Deletion of GPR81 activates CREB/Smad7 pathway and alleviates liver fibrosis in mice.

BACKGROUND: Enhanced glycolysis is a crucial metabolic event that drives the development of liver fibrosis, but the molecular mechanisms have not been fully understood. Lactate is the endproduct of glycolysis, which has recently been identified as a bioactive metabolite binding to G-protein-coupled receptor 81 (GPR81). We then questioned whether GPR81 is implicated in the development of liver fibrosis. METHODS: The level of GPR81 was determined in mice with carbon tetrachloride (CCl4)-induced liver fibrosis and in transforming growth factor beta 1 (TGF-ß1)-activated hepatic stellate cells (HSCs) LX-2. To investigate the significance of GPR81 in liver fibrosis, wild-type (WT) and GPR81 knockout (KO) mice were exposed to CCl4, and then the degree of liver fibrosis was determined. In addition, the GPR81 agonist 3,5-dihydroxybenzoic acid (DHBA) was supplemented in CCl4-challenged mice and TGF-ß1-activated LX-2 cells to further investigate the pathological roles of GPR81 on HSCs activation. RESULTS: CCl4 exposure or TGF-ß1 stimulation significantly upregulated the expression of GPR81, while deletion of GPR81 alleviated CCl4-induced elevation of aminotransferase, production of pro-inflammatory cytokines, and deposition of collagen. Consistently, the production of TGF-ß1, the expression of alpha-smooth muscle actin (α-SMA) and collagen I (COL1A1), as well as the elevation of hydroxyproline were suppressed in GPR81 deficient mice. Supplementation with DHBA enhanced CCl4-induced liver fibrogenesis in WT mice but not in GPR81 KO mice. DHBA also promoted TGF-ß1-induced LX-2 activation. Mechanistically, GPR81 suppressed cAMP/CREB and then inhibited the expression of Smad7, a negative regulator of Smad3, which resulted in increased phosphorylation of Smad3 and enhanced activation of HSCs. CONCLUSION: GPR81 might be a detrimental factor that promotes the development of liver fibrosis by regulating CREB/Smad7 pathway.

Exploring Fibrosis Pathophysiology in Lean and Obese Metabolic-Associated Fatty Liver Disease: An In-Depth Comparison.

While obesity-related nonalcoholic fatty liver disease (NAFLD) is linked with metabolic dysfunctions such as insulin resistance and adipose tissue inflammation, lean NAFLD more often progresses to liver fibrosis even in the absence of metabolic syndrome. This review aims to summarize the current knowledge regarding the mechanisms of liver fibrosis in lean NAFLD. The most commonly used lean NAFLD models include a methionine/choline-deficient (MCD) diet, a high-fat diet with carbon tetrachloride (CCl4), and a high-fructose and high-cholesterol diet. The major pro-fibrogenic mechanisms in lean NAFLD models include increased activation of the extracellular signal-regulated kinase (ERK) pathway, elevated expression of α-smooth muscle actin (α-SMA), collagen type I, and TGF-ß, and modulation of fibrogenic markers such as tenascin-X and metalloproteinase inhibitors. Additionally, activation of macrophage signaling pathways promoting hepatic stellate cell (HSC) activation further contributes to fibrosis development. Animal models cannot cover all clinical features that are evident in patients with lean or obese NAFLD, implicating the need for novel models, as well as for deeper comparisons of clinical and experimental studies. Having in mind the prevalence of fibrosis in lean NAFLD patients, by addressing specific pathways, clinical studies can reveal new targeted therapies along with novel biomarkers for early detection and enhancement of clinical management for lean NAFLD patients.

Serologic extracellular matrix remodeling markers are related to fibrosis stage and prognosis in a phase 2b trial of simtuzumab in patients with primary sclerosing cholangitis.

BACKGROUND: Novel noninvasive predictors of disease severity and prognosis in primary sclerosing cholangitis (PSC) are needed. This study evaluated the ability of extracellular matrix remodeling markers to diagnose fibrosis stage and predict PSC-related fibrosis progression and clinical events. METHODS: Liver histology and serum markers of collagen formation (propeptide of type III collagen [Pro-C3], propeptide of type IV collagen, propeptide of type V collagen), collagen degradation (type III collagen matrix metalloproteinase degradation product and type IV collagen matrix metalloproteinase degradation product), and fibrosis (enhanced liver fibrosis [ELF] score and its components [metalloproteinase-1, type III procollagen, hyaluronic acid]) were assessed in samples from baseline to week 96 in patients with PSC enrolled in a study evaluating simtuzumab (NCT01672853). Diagnostic performance for advanced fibrosis (Ishak stages 3-6) and cirrhosis (Ishak stages 5-6) was evaluated by logistic regression and AUROC. Prognostic performance for PSC-related clinical events and fibrosis progression was assessed by AUROC and Wilcoxon rank-sum test. RESULTS: Among 234 patients, 51% had advanced fibrosis and 11% had cirrhosis at baseline. Baseline Pro-C3 and ELF score and its components provided moderate diagnostic ability for discrimination of advanced fibrosis (AUROC 0.73-0.78) and cirrhosis (AUROC 0.73-0.81). Baseline Pro-C3, ELF score, and type III procollagen provided a moderate prognosis for PSC-related clinical events (AUROC 0.70-0.71). Among patients without cirrhosis at baseline, median changes in Pro-C3 and ELF score to week 96 were higher in those with than without progression to cirrhosis (both p < 0.001). CONCLUSIONS: Pro-C3 correlated with fibrosis stage, and Pro-C3 and ELF score provided discrimination of advanced fibrosis and cirrhosis and predicted PSC-related events and fibrosis progression. The results support the clinical utility of Pro-C3 and ELF score for staging and as prognostic markers in PSC.

Elastography-The New Standard in the Assessment of Fibrosis After Pediatric Liver Transplantation?

BACKGROUND: The development of graft fibrosis after pediatric liver transplantation (PLT) remains a major concern as it can lead to graft failure and ultimately graft loss. Elastography is a non-invasive method to assess liver fibrosis, but its role in the posttransplant setting is unclear. The aim of our study was to evaluate shear wave elastography (SWE) in the assessment of liver fibrosis after PLT, including split-liver recipients. METHODS: We retrospectively analyzed data from PLT recipients who underwent surveillance liver biopsy and concurrent 2D-SWE during the study period from April 2018 to July 2021. Spearman's correlation was used to compare histologic fibrosis stages with liver stiffness measurements (LSM) by 2D-SWE. AUROC analysis was performed to evaluate the performance. One sample t-test was used to compare results with reference values of healthy children. RESULTS: 62 cases were included. 29% showed histologic fibrosis. LSM by 2D-SWE were feasible in all children regardless of age or graft type. There was a significant correlation between LSM and fibrosis stage for all three scoring systems used (Ishak, p = 0.003; METAVIR, p = 0.005; LAF Score, p = 0.003). Patients with a history of biliary complications had increased liver stiffness (p = 0.015). The AUROC of 2D-SWE for predicting significant liver graft fibrosis was 0.81. Liver stiffness after PLT without graft fibrosis was higher than in healthy subjects, but comparable to that in children with chronic liver disease without fibrosis. CONCLUSION: 2D-SWE can reliably detect children with significant liver graft fibrosis, even in split-liver recipients. This study demonstrates the value of a non-invasive tool for fibrosis staging after PLT. 2D-SWE has the potential to improve long-term outcomes after PLT and to reduce the number of surveillance liver biopsies. But elastography is not a substitute for liver biopsy.

DIAGNOSTIC ACCURACY OF THE NON-INVASIVE MARKERS NFLS, NI-NASH-DS, AND FIB-4 FOR ASSESSMENT OF DIFFERENT ASPECTS OF NON-ALCOHOLIC FATTY LIVER DISEASE IN INDIVIDUALS WITH OBESITY: CROSS-SECTIONAL STUDY.

BACKGROUND: Non-invasive markers have been developed to assess the presence and severity of liver abnormalities related to non-alcoholic fatty liver disease (NAFLD). OBJECTIVE: To analyze the diagnostic accuracy of non-invasive NAFLD markers (NAFLD liver fat score [NLFS], non-invasive non-alcoholic steatohepatitis detection score [NI-NASH-DS] and fibrosis score based on four variables [FIB-4]) in individuals with obesity undergoing bariatric surgery. METHODS: A descriptive retrospective cross-sectional study was carried out enrolling 91 individuals who underwent bariatric surgery at a tertiary-level public university hospital. Non-invasive NAFLD markers were calculated using laboratory tests, clinical and anthropometric variables and diagnostic accuracy tests were calculated comparing them in relation to the gold-standard test for this analysis (histopathological evaluation). RESULTS: A total of 85.7% of the participants were female and mean age was 39.1±9.8 years. The average body mass index was 38.4±3.6 kg/m2. At histopathological examination, 84 (92.3%) patients presented with steatosis, 82 (90.1%) with some type of fibrosis; 21 (23.1%) patients were diagnosed with NASH according to the NAFLD activity score criteria. The overall accuracy of NLFS score was 58.2% for general hepatic steatosis and 61.5% for moderate to severe steatosis. The overall accuracy of FIB-4 was 95.4% for advanced fibrosis. NI-NASH-DS had a 74.7% overall accuracy for NASH. CONCLUSION: In a population of individuals with obesity, the FIB-4 score had high overall accuracy in assessing the presence of advanced liver fibrosis, whereas the NFLS and NI-NASH-DS had moderate accuracies for the assessment of steatosis and NASH, respectively.

Longitudinal Analysis of Mitochondrial Function in a Choline-Deficient L-Amino Acid-Defined High-Fat Diet-Induced Metabolic Dysfunction-Associated Steatohepatitis Mouse Model.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is one of the most common chronic liver diseases worldwide. Some patients with MAFLD develop metabolic dysfunction-associated steatohepatitis (MASH), which can lead to severe liver fibrosis. However, the molecular mechanisms underlying this progression remain unknown, and no effective treatment for MASH has been developed so far. In this study, we performed a longitudinal detailed analysis of mitochondria in the livers of choline-deficient, methionine-defined, high-fat-diet (CDAHFD)-fed mice, which exhibited a MASH-like pathology. We found that FoF1-ATPase activity began to decrease in the mitochondria of CDAHFD-fed mice prior to alterations in the activity of mitochondrial respiratory chain complex, almost at the time of onset of liver fibrosis. In addition, the decrease in FoF1-ATPase activity coincided with the accelerated opening of the mitochondrial permeability transition pore (PTP), for which FoF1-ATPase might be a major component or regulator. As fibrosis progressed, mitochondrial permeability transition (PT) induced in CDAHFD-fed mice became less sensitive to cyclosporine A, a specific PT inhibitor. These results suggest that episodes of fibrosis might be related to the disruption of mitochondrial function via PTP opening, which is triggered by functional changes in FoF1-ATPase. These novel findings could help elucidate the pathogenesis of MASH and lead to the development of new therapeutic strategies.

Egr2 drives the differentiation of Ly6Chi monocytes into fibrosis-promoting macrophages in metabolic dysfunction-associated steatohepatitis in mice.

Metabolic dysfunction-associated steatohepatitis (MASH), previously called non-alcoholic steatohepatitis (NASH), is a growing concern worldwide, with liver fibrosis being a critical determinant of its prognosis. Monocyte-derived macrophages have been implicated in MASH-associated liver fibrosis, yet their precise roles and the underlying differentiation mechanisms remain elusive. In this study, we unveil a key orchestrator of this process: long chain saturated fatty acid-Egr2 pathway. Our findings identify the transcription factor Egr2 as the driving force behind monocyte differentiation into hepatic lipid-associated macrophages (hLAMs) within MASH liver. Notably, Egr2-deficiency reroutes monocyte differentiation towards a macrophage subset resembling resident Kupffer cells, hampering hLAM formation. This shift has a profound impact, suppressing the transition from benign steatosis to liver fibrosis, demonstrating the critical pro-fibrotic role played by hLAMs in MASH pathogenesis. Long-chain saturated fatty acids that accumulate in MASH liver emerge as potent inducers of Egr2 expression in macrophages, a process counteracted by unsaturated fatty acids. Furthermore, oral oleic acid administration effectively reduces hLAMs in MASH mice. In conclusion, our work not only elucidates the intricate interplay between saturated fatty acids, Egr2, and monocyte-derived macrophages but also highlights the therapeutic promise of targeting the saturated fatty acid-Egr2 axis in monocytes for MASH management.

Molecular pathogenesis of metabolic dysfunction-associated steatotic liver disease, steatohepatitis, hepatic fibrosis and liver cirrhosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by intense deposition of fat globules in the hepatic parenchyma that could potentially progress to liver cirrhosis and hepatocellular carcinoma. Here, we evaluated a rat model to study the molecular pathogenesis of the spectrum of MASLD and to screen therapeutic agents. SHRSP5/Dmcr rats were fed a high-fat and cholesterol (HFC) diet for a period of 12 weeks and evaluated for the development of steatosis (MASLD), steatohepatitis, fibrosis and cirrhosis. A group of animals were sacrificed at the end of the 4th, 6th, 8th and 12th weeks from the beginning of the experiment, along with the control rats that received normal diet. Blood and liver samples were collected for biochemical and histopathological evaluations. Immunohistochemical staining was performed for α-SMA and Collagen Type I. Histopathological examinations demonstrated steatosis at the 4th week, steatohepatitis with progressive fibrosis at the 6th week, advanced fibrosis with bridging at the 8th week and cirrhosis at the 12th week. Biochemical markers and staining for α-SMA and Collagen Type I demonstrated the progression of steatosis to steatohepatitis, hepatic fibrosis and liver cirrhosis in a stepwise manner. Control animals fed a normal diet did not show any biochemical or histopathological alterations. The results of the present study clearly demonstrated that the HFC diet-induced model of steatosis, steatohepatitis, hepatic fibrosis and cirrhosis is a feasible, quick and appropriate animal model to study the molecular pathogenesis of the spectrum of MASLD and to screen potent therapeutic agents.

An unbiased ranking of murine dietary models based on their proximity to human metabolic dysfunction-associated steatotic liver disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, encompasses steatosis and metabolic dysfunction-associated steatohepatitis (MASH), leading to cirrhosis and hepatocellular carcinoma. Preclinical MASLD research is mainly performed in rodents; however, the model that best recapitulates human disease is yet to be defined. We conducted a wide-ranging retrospective review (metabolic phenotype, liver histopathology, transcriptome benchmarked against humans) of murine models (mostly male) and ranked them using an unbiased MASLD 'human proximity score' to define their metabolic relevance and ability to induce MASH-fibrosis. Here, we show that Western diets align closely with human MASH; high cholesterol content, extended study duration and/or genetic manipulation of disease-promoting pathways are required to intensify liver damage and accelerate significant (F2+) fibrosis development. Choline-deficient models rapidly induce MASH-fibrosis while showing relatively poor translatability. Our ranking of commonly used MASLD models, based on their proximity to human MASLD, helps with the selection of appropriate in vivo models to accelerate preclinical research.

Monomeric C-reactive protein is associated with severity and prognosis of decompensated hepatitis B cirrhosis.

C-reactive protein (CRP) is an acute-phase protein produced by the liver in response to infection and during chronic inflammatory disorders. Systemic inflammation is a major driver of cirrhosis progression from the compensated to the decompensated stage. Previous studies have shown that pentameric CRP (pCRP) to be a weak predictor of disease severity and prognosis in patients with decompensated hepatitis B cirrhosis, with it being only helpful for identifying patients with a higher short-term risk of death under certain conditions. Accumulating evidence indicates that pCRP dissociates to and acts primarily as the monomeric conformation (mCRP) at inflammatory loci, suggesting that mCRP may be a potentially superior disease marker with higher specificity and relevance to pathogenesis. However, it is unknown whether mCRP and anti-mCRP autoantibodies are associated with disease severity, or progression in decompensated hepatitis B cirrhosis. In this study, we evaluated the serum levels of mCRP and anti-mCRP autoantibodies in patients with decompensated cirrhosis of hepatitis B and their association with disease severity and theoretical prognosis. The results showed that patients with high mCRP and anti-mCRP autoantibody levels had more severe liver damage and that coagulation function was worse in patients with high anti-mCRP autoantibodies. Analysis of the correlation between pCRP, mCRP and anti-mCRP autoantibody levels with Model for End-Stage Liver Disease (MELD), Albumin-Bilirubin (ALBI), and Child-Turcotte-Pugh (CTP) prognostic scores showed that mCRP was the most strongly correlated with MELD score, followed by anti-mCRP autoantibodies; conversely, pCRP was not significantly correlated with prognostic score. Therefore, mCRP and anti-mCRP autoantibodies may be more advantageous clinical indicators than pCRP for evaluating the pathological state of decompensated hepatitis B cirrhosis.

Physical frailty, genetic predisposition, and the risks of severe non-alcoholic fatty liver disease and cirrhosis: a cohort study.

BACKGROUND: Frailty, defined as a phenotype of decreased physiological reserves and diminished ability to respond to stressors, has been linked to the development of chronic diseases. Epidemiological evidence connecting frailty to non-alcoholic fatty liver disease (NAFLD) and cirrhosis risks remain sparse. We aimed to assess the longitudinal associations of frailty with the risks of severe NAFLD and cirrhosis in middle-aged to older adults and further explore the modification role of genetic risk on these associations. METHODS: This study included a total of 398 386 participants from the UK Biobank. Incident cases of severe NAFLD and cirrhosis were ascertained through linked hospital records and death registries. Frailty status was assessed by a modified version of the frailty phenotype, encompassing five key components: weight loss, tiredness, physical activity, gait speed, and grip strength. Participants were classified as pre-frailty if they met one or two of these criteria, and as frailty if they met three or more. Genetic predisposition to NAFLD and cirrhosis was estimated by genetic risk score (GRS) and further categorized into high, intermediate, and low genetic risk levels according to tertiles of GRSs. Cox proportional hazards regression model was employed to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for their associations. RESULTS: The mean (standard deviation) age of the study population was 56.6 (8.03) years. 214 408 (53.8%) of the participants was female; 14 924 (3.75%) of participants met the criteria for frailty, 170 498 (42.8%) for pre-frailty, and 212 964 (53.5%) for non-frailty. Over a median follow-up of 12.0 years, we documented 4439 incident severe NAFLD and 3323 incident cirrhosis cases, respectively. Compared with non-frailty, both pre-frailty (HR: 1.50; 95% CI: 1.40-1.60) and frailty (HR: 1.98; 95% CI: 1.77-2.21) were associated with increased risk of NAFLD. Similar associations were observed for cirrhosis, the corresponding HRs (95% CIs) for non-frailty, pre-frailty, and frailty were 1.00 (reference), 1.29 (1.20, 1.38), and 1.90 (1.66, 2.18). Such associations were consistent across all genetic risk levels, with no observed interactions between frailty and GRSs (all P for interactions ≥0.10). Compared with participants with frailty and a low level of genetic risk, the greatest risk increasement in developing severe NAFLD (HR: 3.36; 95% CI: 2.83-3.99) and cirrhosis (HR: 2.81; 95% CI: 2.29-3.44) was both observed in those with frailty and a high level of genetic risk. CONCLUSIONS: Our findings indicate that frailty is a significant predictor of severe NAFLD and cirrhosis, irrespective of genetic predisposition.

Nomogram for predicting post-therapy recurrence in BCLC A/B hepatocellular carcinoma with Child-Pugh B cirrhosis.

Introduction: This study conducts a retrospective analysis on patients with BCLC stage A/B hepatocellular carcinoma (HCC) accompanied by Child-Pugh B cirrhosis, who underwent transarterial chemoembolization (TACE) in combination with local ablation therapy. Our goal was to uncover risk factors contributing to post-treatment recurrence and to develop and validate an innovative 1-, 3-, and 5-year recurrence free survival (RFS) nomogram. Methods: Data from 255 BCLC A/B HCC patients with Child-Pugh B cirrhosis treated at Beijing You'an Hospital (January 2014 - January 2020) were analyzed using random survival forest (RSF), LASSO regression, and multivariate Cox regression to identify independent risk factors for RFS. The prognostic nomogram was then constructed and validated, categorizing patients into low, intermediate, and high-risk groups, with RFS assessed using Kaplan-Meier curves. Results: The nomogram, integrating the albumin/globulin ratio, gender, tumor number, and size, showcased robust predictive performance. Harrell's concordance index (C-index) values for the training and validation cohorts were 0.744 (95% CI: 0.703-0.785) and 0.724 (95% CI: 0.644-0.804), respectively. The area under the curve (AUC) values for 1-, 3-, and 5-year RFS in the two cohorts were also promising. Calibration curves highlighted the nomogram's reliability and decision curve analysis (DCA) confirmed its practical clinical benefits. Through meticulous patient stratification, we also revealed the nomogram's efficacy in distinguishing varying recurrence risks. Conclusion: This study advances recurrence prediction in BCLC A/B HCC patients with Child-Pugh B cirrhosis following TACE combined with ablation. The established nomogram accurately predicts 1-, 3-, and 5-year RFS, facilitating timely identification of high-risk populations.

Alcohol use disorders and liver fibrosis: an update.

Alcoholic liver disease (ALD) is currently, worldwide, the second most common cause of human fatalities every year. Alcohol use disorders (AUDs) lead to 80% of hepatotoxic deaths, and about 40% of cases of cirrhosis are alcohol-related. An acceptable daily intake (ADI) of ethanol is hard to establish and studies somewhat controversially recommend a variety of dosages of ADI, whilst others regard any intake as dangerous. Steatohepatitis should be viewed as "the rate limiting step": generally, it can be overcome by abstinence, although in some patients, abstinence has little effect, with the risk of fibrosis, leading in some cases to hepatocellular carcinoma (HCC). Chronic alcoholism can also cause hypercortisolism, specifically pseudo-Cushing Syndrome, whose diagnosis is challenging. If fibrosis is spotted early, patients may be enrolled in detoxification programs to achieve abstinence. Treatment drugs include silybin, metadoxine and adenosyl methionine. Nutrition and the proper use of micronutrients are important, albeit often overlooked in ALD treatment. Other drugs, with promising antifibrotic effects, are now being studied. This review deals with the clinical and pathogenetic aspects of alcohol-related liver fibrosis and suggests possible future strategies to prevent cirrhosis.

Clinical profile of adult and pediatric patients with hepatic Wilson's disease.

BACKGROUND: The clinical profile varies in patients with Wilson's disease (WD). There is paucity of data regarding adult and pediatric patients with hepatic WD. METHODS: As many as 140 consecutive patients diagnosed with hepatic WD between December 2006 and January 2021 were included in the study. Data was collected regarding the demographic parameters, clinical presentation, extrahepatic organ involvement, liver histology and laboratory investigations. Adult and children (0-14 years) with hepatic WD were compared regarding these features. RESULT: Eighty-eight adults and 52 children were included in the study. The median age of presentation was 17 years (range: 1.1-42 years). Male preponderance was seen (adult 68/88, 69%; children 40/52, 77%). Adults as compared to children presented more commonly as cirrhosis (52/88 vs. 15/52, p = 0.0005) and with hepatic decompensation (35/88 vs. 9/52, p = 0.005). Presentation with acute-on-chronic liver failure (ACLF) was more common in children (10/52 vs. 2/88, p = 0.0005). Twenty-eight-day mortality was 50% (5/10) in children and none in adults presenting with ACLF. Nazer's Prognostic Index (≥ 7) and New Wilson Index were more accurate in predicting mortality among children with ACLF with AUROC 1, while AARC (APASL ACLF Research Consortium) was less accurate with AUROC 0.45. Liver histology findings were similar in adults and children. Extrahepatic involvement was also similar. (8/88 in adults vs. 3/52 children, p value 0.48). CONCLUSION: Most patients with WD present as cirrhosis in adulthood. ACLF is more common in children. Nazer's prognostic index and new Wilson Index score are accurate in predicting mortality in children with ACLF.

[New progress on diagnosis and treatment for indeterminate-phase chronic hepatitis B virus-infected patients].

Authoritative guidelines at home and abroad typically classify chronic hepatitis B virus (HBV) infection into four stages. However, in clinical practice, a considerable number of patients do not meet the guidelines for staging and are called "indeterminate phase" chronic HBV- infected patients. Studies have shown that patients in the indeterminate phase account for about 30%-50% of chronic HBV infection, have significant liver histological changes or even cirrhosis in a large proportion, and are at a higher risk of HCC and death if they do not receive antiviral therapy. Preliminary research shows that patients in the indeterminate phase who receive antiviral treatment have a good virological response and a remarkable reduced HCC risk. To this end, the 2022 publication "Expert Opinions on Expanding Antiviral Treatment for Chronic Hepatitis B" recommends aggressive treatment for patients with an indeterminate phase who have undergone more than a year of follow-up. However, there is still a lack of unified standards to refine the classification, as well as a lack of effective and rapid non-invasive diagnostic methods to identify patients in the indeterminate phase who are at risk for disease progression. This article aims to review the researches on the proportion, clinical characteristics, disease progression, and treatment benefits to further explore how to better manage indeterminate-phase chronic HBV-infected patients.

Non-invasive biomarkers prognostic of decompensation events in NASH cirrhosis: a systematic literature review.

Liver cirrhosis due to nonalcoholic steatohepatitis (NASH) is a life-threatening condition with increasing incidence world-wide. Although its symptoms are unspecific, it can lead to decompensation events such as ascites, hepatic encephalopathy, variceal hemorrhage, and hepatocellular carcinoma (HCC). In addition, an increased risk for cardiovascular events has been demonstrated in patients with NASH. Pharmacological treatments for NASH cirrhosis are not yet available, one of the reasons being the lack in surrogate endpoints available in clinical trials of NASH cirrhosis. The feasibility of non-invasive prognostic biomarkers makes them interesting candidates as possible surrogate endpoints if their change following treatment would result in better outcomes for patients in future clinical trials of NASH cirrhosis. In this systematic literature review, a summary of the available literature on the prognostic performance of non-invasive biomarkers in terms of cardiovascular events, liver-related events, and mortality is outlined. Due to the scarcity of data specific for NASH cirrhosis, this review includes studies on NAFLD whose evaluation focuses on cirrhosis. Our search strategy identified the following non-invasive biomarkers with prognostic value in studies of NASH patients: NAFLD fibrosis score (NFS), Fibrosis-4 (FIB-4), aspartate aminotransferase (AST) to platelet ratio index (APRI), enhanced liver fibrosis (ELF™), BARD (BMI, AST/ALT (alanine aminotransferase) ratio, diabetes), Hepamet Fibrosis Score (HFS), liver enzymes (AST + ALT), alpha-fetoprotein, platelet count, neutrophil to lymphocyte ratio (NLR), Lysyl oxidase-like (LOXL) 2, miR-122, liver stiffness, MEFIB (liver stiffness measured with magnetic resonance elastography (MRE) + FIB-4), and PNPLA3 GG genotype. The aim of the present systematic literature review is to provide the reader with a summary of the non-invasive biomarkers with prognostic value in NASH cirrhosis and give an evaluation of their utility as treatment monitoring biomarkers in future clinical trials.

Sphingosine-1-phosphate promotes liver fibrosis in metabolic dysfunction-associated steatohepatitis.

AIM: Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most prevalent liver diseases and is characterized by steatosis and the accumulation of bioactive lipids. This study aims to understand the specific lipid species responsible for the progression of liver fibrosis in MASH. METHODS: Changes in bioactive lipid levels were examined in the livers of MASH mice fed a choline-deficient diet (CDD). Additionally, sphingosine kinase (SphK)1 mRNA, which generates sphingosine 1 phosphate (S1P), was examined in the livers of patients with MASH. RESULTS: CDD induced MASH and liver fibrosis were accompanied by elevated levels of S1P and increased expression of SphK1 in capillarized liver sinusoidal endothelial cells (LSECs) in mice. SphK1 mRNA also increased in the livers of patients with MASH. Treatment of primary cultured mouse hepatic stellate cells (HSCs) with S1P stimulated their activation, which was mitigated by the S1P receptor (S1PR)2 inhibitor, JTE013. The inhibition of S1PR2 or its knockout in mice suppressed liver fibrosis without reducing steatosis or hepatocellular damage. CONCLUSION: S1P level is increased in MASH livers and contributes to liver fibrosis via S1PR2.

Bystander Effects and Profibrotic Interactions in Hepatic Stellate Cells during HIV and HCV Coinfection.

This study aims to explore the influence of coinfection with HCV and HIV on hepatic fibrosis. A coculture system was set up to actively replicate both viruses, incorporating CD4 T lymphocytes (Jurkat), hepatic stellate cells (LX-2), and hepatocytes (Huh7.5). LX-2 cells' susceptibility to HIV infection was assessed through measurements of HIV receptor expression, exposure to cell-free virus, and cell-to-cell contact with HIV-infected Jurkat cells. The study evaluated profibrotic parameters, including programed cell death, ROS imbalance, cytokines (IL-6, TGF-ß, and TNF-α), and extracellular matrix components (collagen, α-SMA, and MMP-9). The impact of HCV infection on LX-2/HIV-Jurkat was examined using soluble factors released from HCV-infected hepatocytes. Despite LX-2 cells being nonsusceptible to direct HIV infection, bystander effects were observed, leading to increased oxidative stress and dysregulated profibrotic cytokine release. Coculture with HIV-infected Jurkat cells intensified hepatic fibrosis, redox imbalance, expression of profibrotic cytokines, and extracellular matrix production. Conversely, HCV-infected Huh7.5 cells exhibited elevated profibrotic gene transcriptions but without measurable effects on the LX-2/HIV-Jurkat coculture. This study highlights how HIV-infected lymphocytes worsen hepatic fibrosis during HCV/HIV coinfection. They increase oxidative stress, profibrotic cytokine levels, and extracellular matrix production in hepatic stellate cells through direct contact and soluble factors. These insights offer valuable potential therapies for coinfected individuals.