excluded. Patients were followed up until the occurrence of HCC diagnosis, death, or December 31, 2021. A Cox proportional hazards regression model for 10-year risk of HCC was developed and used to create an HCC risk score, and performance in development and validation samples and in patient subgroups was evaluated. One outpatient visit date per person at least 18 months after VA entry, between October 1, 2007, and March 31, 2020, was randomly selected and used as the index date for the start of follow-up. Analyses were performed from March 2023 to May 2024., Exposures: Age, sex, race and ethnicity, body mass index, liver fibrosis (detected with Fibrosis-4 Index [FIB-4]), diabetes status, smoking status, and alcohol use., Main Outcomes and Measures: First HCC diagnosis during follow-up. This information was ascertained from VA national cancer registry topography and histology codes and from International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes for the inpatient or outpatient visits., Results: This study of 6 509 288 veterans included 6 048 917 males (92.9%), with a median (IQR) age of 65 (54-74) years, who identified as being of Hispanic (5.3%), non-Hispanic Black (15.0%), non-Hispanic White (68.9%), or other (4.6%) race and ethnicity. Overall, 15 142 patients (0.2%) developed HCC, 69.5% of whom had FIB-4 of 3.25 or lower at baseline. While FIB-4 was the most important variable, age, sex, race and ethnicity, body mass index, diabetes, smoking, and alcohol use were also informative. Discrimination in the development sample was better than FIB-4 alone (C statistic, 0.83 [95% CI, 0.82-0.85] vs 0.79 [95% CI, 0.77-0.80]). The HCC risk score performed consistently well in the validation sample and in all subgroups. A FIB-4 threshold of 3.25 would screen 5.0% of the cohort at a cost of 28 false-positives for every true-positive; a model risk score of 58 would screen 4.7% of the cohort at a cost of 23 false-positives for every true-positive., Conclusions and Relevance: Results of this study suggest that a multivariable risk score that uses routinely available clinical data outperforms FIB-4 alone in identifying patients at risk of HCC who do not have viral hepatitis or hepatic decompensation at baseline.

Background: Professional guidelines recommend HCC screening in at-risk patients using semi-annual ultrasound with or without alpha-fetoprotein (AFP); however, this strategy has limited effectiveness due to low adherence and sensitivity. Increasing data support the potential role of blood-based biomarker panels, which could improve both aspects. The biomarker panel GALAD, comprised of sex, age, and 3 blood biomarkers (AFP, AFP-L3, and des-carboxy prothrombin des-carboxy prothrombin), has shown high sensitivity and specificity in biomarker phase II (case-control) and phase III (retrospective cohort) validation studies. However, prospective validation in a large phase IV biomarker clinical utility trial is necessary before its adoption in practice., Methods: The National Liver Cancer Screening Trial is an adaptive pragmatic randomized phase IV trial, which began enrollment in January 2024, comparing ultrasound-based versus biomarker-based screening in 5500 patients with chronic hepatitis B infection or cirrhosis from any etiology. Eligible patients are randomly assigned in a 1:1 ratio to semi-annual screening with ultrasound ± alpha-fetoprotein (arm A) or semi-annual screening with GALAD (arm B). Randomization is stratified by enrollment site, liver disease severity (per Child-Pugh class), liver disease etiology (viral, nonviral, and noncirrhotic HBV), and sex. Patients are being recruited from 15 sites (a mix of tertiary care academic referral centers, safety-net health systems, and large community health systems) over a 3-year period, and the primary endpoint, reduction in late-stage HCC, will be assessed at the end of year 5.5., Discussion: The results of this trial will inform the best strategy for HCC screening and early-stage detection in patients with chronic liver diseases. If GALAD shows superiority, HCC screening would primarily shift from an ultrasound-based strategy to the adoption of the biomarker panel., Trial Registration: NCT06084234., Trial Status: The TRACER Study is actively enrolling., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Insights into the mechanisms driving metabolic dysfunction-associated steatotic liver disease (MASLD) in people living with HIV (PLHIV) remain limited. Plasma proteomics holds promise for biomarker discovery and the elucidation of biological mechanisms., Methods: We performed cross-sectional analyses on data from 1036 virally suppressed PLHIV using antiretroviral treatment (ART) from the Dutch multi-centre 2000HIV cohort. Participants underwent transient elastography to assess liver steatosis (controlled attenuation parameter (CAP) ≥263 dB/m) and -fibrosis (liver stiffness measurement (LSM) ≥7.0 kPa). Plasma protein concentrations (n = 2367) (Olink® Explore Panel) were compared between PLHIV with vs. without liver steatosis and PLHIV with vs. without fibrosis. Enriched pathways (using GO, KEGG and Reactome libraries) and correlations with clinical characteristics were assessed, and analyses were stratified by BMI category. In addition, concentrations of 242 proteins were compared between individuals ("controls") with and without liver steatosis (ratio of methylene:methylene and water >5.6% on magnetic resonance spectroscopy) from a separate cohort (300-OB), all having a BMI >26 kg/m 2 ., Findings: Steatosis and fibrosis were associated with 67/2367 (2.2%) and 17/2367 (0.7%) differentially expressed proteins (DEP), respectively, enriched in mostly metabolic pathways. Immunoglobulin superfamily member 9 (IGSF9) was amongst the top DEP associated with both steatosis and fibrosis. Stratifying by BMI revealed 8/2367 DEP associated with steatosis in lean- and 12/2367 DEP in overweight/obese individuals, with two shared DEP (IGSF9 and GHR). Conversely, protein signatures of overweight/obese PLHIV (32/242 DEP) and overweight/obese HIV-uninfected individuals (32/242 DEP) exhibited substantial overlap with 16 shared DEP. Notably, DEP correlated with HIV characteristics in lean individuals but not in overweight/obese PLHIV., Interpretation: Lean and overweight/obese PLHIV exhibit distinct proteomic signatures associated with liver steatosis, with the former being more strongly correlated with HIV-specific factors and ART. In addition, we identified a protein, IGSF9, strongly related to liver fibrosis and steatosis across BMI categories., Funding: The 2000HIV study is funded by ViiV Healthcare., Competing Interests: Declaration of interests The authors have nothing to disclose., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: In patients with metabolic dysfunction-associated steatotic liver disease (MASLD), there are limited data on how changes in FIB4 and liver stiffness measurement (LSM) correlate in non-biopsy cohorts., Aims: Our objective was to evaluate associations between changes in FIB4 and LSM in MASLD patients., Methods: We included MASLD patients with serial VCTE from 2015-2022. The primary predictors were change in FIB4 and presence of diabetes, obesity, and high alanine aminotransferase (ALT). The primary outcome, applied only to patients with LSM1 < 8 kPa, was incident significant fibrosis (SF) defined as a ≥ 20% increase in LSM2 vs. LSM1 and LSM2 ≥ 8 kPa. A secondary outcome was LSM progression with a similar definition but applied to all participants, not only those with LSM1 < 8 kPa., Results: Of 285 included patients, 216 had LSM1 < 8 kPa and were included in the primary analysis; of these, 34 (16%) had incident SF. Changes in FIB4 correlated with changes in LSM (R = 0.16, p = 0.016). Independent predictors of incident SF included comorbid diabetes mellitus (OR 2.43, 95% CI 1.04-6.56), obesity (OR 3.88, 95% CI 1.63-9.25), and baseline ALT ≥ 30 (OR 8.55, 95% CI 1.10-66.29). A model including ALT, diabetes, and obesity outperformed a model with FIB4 change alone., Conclusion: Among patients with MASLD, changes in FIB4 correlated with changes in LSM but more significant correlates of incident significant fibrosis included diabetes mellitus, obesity, and high baseline ALT., Competing Interests: Declarations Conflict of interest VLC received grants from KOWA, Ipsen, and AstraZeneca (paid to his institution). The remaining authors have no conflicts of interest to disclose., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Steatosis is defined by hepatocyte accumulation of lipids. Different types of steatosis are described (macro-, medio- and microvacuolar). Macrovacuolar steatosis is a common lesion, mainly observed during metabolic syndrome and excessive alcohol consumption. Steatohepatitis combines steatosis, the presence of ballooned hepatocytes and lobular inflammatory foci. Liver fibrosis is the main consequence of steatohepatitis. Liver biopsy is the gold standard diagnostic test., (Copyright © 2024. Published by Elsevier Masson SAS.)

Liver cirrhosis is a significant global health concern, and cirrhotic cardiomyopathy (CCM) is a notable complication affecting both adults and children. While CCM is well-studied in adults, understanding its manifestation and diagnostic criteria in pediatric patients remains a challenge. This review explores the evidence for structural and functional cardiac alterations in children with liver cirrhosis. Structural abnormalities, including increased left ventricular mass index (LVMI) and altered left ventricular wall thickness ratios, are prevalent in pediatric CCM. These abnormalities persist even after liver transplantation, highlighting the systemic impact of liver disease. Evidence suggests that altered systolic and diastolic function, as well as electrocardiographic abnormalities such as prolonged QT intervals, are common in pediatric CCM. Blood biomarkers, including brain natriuretic peptide (BNP) and troponin levels, offer insights into cardiac function in pediatric cirrhotic patients. Elevated BNP levels correlate with adverse outcomes, indicating its potential as a prognostic marker. However, further research is needed to elucidate the diagnostic utility of these biomarkers in pediatric CCM., Conclusion: This review provides estimates of the standardized mean difference among selected cardiac parameters in children with and without cirrhosis. Tailored diagnostic criteria and comprehensive assessment methods will be essential for accurate diagnosis and effective management of pediatric CCM., What Is Known: • CCM adds to the burden of care of patients with cirrhosis. • Diagnostic criteria for adults are evolving, but there are no specific criteria for pediatric CCM., What Is New: • Cardiac function in children with cirrhosis indicates some parameters not considered in adults are altered. • Effect size estimations for certain parameters provide a guideline for future research into pediatric CCM., (© 2024. The Author(s).)

Chronic hepatitis C virus infection is a major cause of mortality due to liver cirrhosis globally. Despite the advances in recent therapeutic strategies, there is yet a high burden of HCV-related cirrhosis worldwide concerning low coverage of newly developed antiviral therapies, insufficient validity of the current diagnostic methods for cirrhosis, and incomplete understanding of the pathogenesis in this stage of liver disease. Hence we aimed to clarify the molecular events in HCV-related cirrhosis and identify a liver-specific gene signature to potentially improve diagnosis and prognosis of the disease. Through RNA-seq transcriptome profiling of liver samples of Iranian patients with HCV-related cirrhosis, the differentially expressed genes (DEGs) were identified and subjected to functional annotation including biological process (BP) and molecular function (MF) analysis and also KEGG pathway enrichment analysis. Furthermore, the validation of RNA-seq data was investigated for seven candidate genes using qRT-PCR. Moreover, the diagnostic and prognostic power of validated DEGs were analyzed in both forms of individual DEG and combined biomarkers through receiver operating characteristic (ROC) analysis. Finally, we explored the pair-wise correlation of these six validated DEGs in a new approach. We identified 838 significant DEGs (padj ˂0.05) enriching 375 and 15 significant terms subjected to BP and MF, respectively (false discovery rate ˂ 0.01) and 46 significant pathways (p-value ˂ 0.05). Most of these biological processes and pathways were related to inflammation, immune responses, and cellular processes participating somewhat in the pathogenesis of liver disease. Interestingly, some neurological-associated genes and pathways were involved in HCV cirrhosis-related neuropsychiatric disorders. Out of seven candidate genes, six DEGs, including inflammation-related genes ISLR, LTB, ZAP70, KLRB1, and neuronal-related genes MOXD1 and Slitrk3 were significantly confirmed by qRT-PCR. There was a close agreement in the expression change results between RNA-seq and qRT-PCR for our candidate genes except for SAA2-SAA4 (P= 0.8). High validity and reproducibility of six novel DEGs as diagnostic and prognostic biomarkers were observed. We also found several pair-wise correlations between validated DEGs. Our findings indicate that the six genes LTB, ZAP70, KLRB1, ISLR, MOXD1, and Slitrk3 could stand as promising biomarkers for diagnosing of HCV-related cirrhosis. However, further studies are recommended to validate the diagnostic potential of these biomarkers and evaluate their capability as targets for the prevention and treatment of cirrhosis disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: The liver is known to be protected from steatosis under the influence of high GH/IGF-1. Cytokeratin 18 (CK18) and insulin-like growth factor binding protein 7 (IGFBP7) increase in liver steatosis and fibrosis. The aim of this study was to use quantitative ultrasound techniques and biochemical markers to assess liver steatosis and liver fibrosis in newly diagnosed acromegaly., Methods: This single-center, cross-sectional study included 23 patients with newly diagnosed acromegaly and 46 age, sex, body mass index (BMI) and waist circumference (WC)-matched controls. Liver steatosis was assessed using tissue attenuation imaging (TAI), and stiffness, indicative of fibrosis, was assessed by shear wave elastography (SWE). Serum IGFBP7 and CK18 were studied by ELISA., Results: The acromegaly group had significantly lower liver steatosis (p = 0.006) and higher liver stiffness (p = 0.004), serum IGFBP7 (p = 0.048) and CK18 (p = 0.005) levels than the control group. The presence of fibrosis (p = 0.012) was significantly higher in the acromegaly group than in the control group. Moreover, CK18 was positively correlated with liver stiffness, WC, HOMA-IR, HbA1c, and triglyceride. In the acromegaly group, liver steatosis was negatively correlated with GH level. Stepwise multiple linear regression analysis revealed that BMI (p = 0.008) and CK18 (p = 0.015) were independent risk factors for increased liver stiffness., Conclusion: This study showed that there was an increased presence of liver fibrosis independent of liver steatosis in newly diagnosed acromegaly. Serum CK18 appears to be a potential marker of increased liver fibrosis in acromegaly., (© 2024. The Author(s).)

In clinical practice, the d-dimer levels rule out venous thromboembolism and diagnose disseminated intravascular coagulation. d-dimers increase in both physiological and pathological conditions. Liver cirrhosis, especially in the final stages, is characterized by complex coagulation and fibrinolysis factor disorders. Multiple mechanisms tried to explain the increased d-dimer levels in patients with liver cirrhosis and ascites. The d-dimer cut-off level used to rule out venous thromboembolism in cirrhosis is higher than that used to confirm the diagnosis of VTE or DIC in noncirrhotic patients. The cut-off d-dimer level used for the prognosis of thrombotic events is not standardized in advanced liver cirrhosis. Thus, it is necessary to update the clinical guidelines regarding the usefulness of d-dimer testing in advanced liver cirrhosis and the cut-off d-dimer levels, which should vary based on the detection method., Competing Interests: Declaration of competing interest The authors declare there is no conflict of interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Non-invasive tests (NITs) for liver fibrosis have been recognized for their clinical utility in metabolic dysfunction-associated steatotic liver disease (MASLD). However, their diagnostic efficacy in detecting liver fibrosis is notably reduced in patients with alcohol-related liver disease. Therefore, ascertaining the reliability of NITs in patients with MASLD with moderate alcohol intake (MetALD) is essential., Methods: In this cross-sectional study, we reviewed data from 7,918 health check-up participants who underwent both magnetic resonance elastography (MRE) and ultrasound for the diagnosis of hepatic steatosis. The participants were categorized into MASLD and MetALD groups, and the performance of fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS) were assessed. Advanced hepatic fibrosis (F3) was defined as MRE ≥3.6 kPa., Results: The prevalence of MetALD was 5.8% in this health check-up cohort, and 1.5% of these patients exhibited advanced hepatic fibrosis. Both MetALD and MASLD displayed similar metabolic profiles and hepatic fibrosis burdens. The diagnostic performance of FIB-4 and NFS for MRE ≥3.6 kPa showed no noticeable differences in the area under the receiver-operating characteristic values between the two groups (0.85 vs. 0.80 in FIB-4). Moreover, the sensitivity (71.4%), specificity (77.3%), and both positive (4.6%) and negative (99.4%) predictive values of NITs for MetALD closely mirrored those observed for MASLD., Conclusion: FIB-4 performed well for the initial screening of advanced hepatic fibrosis in MetALD, demonstrating reasonable sensitivity and negative predictive values., Impact and Implications: In this cross-sectional study, data from 7,918 participants who underwent MRE were analyzed to assess the performance of fibrosis-4 (FIB-4) and non-alcoholic fatty liver disease fibrosis scores in metabolic dysfunction-associated steatotic liver disease (MASLD) and MASLD with moderate alcohol intake (MetALD). We found that FIB-4 had high diagnostic accuracy in the newly identified MetALD group, similar to that in the MASLD population. These results highlight the potential of FIB-4 as a reliable screening tool for MetALD, even when specific subgroups are considered. Therefore, FIB-4 is a valuable screening tool for identifying advanced fibrosis in the MetALD population., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Introduction and Objectives: The increasing incidence of hepatocellular carcinoma (HCC) in China is an urgent issue, necessitating early diagnosis and treatment. This study aimed to develop personalized predictive models by combining machine learning (ML) technology with a demographic, medical history, and noninvasive biomarker data. These models can enhance the decision-making capabilities of physicians for HCC in hepatitis B virus (HBV)-related cirrhosis patients with low serum alpha-fetoprotein (AFP) levels., Patients and Methods: A total of 6,980 patients treated between January 2012 and December 2018 were included. Pre-treatment laboratory tests and clinical data were obtained. The significant risk factors for HCC were identified, and the relative risk of each variable affecting its diagnosis was calculated using ML and univariate regression analysis. The data set was then randomly partitioned into validation (20 %) and training sets (80 %) to develop the ML models., Results: Twelve independent risk factors for HCC were identified using Gaussian naïve Bayes, extreme gradient boosting (XGBoost), random forest, and least absolute shrinkage and selection operation regression models. Multivariate analysis revealed that male sex, age >60 years, alkaline phosphate >150 U/L, AFP >25 ng/mL, carcinoembryonic antigen >5 ng/mL, and fibrinogen >4 g/L were the risk factors, whereas hypertension, calcium <2.25 mmol/L, potassium ≤3.5 mmol/L, direct bilirubin >6.8 μmol/L, hemoglobin <110 g/L, and glutamic-pyruvic transaminase >40 U/L were the protective factors in HCC patients. Based on these factors, a nomogram was constructed, showing an area under the curve (AUC) of 0.746 (sensitivity = 0.710, specificity=0.646), which was significantly higher than AFP AUC of 0.658 (sensitivity = 0.462, specificity=0.766). Compared with several ML algorithms, the XGBoost model had an AUC of 0.832 (sensitivity = 0.745, specificity=0.766) and an independent validation AUC of 0.829 (sensitivity = 0.766, specificity = 0.737), making it the top-performing model in both sets. The external validation results have proven the accuracy of the XGBoost model., Conclusions: The proposed XGBoost demonstrated a promising ability for individualized prediction of HCC in HBV-related cirrhosis patients with low-level AFP., Competing Interests: Declaration of interests None., (Copyright © 2024 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: Test results are immediately released to patients through patient portals. We characterized patient and provider time-to-review of liver imaging results., Methods: We identified 401 patients with cirrhosis enrolled in the portal with ≥1 liver imaging. We compared result review times for patients and providers and identified factors associated with rapid review., Results: The median time-to-review for patients was shorter than providers (3.7 vs 17.6 hours, P < 0.001), with more than half of results reviewed by patients first. Rapid patient review was inversely associated with older age and Hispanic ethnicity., Discussion: Patients rapidly review imaging results through the portal, often before providers., (Copyright © 2024 by The American College of Gastroenterology.)

Objective: Previous studies have suggested that microRNA-122 has a relatively high diagnostic value for chronic viral hepatitis detection. In this study, we evaluated the diagnostic value of serum microRNA-122 in different stages of HBV-related cirrhosis，and serum microRNA-122 may serve as a potential biomarker for staging HBV related cirrhosis patients.., Methods: A total of 80 patients with HBV-related cirrhosis were included. Patients were characterized according to Child-Pugh score, laboratory parameters, and complications, and divided into compensated cirrhosis group and decompensated cirrhosis group. Wherein, the compensatory group for liver cirrhosis includes 21 patients, the compensatory group has 59 patients. Blood was collected from all patients, and RT-qPCR analyzed the expression levels of microRNA-122., Results: Serum microRNA-122 was decreased, while Child-Pugh score, Meld score, Prothrombin time, total bilirubin, and Direct bilirubin were higher in a decompensated group compared to the compensated group (all P < .05). For further stage classification, the mean serum microRNA-122 level was higher in stage 1 (11.3±5.1, compensated cirrhosis) compared to stage 2~5 (8.5±4.2, 4.9±1.0, 4.7±1.6, 3.5±1.1, decompensated cirrhosis, all P < .05). The expression of serum microRNA-122 independent of Child-Pugh score and complications, including ascites, varices, HCC (P > .05).However it was affected by Meld score and Prothrombin time (P < .05). Moreover, ROC analysis indicated microRNA-122 could differentiate compensated HBV-related cirrhosis (0.97 of AUC, P < .01). Furthermore, it could differentiate patients in stage 1 (compensated cirrhosis without esophageal varices) from HBV-related cirrhosis (0.91 of AUC, P < .01), with a sensitivity of 77.8% and satisfactory specificity of 88.7%. The significance of the relationship between the decrease in serum microRNA-122 levels and the stage of liver cirrhosis will be beneficial., Conclusion: Our results strongly support the diagnostic value of serum microRNA-122 as a potential biomarker of stage classification in patients with HBV-related cirrhosis, which could facilitate risk stratification and careful management. Provide new biomarkers for the diagnosis of patients with hepatitis B cirrhosis.

Background: As one of the most requested profiles of blood tests, there is a need for standardization among liver function tests (LFT). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are key markers of hepatocellular injury. ALT and AST are used to calculate a Fibrosis-4 (FIB-4) score for assessing liver fibrosis. Despite recommendations by the International Federation of Clinical Chemistry (IFCC) to include pyridoxal-5-phosphate in ALT and AST assay methodologies, most laboratories continue to omit this., Methods: Data from the UK NEQAS for Clinical Chemistry Scheme, Distribution 1160 (November 2023), was reviewed to investigate variation in practice regarding liver blood tests in relation to ALT, AST and FIB-4. In addition, a series of questions audited laboratory practice in relation to liver enzymes., Results: Wide variation was seen in LFT profiles offered by laboratories, with 32 different combinations of tests used. The IFCC-recommended methods for ALT and AST are used by one-third of laboratories and give significantly higher results than non-IFCC methods. Laboratories using IFCC methods also reported significantly higher FIB-4 scores. Reference ranges and cut-offs for these tests also varied, and did not account for method-related differences in results., Conclusions: The lack of standardization of LFTs can have a significant impact on patient care. The difference in results for ALT, AST and FIB-4 in laboratories not using IFCC-recommended methods may lead to misdiagnosis. This issue should be addressed by laboratories using methods including pyridoxal-5-phosphate. Until then, method-related reference ranges and cut-offs for ALT, AST and FIB-4 are required., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

To explore the value of ultrasound elastography combined with serological indicators in the diagnosis of liver fibrosis in chronic hepatitis B. A total of 156 patients with chronic hepatitis B from April 2020 to February 2022 were enrolled in this study as subjects. They were assigned to the liver fibrosis group (n=115) and the non-liver fibrosis group (n=41) according to whether the patients had liver fibrosis. They were divided into S1 stage (n=48), S2 stage (n=38), and S3 stage (n=29) according to histopathological staging criteria. Shear wave elastography (SWE) values, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), procollagen type III (PCIII), and laminin (LN) were compared among patients in each stage. Spearman's method was utilized to analyze the correlation of liver serum biochemical indicators and SWE value with liver fibrosis. The predictive performance of SWE value and serological indicators was analyzed using receiver operating characteristic curves. According to Spearman's method, the liver fibrosis stage was positively correlated with SWE value. Serological indicators combined with ultrasound elastography can accurately assess the degree of liver fibrosis in patients with chronic hepatitis B and provide a basis for clinical judgment.

During recent decades, the metabolic dysfunction-associated steatohepatitis (MASH) field has witnessed several paradigm shifts, including the recognition of liver fibrosis as the main predictor of major adverse liver outcomes. Throughout this evolution, liver histology has been recognised as one of the main hurdles in MASH drug development due to its invasive nature, associated cost, and high inter- and intra-reader variability. Collective experience demonstrates the importance of consistency in the central reading process, where consensus methods have emerged as appropriate ways to mitigate against well-known challenges. Using crystalized knowledge in the field, stakeholders should collectively work towards the next paradigm shift, where non-invasive biomarkers will be considered surrogate endpoints for accelerated approval. In this review, we provide an overview of the evolution of the regulatory histology endpoints and the liver biopsy reading process, within the MASH trial landscape, over recent decades; we then review the biggest challenges associated with liver biopsy endpoints. Finally, we discuss and provide recommendations on the best practices for liver biopsy evaluation in MASH drug development., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Ensemble machine-learning methods, like the superlearner, combine multiple models into a single one to enhance predictive accuracy. Here we explore the potential of the superlearner as a benchmarking tool for clinical risk prediction, illustrating the approach to identifying significant liver fibrosis among patients with NAFLD., Approach and Results: We used 23 demographic/clinical variables to train superlearner(s) on data from the NASH-clinical research network observational study (n = 648) and validated models with data from the FLINT trial (n = 270) and National Health and Nutrition Examination Survey (NHANES) participants with NAFLD (n = 1244). Comparing the superlearner's performance to existing models (Fibrosis-4 [FIB-4], NAFLD fibrosis score, Forns, AST to Platelet Ratio Index [APRI], BARD, and Steatosis-Associated Fibrosis Estimator [SAFE]), it exhibited strong discriminative ability in the FLINT and NHANES validation sets, with AUCs of 0.79 (95% CI: 0.73-0.84) and 0.74 (95% CI: 0.68-0.79) respectively., Conclusions: Notably, the SAFE score performed similarly to the superlearner, both of which outperformed FIB-4, APRI, Forns, and BARD scores in the validation data sets. Surprisingly, the superlearner derived from 12 base models matched the performance of one with 90 base models. Overall, the superlearner, being the "best-in-class" machine-learning predictor, excelled in detecting fibrotic NASH, and this approach can be used to benchmark the performance of conventional clinical risk prediction models., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background and Aims: The global rise of chronic hepatitis B (CHB) superimposed on hepatic steatosis (HS) warrants noninvasive, precise tools for assessing fibrosis progression. This study leveraged machine learning (ML) to develop diagnostic models for advanced fibrosis and cirrhosis in this patient population., Methods: Treatment-naive CHB patients with concurrent HS who underwent liver biopsy in 10 medical centers were enrolled as a training cohort and an independent external validation cohort (NCT05766449). Six ML models were implemented to predict advanced fibrosis and cirrhosis. The final models, derived from SHAP (Shapley Additive exPlanations), were compared with Fibrosis-4 Index, nonalcoholic fatty liver disease Fibrosis Score, and aspartate aminotransferase-to-platelet ratio index using the area under receiver-operating characteristic curve (AUROC) and decision curve analysis (DCA)., Results: Of 1,198 eligible patients, the random forest model achieved AUROCs of 0.778 (95% confidence interval [CI], 0.749-0.807) for diagnosing advanced fibrosis (random forest advanced fibrosis model) and 0.777 (95% CI, 0.748-0.806) for diagnosing cirrhosis (random forest cirrhosis model) in the training cohort, and maintained high AUROCs in the validation cohort. In the training cohort, the random forest advanced fibrosis model obtained an AUROC of 0.825 (95% CI, 0.787-0.862) in patients with hepatitis B virus DNA ≥10 5 IU/mL, and the random forest cirrhosis model had an AUROC of 0.828 (95% CI, 0.774-0.883) in female patients. The 2 models outperformed Fibrosis-4 Index, nonalcoholic fatty liver disease Fibrosis Score, and aspartate aminotransferase-to-platelet ratio index in the training cohort, and also performed well in the validation cohort., Conclusions: The random forest models provide reliable, noninvasive tools for identifying advanced fibrosis and cirrhosis in CHB patients with concurrent HS, offering a significant advancement in the comanagement of the 2 diseases., Clinicaltrials: gov, Number: NCT05766449., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Acute kidney injury (AKI) frequently complicates the course of hospitalized patients with cirrhosis and negatively affects their prognosis. How AKI response influences the timing of liver transplantation (LT) remains unclear. We sought to assess the impact of AKI response to treatment on survival and LT rates in patients with cirrhosis awaiting LT. This was a retrospective multicenter study of cirrhosis patients waitlisted for LT and hospitalized with AKI in 2019. The exposure was AKI response versus no response during hospitalization. Outcomes were 90-day overall and transplant-free survival, and rates of LT with time to transplant. We adjusted for age, sex, race, cirrhosis etiology, site, and Model for End-Stage Liver Disease-Sodium (MELD-Na) score. Among the 317 patients in this study, 170 had an AKI response (53.6%), and 147 had no response (46.4%). Compared to nonresponders, responders had better 90-day overall survival (89.4% vs. 76.2%, adjusted subhazard ratio for mortality 0.34, p =0.001), and transplant-free survival (63.5% vs. 25.2%, aHR for probability of death or transplant 0.35, p <0.001). The LT rate was lower in responders (45.9% vs. 61.2%, adjusted subhazard ratio 0.55, p =0.005); 79% of transplants in responders occurred after discharge, at a median of 103 days, while 62% of transplants in nonresponders occurred during hospitalization, with the remainder occurring postdischarge at a median of 58 days. In patients with cirrhosis waitlisted for LT who are hospitalized with AKI, AKI response to therapy is associated with improved 90-day survival, despite a reduced LT rate and longer time to LT., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Introduction and Objectives: Although the Psychometric Hepatic Encephalopathy Score (PHES) remains the gold standard in diagnosing minimal hepatic encephalopathy (MHE), its complexity limits its application in clinical practice. While more convenient tests, such as the Stroop test, Quickstroop, and the 1-min animal naming test (ANT-1), have emerged, they haven't been validated in our setting. Our objective was to validate these tests in our population., Patients and Methods: This multicenter, observational, descriptive, and cross-sectional study was conducted in three hospitals in northeastern Mexico. MHE was defined as a PHES <-4. We included patients with cirrhosis aged >15 years without a history of overt hepatic encephalopathy. Data regarding sex, age, education, Child-Pugh/MELD-Na scores, etiology of cirrhosis, diabetes, hypertension, obesity, ascites, and clinically significant portal hypertension was collected. Fisher's exact test, Mann-Whitney U test, and receiver operating characteristic (ROC) curves were used for statistical analysis., Results: Of the 121 patients included, 35.5 % were diagnosed with MHE. The presence of MHE was significantly associated with education level, years of study, and scores in the Stroop test, Quickstroop, and ANT-1. The AUROC curves were 77.9 %, 74.6 %, and 72.7 % for the Stroop test, Quickstroop, and ANT-1, respectively. The resulting cut-off points were 218.398 (sensitivity: 74 %; specificity: 74 %), 40.535 (sensitivity: 77 %; specificity: 68 %), and <16 animals (sensitivity: 58 %; specificity: 79 %), respectively., Conclusions: These tests are valid diagnostic tools for detecting MHE in our population. Their simpler use and applicability could increase the early diagnosis of MHE and prompt primary prophylaxis initiation for overt hepatic encephalopathy., Competing Interests: Conflicts of interest None., (Copyright © 2024 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is characterized by liver fibrosis, which serves as a crucial indicator of its progression and prognosis. Owing to the limitations of biopsy, which is the gold standard for measuring liver fibrosis, a reliable and noninvasive marker is required. We evaluated the diagnostic role of the fibrosis-4 (FIB-4) index and nonalcoholic fatty liver disease fibrosis score (NFS) in patients with NAFLD with varying severities of liver fibrosis. The FIB-4 index and NFS were calculated using laboratory data from 121 patients who underwent liver biopsies between January 2022 and December 2023. The results were compared with those of the Scheuer scoring system for liver biopsies (F0, F1 + F2, and F3 + F4) to determine the sensitivity and specificity of the FIB-4 index and the liver disease fibrosis score in detecting and staging liver fibrosis. Twenty-one patients had advanced fibrosis (F3-F4), and 100 had minimal or mild fibrosis (F0-F2). The degree of liver fibrosis increased with decreased albumin, alanine aminotransferase and platelet count levels, and increasing age. Receiver operating characteristic curve analysis for the FIB-4 index and NFS revealed that the areas under the curve for the FIB-4 index and NFS were 0.895 (95% confidence interval: 0.836-0.954) and 0.882 (95% confidence interval: 0.813-0.952), respectively. The FIB-4 indices showed 95.24% sensitivity at a cutoff point of 1.30, and 85% specificity at a cutoff point of 2.67, while the NFS indices showed 95.24% sensitivity at -1.455 cutoff point and 95% specificity at a cutoff point of 0.676. The FIB-4 index and NFS may replace biopsy for the detection of fibrosis in patients with NAFLD., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is increasing, affecting over one-third of the global population and contributing to significant morbidity and mortality. Diagnosing MAFLD, especially with advanced fibrosis, remains challenging due to the limitations of liver biopsy, the current gold standard. Non-invasive tests are crucial for early detection and management. Among these, the fibrosis-4 index (Fib-4) is widely recommended as a first-line test for screening for liver fibrosis. Advanced imaging techniques, including ultrasound-based elastography and magnetic resonance elastography, offer high accuracy but are limited by cost and availability. Combining biomarkers, such as in the enhanced liver fibrosis score and FibroScan-AST score, enhances diagnostic precision and is recommended to further stratify patients who are considered to be intermediate or high risk from the Fib-4 score. We believe that the future lies in the combined use of biomarkers to improve diagnostic accuracy., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Thrombocytopenia in cirrhosis is causing puzzlement in clinical practice. Therefore, in order to help clinical practitioners grasp quickly and standardize the diagnosis and treatment of thrombocytopenia in cirrhosis, liver fibrosis, and portal hypertension, the Group of the Chinese Society of Hepatology of the Chinese Medical Association has organized relevant field experts to formulate the "Concise Guidelines for Clinical Management of Thrombocytopenia in Cirrhosis" with aim of providing guidance for the clinical diagnosis and treatment.

Background: Dyslipidemia is a known independent risk factor for Nonalcoholic fatty liver disease (NAFLD). However, the relationship between NAFLD and the serum non-high-density lipoprotein cholesterol (non-HDL-C) to high-density lipoprotein cholesterol (HDL-C) ratio remains unclear. This study examined the association between the non-HDL-C to HDL-C ratio and NAFLD prevalence, including liver steatosis and fibrosis levels in the population., Methods: We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018, including 4798 participants. Liver ultrasound and Transient Elastography (TE) were used to assess fibrosis and steatosis. Adjusted multivariable regression analyses, subgroup analyses based on BMI and sex, and a generalized additive model were employed to investigate the relationship between the non-HDL-C/HDL-C ratio and NAFLD., Results: Among the 4798 participants, 39.27% (n = 1,884) had NAFLD. Significant positive correlations between non-HDL-C/HDL-C and NAFLD risk were found across all models, with sex-stratified analyses indicating higher risk in men. Liver fibrosis was also associated with non-HDL-C/HDL-C ratios. The Receiver operating characteristic (ROC) analysis shows non-HDL-C/HDL-C as a better predictor for NAFLD than non-HDL-C or HDL-C alone., Conclusion: Elevated non-HDL-C/HDL-C levels are independently associated with increased NAFLD and liver fibrosis risk in the American population, suggesting its utility in predicting NAFLD and related liver fibrosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xuan, Zhu, Xu, Huangfu, Li, Liu and Zhou.)

Cirrhosis represents a significant global health challenge, characterized by high morbidity and mortality rates that severely impact human health. Timely and precise prognostic assessments of liver cirrhosis are crucial for improving patient outcomes and reducing mortality rates as they enable physicians to identify high-risk patients and implement early interventions. This paper features a thorough literature review on the prognostic assessment of liver cirrhosis, aiming to summarize and delineate the present status and constraints associated with the application of traditional prognostic tools in clinical settings. Among these tools, the Child-Pugh and Model for End-Stage Liver Disease (MELD) scoring systems are predominantly utilized. However, their accuracy varies significantly. These systems are generally suitable for broad assessments but lack condition-specific applicability and fail to capture the risks associated with dynamic changes in patient conditions. Future research in this field is poised for deep exploration into the integration of artificial intelligence (AI) with routine clinical and multi-omics data in patients with cirrhosis. The goal is to transition from static, unimodal assessment models to dynamic, multimodal frameworks. Such advancements will not only improve the precision of prognostic tools but also facilitate personalized medicine approaches, potentially revolutionizing clinical outcomes., (© 2024. The Author(s).)

The purpose of this study was to explore the correlation between Hashimoto's thyroiditis and Metabolic dysfunction-associated fatty liver disease (MAFLD), and at the same time to screen high-risk groups for liver fibrosis in MAFLD, find out the high-risk related indicators. The physical examination population was included as the study subjects and was grouped according to the diagnostic criteria for MAFLD. APRI > 1 or NFS > 0.676 or FIB-4 > 2.67were used to assess people at high risk of liver fibrosis, and logistic regression analysis was used to identify risk factors associated with high risk of liver fibrosis in MAFLD. ROC curves are used to look for indicators of diagnostic value. The proportion of people with Hashimoto's thyroiditis was lower in the MAFLD group. The MAFLD high-risk group for liver fibrosis had higher TSH levels, lower FT3 and FT4 levels, higher TGAB levels, and differences in biochemical markers. Age, BMI, FBG, and AST are risk factors for the high risk of liver fibrosis in MAFLD patients. ROC curve analysis showed that the AUC of age was 0.741 (0.721-0.761), and the optimal stage value was 57.5 years, while the AUC of AST was 0.729 (0.707-0.751), and the optimal cut-off value was 39.5 U/L. Age, BMI, FBG, and AST are risk factors for the high risk of liver fibrosis in MAFLD patients.The age is greater than or equal to 57.5 years, or the AST is greater than or equal to 39.5 U/L, indicating that the MAFLD patients are at high risk of liver fibrosis., (© 2024. The Author(s).)

This study aimed to address the diagnostic challenges in distinguishing between alcohol-related liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD). We utilized whole-slide imaging technology to conduct a comprehensive digital analysis of liver specimens collected from patients undergoing transplantation. This study included 36 and 17 patients with ALD and MASLD cirrhosis, respectively, who underwent transplantation at our institution. Digital slides were analyzed for fibrosis patterns using FibroNest™. Patient background characteristics were comparable between ALD (n = 36) and MASLD (n = 17) groups, except for sex. The ALD group exhibited thicker collagen per strand, longer and more flexural fibrosis, and a more heterogeneous distribution than the MASLD group. In patients with ALD and concomitant metabolic dysfunction, fiber distribution became relatively uniform, resembling MASLD. Application of the phenotypic fibrosis composite score achieved 100% sensitivity and specificity for ALD/MASLD diagnosis. Digital pathological analysis of the fibrosis patterns showed morphological differences between ALD and MASLD. This approach holds promise for histological differentiation, providing valuable insights beyond the current definitions based solely on alcohol intake. This study emphasizes the potential of digital pathology in refining the diagnostic criteria for hepatic disorders., (© 2024. The Author(s).)

Introduction: Esophageal variceal bleeding (EVB) is one of the main causes of mortality and morbidity in cirrhotic patients. Non-invasive tests (NIT) of liver fibrosis have been developed to predict the presence of esophageal varices (EV)., Aim: To evaluate the performance of NIT of liver fibrosis such as liver transient elastography (TE) and serum scores in predicting EV., Methods: We conducted a retrospective collecting patients with chronic liver disease. TE and serum scores were evaluated for all patients and correlated with endoscopic data., Results: One hundred and fifty patients were included with an average age of 58.98 years and a sex ratio of 0.68. Sixty-seven patients were cirrhotic. Viral origin C was found in 72% of cases. Thirty-three patients had EV. NIT of liver fibrosis such as TE and serum scores were statistically correlated to the presence of EV. TE had the better performance for the prediction of EV with a Cut-off of 13.5 Kpa and AUC of 0.855. In multivariate analysis, TE, AST to ALT ratio and platelet count were independent predictors of EV., Conclusion: The performance of TE and serum scores in the diagnosis of EV and LEV was demonstrated. These results suggest that NIT of liver fibrosis make it possible to select patients who are candidates for gastroscopy.

Introduction: Several non-invasive tests (NIT) have been reported for predicting liver fibrosis to avoid percutaneous liver biopsy (PLB)., Aim: To evaluate the performance of NIT in Tunisian patients with chronic hepatitis B (CHB)., Methods: We calculated the ASAT/platelet ratio index (APRI), GGT-to-platelet ratio (GPR), Fibrosis-4 score (FIB-4), and RDW/platelet ratio (RPR). The accuracy of NIT was compared with the Metavir score for the detection of liver fibrosis stage using the area under the ROC curves (AUROC)., Results: Seventy-seven CHB patients were included. For predicting significant fibrosis, the AUROC of GPR (0.81; CI95% [0.68-0.93]; P < 0.001) was significantly higher than that of RPR (0.67; CI95% [0.52-0.82]; P = 0.03) and FIB-4 (0.746; CI95% [0.61-0.88]; P = 0.002), but was similar to APRI (0.88; CI95% [0.79-0.97]; P < 0.001). For advanced fibrosis, the AUROC of GPR (0.93; CI95% [0.84-1]; P < 0.001) was higher than that of RPR (0.83; CI95% [0.69-0.97]; P < 0.001) and FIB-4 (0.88; CI95% [0.76-0.99]; P < 0.001), but similar to APRI (0.93; CI95% [0.87-0.99]; P < 0.001). For predicting cirrhosis, the AUROC of GPR (0.98; CI95% [0.95-1]; P < 0.001) was higher than that of APRI (0.95; CI95% [0.90-1]; P = 0.02), similar to RPR (0.99; CI95% [0.98-1]; P < 0.001) but lower than that of FIB-4 (1; CI95% [1-1]; P < 0.001). In multivariate analysis, APRI (OR = 3.78; P = 0.002) and FIB-4 (OR = 2.65; P = 0.01) were independent predictors of significant fibrosis. GPR was the only independent predictor of advanced fibrosis (OR = 4.64; P = 0.001) and FIB-4 was the independent predictor of cirrhosis (OR = 2.85; P < 0.001)., Conclusion: GPR does not demonstrate significant advantages over APRI, FIB-4, and RPR in identifying liver fibrosis in patients with chronic hepatitis B (CHB).

Patients with cirrhosis face a heightened risk of complications, underscoring the importance of identification. We have developed a Connectome strategy that combines metabolites with peptide spectral matching (PSM) in proteomics to integrate metabolomics and proteomics, identifying specific metabolites bound to blood proteins in cirrhosis using open search proteomics methods. Analysis methods including Partial Least Squares Discriminant Analysis (PLS-DA), Uniform Manifold Approximation and Projection (UMAP), and hierarchical clustering were used to distinguish significant differences among the Cirrhosis group, Chronic Hepatitis B (CHB) group, and Healthy group. In this study, we identified 81 cirrhosis-associated connectomes and established an effective model distinctly distinguishing cirrhosis from chronic hepatitis B and healthy samples, confirmed by PLS-DA, hierarchical clustering analysis, and UMAP analysis, and further validated using six new cirrhosis samples. We established a Unified Indicator for Identifying cirrhosis, including tyrosine, Unnamed&#95;189.2, thiazolidine, etc., which not only enables accurate identification of cirrhosis groups but was also further validated using six new cirrhosis samples and extensively supported by other cirrhosis research data (PXD035024). Our study reveals that characteristic cirrhosis connectomes can reliably distinguish cirrhosis from CHB and healthy groups. The established unified cirrhotic indicator facilitates the identification of cirrhosis cases in both this study and additional research data.

Objectives: To evaluate the risk of liver fibrosis and associated factors with the non-invasive fibrosis score-4 (FIB-4) index in patients with inflammatory arthritis using methotrexate (MTX)., Methods: Patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) who were followed up in the rheumatology outpatient clinic, who were on methotrexate only and for whom FIB-4 index was could be calculated at methotrexate initiation and follow-up were included. The FIB-4 index was calculated according to the following formula: age (years) × AST(IU/L)/(platelet count(10 (9)/L) × √ALT(IU/L)). The patients' demographics, comorbidities, other treatments, cumulative MTX dose, and reasons for MTX cessation were assessed. For the multivariate analysis, possible factors associated with intermediate-high risk FIB-4 index at last visit were determined., Results: A total of 107 patients were enrolled in the study, of whom 82 (76.6%) had RA and 25 (23.4%) had PsA. At the initiation of MTX, 24 (22.4%) patients had intermediate-high risk FIB-4 index. Comorbidities and the rate of ≥3-4 Charlson comorbidity index were more common in patients with intermediate-high risk FIB-4 index. A total of 37 (34.5%) patients had intermediate-high risk FIB-4 index at the last visit after median 3.6 (0.3-22.06) years follow-up. The median cumulative MTX dose was 2550 mg (1050-13.991). Cumulative MTX dose [OR 1.18 (1.01-1.33), p = .03] and diabetes mellitus [OR 4.60 (1.74-12.50), p = .002] were associated factors with intermediate-high risk FIB-4 index. The concomitant use of hydroxychloroquine (HCQ) was found to be a low-risk factor for FIB-4 index [OR 0.28 (0.10-0.78) p = .015]., Conclusion: The FIB-4 index is a non-invasive method that can be used in daily rheumatology practice for the evaluation and follow-up of patients who will use methotrexate. Comorbidities and cumulative MTX dose seem to be related with the risk of liver fibrosis. Concomitant use of HCQ with MTX may reduce the risk of liver fibrosis., (© 2024 The Author(s). International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Thymosin Beta 10 (TMSB10) is a thymosin family member that has been identified as being overexpressed in a wide variety of human cancers. This study aimed to determine the expression level of TMSB10 in sera of patients with hepatocellular carcinoma (HCC) and liver cirrhosis. And to reveal the association between TMSB10 and different stages in patients with HCC. We also wanted to know how TMSB10 is predictive in HCC patients and its relation to the Barcelona Clinic's staging system. The study included 41 HCC patients, 15 liver cirrhosis patients, and 15 normal control subjects. The enzyme-linked immunosorbent assay was used to determine serum levels of TMSB10 and alpha-fetoprotein (AFP) in serum of normal control individuals and patients with liver cirrhosis and different stages of HCC, and to evaluate the relationship of AFP with TMSB10. The TMSB10 levels in patients with HCC were statistically different than in the control group and in the different stages of HCC. We found a statistically significant difference in the distribution of TMSB10 between the three study groups (p < 0.001). There was an association between TMSB10 concentration and AFP. The level of TMSB10 in the serum of the HCC subgroups was then analyzed. The TMSB10 level increased with the advance of HCC stages. The TMSB10 level in HCC patients did not correlate with levels of liver function tests including aminotransferase, aspartate aminotransferase, albumin, prothrombin, bilirubin, or alkaline phosphatase. In conclusion, serum TMSB10 levels can be used as a potential prognostic marker for clinical stages of HCC., (Copyright© by the Egyptian Association of Immunologists.)

Background: The accuracy of administrative codes to capture patients with both primary biliary cholangitis (PBC) and cirrhosis could be challenging because of the potential for incorrect coding due to the old nomenclature "Primary Biliary Cirrhosis." Therefore, the aim of this study was to examine the positive predictive value (PPV) of International Classification of Diseases (ICD) codes for PBC and cirrhosis., Methods: This was a retrospective cohort study using data from the VA Corporate Data Warehouse. Eligibility criteria included adult patients diagnosed to have PBC and cirrhosis based on one inpatient or two outpatient ICD 9 or 10 codes, and were validated against chart review of each participant., Results: We identified 1408 patients who were found to have ICD codes for both cirrhosis and PBC. The ICD 9/10 codes for PBC and cirrhosis had a PPV of 0.75 (95% CI 0.73-0.75) for cirrhosis, 0.75 for PBC (95% CI 0.73-0.78), and 0.52 (0.50-0.55) for PBC and cirrhosis. When portal hypertension was combined with ICD 9/10 codes, the PPV of cirrhosis improved to 0.92 (0.90-0.94), and that of PBC cirrhosis improved to 0.64 (0.60-0.67). By combining ICD 9/10 codes for portal hypertension and receipt of ursodeoxycholic acid (UDCA), the PPV for cirrhosis improved to 0.91 (0.88-0.94), PBC increased to 0.78 (0.74-0.82), and that for PBC cirrhosis to 0.69 (0.65-0.74)., Conclusions: In a large national cohort, the use of ICD 9/10 codes had modest reliability for identifying participants with PBC and cirrhosis. The PPV for cirrhosis can be improved by incorporating ICD 9/10 codes for portal hypertension with receipt of UDCA., (© 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Objectives: The influence of advancing fibrosis on graft survival in the context of pediatric liver transplantation accentuates the critical role of protocol-driven liver biopsies, a practice adopted by numerous medical centers. Consequently, the exigency for noninvasive methodologies to assess graft fibrosis assumes heightened importance when conventional clinical and laboratory parameters fail to reveal signs of liver damage., Methods: This study aimed to assess the reliability of transient elastography (TE) in pediatric liver transplant recipients to detect graft fibrosis and compare the results of TE in patients who underwent biopsy., Results: This prospective cohort study included liver transplanted children who underwent biopsy at Ege University Children's Hospital between October 1, 2021, and October 31, 2022, and a healthy control group. According to TE, fibrosis was detected in 40 patients, and no fibrosis was detected in 50. The median time to develop fibrosis was 100 months (95% CI [83.1-116.8]). A statistically significant positive correlation existed between LSM and METAVIR fibrosis score (r = 0.562, p = 0.001). There was a statistically significant difference in LSM between patients with F2 fibrosis (7.8-8.8 kPa ± 3.2) compared to patients with F0 fibrosis (5.2 kPa ± 0.7) (p = 0.005) and F1 fibrosis (6.1 kPa ± 1.5) (p = 0.041), on ANOVA., Conclusion: Liver allograft fibrosis is common in long-term follow-up in children who have undergone liver transplantation. Abnormal TE may guide physicians to consider liver biopsy to detect late allograft fibrosis in these children., (© 2024 The Author(s). Clinical Transplantation published by Wiley Periodicals LLC.)

Introduction: Hepatocellular carcinoma (HCC) is the fastest-rising and fourth most common cause of cancer death worldwide. Liver cirrhosis is the largest underlying risk factor for HCC. Therefore, patients with cirrhosis should have regular ultrasound and biochemical screening to pick up early HCC. Early HCC can be cured; more advanced HCCs have limited treatment options and poor prognosis. Current screening methods are suboptimal with poor sensitivity in picking up early disease. In this study, the investigators aim to recruit people with liver cirrhosis into a Prospective cohort for early detection of liver cancer-the Pearl cohort. The investigators believe that by using state-of-the-art tests we can improve the detection of early HCC., Methods and Analysis: This is a UK-based prospective, longitudinal, diagnostic, prognostic, multicentre, non-CTIMP study. Aiming to recruit 3000 patients with liver cirrhosis without a HCC diagnosis, the Pearl cohort will be followed actively for 3 years from recruitment and then passively via registry data for ten years thereafter. Blood and urine samples will be taken and information from routine care will be gathered. These will be used to assess novel diagnostic approaches for the detection early HCC and to develop models to identify those most at risk for developing HCC.Participants will be linked to national UK health registries to ensure long-term capture of HCC incidence and other relevant endpoints. Approximately 75 patients are predicted to develop de novo HCC within the 3-year follow up period. After this period, the study teams will obtain data on participants for at least 10 years after the last contact. This cohort will help develop an understanding of the incidence of HCC in a UK population stratified by underlying cirrhosis aetiology., Ethics and Dissemination: Ethical approval has been granted by REC and the trial is registered on ClinicalTrials.gov. The results will be published in peer-reviewed journals and presented at relevant meetings., Trial Registration Number: NCT05541601., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide including sub-Saharan Africa. The GALAD score, derived from Gender, Age, Lens culinaris agglutinin-reactive fraction of alpha fetoprotein, Alpha fetoprotein, and Des-carboxy-prothrombin, has high accuracy in diagnosing HCC in Asia, Europe, and North America; however, it has not been validated in an African cohort. The aim of this study was to assess the performance of the GALAD score in the diagnosis of HCC in sub-Saharan Africa. Clinical data from patients with cirrhosis (n = 93) or HCC (n = 78) from outpatient hepatology clinics at three teaching hospitals in Ghana were abstracted, and serum samples were analyzed. A logistic regression model predicting HCC status based on the GALAD score was constructed to obtain the ROC curve for GALAD. The AUC with 95% confidence interval (CI) was calculated. The median GALAD score was higher among patients with HCC versus cirrhosis controls (8.0 vs. -4.1, P < 0.01). The AUC of the GALAD score for HCC detection was 0.86 (95% CI, 0.79-0.92). At a cut-off value of -0.37, the GALAD score had a sensitivity of 0.81 and a specificity of 0.86. The AUC (95% CI) was 0.87 (0.80-0.95) and 0.81 (0.67-0.94) in hepatitis B virus-positive and hepatitis B virus-negative patients, respectively. The GALAD score has a high accuracy for HCC detection. It has great potential to improve HCC surveillance in sub-Saharan Africa where imaging resources are limited. Significance: The GALAD score or its relevant modifications have the potential to aid in improving HCC surveillance efforts in low-resource settings in sub-Saharan Africa. This could enhance early detection rates of HCC and potentially improve survival rates in resource-limited settings., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Chronic liver diseases (CLD), cirrhosis, and hepatocellular carcinoma (HCC) cause significant morbidity and mortality. Unfortunately, patients with CLD often go undiagnosed until progression to cirrhosis and HCC. We aimed to determine the proportion of primary care patients with severe liver disease outcomes that had missed or delayed CLD diagnoses., Methods: This retrospective cohort study evaluated primary care patients with a diagnosis of cirrhosis, HCC, or other severe liver disease outcome between 2012 and 2021. The outcomes of interest were missed and delayed diagnoses of CLD, defined as the absence of a CLD diagnosis (missed) or first appearance of CLD on the same day as the cirrhosis diagnosis (delayed). Univariate analyses were performed to describe the cohort. Multivariable logistic regression models analyzed the association of aminotransferase elevations with the outcomes of interest., Results: Of 667 patients with cirrhosis or HCC, 133 (20%) had a missed CLD diagnosis, and 243 (36%) had a delayed CLD diagnosis. Alcohol-related liver disease was the most common etiology among patients with missed/delayed diagnoses. A lower proportion of patients with missed/delayed diagnoses had an elevation in ALT or AST compared to patients with timely diagnoses (61% vs. 77%, p < 0.001). Elevated aminotransferase values were associated with lower odds of a missed/delayed diagnosis (OR 0.47; 95%CI 0.34-0.66)., Conclusions: Most patients with cirrhosis or HCC had missed or delayed diagnoses of CLD in the context of probable overreliance on aminotransferase elevation for CLD detection. Enhanced screening for high prevalence CLD, especially alcohol, in primary care is needed., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background/aims: Shifts in the gut microbiota and metabolites are interrelated with liver cirrhosis progression and complications. However, causal relationships have not been evaluated comprehensively. Here, we identified complication-dependent gut microbiota and metabolic signatures in patients with liver cirrhosis., Methods: Microbiome taxonomic profiling was performed on 194 stool samples (52 controls and 142 cirrhosis patients) via V3-V4 16S rRNA sequencing. Next, 51 samples (17 controls and 34 cirrhosis patients) were selected for fecal metabolite profiling via gas chromatography mass spectrometry and liquid chromatography coupled to time-of-flight mass spectrometry. Correlation analyses were performed targeting the gut-microbiota, metabolites, clinical parameters, and presence of complications (varices, ascites, peritonitis, encephalopathy, hepatorenal syndrome, hepatocellular carcinoma, and deceased)., Results: Veillonella bacteria, Ruminococcus gnavus, and Streptococcus pneumoniae are cirrhosis-related microbiotas compared with control group. Bacteroides ovatus, Clostridium symbiosum, Emergencia timonensis, Fusobacterium varium, and Hungatella&#95;uc were associated with complications in the cirrhosis group. The areas under the receiver operating characteristic curve (AUROCs) for the diagnosis of cirrhosis, encephalopathy, hepatorenal syndrome, and deceased were 0.863, 0.733, 0.71, and 0.69, respectively. The AUROCs of mixed microbial species for the diagnosis of cirrhosis and complication were 0.808 and 0.847, respectively. According to the metabolic profile, 5 increased fecal metabolites in patients with cirrhosis were biomarkers (AUROC >0.880) for the diagnosis of cirrhosis and complications. Clinical markers were significantly correlated with the gut microbiota and metabolites., Conclusion: Cirrhosis-dependent gut microbiota and metabolites present unique signatures that can be used as noninvasive biomarkers for the diagnosis of cirrhosis and its complications.

Background: Long specialist outpatient waiting lists are a source of clinical risk. Triage assignment is based on subjective assessment of referrals and fails to account for dynamic changes in disease status while patients await clinical review., Aims: To pilot an innovative triage method using a trifold approach to conduct noninvasive assessment of fibrosis and to determine the feasibility of reflex hepatitis C virus (HCV) polymerase chain reaction (PCR) testing., Methods: A total of 1006 patients awaiting an initial liver clinic appointment at a tertiary Australian hospital were sent a short message service (SMS) requesting a blood test be completed. The first 60 patients received an SMS only, and the subsequent 946 patients also received a phone call from a Liver Care Guide (LCG), a nonclinician employed to increase patient engagement. Liver fibrosis assessment through noninvasive testing was performed using an aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 (FIB4) score. Patients with an APRI ≥1, FIB4 ≥3.25 or positive HCV PCR were retriaged to Category 1., Results: Four hundred ninety (49%) patients completed testing and 40 (4%) were triaged to Category 1. Subanalyses demonstrated increased response rates with LCG input (P = 0.012). Retriaged patients had been on the waitlist for a median of 216 days, exceeding initial category recommendations., Conclusion: This study successfully implemented a semiautomated strategy that prioritises patients with probable advanced liver disease or active HCV, demonstrating enhanced patient engagement with LCG support. It highlights the burden of patients referred for specialist care and the need for innovative strategies for monitoring and objective risk stratification., (© 2024 The Author(s). Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Background and Aim: Liver stiffness measurements (LSMs) are promising for monitoring disease progression or regression. We assessed the prognostic significance of dynamic changes in LSM over time on liver-related events (LREs) and death in patients with chronic hepatitis B (CHB) and compensated advanced chronic liver disease (cACLD)., Methods: This retrospective study included 1272 patients with CHB and cACLD who underwent at least two measurements, including LSM and fibrosis score based on four factors (FIB-4). ΔLSM was defined as [(follow-up LSM - baseline LSM)/baseline LSM × 100]. We recorded LREs and all-cause mortality during a median follow-up time of 46 months. Hazard ratios (HRs) and confidence intervals (CIs) for outcomes were calculated using Cox regression., Results: Baseline FIB-4, baseline LSM, ΔFIB-4, ΔLSM, and ΔLSM/year were independently and simultaneously associated with LREs (adjusted HR, 1.04, 95% CI, 1.00-1.07; 1.02, 95% CI, 1.01-1.03; 1.06, 95% CI, 1.03-1.09; 1.96, 95% CI, 1.63-2.35, 1.02, 95% CI, 1.01-1.04, respectively). The baseline LSM combined with the ΔLSM achieved the highest Harrell's C (0.751), integrated AUC (0.776), and time-dependent AUC (0.737) for LREs. Using baseline LSM and ΔLSM, we proposed a risk stratification method to improve clinical applications. The risk proposed stratification based on LSM performed well in terms of prognosis: low risk (n = 390; reference), intermediate risk (n = 446; HR = 3.38), high risk (n = 272; HR = 5.64), and extremely high risk (n = 164; HR = 11.11)., Conclusions: Baseline and repeated noninvasive tests measurement allow risk stratification of patients with CHB and cACLD. Combining baseline and dynamic changes in the LSM improves prognostic prediction., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: LIVERSTAT is an artificial intelligence-based noninvasive test devised to screen for and provide risk stratification for metabolic dysfunction-associated fatty liver disease (MAFLD) by using simple blood biomarkers and anthropometric measurements. We aimed to study LIVERSTAT in patients with MAFLD and to explore its role for the diagnosis of advanced fibrosis., Methods: This is a retrospective study of data from MAFLD patients who underwent a liver biopsy. Patients with type 2 diabetes who underwent transient elastography and had liver stiffness measurement (LSM) < 5 kPa were included as patients with no fibrosis. Among these patients, controlled attenuation parameter <248 dB/m was considered as no steatosis. The LIVERSTAT results were generated based on a proprietary algorithm, blinded to the histological and LSM data., Results: The data for 350 patients were analyzed (mean age 53 years, 45% male, advanced fibrosis 22%). The sensitivity, specificity, positive predictive value, negative predictive value, and misclassification rate of LIVERSTAT to diagnose advanced fibrosis were 90%, 50%, 30%, 95%, and 42%, respectively. The corresponding rates for Fibrosis-4 score (FIB4) were 56%, 83%, 44%, 89%, and 22%, respectively. When LSM was used as a second test, the corresponding rates for LIVERSTAT were 60%, 97%, 76%, 94%, and 8%, respectively, while the corresponding rates for FIB4 were 38%, 99%, 83%, 89%, and 11%, respectively., Conclusion: LIVERSTAT had a higher negative predictive value compared with FIB4 and a lower misclassification rate compared with FIB4 when used in a two-step approach in combination with LSM for the diagnosis of advanced fibrosis., (© 2024 The Author(s). Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: The steatosis-associated fibrosis estimator (SAFE) score has been developed to distinguish clinically significant fibrosis in patients with steatotic liver disease (SLD). However, validation of its performance in Asian subjects is limited. This study aimed to evaluate the performance of the SAFE score in Asian subjects with biopsy-proven SLD and in different subgroups according to age, sex, and body mass index., Methods: We retrospectively analyzed 6383 living liver donors who underwent a liver biopsy between 2005 and 2023. Of these, 1551 subjects with biopsy-proven SLD were included. The performance of the SAFE score was evaluated using areas under the curve and compared with those of the nonalcoholic fatty liver disease fibrosis score (NFS) and fibrosis-4 index (FIB-4)., Results: The prevalence of clinically significant fibrosis in the cohort was 2.2%. The proportion of subjects with a "low-risk" SAFE score was the highest (91.0%), followed by those with "intermediate-risk" (7.8%) and "high-risk" (1.2%) scores. The prevalence of fibrosis in subjects with low-risk, intermediate-risk, and high-risk scores was 1.6%, 6.6%, and 21.1%, respectively. The SAFE outperformed FIB-4 and NFS (area under the curve: 0.70 vs 0.64 for both NFS and FIB-4). However, it showed low diagnostic accuracy and sensitivity (27%) at the low cutoff (SAFE < 0) in subjects aged 30-39 years (fibrosis: 1.2%), despite having a high negative predictive value (0.99)., Conclusion: While the SAFE score demonstrates superior performance compared with other noninvasive tests in Asian subjects with SLD, its performance varies across age groups. In younger subjects, particularly, its performance may be more limited., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Circulating polymerized mutant Z-alpha-1 antitrypsin (Z-polymer) constitutes a characteristic feature in alpha-1 antitrypsin deficiency (AATD), but there is limited knowledge about its association with adverse clinical outcomes and liver fibrosis. We explored this association using data from a large cohort of adults with AATD., Methods: A total of 836 (431 PiZZ, 405 PiMZ) adults with AATD and 312 controls (PiMM) from the European Alpha-1 Liver Cohort (2015-2020) were included. Time-to-event analyses were conducted for adults with the PiZZ genotype followed for adverse clinical outcomes (earliest occurrence of liver-related hospitalization, liver transplant or all-cause mortality). Cox proportional hazard models were used to describe the association between binary circulating Z-polymer levels and adverse clinical outcomes. Correlations between baseline circulating Z-polymer levels and baseline liver fibrosis (liver stiffness measurement [LSM] determined by transient elastography [FibroScan®]) were evaluated. The analyses were stratified by augmentation therapy status., Results: Of 324 adults with the PiZZ genotype and longitudinal follow-up data, 28 reported adverse clinical outcomes. Higher baseline circulating Z-polymer levels were associated with an increased risk of adverse clinical outcomes in both crude (hazard ratio [95% confidence interval, CI], 2.88 [1.21, 6.87]) and age-adjusted (1.96 [0.78, 4.94]) analyses. In adults with the PiZZ genotype, circulating Z-polymer levels were weakly positively correlated with baseline LSM (Spearman's rho [95% CI]: 0.21 [0.11, 0.31]). Similar results were observed after stratification by augmentation therapy status., Conclusions: In adults with the PiZZ genotype, higher circulating Z-polymer levels were associated with a shorter time to adverse clinical outcome, and positively correlated with baseline LSM. Circulating Z-polymer levels may be a prognostic biomarker of clinically relevant disease in AATD., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: Evaluation of liver fibrosis played a monumental role in the diagnosis and monitoring of chronic hepatitis B (CHB). We aimed to explore the value of serum N-glycan markers in liver fibrosis., Methods: This multi-center (33 hospitals) study recruited 760 treatment-naïve CHB patients who underwent liver biopsy. Serum N-glycan markers were analyzed by DNA sequencer-assisted fluorophore-assisted with capillary electrophoresis (DSA-FACE) technology. First, we explore the relationship between 12 serum N-glycan markers and the fibrosis stage. Then, we developed a Px score for diagnosing significant fibrosis using the LASSO regression. Next, we compared the diagnostic performances between Px, LSM, APRI, and FIB-4. Finally, we explored the relationships between glycosyltransferase gene and liver fibrosis with RNA-transcriptome sequencing., Results: We included 622 CHB participants: male-dominated (69.6%); median age 42.0 (IQR 34.0-50.0); 287 with normal ALT; 73.0% with significant fibrosis. P5(NA2), P8(NA3), and P10(NA4) were opposite to the degree of fibrosis, while other profiles (except for P0[NGA2]) increased with the degree of fibrosis. Seven profiles (P1[NGA2F], P2[NGA2FB], P3[NG1A2F], P4[NG1A2F], P7[NA2FB], P8[NA3], and P9[NA3Fb]) were selected into Px score. Px score was associated with an increased risk of significant fibrosis (for per Px score increase, the risk of significant fibrosis was increased by 3.54 times (OR = 4.54 [2.63-7.82]) in the fully-adjusted generalized linear model. p for trend was <0.001. The diagnostic performance of the Px score was superior to others. Glycosyltransferase genes were overexpressed in liver fibrosis, and glycosylation and glycosyltransferase-related pathways were significantly enriched., Conclusions: Serum N-glycan markers were positively correlated with liver fibrosis. Px score had good performance in distinguishing significant fibrosis., (© 2024. The Author(s).)