Liver Fibrosis Stage Research Articles

Utility of Mac-2 binding protein glycosylation isomer as an excellent biomarker for the prediction of liver fibrosis, activity, and hepatocellular carcinoma onset: an expert review.

Mac-2 binding protein glycosylation isomer (M2BPGi) is a liver fibrosis biomarker that originated in Japan and has been covered by health insurance for 10years. M2BPGi is useful not only for liver fibrosis stage prediction but also for assessment of the degree of liver inflammation and prediction of hepatocellular carcinoma development. The usefulness of M2BPGi for assessing disease progression in patients with various chronic liver diseases has been demonstrated over the past decade in a large number of patients. Recently, there have been many reports from outside Japan, including reports from South Korea, Taiwan, Hong Kong, and China. These studies demonstrated that M2BPGi is an excellent biomarker that can evaluate the progression of liver fibrosis in chronic liver disease. It is also an excellent indicator of liver activity. Recently, a quantitative M2BPGi (M2BPGi-Qt) assay was developed, and future validation in real-world settings is expected. This will enable diagnosis of the progression of liver fibrosis based on more precise test results and is expected to contribute to the early detection and follow-up of diseases caused by chronic hepatitis, as well as post-treatment monitoring. The significance of the M2BPGi-Qt assay will likely become clearer as real-world data accumulate. If new cutoff values for each chronic liver disease stage and activity level using the M2BPGi-Qt assay are set based on real-world data, it is expected that this will become a useful tool to identify cases of liver fibrosis and monitor the progression of chronic liver disease.

Diagnostic performance of FibroTouch® in assessing hepatic steatosis and fibrosis in patients with metabolic dysfunction-associated steatotic liver disease: An Asian experience.

FibroTouch® has shown efficacy in staging hepatic fibrosis in patients with chronic viral hepatitis B, but its performance in assessing liver steatosis and fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD) patients remains understudied. We aimed to evaluate the diagnostic performance of FibroTouch® in assessing steatosis and fibrosis in the MASLD population. Liver stiffness measurements and steatosis were assessed using FibroTouch® and FibroScan®, with FibroScan® as the reference standard. Pearson's correlation test evaluated correlations, and kappa statistics determined agreement between the two methods. Optimal cut-off values of FibroTouch® for predicting hepatic steatosis and fibrosis stages were determined through ROC curve analysis with the Youden index method. Strong correlations were observed between FibroTouch® UAP and FibroScan® CAP (rho=0.74) and LSM values (rho=0.87) (p<0.001 for both) in a total of 380 patients. The mean CAP value for the entire cohort was 285±51 dB/m, and the median LSM for the cohort was 5.3kPa. The optimal FibroTouch® UAP cutoffs were 229 dB/m for S0 vs. S1, 267 dB/m for S1 vs. S2, and 294 dB/m for S2 vs. S3. For FibroTouch® LSM, the optimal cutoffs were 6.0kPa for F0-F1 vs. F2, 7.9kPa for F2 vs. F3, and 10.6kPa for F3 vs. F4. Moreover, FibroTouch® effectively assessed hepatic steatosis and fibrosis in patients with different BMIs. FibroTouch® proved valuable in assessing hepatic steatosis and liver fibrosis staging in MASLD patients, enhancing its applicability in various clinical settings as a suitable and convenient option for MASLD patients.

Morphological Changes of Liver Among Post-Fontan Surgery Patients

PurposeLiver screening and longitudinal study of Fontan Associated Liver Diseases (FALD) is essential to identifying hepatomegaly and how hepatomegaly relates to various stages of liver fibrosis. In this study, we investigated longitudinal liver shape changes and liver stiffness in a cohort of patients with Fontan Associated Liver Disease.MethodsWe used 170 image volumes of 40 Fontan stage 3 completion patients. We also used 65 computed tomography images of healthy individuals from three datasets for comparison. Thirteen radiomic shape features of Fontan patients and individuals with a healthy liver were extracted and analyzed longitudinally. We studied correlations among features, liver spleen ratio, and liver stiffness with shape features.ResultsThe enlargement of the liver, along with all shape features, was observed in all post-surgery intervals related to hepatomegaly and fibrosis. The shape features of healthy individuals and Fontan cases differ significantly in the longitudinal analysis and in the liver-spleen ratio. There is a positive correlation among body mass index, body surface area, age, Fontan surgery years, and liver stiffness.ConclusionThe changes in shape features between Fontan patients and healthy subjects are statistically significant, which shows the relation for hepatomegaly and liver fibrosis. Accurate delineation of these features with artificial intelligence-based segmentation could serve as a valuable adjunct for the clinical follow-up of Fontan patients.

Predictors of Atherosclerotic Cardiovascular Disease Events in Patients with Metabolic Dysfunction-associated Steatotic Liver Disease.

Objective Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease associated with metabolic comorbidities. However, the risk factors for atherosclerotic cardiovascular disease (ASCVD) in these patients remain unclear. Therefore, this study investigated predictors of ASCVD in patients with MASLD. Methods This single-center retrospective study examined 372 patients with MASLD ≥40 years old with liver biopsies and available Hisayama scores (median follow-up, 7.4 years; range, 0.6-22 years). We compared baseline characteristics, liver histology (stage, lobular inflammation, steatosis, and hepatocellular ballooning), fibrosis-4 (FIB-4) index (<1.3/1.3-2.66/≥2.67), and laboratory data between patients with and without ASCVD. A predictive model for the onset of ASCVD based on the Hisayama score (low/intermediate/high) and ASCVD incidence was evaluated according to the liver fibrosis stage and FIB-4 index. Results ASCVD incidence was 11.1/1,000 person-years, with cumulative incidences of 4.4%, 9.0%, 14%, and 32% at 5, 10, 15, and 20 years, respectively. Regarding the incidence of ASCVD, the liver fibrosis stage and an FIB-4 index ≥2.67 were not significant predictors, but type IV collagen 7S was a significant predictor. The incidence of ASCVD was higher in the intermediate- and high-risk Hisayama score groups than in the low-risk group. In the multivariate Cox proportional hazards model, the Hisayama score and type IV collagen 7S predicted the incidence of ASCVD more accurately than an FIB-4 index ≥2.67. Conclusions The Hisayama score predicted ASCVD risk in patients with MASLD. These findings will help predict and improve the prognosis of MASLD.

How far are we? Assessing progress in hepatitis C response towards the WHO 2030 elimination goals by the civil society monitoring in 25 European countries, period 2020 to 2023

BackgroundWith the advent of direct acting antivirals (DAAs) the World Health Organisation (WHO) adopted global strategy to eliminate hepatitis C virus (HCV) infection by 2030. In Europe, people who inject drugs (PWID) account for the majority of new cases, however testing and treatment remain suboptimal. The aim was to monitor progress in HCV policy and cascade-of-care for PWID, led by the civil society organisations (CSO) that provide harm reduction services for PWID across Europe.MethodsIn period 2020–2023, CSOs representing focal points of Correlation-European Harm Reduction Network were annually invited to complete online questionnaire on use/impact of HCV test-and-treat guidelines for PWID, availability/functioning of continuum-of-care, and role/limitations of harm reduction services for PWID. A retrospective longitudinal analysis of responses to questions answered each year by the same respondents was performed, and a comparison among the studied years was made.ResultsTwenty-five CSOs from cities in 25 European countries were included and responded to 25 questions. Between 2020 and 2023, there was positive trend in number of HCV treatment guidelines, separate guidelines for PWID, and their positive impact on acess to testing/treatment (24/25, 5/25, and 16/25 in 2023, respectively). DAAs were available in all countries, predominantly prescribed by specialist physicians only (slight increase at primary care), with restrictions including active drug use, stage of liver fibrosis or/and reimbursement policies (2/25, 4/25, and 3/25 in 2023, respectively). A decrease in HCV testing sites was noted. Treatment was consistently most common at clinical settings, however an increase outside the specialist settings was detected, particularly in prisons (12/25 and 15/25 in 2020–2021, respectively). Comparing 2022–2023, number of HCV-testing services increased in many cities with positive dynamic in nearly all the settings; increase in treatment at harm reduction services/community centres was noted (6/25 to 8/25, respectively). Between 2020 and 2023 the frequency of various limitations to CSOs addressing HCV was oscillating, presenting an increase between 2022 and 2023 (9/25 to 14/25, respectively).ConclusionThe overall progress towards WHO HCV elimination goals across Europe remains insufficient, most probably also due to the influence of Covid-19 pandemic. Further improvements are needed, also by including CSOs for PWID in continuum-of-care services, and in monitoring progress.

Artificial Intelligence and Image Analysis-Assisted Diagnosis for Fibrosis Stage of Metabolic Dysfunction-Associated Steatotic Liver Disease Using Ultrasonography: A Pilot Study.

Elastography increased the diagnostic accuracy of liver fibrosis. However, several challenges persist, including the widespread utilization of equipment, difficulties in measuring certain cases, and the influence of viscosity factors. A rough surface and a blunted hepatic margin have long been acknowledged as valuable characteristics indicative of hepatic fibrosis. The objective of this study was to conduct an image analysis and quantitative assessment of the contour of the sagittal section of the left lobe of the liver. Between February and October 2020, 486 consecutive outpatients underwent ultrasound examinations at our hospital. A total of 214 images were manually annotated by delineating the liver contour to create annotation images. U-Net was employed for liver segmentation, with the dataset divided into training (n = 128), testing (n = 42), and validation (n = 44) subsets. Additionally, 43 Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) cases with pathology data from between 2015 and 2020 were included. Segmentation was performed using the program developed in the first step. Subsequently, shape analysis was conducted using ImageJ. Liver segmentation exhibited high accuracy, as indicated by Dice loss of 0.044, Intersection over Union of 0.935, and an F score of 0.966. The accuracy of the classification of the liver surface as smooth or rough via ResNet 50 was 84.6%. Image analysis showed MinFeret and Minor correlated with liver fibrosis stage (p = 0.046, 0.036, respectively). Sensitivity, specificity, and AUROC of Minor for ≥F3 were 0.571, 0.862, and 0.722, respectively, and F4 were 1, 0.600, and 0.825, respectively. Deep learning segmentation of the sagittal cross-sectional contour of the left lobe of the liver demonstrated commendable accuracy. The roughness of the liver surface was correctly judged by artificial intelligence. Image analysis showed the thickness of the left lobe inversely correlated with liver fibrosis stage.

Application of the Chinese Visceral Adiposity Index in the Diagnosis of Hepatic Steatosis and Liver Fibrosis: A Cross-Sectional Study

Background: Visceral fat exerts a significant impact on the histopathology of metabolic dysfunction-associated steatotic liver disease (MASLD). Hence, we evaluated the application of the Chinese Visceral Adiposity Index (CVAI), a novel visceral fat marker, in predicting and diagnosing hepatic steatosis and liver fibrosis. Methods: After excluding individuals with liver disease or significant alcohol consumption, a total of 273 patients (57.9% males) aged over 18 were eligible for this cross-sectional study. Chinese Visceral Adiposity Index was calculated by age, Body Mass Index (BMI), waist circumference )WC(, triglyceride, and high-density lipoprotein cholesterol (HDL-C). Hepatic steatosis and fibrosis were measured by elastography. A P-value of less than 0.05 was considered significant. Results: After adjusting for age, gender, metabolic diseases, and visceral obesity indices, each unit increase in CVAI elevated the odds of hepatic steatosis and liver fibrosis by 3.3% (P = 0.002) and 2.9% (P = 0.001), respectively. According to the analysis of variance (ANOVA), the grades of liver steatosis had a great impact on CVAI (P &lt; 0.001), and CVAI well-discriminated grades of liver steatosis. Furthermore, the stages of liver fibrosis greatly impacted CVAI (P &lt; 0.001), but it cannot distinguish the stages of liver fibrosis. The Area Under the Receiver Operating Characteristic Curve (AUROC) for S ≥ S1 was 0.800 (0.747 to 0.846), and for F ≥ F2 was 0.810 (0.759 to 0.855). Conclusions: We concluded that CVAI is a strong predictor and accurate diagnostic factor for liver steatosis and significant fibrosis; thus, it could be a tool for screening individuals at risk of liver steatosis and the irreversible complications of fibrosis.

Significant Within-Individual Variability in VCTE Liver Stiffness Measurements at Two Intercostal Spaces in Subjects with MASLD: Implications for Evaluating Improvement in Liver Fibrosis After Weight-Loss or Liver-Directed Therapy.

Studies have compared the group-averages of liver stiffness measures (LSMs) from multiple rib spaces by vibration-controlled transient elastography (VCTE) to stage liver fibrosis. No previous study has assessed within-individual liver stiffness variation from two rib spaces in individuals with metabolic-dysfunction associated steatotic liver disease (MASLD). We evaluated within-individual LSM variation according to body weight classification and its clinical implication. From October 2019 to March 2024, VCTE was performed on MASLD patients or those at high risk, in accordance with FibroScan guidelines. The LSMs were categorized into stages: <5 kPa (stage 0), 5-7.99 kPa (stage 1), 8-9.99 kPa (stage 2), 10-13.99 kPa (stage 3), and 14+ kPa (stage 4). Measurements with 10 values and IQR/median ≤ 0.30 were included, using SPSS V25.0 for analysis. Among 1107 subjects (age 54.4 ± 13.9 years, 56.9% female), 7.7% were normal weight, 20.7% overweight, 28.9% class 1 obesity, 21.3% class 2 obesity, and 21.2% class 3 obesity. Significant within-individual variation was noted: 67% (0-2 kPa) variation, 23.4% (2.1-6 kPa), and 10% (≥6.1 kPa). Class 3 obese individuals had the maximum variation. Comparing the group-average of LSM at each ICS site showed that 95% of individuals were within one fibrosis stage. While LSM group-averages at different rib sites provides reliable fibrosis staging, significant within-individual variability exists especially in class 3 obesity. This should be considered when serial LSM assessments are used to assess medical therapeutic efficacy.

Development of fully automated models for staging liver fibrosis using non-contrast MRI and artificial intelligence: a retrospective multicenter study

Accurate staging of liver fibrosis (LF) is essential for clinical management in chronic liver disease. While non-contrast MRI (NC-MRI) yields valuable information for liver assessment, its effectiveness in predicting LF remains underexplored. This study aimed to develop and validate artificial intelligence (AI)-powered models utilizing NC-MRI for staging LF. A total of 1726 patients from Shengjing Hospital of China Medical University, registered between October 2003 and October 2022, were retrospectively collected, and divided into development (n=1208) and internal test (n=518) cohorts. An external test cohort consisting of 337 individuals from six centers, registered between June 2015 and November 2022, were also included. All participants underwent NC-MRI (T1-weighted imaging, T1WI; and T2-fat-suppressed imaging, T2FS) and liver biopsies. Two classification models (CMs), named T1 and T2FS, were trained on respective image types using 3D contextual transformer networks and evaluated on both test cohorts. Additionally, three CMs-Clinic, Image, and Fusion-were developed using clinical features, T1 and T2FS scores, and their integration via logistic regression. Classification effectiveness of CMs was assessed using the area under the receiver operating characteristic curve (AUC). A comparison was conducted between the optimal models (OMs) with highest AUC and other methods (transient elastography, five serum biomarkers, and six radiologists). Fusion models (i.e., OM) yielded the highest AUC among the CMs, achieving AUCs of 0.810 for significant fibrosis, 0.881 for advanced fibrosis, and 0.918 for cirrhosis in the internal test cohort, and 0.808, 0.868, and 0.925, respectively, in the external test cohort. The OMs demonstrated superior performance in AUC, significantly surpassing transient elastography (only for staging≥F2 and ≥ F3 grades), serum biomarkers, and three junior radiologists for staging LF. Radiologists, with the aid of the OMs, can achieve a higher AUC in LF assessment. AI-powered models utilizing NC-MRI, including T1WI and T2FS, accurately stage LF. National Natural Science Foundation of China (No. 82071885); General Program of the Liaoning Provincial Department of Education (LJKMZ20221160); Liaoning Province Science and Technology Joint Plan (2023JH2/101700127); the Leading Young Talent Program of Xingliao Yingcai in Liaoning Province (XLYC2203037).

Accurate non-invasive detection of MASH with fibrosis F2-F3 using a lightweight machine learning model with minimal clinical and metabolomic variables

BackgroundThere are no known non-invasive tests (NITs) designed for accurately detecting metabolic dysfunction-associated steatohepatitis (MASH) with liver fibrosis stages F2-F3, excluding cirrhosis—the FDA-defined range for prescribing Resmetirom and other drugs in clinical trials. We aimed to validate and re-optimize known NITs, and most importantly to develop new machine learning (ML)-based NITs to accurately detect MASH F2-F3. MethodsClinical and metabolomic data were collected from 443 patients across three countries and two clinic types (metabolic surgery, gastroenterology/hepatology) covering the entire spectrum of biopsy-proven MASLD, including cirrhosis and healthy controls. Three novel types of ML models were developed using a categorical gradient boosting machine pipeline. These were compared with 24 biomarker, imaging, and algorithm-based NITs with both known cutoffs for MASH F2-F4 and re-optimized cutoffs for MASH F2-F3. ResultsNFS at a − 1.455 cutoff attained an AUC of 0.59, the highest sensitivity (90.9 %, 95 % CI 84.3–95.4), and NPV of 87.2 %. FIB4 risk stratification followed by elastography (8 kPa) had the best specificity (86.9 %) and PPV (63.3 %), with an AUC of 0.57. NFS followed by elastography improved the PPV to 65.3 % and AUC to 0.62. Re-optimized FibroScan-AST (FAST) at a 0.22 cutoff had the highest PPV (69.1 %). ML models using aminotransferases, metabolic syndrome components, BMI, and 3-ureidopropionate achieved an AUC of 0.89, which further increased to 0.91 following hyperparameter optimization and the addition of alpha-ketoglutarate. These new ML models outperformed all other NITs and displayed accuracy, sensitivity, specificity, PPV, and NPV up to 91.2 %, 85.3 %, 97.0 %, 92.4 %, and 90.7 % respectively. The models were reproduced and validated in a secondary sensitivity analysis, that used one of the cohorts as feature selection/training, and the rest as independent validation, likewise outperforming all other NITs. ConclusionsWe report for the first time the diagnostic characteristics of non-invasive, metabolomics-based biomarker models to detect MASH with fibrosis F2-F3 required for Resmetirom treatment and inclusion in ongoing phase-III trials. These models may be used alone or in combination with other NITs to accurately determine treatment eligibility.

Cytokine profiling of plasma in patients with viral hepatitis C

Chronic hepatitis C (CHC) represents a significant public health concern. In the majority of cases, the infection progresses to a chronic form, which is characterised by the development of fibrosis and cirrhosis of the liver. A plethora of cytokines and chemokines are generated as a consequence of inflammatory processes within the liver. These can exert a dual effect, both protective and damaging, particularly in relation to the death of hepatocytes and the progression of liver fibrosis. Furthermore, a number of growth factors have been identified as playing a role in the pathogenesis of CHC. The objective of the study was a comprehensive evaluation of a wide range of cytokines, chemokines and growth factors in the blood plasma of patients with CHC at varying stages of liver fibrosis. The study cohort comprised 63 patients diagnosed with CHC, who were divided into three groups according to the stage of liver fibrosis. The control group comprised healthy individuals (n = 32). Concentrations of the following cytokines were determined in plasma: Interleukins and some cytokines (IL-1α, IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17A, IL-17-E/IL-25, IL-17F, IL-18, IL-27, IFNα, IFNγ, TNFα, TNFβ); chemokines (CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1β, CCL7/MCP-3, CCL11/Eotaxin, CCL22/MDC, CXCL1/GROα, CXCL8/IL-8, CXCL9/MIG, CXCL10/IP-10, CX3CL1/Fractalkine) and growth factors (EGF, FGF-2, Flt-3L, G-CSF, M-CSF, PDGF-AA, PDGF-AB/BB, TGF-α, VEGF-A) by multiplex analysis based on xMAP technology. Nonparametric statistics methods were used for statistical analysis. As a result of the study, increased concentrations of cytokines IL-12 (p40), IL-15, IL-17E/IL-25, IL-27, IFNγ, TNFα, chemokines CXCL9/MIG and CXCL-10/IP-10 and growth factors FGF-2 and M-CSF were found at all stages of liver fibrosis. Elevated concentrations of cytokines IL-1α, IL-1β, IL-2, IL-6, IL-9, IL-10, IL-17F, IFNα, TNFβ, chemokines CCL2/MCP-1, CCL11/Eotaxin, CCL22/MDC and growth factors G-CSF, TGF-α, Flt-3L were found in severe liver fibrosis/cirrhosis. Correlation analysis revealed a relationship of high significance between the severity of liver fibrosis and the content of cytokines IL-6, IFNγ, TNFα, IL-7, chemokines CCL2/MCP-1, CCL11/Eotaxin, CXCL9/MIG, CXCL10/IP-10, CXCL1/GROα, growth factors TGF-α, PDGF-AA, PDGF-AB/BB. Thus, a certain profile of cytokines characteristic for CHC was revealed, cytokines, chemokines and growth factors significant for liver fibrosis in CHC were found.

Relationship between fibrosis-4 index and new onset hypertension in the general population

Abstract Background/Introduction Non-alcoholic fatty liver disease (NAFLD) is a risk for cardiovascular events and malignant tumors as well as liver cirrhosis, and the risk increases with increasing fibrosis of the liver. Thus, the fibrosis-4 (FIB-4) index, developed as a noninvasive test to stage liver fibrosis, may predict the development of hypertension. Purpose The present study investigated the relationship of FIB-4 index with the prevalence and future development of hypertension in the general population. Methods A total of 16125 participants who visited our hospital for a physical check-up at least twice from 2008 to 2018 (male=9700, 52.0±12.3 year-old) were subjected for cross-sectional analysis. Among them, 3995 participants were hypertensive. The remaining 12111 normotensive participants (male=6984, 49.5±11.9 year-old) were followed up for the median of 1643 days with the endpoint being the development of hypertension, defined as systolic blood pressure ≥140mmHg, diastolic blood pressure ≥90mmHg or the use of antihypertensive medication. FIB-4 index was calculated as follows; (age×AST)/(platelet number×√ALT). Results Cross-sectional analysis revealed that FIB-4 index was higher in hypertensive than normotensive participants (1.40±0.74 vs. 1.09±0.54, p&amp;lt;0.001). During the follow-up, 2819 participants (45.7 per 1000 person-year) developed hypertension. The incidence was more frequent in male (55.6 per 1000 person-year) than female participants (32.7 per 1000 person-year, p&amp;lt;0.001). High level of FIB-4 index (≥2.67, n=194) showed a significant impact on the incident hypertension (80.5 per 1000 person-year) as compare with middle (≥1.30, &amp;lt;2.67, n=3082) or low level (&amp;lt;1.30, n=8835) of FIB-4 index (65.4 and 38.8 per 1000 person-year, respectively). Non-adjusted hazard ratio (HR) (95% confidence interval [CI]) of FIB-4 index for the new onset of hypertension was 1.483 (1.416-1.553). In multivariate Cox hazard analysis adjusted for sex, body mass index, systolic blood pressure, pulse rate, serum creatinine, uric acid, HbA1c, LDL-cholesterol, triglyceride, hemoglobin, current smoking, frequent alcohol consumption and family history of hypertension, FIB-4 index was an independent predictor of the development of hypertension (HR 1.321, 95%CI [1.213-1.438]). Similar results were obtained in analyses of male (HR 1.382, 95%CI [1.300-1.470]) and female subgroups (HR 1.369, 95%CI [1.230-1.524]). History of viral hepatitis or frequent alcohol consumption did not affect the results (data not shown). Conclusions FIB-4 index is a useful predictor of the development of hypertension in the general population. Increased risk of cardiovascular events in patients with NAFLD may partially be attributable to the development of or coexistence with hypertension.

Platelet counts to spleen diameter ratio: A promising noninvasive tool for predicting esophageal varices in cirrhosis patients.

Liver cirrhosis is the end stage of progressive liver fibrosis as a consequence of chronic liver inflammation, wherein the standard hepatic architecture is replaced by regenerative hepatic nodules, which eventually lead to liver failure. Cirrhosis without any symptoms is referred to as compensated cirrhosis. Complications such as ascites, variceal bleeding, and hepatic encephalopathy indicate the onset of decompensated cirrhosis. Gastroesophageal varices are the hallmark of clinically significant portal hypertension. To determine the accuracy of the platelet count-to-spleen diameter (PC/SD) ratio to evaluate esophageal varices (EV) in patients with cirrhosis. This retrospective observational study was conducted at Tikur Anbessa Specialized Hospital and Adera Medical Center from January 1, 2019, to December 30, 2023. Data were collected via chart review and direct patient interviews using structured questionnaires. The data were exported to the SPSS software version 26 for analysis and clearance. A receiver operating characteristic curve was plotted for splenic diameter, platelet count, and PC/SD ratio to obtain sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio. Of the 140 participants, 67% were men. Hepatitis B (38%) was the most common cause of cirrhosis, followed by cryptogenic cirrhosis (28%) and hepatitis C (16%). Approximately 83.6% of the participants had endoscopic evidence of EV, whereas 51.1% had gastric varices. Decompensated cirrhosis and PC were associated with the presence of EV with adjusted odds ratios of 12.63 (95%CI: 3.16-67.58, P = 0.001) and 0.14 (95%CI: 0.037-0.52, P = 0.004), respectively. A PC/SD ratio < 1119 had a sensitivity of 86.32% and specificity of 70% with area under the curve of 0.835 (95%CI: 0.736-0.934, P < 0.001). A PC/SD ratio < 1119 predicts EV in patients with cirrhosis. It is a valuable, noninvasive tool for EV risk assessment in resource-limited settings.

Diagnostic role of the fibrosis-4 index and nonalcoholic fatty liver disease fibrosis score as a noninvasive tool for liver fibrosis scoring.

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.

CLINICAL AND DIAGNOSTIC CRITERIALS OF LIVER FIBROSIS FORMATION IN PATIENTS WITH CHRONIC VIRAL HEPATITIS C WITH EXTRAHEPATIVE MANIFESTATIONS

Background: Chronic viral hepatitis C (CVHC) is often associated with various extrahepatic manifestations, which may complicate the disease's progression. Specific Background: Cryoglobulinemia, characterized by the presence of cryoglobulins in the blood, has been implicated in the exacerbation of liver conditions, yet its role in CVHC remains inadequately explored. Knowledge Gap: Despite existing knowledge of the relationship between cryoglobulinemia and liver disease, the specific impact of cryoglobulinemia on the severity of liver fibrosis and associated extrahepatic manifestations in CVHC patients requires further elucidation. Aims: This study aims to investigate the prevalence of extrahepatic manifestations and the extent of liver fibrosis in patients with CVHC who also present with cryoglobulinemia, thereby determining the clinical implications of cryoglobulin presence. Results: Our findings indicate that patients with cryoglobulinemia demonstrate a significantly higher prevalence of extrahepatic manifestations and advanced stages of liver fibrosis compared to those without cryoglobulinemia. Novelty: This research contributes novel insights into the aggravating role of cryoglobulins in the clinical course of CVHC, highlighting their potential as biomarkers for disease severity. Implications: These results underscore the need for enhanced clinical monitoring and tailored therapeutic approaches for CVHC patients with cryoglobulinemia, as their condition may predict a more severe disease trajectory and necessitate more aggressive management strategies.

Hepatic Bone Morphogenetic Protein and Activin Membrane-Bound Inhibitor Levels Decline in Hepatitis C but Are Not Associated with Progression of Hepatocellular Carcinoma.

Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is an antagonist of transforming growth factor (TGF)-β type 1 signaling. BAMBI functions as an anti-fibrotic protein and exerts pro- as well as anti-cancerogenic activities. Our study aimed to correlate hepatocyte BAMBI protein levels in hepatocellular carcinoma (HCC) with T stage, lymph node invasion, vessel invasion, grading, tumor size and Union for International Cancer Control (UICC) stage, as well as with liver inflammation and fibrosis stages. Hepatocyte BAMBI protein expression was assessed by immunohistochemistry in HCC tissues of 320 patients and non-tumor tissues of 51 patients. In the HCC tissues of the whole cohort and sex-specific analysis, BAMBI protein was not related to T stage, vessel invasion, lymph node invasion, histologic grade, UICC stage and tumor size. Accordingly, BAMBI was not associated with overall survival, recurrence-free and metastasis-free survival. BAMBI protein levels in tumor and non-tumor tissues were not related to inflammation and fibrosis grade. BAMBI protein levels in HCC tissues and non-tumor tissues from HCC patients, which were analyzed by immunoblot in a small cohort and by immunohistochemistry in the tissues of patients described above, were similar. Notably, BAMBI protein was low-abundant in HCC tissues of hepatitis C virus (HCV) compared to hepatitis B virus (HBV)-infected patients with comparable disease severity. Immunoblot analysis revealed reduced BAMBI protein in non-tumor tissues of patients with HCV in comparison to patients with HBV and normal human liver tissues. In summary, this analysis showed that hepatocyte BAMBI protein levels of patients with HCC are related to HCV infection rather than the severity of the underlying liver disease and cancer staging.

A Multi-Institutional Study on Ultrasound Image Analysis for Staging HBV-Derived Liver Fibrosis: A Potential Noninvasive Alternative to Liver Stiffness Measurement.

Liver stiffness measurement is principal for staging liver fibrosis but not included in routine examinations. We investigated whether comparable diagnostic performance can be achieved by mining ultrasound images and developing a novel serum index (NSI). Texture features were extracted from ultrasound images. Spearman correlation and logistics regression selected independent variables for significant (F ≥ 2) and advanced (F ≥ 3) fibrosis. We compared the diagnostic performance of transient elastography (TE), ultrasound image biomarker, conventional serum indices (aspartate aminotransferase-to-platelet ratio index, fibrosis-4 index, gamma-glutamyl transpeptidase-to-platelet ratio), and NSI in 365 patients with chronic hepatitis B. Among patients, 52.1% had significant fibrosis and 24.2% had advanced fibrosis. PLT, gamma-glutamyl transferase, prealbumin, and globulin were incorporated into NSI. In the validation group, TE achieved the best performance (area under the curve [AUC]: 0.765 [0.690-0.849] for significant fibrosis; 0.812 [0.745-0.878] for advanced fibrosis), followed by ultrasound image biomarker (AUC: 0.712 [0.629-0.795]; 0.678 [0.595-0.763]) and NSI (AUC: 0.630 [0.534-0.725]; 0.659 [0.572-0.745]), outperforming conventional indices. Texture analysis enhances ultrasound's diagnostic utility, but TE remains superior. When TE is unavailable, ultrasound image analysis and NSI, incorporating prealbumin, can serve as alternative tools for fibrosis staging.

Recent advances of nanomaterials in imaging liver fibrosis

AbstractLiver fibrosis is a pathological process resulting from prolonged exposure to various injury factors. It is characterized by the abnormal proliferation and activation of hepatic stellate cells and excessive deposition of extracellular matrix. If left untreated, it can progress to cirrhosis, liver failure, and even liver cancer. There is currently no efficient and accurate clinical diagnostic method for early liver fibrosis. Therefore, there is an urgent need to address the challenge of accurate staging and early diagnosis of liver fibrosis in clinical practice. Recently, nanomaterials have demonstrated significant potential for enhancing the diagnosis of liver fibrosis. Nanomaterials possess the ability to precisely identify and target the microenvironment associated with liver fibrosis. By enhancing their enrichment in the target area, nanomaterials can improve imaging contrast of fibrosis lesions in the liver, thereby enabling accurate diagnosis of liver fibrosis. Accordingly, this review delves into the latest research and advancements concerning nanomaterials in liver fibrosis diagnosis.

Comparison of Two-Dimensional Shear Wave Elastography Between Two Different Instruments for Hepatocellular Carcinoma Patients.

This study aimed to investigate and compare 2-dimensional shear wave elastography (2D-SWE) measurements and influencing factors among 2 different devices and to evaluate the ability and influencing factors of these measurements to assess liver fibrosis. From October 2022 to September 2023, 290 hepatocellular carcinoma (HCC) patients and 30 healthy volunteers were prospectively included. The 2D-SWE measurements were performed using AixPlorer V (SEmean) and APLIO i900 (CEmean). This study compared 2D-SWE measurements between instruments for evaluating the liver fibrosis stage and analyzed the potential influencing factors. The 2D-SWE measurements obtained by the 2 instruments were significantly different (P < .001), but the differences were significant only for patients with stage F4 liver fibrosis (P < .001) and not for volunteers or patients with stage F0-F3 liver fibrosis (all P > .050). Multivariate linear regression analysis revealed that the factors independently influencing the SEmean were alanine aminotransferase (ALT) (P = .034) and liver fibrosis stage (P < .001), while fibrosis stage (P = .028) was the only factor influencing the CEmean. Although 2D-SWE from the 2 different instruments was capable of detecting liver fibrosis, it yielded varying results in HCC patients. These discrepancies were predominantly observed in patients with F4 liver fibrosis but not in healthy adults or patients with F0-F3 liver fibrosis. One potential contributing factor to the differences between instruments could be ALT levels.

Cellular fibronectin-targeted fluorescent aptamer probes for early detection and staging of liver fibrosis

Liver fibrosis is a key process in the progression of chronic liver disease to cirrhosis. Currently, early diagnosis and precise staging of liver fibrosis remain great challenges. Extracellular matrix (ECM) molecules expressed specifically during liver fibrosis are ideal targets for bioimaging and detection of liver fibrosis. Here, we report that fluorescent probes based on a nucleic acid aptamer (ZY-1) targeting cellular fibronectin (cFN), a critical ECM molecule significantly accumulating during liver fibrosis, are promising bioimaging agents for the staging of liver fibrosis. In the work, the outstanding binding affinity of ZY-1 to cFN was validated through an in vitro model of human-derived hepatic stellate cells (HSCs). Subsequently, we constructed different ZY-1-based fluorescent probes and explored the real-time imaging performance of these fluorescent probes in CCl4-induced mouse models of different liver fibrosis stages. The ZY-1-based fluorescent probes, for the first time, effectively identified and distinguished early-stage liver fibrosis (stage 3 of Ishak 6) from advanced liver fibrosis (stage 5 of Ishak 6). The proof-of-concept study provides compelling evidences that ZY-1-based probes are a promising tool for the early diagnosis and staging of liver fibrosis and paves the way for further development of clinical-related diagnosis strategies for fibrotic diseases of the liver and other organs. Statement of significanceCurrently, early diagnosis and accurate staging of liver fibrosis continue to present significant challenges. This study demonstrates that fluorescent probes based on the nucleic acid aptamer ZY-1, which targets cellular fibronectin (cFN)—a crucial extracellular matrix (ECM) molecule that significantly accumulates during liver fibrosis—are promising bioimaging agents for staging liver fibrosis. The ZY-1-based fluorescent probes effectively identified and differentiated early-stage liver fibrosis from advanced liver fibrosis. This proof-of-concept study not only provides compelling evidence that ZY-1-based probes show promise for the early diagnosis and staging of liver fibrosis but also paves the way for further investigations into the use of ZY-1 in detecting other diseases associated with cFN.