Fibrosis Stage Research Articles

The influence of peritumoral parenchyma on local tumor progression of hepatocellular carcinoma after thermal ablation: a retrospective multicenter study.

With the increasing importance of thermal ablation (TA) in hepatocellular carcinoma (HCC) treatment, local tumor progression (LTP) has become a nonignorable recurrence type after ablation. To analyze the influence of peritumoral liver parenchyma on LTP and to explore the possible reasons for this influence. Ablated HCCs with peritumoral parenchymal biopsy and ablation margins greater than 5mm were included from two hospitals. The grade of necroinflammatory activity (G) and stage of fibrosis (S) of the parenchyma were evaluated by Scheuer staging system. Univariate/multivariate Cox model was used to analyze the possible factors influencing LTP. Peritumoral satellite focus rate, ablation energy, ablation volume after treatment, ablation volume after one-month, and volume reduction rate were collected and analyzed to explore the possible reasons for influence. Propensity score matching (PSM) was used to balance baselines across different groups. 346 HCCs (64 with LTP, 282 without LTP) were enrolled from January 2013 to June 2022, with a median follow-up of 27 months. Univariate/multivariate analysis showed fibrosis was a protective factor in LTP (OR = 0.70, 95%CI: 0.55-0.89). The low-fibrosis group exhibited higher satellite focus rate (15.6% vs. 8.4%, p = 0.048), lower ablation energy (22637 ± 9424J vs. 33352 ± 13779J, p < 0.001) and higher volume reduction rate (0.33 ± 0.06 vs. 0.25 ± 0.06, p < 0.001) than the high-fibrosis group. Therefore, we speculated that the protective effect of fibrosis was due to its blocking of tumor invasion and reduction of sublethal zones. Fibrosis of the peritumoral liver parenchyma is a stable protective factor in LTP occurrence.

Association between serum remnant cholesterol level and metabolic dysfunction-associated steatotic liver histology.

Estimated remnant cholesterol (Rem-C) level, a risk factor for cardiovascular disease (CVD), is associated with metabolic dysfunction-associated steatotic liver disease (MASLD) diagnosed via ultrasonography. However, the relationship between accurate serum Rem-C level measurements and histological findings of MASLD remains unclear. We aimed to elucidate the relationship between accurately measured serum Rem-C levels and histological findings of MASLD. Cross-sectional single-center observational study. We assessed 222 patients (94 men and 128 women; age 20-80) who were diagnosed with MASLD via liver biopsy with available medical history, physical examination, and biochemical measurement data. Serum ester-type cholesterol and free cholesterol contents in the remnant lipoproteins were measured using an enzymatic method. Serum Rem-C levels were significantly higher in patients with NAFLD activity score (NAS) 5-8, ＞66% steatosis grade, lobular inflammation with ≥5 foci, and many cells/prominent ballooning cells (a contiguous patch of hepatocytes showing prominent ballooning injury) than in patients with NAS 1-4, <33% steatosis grade, lobular inflammation with <2 foci, and few ballooning cells (several scattered balloon cells), respectively. While univariate analysis revealed no significant association between Rem-C levels and advanced fibrosis, a significant association between Rem-C levels and NAS was evident. This relationship remained significant in multivariate analysis adjusted for confounders. Furthermore, in the analysis by sex, these relationships were significant for men but not for women. High serum Rem-C levels were associated with high NAS, but not with fibrosis stage, particularly in men. Controlling serum Rem-C level may improve MASLD activity.

Efficiency of Thyme and Oregano Essential Oils in Counteracting the Hazardous Effects of Malathion in Rats.

The widespread use of MLT may pose numerous hazards to animal breeding, health, and resilience due to the presence of MLT residues in animal feedstuffs, pastures, hay, and cereals. Many medicinal plants provide what is called a generalized anti-toxic remedy. The current study examined hazardous biochemical and histological reactions to MLT and the efficiency of ThEO and OEO essential oils as anti-toxic therapies to return to a natural state after MLT exposure. A total of 75 male albino rats were randomly assigned to two groups: (i) C - MLT, comprising 25 rats, served as the control group; and (ii) C + MLT, with 50 rats that were exposed to 5 mg/kg/BW. After exposure to MLT for 21 days, a return to normal status was determined by subdividing the C + MLT group into two equal groups: ThEO and OEO were used as treatments, with 100 mg/kg body weight of thyme and oregano essential oils, respectively, being administered for 21 days. The results showed a significant decrease in body weight gain (BWG) and final weight (FW) compared to C - MLT, while the therapeutic effects of ThEO and OEO enhanced FW and BWG. Our results indicated that MLT exposure resulted in deficient serum liver function, but that OEO and ThEO therapy brought about a significant improvement in liver enzyme function. Although there was no significant difference in serum aspartate transaminase (AST) or alkaline phosphatase (ALK-Ph) and a significant drop in alanine transaminase (ALT) and acetyl choline-esterase (AChE) levels, the C + MLT group showed hepatic fibrosis in the third stage. Furthermore, histological sections of the OEO and ThEO groups showed reduced hepatocellular damage, inflammation, and hepatic fibrosis. However, there was a significant increase in serum creatinine between the C + MLT and C - MLT groups following exposure to MLT. Histological sections of renal tissue from rats treated with OEO and ThEO showed reduced tubular damage, reduced interstitial inflammation, and preserved renal tissue architecture. In conclusion, OEO and ThEO are potential compounds for use as anti-toxic therapies to return to a natural state after MLT exposure. These compounds could serve as an experimental therapeutic approach against natural toxins, providing a solution to the problems of raising livestock that are exposed to nutritional toxicity.

Association between Helicobacter pylori infection, MASLD, and liver fibrosis in patients with severe obesity: a single-center experience.

Our study sought to evaluate if an association exists between Helicobacter pylori (H. pylori), metabolic dysfunction- associated steatotic liver disease (MASLD), and liver fibrosis in patients with severe obesity (BMI > 35). Our retrospective study included 584 patients over the age of 18years with severe obesity, who underwent preoperative liver transient elastography (VCTE), upper endoscopy, blood work, and intra-operative liver biopsy concurrent with bariatric surgery at a single institution from July 2020 to September 2021. Liver fibrosis scores including FIB-4, APRI, NAFLD fibrosis score, BARD score, AST: ALT ratio, and NAFLD activity score (NAS) were calculated from the laboratory results and liver biopsy findings. The presence or absence of H. pylori was determined based on gastric biopsies obtained during upper endoscopy. Other variables collected included age, gender, mean preoperative weight, BMI, and the presence or absence of comorbidities. Student's t-test and non-parametric testing were used for the analysis of continuous variables and Chi-square analysis was used for categorical data. Of the 584 patients, 14.7% were H. pylori positive and 85.3% were negative. Liver fibrosis scores including FIB-4, APRI, and NAFLD fibrosis scores were significantly higher in the positive group (p < 0.05), but there was no difference in AST: ALT ratio and BARD score. A significantly higher VCTE steatosis and fibrosis scores were noted in the H. pylori-positive group (p < 0.05). Similarly, a significantly higher NAS (NAFLD activity score) on liver biopsies was noted in the positive group, with all the individual components of NAS (steatosis, lobular inflammation, and hepatocyte ballooning) being significantly higher in the positive group (p < 0.05). A significantly higher incidence of fibrosis on liver biopsies was noted in the positive group overall and across all stages of fibrosis (p < 0.05). There were no significant differences between the groups in relation to gender, mean weight, BMI, presence of comorbidities including Diabetes Mellitus, and laboratory values. Our study demonstrates that H. pylori colonization or infection is associated with a higher risk of development of MASLD and progression to fibrosis. Further, population-based studies are needed to corroborate our findings.

Cardiovascular risk in US adults with nonalcoholic steatohepatitis (NASH) vs. matched non-NASH controls, National Health and Nutrition Examination Survey, 2017-2020.

NASH is considered a contributor to atherosclerotic cardiovascular disease (ASCVD) risk; however, its contribution beyond traditional risk factors for CVD, particularly diabetes, is less clearly understood. This study aimed to quantify the cardiovascular-event risk associated with NASH, independent of diabetes status. A cross-sectional analysis was conducted using the 2017-2020 NHANES pre-pandemic cycle. NASH was defined based on presence of steatosis without other causes of liver disease, and FibroScan+AST score from vibration-controlled transient elastography (VCTE). Significant fibrosis (stages F2-F4) was identified by liver stiffness measurement from VCTE. Predicted primary CV-event risk was estimated using both the Pooled Cohort Equations (PCE) and the Framingham Risk Score (FRS). NASH patients were matched with non-NASH controls on age, sex, race/ethnicity, and diabetes status. Weighted logistic regression was conducted, modeling elevated predicted CV risk (binary) as the dependent variable and indicators for NASH / fibrosis stages as independent variables. A sample of 125 NASH patients was matched with 2585 controls. NASH with significant fibrosis was associated with elevated predicted 10-year CV risk, although this association was only statistically significant in PCE analyses (odds ratio and 95% CI 2.34 [1.25, 4.36]). Analyses restricting to ages <65 years showed similar results, with associations of greater magnitude. Independent of diabetes, a significant association was observed between NASH with significant liver fibrosis and predicted primary CV-event risk in US adults, particularly for those <65. These findings suggest the importance of accounting for NASH and liver-fibrosis stage in predicting CV-event risk.

Lactylation signature identifies liver fibrosis phenotypes and traces fibrotic progression to hepatocellular carcinoma.

Precise staging and classification of liver fibrosis are crucial for the hierarchy management of patients. The roles of lactylation are newly found in the progression of liver fibrosis. This study is committed to investigating the signature genes with histone lactylation and their connection with immune infiltration among liver fibrosis with different phenotypes. Firstly, a total of 629 upregulated and 261 downregulated genes were screened out of 3 datasets of patients with liver fibrosis from the GEO database and functional analysis confirmed that these differentially expressed genes (DEGs) participated profoundly in fibrosis-related processes. After intersecting with previously reported lactylation-related genes, 12 DEGs related to histone lactylation were found and narrowed down to 6 core genes using R algorithms, namely S100A6, HMGN4, IFI16, LDHB, S100A4, and VIM. The core DEGs were incorporated into the Least absolute shrinkage and selection operator (LASSO) model to test their power to distinguish the fibrotic stage. Advanced fibrosis presented a pattern of immune infiltration different from mild fibrosis, and the core DEGs were significantly correlated with immunocytes. Gene set and enrichment analysis (GSEA) results revealed that core DEGs were closely linked to immune response and chemokine signaling. Samples were classified into 3 clusters using the LASSO model, followed by gene set variation analysis (GSVA), which indicated that liver fibrosis can be divided into status featuring lipid metabolism reprogramming, immunity immersing, and intermediate of both. The regulatory networks of the core genes shared several transcription factors, and certain core DEGs also presented dysregulation in other liver fibrosis and idiopathic pulmonary fibrosis (IPF) cohorts, indicating that lactylation may exert comparable functions in various fibrotic pathology. Lastly, core DEGs also exhibited upregulation in HCC. Lactylation extensively participates in the pathological progression and immune infiltration of fibrosis. Lactylation and related immune infiltration could be a worthy focus for the investigation of HCC developed from liver fibrosis.

Ultrasonic Assessment of Liver Fibrosis Using One-Dimensional Convolutional Neural Networks Based on Frequency Spectra of Radiofrequency Signals with Deep Learning Segmentation of Liver Regions in B-Mode Images: A Feasibility Study.

The early detection of liver fibrosis is of significant importance. Deep learning analysis of ultrasound backscattered radiofrequency (RF) signals is emerging for tissue characterization as the RF signals carry abundant information related to tissue microstructures. However, the existing methods only used the time-domain information of the RF signals for liver fibrosis assessment, and the liver region of interest (ROI) is outlined manually. In this study, we proposed an approach for liver fibrosis assessment using deep learning models on ultrasound RF signals. The proposed method consisted of two-dimensional (2D) convolutional neural networks (CNNs) for automatic liver ROI segmentation from reconstructed B-mode ultrasound images and one-dimensional (1D) CNNs for liver fibrosis stage classification based on the frequency spectra (amplitude, phase, and power) of the segmented ROI signals. The Fourier transform was used to obtain the three kinds of frequency spectra. Two classical 2D CNNs were employed for liver ROI segmentation: U-Net and Attention U-Net. ROI spectrum signals were normalized and augmented using a sliding window technique. Ultrasound RF signals collected (with a 3-MHz transducer) from 613 participants (Group A) were included for liver ROI segmentation and those from 237 participants (Group B) for liver fibrosis stage classification, with a liver biopsy as the reference standard (Fibrosis stage: F0 = 27, F1 = 49, F2 = 51, F3 = 49, F4 = 61). In the test set of Group A, U-Net and Attention U-Net yielded Dice similarity coefficients of 95.05% and 94.68%, respectively. In the test set of Group B, the 1D CNN performed the best when using ROI phase spectrum signals to evaluate liver fibrosis stages ≥F1 (area under the receive operating characteristic curve, AUC: 0.957; accuracy: 89.19%; sensitivity: 85.17%; specificity: 93.75%), ≥F2 (AUC: 0.808; accuracy: 83.34%; sensitivity: 87.50%; specificity: 78.57%), and ≥F4 (AUC: 0.876; accuracy: 85.71%; sensitivity: 77.78%; specificity: 94.12%), and when using the power spectrum signals to evaluate ≥F3 (AUC: 0.729; accuracy: 77.14%; sensitivity: 77.27%; specificity: 76.92%). The experimental results demonstrated the feasibility of both the 2D and 1D CNNs in liver parenchyma detection and liver fibrosis characterization. The proposed methods have provided a new strategy for liver fibrosis assessment based on ultrasound RF signals, especially for early fibrosis detection. The findings of this study shed light on deep learning analysis of ultrasound RF signals in the frequency domain with automatic ROI segmentation.

Regression of liver fibrosis after HBsAg loss: A prospective matched case-control evaluation using transient elastography and serum enhanced liver fibrosis test.

We assessed the effect of hepatitis B surface antigen (HBsAg) seroclearance (HBsAg-loss) on liver fibrosis regression in patients with chronic hepatitis B (CHB) infection. CHB patients with recent documented HBsAg-loss were age- and gender-matched with treatment-naïve HBeAg-negative CHB infection. Paired assessment with transient elastography and enhanced liver fibrosis (ELF) measurements were performed and repeated at 3years. Fibrosis regression was arbitrarily defined as decrease in ≥1 fibrosis stage by ELF, or combining with reduction >30% in liver stiffness. A total of 142 HBsAg-loss and 142 CHB subjects were recruited (median age 58.1years, 51.4% male). A total of 1.8% (1.4% HBsAg-loss vs 2.1% CHB) achieved combined endpoint of fibrosis regression at 3years. When ELF-only definition of fibrosis regression was used, 14.5% HBsAg-loss and 16.9% CHB subjects achieved this endpoint, which was significantly associated with baseline ELF (hazard ratio (HR) 1.827, 95% confidence interval (CI) 1.085-3.075) and time since HBsAg-loss (HR 2.688, 95% CI 1.257-5.748). While increasing time since HBsAg-loss increased the proportion of ELF-defined fibrosis regression, increasing age was also associated with significant fibrosis. Age of achieving HBsAg-loss (ageSC) was independently associated with high baseline ELF values. Up to 52.3% and 63.8% subjects with ageSC>50 had advanced fibrosis/cirrhosis at baseline and 3years, respectively, compared with 5.9% and 20.6% in subjects with ageSC<50. Fibrosis regression occurred in a minority of subjects achieving HBsAg-loss, which was not significantly different compared with subjects with persistent overt CHB. Subjects after achieving HBsAg-loss, especially among those with ageSC>50, should receive ongoing surveillance for liver-related complications.

Elevated ALT/AST ratio as a marker for NAFLD risk and severity: insights from a cross-sectional analysis in the United States.

The prevalence and incidence of Nonalcoholic fatty liver disease (NAFLD) are increasing worldwide, and NAFLD has emerged as a prominent global health concern. The link between serum alanine aminotransferase (ALT) to aspartate aminotransferase (AST) ratio and NAFLD remains unclear. This study investigated the association between the ALT/AST ratio and NAFLD prevalence, including liver steatosis and fibrosis levels in the population. We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018, including 4753 participants. Subgroup analyses, stratified by age, gender, and body mass index (BMI), were performed, along with adjusted multivariable logistic regression analyses to evaluate the relationship between ALT/AST levels and the likelihood of NAFLD, liver steatosis, and hepatic fibrosis stage. A generalized additive model examined the non-linear relationship between ALT/AST and the probability of developing NAFLD. Among 4753 participants, 1508 (31.73%) were diagnosed with NAFLD. Significant positive correlations between ALT/AST and NAFLD risk were found across all models. In addition, the subgroup analysis by gender, age, and BMI suggested that ALT/AST showed a positive correlation with NAFLD. The ALT/AST ratio was positively correlated with the degree of liver steatosis and liver fibrosis. The correlation between ALT/AST and the incidence of NAFLD showed a non-linear pattern. In women, the non-linear trend is particularly evident, showing an inverted U-shaped curve with an inflection point of 1.302.A receiver operating characteristic (ROC) analysis showed that the predictive value of ALT/AST for NAFLD was better than that of traditional liver enzyme parameters. A higher ALT/AST ratio was independently associated with a significantly higher risk of NAFLD and liver fibrosis within American cohorts. This link is robust among females, children, and adolescents. ALT/AST ratio can be used as a simple and effective noninvasive biomarker to identify individuals with high risk of NAFLD.

Cost-Effectiveness Analysis of Deep Brain Stimulation for the Treatment of Alcohol Use Disorder and Alcoholic Liver Disease.

Alcohol use disorder (AUD) is a major public health concern and cause of mortality and morbidity. Alcohol-associated liver disease (ALD) is a debilitating complication of AUD, mitigated by abstinence from alcohol use. Deep brain stimulation (DBS) is emerging as a potential treatment for AUD. However, its cost-effectiveness compared to the standard medical treatment is unclear. To estimate the cost-effectiveness of DBS compared to medical management for patients with AUD and ALD. We utilized a decision analytic model based on published literature to conduct a cost-effectiveness analysis of costs and health outcomes for DBS and medical management in patients with AUD and ALD. We also carried out a threshold analysis to determine the probability of success necessary for DBS to be cost-effective. Costs were measured in 2024 US dollars and effectiveness in quality-adjusted life years (QALYs). We used a time horizon of 1-2 years and adopted a societal perspective. Our results show that for AUD patients in general, DBS is not cost-effective at any DBS success rate. However, for advanced ALD patients, defined as fibrosis stage 3 or beyond DBS becomes cost-effective. For these patients, DBS is cost-effective over a two-year period at a $100,000 willingness-to-pay threshold at DBS success rates greater than 53%. For advanced decompensated ALD patients, DBS is cost-effective over a one-year period at DBS success rate greater than 35%. Should it prove efficacious, DBS may be cost-effective for patients with AUD and ALD. Thus, future randomized controlled trials to evaluate its efficacy are warranted.

NLRP3 inflammasome pathway involved in the pathogenesis of metabolic associated fatty liver disease

The prevalence of Metabolic-associated fatty liver disease (MAFLD) has been steadily increasing worldwide, paralleling the global epidemic of obesity and diabetes. It is estimated that approximately one-quarter of the global population is affected by MAFLD. Despite its high prevalence, MAFLD often goes undiagnosed due to the lack of specific symptoms in its early stages. However, as the disease progresses, it can lead to more severe liver-related complications such as fibrosis, cirrhosis, and hepatocellular carcinoma. Therefore, we aimed to investigate the expression levels of the nucleotide-binding oligomerization domain, leucine-rich repeat (LRR)—containing proteins (NLR) family pyrin domain-containing protein 3 [NLRP3] inflammasome pathway components, NLRP3 and interleukin 1β (IL-1β) genes in patients with MAFLD with various degrees of steatosis and fibrosis. Participants were classified into two equal groups; MAFLD group: consisted of 120 patients with different degrees of hepatic fibrosis and steatosis based on fibro scan results. The non-MAFLD group was comprised of 107 participants. Molecular analysis of pyrin domain-containing protein 3 and IL-1β relative gene expressions was performed in the blood of all participants, using Real-time quantitative polymerase chain reaction (RT-qPCR). Patients with post-MAFLD hepatic fibrosis had significantly higher relative gene expression levels of IL-1β and NLRP3; with IL-1β > 1.1 had AUC of 0.919, sensitivity of 88.33, specificity of 96.26, PPV of 96.4, and NPV of 88 and 92.3 accuracy (p value < 0.001). NLRP3 > 1.33 had a sensitivity of 97.5, specificity of 99.07, PPV of 99.2, NPV of 97.2, and 98.3 accuracy with an AUC of 0.991 (p value < 0.001) as predictors of post-MAFLD hepatic fibrosis.. A significant increase in the mean relative gene expression levels of both IL-1β and NLRP3 found in patients with early fibrosis (F0-F1-2); 31.97 ± 11.8 and 6.76 ± 2.18, respectively; compared with patients with advanced hepatic fibrosis stages (F2-F3); 2.62 ± 3.71 and 4.27 ± 2.99 (p < 0.001 each). The present study provides novel evidence for the possible involvement of IL-1β and NLRP3 inflammasome in metabolic-associated fatty liver disease pathogenesis and could be valid markers for the early detection of post-MAFLD hepatic fibrosis.

Optimal cut-offs of vibration-controlled transient elastography and magnetic resonance elastography in diagnosing advanced liver fibrosis in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis.

Opinions differ regarding vibration-controlled transient elastography and magnetic resonance elastography (VCTE/MRE) cut-offs for diagnosing advanced fibrosis (AF) in patients with non-alcoholic fatty liver disease (NAFLD). We investigated the diagnostic performance and optimal cut-off values of VCTE and MRE for diagnosing AF. Literature databases, including Medline, EMBASE, Cochrane Library, and KoreaMed, were used to identify relevant studies published up to June 13, 2023. We selected studies evaluating VCTE and MRE regarding the degree of liver fibrosis using liver biopsy as the reference. The sensitivity, specificity, and area under receiver operating characteristics curves (AUCs) of the pooled data for VCTE and MRE for each fibrosis stage and optimal cut-offs for AF were investigated. A total of 19,199 patients from 63 studies using VCTE showed diagnostic AUC of 0.83 (95% confidence interval: 0.80-0.86), 0.83 (0.80-0.86), 0.87 (0.84-0.90), and 0.94 (0.91-0.96) for ≥F1, ≥F2, ≥F3, and F4 stages, respectively. Similarly, 1,484 patients from 14 studies using MRE showed diagnostic AUC of 0.89 (0.86-0.92), 0.92 (0.89-0.94), 0.89 (0.86-0.92), and 0.94 (0.91-0.96) for ≥F1, ≥F2, ≥F3, and F4 stages, respectively. The diagnostic AUC for AF using VCTE was highest at 0.90 with a cut-off of 7.1-7.9 kPa, and that of MRE was highest at 0.94 with a cut-off of 3.62-3.8 kPa. VCTE (7.1-7.9 kPa) and MRE (3.62-3.8 kPa) with the suggested cut-offs showed favorable accuracy for diagnosing AF in patients with NAFLD. This result will serve as a basis for clinical guidelines for non-invasive tests and differential diagnosis of AF.

Diagnostic accuracy of vibration-controlled transient elastography for staging liver fibrosis in autoimmune liver diseases: A systematic review and meta-analysis.

The assessment of liver fibrosis is crucial for managing autoimmune liver diseases such as primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC). However, data on the efficacy of noninvasive tests for these diseases are limited. This meta-analysis evaluated the diagnostic accuracy of vibration-controlled transient elastography (VCTE) for staging fibrosis in patients with autoimmune liver disease. Searches were conducted in PubMed, Embase, CINAHL, Web of Science, and Cochrane Library databases to assess the diagnostic accuracy of VCTE against histology as the reference standard in adult patients with autoimmune liver disease. The summary area under the curve (sAUC) and diagnostic odds ratio were calculated for significant fibrosis (SF), advanced fibrosis (AF), and cirrhosis, according to liver biopsy. Fourteen articles were included, comprising 559 PBC patients from six studies, 388 AIH patients from five studies, and 151 PSC patients from three studies. VCTE demonstrated good performance for fibrosis staging in PBC, AIH, and PSC. In PBC, sAUCs of VCTE were 0.87, 0.89, and 0.99 for staging SF, AF, and cirrhosis, respectively. In AIH, the sAUCs were 0.88, 0.88, and 0.92, respectively, while in PSC, they were 0.88, 0.95, and 0.92, respectively. The cutoff values for AF were 7.5-17.9 kPa in PBC, 8.18-12.1 kPa in AIH, and 9.6 kPa in PSC. VCTE shows high diagnostic accuracy for staging liver fibrosis in patients with autoimmune liver diseases. This non-invasive method serves as a valuable tool for the evaluation and monitoring of fibrosis in these lifelong diseases.

Conditional deletion of CEACAM1 in hepatic stellate cells causes their activation

ObjectivesHepatic CEACAM1 expression declines with advanced hepatic fibrosis stage in patients with metabolic dysfunction-associated steatohepatitis (MASH). Global and hepatocyte-specific deletions of Ceacam1 impair insulin clearance to cause hepatic insulin resistance and steatosis. They also cause hepatic inflammation and fibrosis, a condition characterized by excessive collagen production from activated hepatic stellate cells (HSCs). Given the positive effect of PPARγ on CEACAM1 transcription and on HSCs quiescence, the current studies investigated whether CEACAM1 loss from HSCs causes their activation. MethodsWe examined whether lentiviral shRNA-mediated CEACAM1 donwregulation (KD-LX2) activates cultured human LX2 stellate cells. We also generated LratCre + Cc1fl/fl mutants with conditional Ceacam1 deletion in HSCs and characterized their MASH phenotype. Media transfer experiments were employed to examine whether media from mutant human and murine HSCs activate their wild-type counterparts. ResultsLratCre + Cc1fl/fl mutants displayed hepatic inflammation and fibrosis but without insulin resistance or hepatic steatosis. Their HSCs, like KD-LX2 cells, underwent myofibroblastic transformation and their media activated wild-type HSCs. This was inhibited by nicotinic acid treatment which blunted the release of IL-6 and fatty acids, both of which activate the epidermal growth factor receptor (EGFR) tyrosine kinase. Gefitinib inhibition of EGFR and its downstream NF-κB/IL-6/STAT3 inflammatory and MAPK-proliferation pathways also blunted HSCs activation in the absence of CEACAM1. ConclusionsLoss of CEACAM1 in HSCs provoked their myofibroblastic transformation in the absence of insulin resistance and hepatic steatosis. This response is mediated by autocrine HSCs activation of the EGFR pathway that amplifies inflammation and proliferation.

Role of multiparametric US in the preoperative assessment of hepatic parenchyma in patients with liver tumors.

The aim of this study was to evaluate the diagnostic performance of shear wave elastography (SWE), shear wave dispersion (SWD), and attenuation imaging (ATI) in assessment of hepatic parenchyma in patients with liver tumors before resection. Patients with liver tumors were prospectively enrolled in this study. All participants underwent SWE, SWD, and ATI examinations. Fibrosis stage, necroinflammatory activity and hepatic steatosis grade were determined histopathologically. We evaluated the stability of ATI, SWE and SWD examinations. Multivariable linear regression analyses were conducted to determine the determinant factors for SWE, SWD, attenuation coefficient (AC) values. A receiver operating characteristic (ROC) curve analysis was used to evaluate diagnostic performance of multiparametric US (ultrasond). A total of 280 participants were enrolled in this study. TG (triglyceride) and steatosis for AC value were significant determinant factors. PLT (platelet), PT (prothrombin time), GGT (glutamyl transpeptidase), and fibrosis stage for SWE value were significant determinant factors. PLT, fibrosis stage and inflammation activity for SWD value were significant determinant factors. AC value was correlated with hepatic steatosis. Both SWE and SWD values were correlated with fibrosis stage, inflammation activity, respectively. The area under the ROC (AUROC) curve of ATI for predicting hepatic steatosis grade were 0.910(≥ S1), 0.927(≥ S2), 0.962(= S3), respectively. The AUROC curve of SWE for predicting fibrosis stage were 0.923(≥ S1), 0.934(≥ S2), 0.930(≥ S3), 0.895(= S4), respectively. The AUROC curve of SWD for predicting fibrosis stage were 0.858(≥ S1), 0.886(≥ S2), 0.866(≥ S1) (≥ S3), 0.825(= S4). The AUROC curve of SWE for predicting inflammation activity were 0.846(≥ G1), 0.724(≥ G2), 0.787 (≥ G3), respectively. The AUROC curve of SWD for predicting inflammation activity were 0.777(≥ G1), 0.727(≥ G2), 0.803 (≥ G3), respectively. For patients with liver tumors, ATI technology showed excellent feasibility and diagnostic performance for detecting and grading hepatic steatosis, SWE was more accurate in detecting fibrosis stage than SWD, SWD was not superior to SWE in detecting inflammation activity.

Plasma microRNA-15a/16-1 serves as a non-invasive indicator of liver fibrosis severity in individuals with chronic hepatitis B

BackgroundThe lack of effective non-invasive diagnostic methods for liver fibrosis hinders timely treatment for chronic hepatitis B (CHB) patients, leading to the progression of advanced liver disease. Circulating microRNAs offer a non-invasive approach to fibrosis assessment. MicroRNA-15a/16-1 (miR-15a/16) was reported to be implicated in fibrosis development, but the role of plasma miR-15a/16 in liver fibrosis assessment remains poorly understood. This study explored the importance of plasma miR-15a/16 in assessing liver fibrosis severity of CHB patients. MethodsQuantitative PCR was utilized to measure the levels of plasma miR-15a/16 in 435 patients with CHB and 74 healthy controls. We assessed the correlation between plasma miR-15a/16 levels and liver fibrosis and cirrhosis using Pearson correlation coefficients, multivariate linear and logistic regression models, and smooth curve fitting. Utilizing the receiver operating characteristic (ROC) curve, we examined the diagnostic potential of plasma miR-15a/16 in severe fibrosis and cirrhosis. ResultsPlasma levels of miR-15a/16 in patients with CHB were significantly reduced compared to those in healthy controls. In the CHB cohort, levels were notably decreased in individuals with severe fibrosis or cirrhosis compared to those without severe fibrosis or cirrhosis. Plasma miR-15a/16 levels exhibited a negative relationship with the severity of liver fibrosis, gradually decreasing as the histological fibrosis stage progressed from S0 to S4. Reduced levels of plasma miR-15a/16 were linked to an elevated risk of severe liver fibrosis (miR-15a: odds ratio [OR] = 0.243; 95 % confidence interval [CI]: 0.138, 0.427; miR-16: OR = 0.201; 95 % CI: 0.097, 0.417) and cirrhosis (miR-15a: OR = 0.153; 95 % CI: 0.079, 0.298; miR-16: OR = 0.064; 95 % CI: 0.025, 0.162). MiR-15a achieved an area under the ROC curve of 0.886 and 0.832 for detecting moderate-to-severe fibrosis (S2-S4) and cirrhosis, respectively. MiR-16 demonstrated similar diagnostic values. ConclusionPlasma miR-15a/16 levels were negatively correlated with the severity of liver fibrosis in CHB patients and could serve as a new non-invasive indicator in evaluating liver fibrosis.

Extracellular NAD+ response to post-hepatectomy liver failure: bridging preclinical and clinical findings

Liver fibrosis progressing to cirrhosis is a major risk factor for liver cancer, impacting surgical treatment and survival. Our study focuses on the role of extracellular nicotinamide adenine dinucleotide (eNAD+) in liver fibrosis, analyzing liver disease patients undergoing surgery. Additionally, we explore NAD+’s therapeutic potential in a mouse model of extended liver resection and in vitro using 3D hepatocyte spheroids. eNAD+ correlated with aspartate transaminase (AST) and bilirubin after liver resection (AST: r = 0.2828, p = 0.0087; Bilirubin: r = 0.2584, p = 0.0176). Concordantly, post-hepatectomy liver failure (PHLF) was associated with higher eNAD+ peaks (n = 10; p = 0.0063). Post-operative eNAD+ levels decreased significantly (p < 0.05), but in advanced stages of liver fibrosis or cirrhosis, this decline not only diminished but actually showed a trend towards an increase. The expression of NAD+ biosynthesis rate-limiting enzymes, nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3), were upregulated significantly in the liver tissue of patients with higher liver fibrosis stages (p < 0.0001). Finally, the administration of NAD+ in a 3D hepatocyte spheroid model rescued hepatocytes from TNFalpha-induced cell death and improved viability (p < 0.0001). In a mouse model of extended liver resection, NAD+ treatment significantly improved survival (p = 0.0158) and liver regeneration (p = 0.0186). Our findings reveal that eNAD+ was upregulated in PHLF, and rate-limiting enzymes of NAD+ biosynthesis demonstrated higher expressions under liver fibrosis. Further, eNAD+ administration improved survival after extended liver resection in mice and enhanced hepatocyte viability in vitro. These insights may offer a potential target for future therapies.

Liver fibrosis stage based on the four factors (FIB-4) score or Forns index in adults with chronic hepatitis C.

Liver fibrosis stage based on the four factors (FIB-4) score or Forns index in adults with chronic hepatitis C.

The relationship between CXCR6+CD8+T cells and clinicopathological parameters in patients with primary biliary cholangitis.

CXCR6+CD8+T cells have been implicated in the pathogenesis of various liver and autoimmune diseases. However, their involvement in primary biliary cholangitis (PBC) has not been elucidated. We used immunohistochemistry and flow cytometry to quantify CXCR6+CD8+T cells in hepatic tissue and peripheral blood samples obtained from CXCR6+CD8+T cells obtained from PBC patients. Then, we performed comprehensive statistical analyses to access the correlation between the abundance of these cells and clinical as well as pathological data across different stages of PBC. Our research revealed that CXCR6+ cell frequencies in CD3+CD8+T cells from PBC patients significantly exceeded that of healthy controls (HCs) (2.24 vs. 0.61%, p < 0.01). A similar pattern emerged for hepatic CXCR6+CD8+T cell counts, which were notably higher in the PBC cohort compared to HCs. Our cohort consisted of 118 PBC patients, categorized into 62 early-stage (E-PBC) and 56 late-stage (L-PBC) cases. Notably, significant disparities existed between these groups in terms of liver enzyme and lipid profile levels (p < 0.05), with no notable differences observed in gender, age, blood counts, cholesterol levels, or autoantibodies (p > 0.05). Intriguingly, the quantity of hepatic CXCR6+CD8+T cells per high power field (HPF) was significantly elevated in both E-PBC and L-PBC patients as opposed to normal liver samples, indicating a substantial increase in these cells across all stages of PBC (p = 0.000). Spearman's rank correlation analysis showed a positive correlation between CXCR6+CD8+T cell counts and serum levels of Alkaline Phosphatase (AKP) and Gamma-Glutamyl Transferase (GGT), ANA, IgG and IgM, while revealing a negligible correlation with Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST). Subsequent findings indicated significant variances in CXCR6+ cell numbers not only among different PBC stages but also across various degrees of inflammation and fibrosis (p ≤ 0.007). In a follow-up study post-Ursodeoxycholic Acid (UDCA) treatment, stark differences were identified in biochemical and immunohistochemical profiles between responder (31 patients) and non-responder (33 patients) groups (p < 0.05). A Wilcoxon rank-sum test further demonstrated a significant difference in the level of hepatic CXCR6+CD8+T cells between these two response groups (p = 0.002). CXCR6+CD8+T cells play a vital role in the pathogenesis of PBC, exhibiting correlations with the extent of inflammation, staging of liver fibrosis, and response to pharmacological interventions in PBC patients.

AI-based automation of enrollment criteria and endpoint assessment in clinical trials in liver diseases.

Clinical trials in metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis) require histologic scoring for assessment of inclusion criteria and endpoints. However, variability in interpretation has impacted clinical trial outcomes. We developed an artificial intelligence-based measurement (AIM) tool for scoring MASH histology (AIM-MASH). AIM-MASH predictions for MASH Clinical Research Network necroinflammation grades and fibrosis stages were reproducible (κ = 1) and aligned with expert pathologist consensus scores (κ = 0.62-0.74). The AIM-MASH versus consensus agreements were comparable to average pathologists for MASH Clinical Research Network scores (82% versus 81%) and fibrosis (97% versus 96%). Continuous scores produced by AIM-MASH for key histological features of MASH correlated with mean pathologist scores and noninvasive biomarkers and strongly predicted progression-free survival in patients with stage 3 (P < 0.0001) and stage 4 (P = 0.03) fibrosis. In a retrospective analysis of the ATLAS trial (NCT03449446), responders receiving study treatment showed a greater continuous change in fibrosis compared with placebo (P = 0.02). Overall, these results suggest that AIM-MASH may assist pathologists in histologic review of MASH clinical trials, reducing inter-rater variability on trial outcomes and offering a more sensitive and reproducible measure of patient responses.