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Background and Aims Methods Results Conclusion Metabolic dysfunction‐associated steatohepatitis (MASH) with bridging fibrosis is a critical stage in the evolution of fatty liver disease. Second harmonic generation/two‐photon excitation fluorescence (SHG/TPEF) microscopy with artificial intelligence (AI) provides sensitive and reproducible quantitation of liver fibrosis. This methodology was applied to gain an in‐depth understanding of intra‐stage fibrosis changes and septa analyses in a homogenous, well‐characterised group with MASH F3 fibrosis.Paired liver biopsies (baseline [BL] and end of treatment [EOT]) of 57 patients (placebo, n = 17 and tropifexor n = 40), with F3 fibrosis stage at BL according to the clinical research network (CRN) scoring, were included. Unstained sections were examined using SHG/TPEF microscopy with AI. Changes in liver fibrosis overall and in five areas of liver lobules were quantitatively assessed by qFibrosis. Progressive, regressive septa, and 12 septa parameters were quantitatively analysed.qFibrosis demonstrated fibrosis progression or regression in 14/17 (82%) patients receiving placebo, while the CRN scoring categorised 11/17 (65%) as ‘no change’. Radar maps with qFibrosis readouts visualised quantitative fibrosis dynamics in different areas of liver lobules even in cases categorised as ‘No Change’. Measurement of septa parameters objectively differentiated regressive and progressive septa (p < .001). Quantitative changes in individual septa parameters (BL to EOT) were observed both in the ‘no change’ and the ‘regression’ subgroups, as defined by the CRN scoring.SHG/TPEF microscopy with AI provides greater granularity and precision in assessing fibrosis dynamics in patients with bridging fibrosis, thus advancing knowledge development of fibrosis evolution in natural history and in clinical trials. [ABSTRACT FROM AUTHOR]

Background and Purpose: Liver fibrosis is a wound‐healing reaction which is the main cause of chronic liver diseases worldwide. The activated hepatic stellate cell (aHSC) is the main driving factor in the development of liver fibrosis. Inhibiting autophagy of aHSC can prevent the progression of liver fibrosis, but inhibiting autophagy of other liver cells has opposite effects. Hence, targeted inhibition of autophagy in aHSC is quite necessary for the treatment of liver fibrosis, which prompts us to explore the targeted delivery system of small molecule autophagy inhibitor hydroxychloroquine (HCQ) that can target aHSC and alleviate the liver fibrosis. Methods: The delivery system of HCQ@retinol‐liposome nanoparticles (HCQ@ROL‐LNPs) targeting aHSC was constructed by the film dispersion and pH‐gradient method. TGF‐β‐induced HSC activation and thioacetamide (TAA)‐induced liver fibrosis mice model were established, and the targeting ability and therapeutic effect of HCQ@ROL‐LNPs in liver fibrosis were studied subsequently in vitro and in vivo. Results: HCQ@ROL‐LNPs have good homogeneity and stability. They inhibited the autophagy of aHSC selectively by HCQ and reduced the deposition of extracellular matrix (ECM) and the damage to other liver cells. Compared with the free HCQ and HCQ@LNPs, HCQ@ROL‐LNPs had good targeting ability, showing enhanced therapeutic effect and low toxicity to other organs. Conclusion: Construction of HCQ@ROL‐LNPs delivery system lays a theoretical and experimental foundation for the treatment of liver fibrosis and promotes the development of clinical therapeutic drugs for liver diseases. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Socioeconomic status (SES) is a driver of health disparities and chronic diseases. People with HIV (PWH) are at risk for chronic liver diseases. We evaluated the association between low SES and hepatic outcomes in PWH.We included PWH from a prospective cohort. SES was assessed by the Pampalon material and social deprivation index to classify the cohort into quintiles of deprivation. Multivariable linear regression was used to investigate associations of material and social deprivation with liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) as markers of hepatic fibrosis and steatosis, respectively. Incidence of outcomes was evaluated through survival analysis.Among the 804 PWH included, 45% and 72% were living in areas of the highest material and social deprivation, respectively. Materially deprived PWH were more frequently female and of non‐white ethnicity and had higher prevalence of metabolic comorbidities. After adjustments, material deprivation correlated with increased LSM (β = 1.86, 95% CI 0.53–3.17) but not with CAP (β = 6.47, 95% CI −5.55–18.49). Patients were observed for a median follow‐up of 3.8 years. Incidence of liver‐related events was higher in most materially deprived compared to most privileged PWH (hazard ratio 3.03, 95% CI 1.03–8.92), while there was no difference in extrahepatic outcomes or all‐cause mortality. Social deprivation showed no association with either LSM or clinical outcomes.Living in materially deprived neighbourhoods as a proxy for lower SES, is associated with LSM and liver‐related events in PWH. Future strategies should explore mechanisms underlying these relationships and whether enhanced material security improves hepatic outcomes. [ABSTRACT FROM AUTHOR]

Since organoids were developed 15 years ago, they are now in their adolescence as a research tool. The ability to generate 'tissue in a dish' has created enormous opportunities for biomedical research. We examine the contributions that hepatic organoids have made to three areas of liver research: as a source of cells and tissue for basic research, for drug discovery and drug safety testing, and for understanding disease pathobiology. We discuss the features that enable hepatic organoids to provide useful models for human liver diseases and identify four types of advances that will enable them to become a mature (i.e., adult) research tool over the next 5 years. During this period, advances in single‐cell RNA sequencing and CRISPR technologies coupled with improved hepatic organoid methodology, which enables them to have a wider range of cell types that are present in liver and to be grown in microwells, will generate discoveries that will dramatically advance our understanding of liver development and the pathogenesis of liver diseases. It will generate also new approaches for treating liver fibrosis, which remains a major public health problem with few treatment options. [ABSTRACT FROM AUTHOR]

Background and Aims: Abnormal liver chemistries are common in Turner syndrome (TS). Guidelines suggest that TS patients undergo annual screening of liver enzymes, but the role of non‐invasive screening for steatosis and fibrosis is not clearly defined. We compared the prevalence of hepatic steatosis and fibrosis among TS patients to healthy controls using ultrasound with shear‐wave elastography (SWE) and assessed for risk factors associated with steatosis and fibrosis in TS. Methods: Prospective case–control study of TS versus control patients from 2019 to 2021. All patients underwent abdominal ultrasound with doppler and SWE to assess hepatic fibrosis and steatosis. Risk factors were compared between TS and controls, as well as within the TS group. Results: A total of 55 TS and 50 control patients were included. Mean age was 23.6 years vs. 24.6 years in the control group (p =.75). TS patients had significantly more steatosis (65% vs. 12%, stage 1 vs. 0, p <.0001) and fibrosis (39% vs. 2%, average Metavir F2 vs. F0, p <.00001) than controls. These findings remained significant after adjusting for body mass index (BMI) (p <.01). GGT is more sensitive than AST or ALT in identifying these changes. Conclusion: TS is associated with an increased prevalence of hepatic steatosis and fibrosis compared to healthy controls. Our findings suggest that serum GGT and ultrasound with SWE may help identify TS patients with liver disease. Early risk factor mitigation including timely oestrogen replacement, weight control, normalization of lipids and promoting multidisciplinary collaboration should be encouraged. [ABSTRACT FROM AUTHOR]

Background: Metabolic dysfunction‐associated fatty liver disease (MAFLD) is an emerging risk factor for chronic kidney disease (CKD). N‐terminal propeptide of collagen type 3 (PRO‐C3) is a biomarker of advanced fibrosis in MAFLD and PRO‐C3 may be involved in renal fibrosis. We aimed to use PRO‐C3 measurements to generate a new algorithmic score to test the prediction of MAFLD with chronic kidney disease (MAFLD–CKD). Methods: A derivation and independent validation cohort of 750 and 129 Asian patients with biopsy‐confirmed MAFLD were included. Serum PRO‐C3 concentration was measured and regression analyses were performed to examine associations with MAFLD–CKD. A derivative algorithm for MAFLD–CKD risk prediction was evaluated with receiver operator characteristic (ROC) curve analysis. Results: The study included two Asian cohorts (n = 180 with MAFLD–CKD; mean‐eGFR: 94.93 mL/min/1.73 m2; median‐urinary albumin‐to‐creatinine ratio: 6.58 mg/mmol). PRO‐C3 was associated with the severity of MAFLD‐CKD and independently associated with MAFLD–CKD (adjusted odds ratio = 1.16, 95% confidence interval [CI]: 1.08–1.23, p <.001). A new non‐invasive score (termed PERIOD) including PRO‐C3 efficiently predicted MAFLD‐CKD (AUROC =.842, 95% CI:.805–.875). Accuracy, specificity and negative predictive values were 80.2%, 85.1% and 88.4%, respectively. In the validation cohort, the PERIOD score had good diagnostic performance (AUROC =.807, 95% CI:.691–.893) with similar results in all patient subgroups. In the MAFLD–CKD subgroup, the accuracy for identifying advanced fibrosis was further improved by combining the PRO‐C3‐based ADAPT with the Agile 3+ scores (AUROC =.90, 95% CI:.836–.964). Conclusions: The PERIOD score is helpful for accurately predicting the risk of MAFLD–CKD. PRO‐C3 can also be used to assess liver fibrosis in people with MAFLD–CKD. [ABSTRACT FROM AUTHOR]

Background & Aims: FibroScan® Expert 630 and FibroScan® Mini+430 are novel vibration‐controlled transient elastography devices equipped with the same SmartExam software, which allows continuous measurement of controlled attenuation parameter (CAP) during the entire examination. This study aims to compare the CAP variabilities and the quantification for liver fibrosis and steatosis between the conventional FibroScan and the SmartExam‐equipped machines in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD). Methods: This retrospective study included 118 patients with biopsy‐proven MASLD who underwent liver biopsy at two tertiary centres between 2021 and 2023. Liver stiffness and steatosis measurements were performed using both FibroScan machines and M and XL probes for each individual. Liver histology was used as the reference standard for liver fibrosis and steatosis staging. Results: Standard deviations of continuous CAP (cCAP) were significantly lower than those of CAP for all probes (p <.0001). CAP variability was significantly associated with body mass index (p <.01), probe selection (p <.001) as well as the random effect of centre. Only the effect of probe selection (p <.001) was significantly associated with cCAP variability. No significant difference was found in the performance of staging liver fibrosis and steatosis between two types of machines at the same cut‐offs. Conclusions: The SmartExam‐based VCTE reduces the variability of CAP measurement and achieves a similar accuracy as the FibroScan 502 device for the estimation of both hepatic steatosis and fibrosis. Future studies should determine if cCAP is a better tool to monitor changes in steatosis than the original CAP. [ABSTRACT FROM AUTHOR]

Metabolic‐associated steatotic liver disease (MASLD) encompasses a wide spectrum of metabolic conditions associated with an excess of fat accumulation in the liver, ranging from simple hepatic steatosis to cirrhosis and hepatocellular carcinoma. Finding appropriate tools to study its development and progression is essential to address essential unmet therapeutic and staging needs. This review discusses advantages and shortcomings of different dietary, chemical and genetic factors that can be used to mimic this disease and its progression in mice from a hepatic and metabolic point of view. Also, this review will highlight some additional factors and considerations that could have a strong impact on the outcomes of our model to end up providing recommendations and a checklist to facilitate the selection of the appropriate MASLD preclinical model based on clinical aims. [ABSTRACT FROM AUTHOR]

Objective: Progressive hepatic fibrosis can be considered the final stage of chronic liver disease. Hepatic stellate cells (HSC) play a central role in liver fibrogenesis. Thyroid hormones (TH, e.g. thyroxine; T4 and triiodothyronine; T3) significantly affect development, growth, cell differentiation and metabolism through activation of TH receptor α and/or β (TRα/β). Here, we evaluated the influence of TH in hepatic fibrogenesis. Design: Human liver tissue was obtained from explanted livers following transplantation. TRα‐deficient (TRα‐KO) and wild‐type (WT) mice were fed a control or a profibrogenic methionine‐choline deficient (MCD) diet. Liver tissue was assessed by qRT‐PCR for fibrogenic gene expression. In vitro, HSC were treated with TGFβ in the presence or absence of T3. HSC with stable TRα knockdown and TRα deficient mouse embryonic fibroblasts (MEF) were used to determine receptor‐specific function. Activation of HSC and MEF was assessed using the wound healing assay, Western blotting, and qRT‐PCR. Results: TRα and TRβ expression is downregulated in the liver during hepatic fibrogenesis in humans and mice. TRα represents the dominant isoform in HSC. In vitro, T3 blunted TGFβ‐induced expression of fibrogenic genes in HSC and abrogated wound healing by modulating TGFβ signalling, which depended on TRα presence. In vivo, TRα‐KO enhanced MCD diet‐induced liver fibrogenesis. Conclusion: These observations indicate that TH action in non‐parenchymal cells is highly relevant. The interaction of TRα with TH regulates the phenotype of HSC via the TGFβ signalling pathway. Thus, the TH–TR axis may be a valuable target for future therapy of liver fibrosis. [ABSTRACT FROM AUTHOR]

Background and Aims: As screening for the liver disease and risk‐stratification pathways are not established in patients with type‐2 diabetes mellitus (T2DM), we evaluated the diagnostic performance and the cost‐utility of different screening strategies for MASLD in the community. Methods: Consecutive patients with T2DM from primary care underwent screening for liver diseases, ultrasound, ELF score and transient elastography (TE). Five strategies were compared to the standard of care: ultrasound plus abnormal liver function tests (LFTs), Fibrosis score‐4 (FIB‐4), NAFLD fibrosis score, Enhanced liver fibrosis test (ELF) and TE. Standard of care was defined as abnormal LFTs prompting referral to hospital. A Markov model was built based on the fibrosis stage, defined by TE. We generated the cost per quality‐adjusted life year (QALY) gained and calculated the incremental cost‐effectiveness ratio (ICER) over a lifetime horizon. Results: Of 300 patients, 287 were included: 64% (186) had MASLD and 10% (28) had other causes of liver disease. Patients with significant fibrosis, advanced fibrosis, and cirrhosis due to MASLD were 17% (50/287), 11% (31/287) and 3% (8/287), respectively. Among those with significant fibrosis classified by LSM≥8.1 kPa, false negatives were 54% from ELF and 38% from FIB‐4. On multivariate analysis, waist circumference, BMI, AST levels and education rank were independent predictors of significant and advanced fibrosis. All the screening strategies were associated with QALY gains, with TE (148.73 years) having the most substantial gains, followed by FIB‐4 (134.07 years), ELF (131.68 years) and NAFLD fibrosis score (121.25 years). In the cost‐utility analysis, ICER was £2480/QALY for TE, £2541.24/QALY for ELF and £2059.98/QALY for FIB‐4. Conclusion: Screening for MASLD in the diabetic population in primary care is cost‐effective and should become part of a holistic assessment. However, traditional screening strategies, including FIB‐4 and ELF, underestimate the presence of significant liver disease in this setting. [ABSTRACT FROM AUTHOR]

Background & Aims: The steatosis‐associated fibrosis estimator (SAFE) score was developed to detect clinically significant liver fibrosis in patients with NAFLD in the United States. We compare the performance of the SAFE score and other non‐invasive tests to diagnose liver fibrosis and to correlate the scores with liver‐related outcomes in patients with NAFLD in Hong Kong. Methods: This was a retrospective cohort study involving two data sets. The first cohort was a biopsy cohort of NAFLD patients (n = 279), and the second was a territory‐wide cohort of NAFLD patients (n = 4603) retrieved from a territory‐wide electronic healthcare database in Hong Kong. Results: In detecting significant fibrosis, liver stiffness measured by transient elastography had the highest area under the receiver operating characteristic curve (AUROC) (.844), followed by SAFE score (.773). SAFE score had the highest AUROC among blood‐based algorithms (.773 vs..746 for FIB‐4,.697 for APRI). Based on cut‐off values of SAFE score (0 and 100 points), 854 (18.6%), 1596 (34.6%) and 2153 (46.8%) were in the low‐, intermediate‐ and high‐risk groups, respectively, in the territory‐wide cohort. Six (.7%), 15 (.9%) and 59 (2.7%) developed liver‐related events in those three groups respectively. Among patients who had liver‐related events at 5 years, using the high cut‐off, SAFE score could predict 84.9% of patients accurately, compared to 40.9% for FIB‐4 and 27.2% for APRI. Conclusion: The SAFE score performed well and better than other blood‐based markers in diagnosing significant fibrosis and predicting liver‐related events in Asian patients with NAFLD. [ABSTRACT FROM AUTHOR]

Background and Aims: Schistosoma mansoni infection is one of the worldwide leading causes of liver fibrosis and portal hypertension. The objective of this study was to evaluate whether polyhydroxylated bile acids (BAs), known to protect mice from the development of acquired cholestatic liver injury, counteract S. mansoni‐induced inflammation and fibrosis. Methods: Adult FVB/N wild type (WT) and Abcb11/Bsep−/− mice were infected with either 25 or 50 S. mansoni cercariae. Eight weeks post infection, effects on liver histology, serum biochemistry, gene expression profile of proinflammatory cytokines and fibrotic markers, hepatic hydroxyproline content and FACS analysis were performed. Results: Bsep−/− mice infected with S. mansoni showed significantly less hepatic inflammation and tendentially less fibrosis compared to infected WT mice. Despite elevated alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase levels in infected Bsep−/− mice, inflammatory cells such as M2 macrophages and Mac‐2/galectin‐3+ cells were reduced in these animals. Accordingly, mRNA‐expression levels of anti‐inflammatory cytokines (IL‐4 and IL‐13) were increased in Bsep−/− mice upon infection. Furthermore, infected Bsep−/− mice exhibited decreased hepatic egg load and parasite fecundity, consequently affecting the worm reproduction rate. This outcome could arise from elevated serum BA levels and lower blood pH in Bsep−/− mice. Conclusions: The loss of Bsep and the resulting changes in bile acid composition and blood pH are associated with the reduction of parasite fecundity, thus attenuating the development of S. mansoni‐induced hepatic inflammation and fibrosis. [ABSTRACT FROM AUTHOR]

Background and Purpose: Liver fibrosis is a wound‐healing reaction that eventually leads to cirrhosis. Hydronidone is a new pyridine derivative with the potential to treat liver fibrosis. In this study, we explored the antifibrotic effects of hydronidone and its potential mode of action. Methods: The anti‐hepatic fibrosis effects of hydronidone were studied in carbon tetrachloride (CCl4)‐ and 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC)‐ induced animal liver fibrosis. The antifibrotic mechanisms of hydronidone were investigated in hepatic stellate cells (HSCs). The antifibrotic effect of hydronidone was further tested after Smad7 knockdown in HSCs in mouse models of fibrosis. Results: In animal models, hydronidone attenuated liver damage and collagen accumulation, and reduced the expression of fibrosis‐related genes. Hydronidone decreased the expression of fibrotic genes in HSCs. Impressively, hydronidone significantly upregulated Smad7 expression and promoted the degradation of transforming growth factor β receptor I (TGFβRI) in HSCs and thus inhibited the TGFβ‐Smad signalling pathway. Specific knockdown of Smad7 in HSCs in vivo blocked the antifibrotic effect of hydronidone. Conclusion: Hydronidone ameliorates liver fibrosis by inhibiting HSCs activation via Smad7‐mediated TGFβRI degradation. Hydronidone is a potential drug candidate for the treatment of liver fibrosis. [ABSTRACT FROM AUTHOR]

Background & Aims: Transcription co‐activator factor 20 (TCF20) is a regulator of transcription factors involved in extracellular matrix remodelling. In addition, TCF20 genomic variants in humans have been associated with impaired intellectual disability. Therefore, we hypothesized that TCF20 has several functions beyond those described in neurogenesis, including the regulation of fibrogenesis. Methods: Tcf20 knock‐out (Tcf20−/−) and Tcf20 heterozygous mice were generated by homologous recombination. TCF20 gene genotyping and expression was assessed in patients with pathogenic variants in the TCF20 gene. Neural development was investigated by immufluorescense. Mitochondrial metabolic activity was evaluated with the Seahorse analyser. The proteome analysis was carried out by gas chromatography mass‐spectrometry. Results: Characterization of Tcf20−/− newborn mice showed impaired neural development and death after birth. In contrast, heterozygous mice were viable but showed higher CCl4‐induced liver fibrosis and a differential expression of genes involved in extracellular matrix homeostasis compared to wild‐type mice, along with abnormal behavioural patterns compatible with autism‐like phenotypes. Tcf20−/− embryonic livers and mouse embryonic fibroblast (MEF) cells revealed differential expression of structural proteins involved in the mitochondrial oxidative phosphorylation chain, increased rates of mitochondrial metabolic activity and alterations in metabolites of the citric acid cycle. These results parallel to those found in patients with TCF20 pathogenic variants, including alterations of the fibrosis scores (ELF and APRI) and the elevation of succinate concentration in plasma. Conclusions: We demonstrated a new role of Tcf20 in fibrogenesis and mitochondria metabolism in mice and showed the association of TCF20 deficiency with fibrosis and metabolic biomarkers in humans. [ABSTRACT FROM AUTHOR]

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is a major health burden associated with the metabolic syndrome leading to liver fibrosis, cirrhosis and ultimately liver cancer. In humans, the PNPLA3 I148M polymorphism of the phospholipase patatin‐like phospholipid domain containing protein 3 (PNPLA3) has a well‐documented impact on metabolic liver disease. In this study, we used a mouse model mimicking the human PNPLA3 I148M polymorphism in a long‐term high fat diet (HFD) experiment to better define its role for NAFLD progression. Methods: Male mice bearing wild‐type Pnpla3 (Pnpla3WT), or the human polymorphism PNPLA3 I148M (Pnpla3148M/M) were subjected to HFD feeding for 24 and 52 weeks. Further analysis concerning basic phenotype, inflammation, proliferation and cell death, fibrosis and microbiota were performed in each time point. Results: After 52 weeks HFD Pnpla3148M/M animals had more liver fibrosis, enhanced numbers of inflammatory cells as well as increased Kupffer cell activity. Increased hepatocyte cell turnover and ductular proliferation were evident in HFD Pnpla3148M/M livers. Microbiome diversity was decreased after HFD feeding, changes were influenced by HFD feeding (36%) and the PNPLA3 I148M genotype (12%). Pnpla3148M/M mice had more faecal bile acids. RNA‐sequencing of liver tissue defined an HFD‐associated signature, and a Pnpla3148M/M specific pattern, which suggests Kupffer cell and monocytes‐derived macrophages as significant drivers of liver disease progression in Pnpla3148M/M animals. Conclusion: With long‐term HFD feeding, mice with the PNPLA3 I148M genotype show exacerbated NAFLD. This finding is linked to PNPLA3 I148M‐specific changes in microbiota composition and liver gene expression showing a stronger inflammatory response leading to enhanced liver fibrosis progression. [ABSTRACT FROM AUTHOR]

Our previous study found that double negative T cells (DNTs) could promote the NLRP3 activation through high expression of TNF‐α, thereby leading to hepatic fibrosis progression. We focused on investigating the role and mechanism of DNTs in regulating the Th9 cells differentiation in liver fibrosis. In our results, among patients with liver fibrosis, the proportions of peripheral blood DNTs and Th9 cells were up‐regulated and positively correlated. While promoting the progression of liver fibrosis in mice, DNTs could elevate the proportion of Th9 cells and activate the TNFR2‐STAT5‐NF‐κB pathway. The use of IL‐9 and TNF‐α monoclonal antibodies (mAbs) inhibited the effect of DNTs and lowered the proportion of Th9 cells in tissues. In vitro experiments showed that DNTs could promote the Th9 cells differentiation of Naive T cells, while TNF‐α mAbs could inhibit such effect of DNTs to lower the proportion of Th9 cells. We found that DNTs can activate TNFR2‐STAT5‐NF‐κB pathway by secreting TNF‐α, thereby promoting the Th9 Cells differentiation to facilitate the progression of liver fibrosis. There is interaction between DNTs and Th9 cells. [ABSTRACT FROM AUTHOR]

Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Aberrant lipid metabolism and accumulation of extracellular matrix proteins are hallmarks of the disease, but the underlying mechanisms are largely unknown. This study aims to elucidate the key role of sine oculis homeobox homologue 1 (SIX1) in the development of NAFLD. Methods: Alb‐Cre mice were administered the AAV9 vector for SIX1 liver‐specific overexpression or knockdown. Metabolic disorders, hepatic steatosis, and inflammation were monitored in mice fed with HFHC or MCD diet. High throughput CUT&Tag analysis was employed to investigate the mechanism of SIX1 in diet‐induced steatohepatitis. Results: Here, we found increased SIX1 expression in the livers of NAFLD patients and animal models. Liver‐specific overexpression of SIX1 using adeno‐associated virus serotype 9 (AAV9) provoked more severe inflammation, metabolic disorders, and hepatic steatosis in the HFHC or MCD‐induced mice model. Mechanistically, we demonstrated that SIX1 directly activated the expression of liver X receptor α (LXRα) and liver X receptor β (LXRβ), thus inducing de novo lipogenesis (DNL). In addition, our results also illustrated a critical role of SIX1 in regulating the TGF‐β pathway by increasing the levels of type I and II TGF‐β receptor (TGFβRI/TGFβRII) in hepatic stellate cells (HSCs). Finally, we found that liver‐specific SIX1 deficiency could ameliorate diet‐induced NAFLD pathogenesis. Conclusion: Our findings suggest a detrimental function of SIX1 in the progression of NAFLD. The direct regulation of LXRα/β and TGF‐β signalling by SIX1 provides a new regulatory mechanism in hepatic steatosis and fibrosis. [ABSTRACT FROM AUTHOR]

Background and Aims: Liver diseases present a wide range of fibrosis, from fatty liver with no inflammation to steatohepatitis with varying degrees of fibrosis, to established cirrhosis leading to HCC. In a multivariate analysis, serum levels of spermidine were chosen as the top metabolite from 237 metabolites and its levels were drastically reduced along with progression to advanced steatohepatitis. Our previous studies that showed spermidine supplementation helps mice prevent liver fibrosis through MAP1S have prompted us to explore the possibility that spermidine can alleviate or cure already developed liver fibrosis. Methods: We collected tissue samples from patients with liver fibrosis to measure the levels of MAP1S. We treated wild‐type and MAP1S knockout mice with CCl4‐induced liver fibrosis with spermidine and isolated HSCs in culture to test the effects of spermidine on HSC activation and liver fibrosis. Results: Patients with increasing degrees of liver fibrosis had reduced levels of MAP1S. Supplementing spermidine in mice that had already developed liver fibrosis after 1 month of CCl4 induction for an additional 3 months resulted in significant reductions in levels of ECM proteins and a remarkable improvement in liver fibrosis through MAP1S. Spermidine also suppressed HSC activation by reducing ECM proteins at both the mRNA and protein levels, and increasing the number of lipid droplets in stellate cells. Conclusions: Spermidine supplementation is a potentially clinically meaningful approach to treating and curing liver fibrosis, preventing cirrhosis and HCC in patients. [ABSTRACT FROM AUTHOR]

Background and Aims: Liver fibrosis is an excessive wound‐healing response governed by activated hepatic stellate cells (HSCs). To date, there is no drug available for liver fibrosis. Although ferulic acid (FA) has multiple pharmacological functions, its anti‐hepatic fibrosis activity is weak. Based on the activity modification of the FA structure, we synthesized a series of phenylacrylic derivatives and found a superior compound, FA11. In this study, we investigated its antifibrotic effect and mechanism. Methods: Activated HSC and CCl4‐induced mouse liver fibrosis were established and followed by FA11 treatment. Cell viability was measured by CCK‐8 assay. Apoptosis and cell cycle analysis were conducted by flow cytometry. Western blot and Real‐time qPCR were used to examine the expression of fibrotic and M1/M2‐type macrophages markers. Degree of liver fibrosis was shown by histological staining. Results: In vitro, FA11 inhibited TGF‐β1‐induced LX‐2 proliferation and led to apoptosis and cycle arrest. Furthermore, elevation of fibrotic markers in TGF‐β1‐induced LX‐2 and primary activated HSC was reversed by FA11. In vivo, FA11 administration alleviated collagen deposition and blocked HSC activation and epithelial‐mesenchymal transition (EMT). Additionally, FA11 reduced macrophage infiltration in fibrotic liver and prevented macrophage polarization to a profibrotic phenotype. Meanwhile, the systemic toxicity of CCl4 was also ameliorated by FA11. Mechanistically, FA11 reversed the phosphorylation of canonical and noncanonical TGF‐β1 signalling, as well as FGFR1 signalling. Conclusions: We reported an oral phenylacrylic acid derivative, FA11, which showed excellent antifibrotic activity and was expected to be an anti‐hepatic fibrosis candidate. [ABSTRACT FROM AUTHOR]

Background and Aims: Cardiovascular disease (CVD) is the main cause of mortality in subjects with non‐alcoholic fatty liver disease (NAFLD). We investigated the association between CVD risk and metabolic dysfunction‐associated fatty liver disease (MAFLD) or NAFLD and the influence of significant liver fibrosis on the CVD risk. Methods: Subjects who underwent a comprehensive medical check‐up were recruited (2014–2019). Significant liver fibrosis was defined using NAFLD fibrosis score, fibrosis‐4 index, aspartate aminotransferase to platelet ratio index, or FibroScan‐aspartate aminotransferase score. High probability of atherosclerotic CVD (ASCVD) was defined as ASCVD risk score > 10%. Results: Of the study population (n = 78 762), 27 047 (34.3%) and 24 036 (30.5%) subjects had MAFLD and NAFLD respectively. A total of 1084 (4.0%) or 921 (3.8%) subjects had previous CVD history in MAFLD or NAFLD subgroup respectively. The previous CVD history and high probability of ASCVD were significantly higher in MAFLD or NAFLD subgroup with significant liver fibrosis than in the other groups (all p <.001). In multivariable analysis, MAFLD was independently associated with previous CVD history after adjusting for confounders (adjusted odds ratio [aOR] = 1.10, p =.038), whereas NAFLD was not (all p >.05). MAFLD (aOR = 1.40) or NAFLD (aOR = 1.22) was independently associated with high probability of ASCVD after full adjustment respectively (all p <.001). Significant liver fibrosis was independently associated with previous CVD history and high probability of ASCVD after adjustment in MAFLD or NAFLD subgroup respectively (all p <.05). Conclusion: MAFLD might better identify subjects with CVD risk than NAFLD. Fibrosis assessment might be helpful for detailed prognostication in subjects with MAFLD. [ABSTRACT FROM AUTHOR]

Introduction: Lomitapide is a microsomal triglyceride transfer protein inhibitor for patients with homozygous familial hypercholesterolaemia. Due to its mechanism of action, potential hepatic effects of lomitapide are of clinical interest. This study aimed to determine the long‐term hepatic safety of lomitapide. Methods: Data were aggregated from the pivotal phase 3 and extension phase clinical trial with lomitapide (median 5.1 years; serum total bilirubin, transaminases, cytokeratin‐18 [CK‐18] and enhanced liver fibrosis [ELF] score, fat‐soluble vitamins and essential fatty acids), 8‐year data from the Lomitapide Observational Worldwide Evaluation Registry (LOWER) and real‐world evidence from a cohort of patients treated with lomitapide in Italy (hepatic elastography, and FIB‐4 score for hepatic fibrosis). Results: In the phase 3 trial and the LOWER registry, any asymptomatic excursions in liver transaminase levels were not associated with elevations in bilirubin, and no Hy's law cases were detected in up to 8 years follow‐up. There were no clinically relevant increases among hepatic biomarkers CK‐18, CK‐18 fragments or ELF score and fat‐soluble vitamins and essential fatty acids remained above normal levels. In 34 patients treated in Italy with lomita pide for more than 9 years, elevations in hepatic fat were mild‐to‐moderate; hepatic stiffness remained normal, and the mean FIB‐4 score remained below the fibrosis threshold value of 2.67. Conclusions: These data indicate that the hepatic safety of lomitapide remains favourable with no clinically significant elevations in hepatic biomarkers and hepatic stiffness remained normal for more than 9 years follow‐up. Phase 3 trial: NCT00730236; extension phase: NCT00943306; LOWER: NCT02135705. [ABSTRACT FROM AUTHOR]

Non‐alcoholic fatty liver disease (NAFLD) affects at least 25% of the general population and is an increasingly important cause of cirrhosis and hepatocellular carcinoma. Although it is the research focus of the hepatology field, it is clear that primary care physicians are seeing the majority of NAFLD patients and are in a pivotal position to provide quality care. In this article, we review the role of primary care in the management of NAFLD. NAFLD is common in patients with diabetes, obesity and other metabolic risk factors. Abdominal ultrasonography is the most commonly used method to diagnose fatty liver. Simple fibrosis scores have high negative predictive values in excluding advanced liver fibrosis and future liver‐related events and can be used in primary care as initial evaluation. An abnormal result should be followed by subsequent workup or specialist referral. Primary care is the ideal setting to institute multidisciplinary care, especially the involvement of dietitians and physical activity trainers in lifestyle intervention, as well as initiating the discussion of bariatric surgery in patients with severe obesity. Although specific drug treatment for steatohepatitis would require a more precise diagnosis, metabolic drugs that improve both steatohepatitis and cardiovascular outcomes (e.g. glucagon‐like peptide‐1 receptor agonists) may be considered in patients with NAFLD. [ABSTRACT FROM AUTHOR]

Purpose: The purpose was to explore the value of liver fibrosis scores (fibrosis‐4, BAAT score and BARD score) for incidence risk of stroke in a cohort study. Methods: A total of 9088 participants without stroke history enrolled the follow‐up. Three liver fibrosis scores (LFSs) including FIB‐4, BARD score and BAAT score were adopted. The end point was stroke. Cox regression analysis was used to calculate hazard ratios and 95% confidence interval. Kaplan–Meier curve was used to show the probability of stoke in different levels of LFSs. Subgroup analysis showed the association between LFSs and stroke under different stratification. Restricted cubic spline could further explore whether there is a linear relationship between LFSs and stroke. Finally, we used C‐statistics, Net Reclassification Index (NRI) and Integrated Discrimination Improvement (IDI) to assess the discriminatory power of each LFS for stroke. Results: During a median follow‐up time of 4.66 years, 272 participants had a stroke. Through the baseline characteristics, we observed that the stroke incidence population tends to be male and older. It was shown by Kaplan–Meier that three LFSs were associated with stroke and high levels of LFSs significantly increase the probability of stroke. In the univariate Cox regression analysis, the HR of stroke risk was 6.04 (4.14–8.18) in FIB‐4, 2.10 (1.45–3.04) in BAAT score and 1.81 (1.38–2.38) in BARD score by comparing the high level with the low level at each LFSs. The adjusted HRs for three LFSs were 2.05 (1.33–3.15) in FIB‐4, 1.61 (1.10–2.35) in BAAT score and 1.54 (1.17–2.04) in BARD score by comparing the high group with low group. We found that multivariable‐adjusted HRs of three LFSs still increased for stroke when stratified by various factors in subgroup analysis. Moreover, after adding LFSs to original risk prediction model which consist of age, sex, drinking, smoking, hypertension, diabetes, low‐density lipoprotein cholesterol, total cholesterol and triglycerides, we found that new models have higher C‐statistics of stroke. Furthermore, we calculated Net Reclassification Index (NRI) and Integrated Discrimination Improvement (IDI) to show the ability of LFSs to predict stroke. Conclusions: Our study showed that three LFSs were associated with stroke amongst middle‐aged populations in rural areas of Northeast China. Furthermore, it suggests that LFSs can be used as a risk stratification tool to predict stroke. [ABSTRACT FROM AUTHOR]

Background and Aims: ElastPQ is a point shear wave elastography technique used to non‐invasively assess liver fibrosis. We compared liver stiffness measurements (LSM) by ElastPQ and fibroscan transient elastography (F‐TE) in a cohort of patients with non‐alcoholic fatty liver disease (NAFLD). We further evaluated the performance of ElastPQ in a subgroup of patients with available liver histology. Materials and Methods: We included patients with NAFLD who presented in a dedicated multidisciplinary clinic. Anthropometric parameters, blood tests and elastography measurements were obtained using F‐TE and ElastPQ as part of routine clinical care. Results: We enrolled 671 patients with NAFLD, mean age 55.8 ± 13 years, body mass index (BMI) 31.5 ± 5.7 kg/m2, 56.6% males, 41% diabetes, 53.7% hypertension, 68% dyslipidaemia. ElastPQ showed an excellent correlation with F‐TE (Spearman's r = 0.80, p <.001), which was better for mild/moderate stages of fibrosis. Independent predictors of a >2 kPa discrepancy between the two techniques were a larger waist circumference and F‐TE ≥10 kPa. In the subgroup of 159 patients with available histology, ElastPQ showed similar diagnostic accuracy with F‐TE in staging liver fibrosis (ElastPQ area under the curves 0.84, 0.83, 0.86 and 0.95, for F ≥ 1, F ≥ 2, F ≥ 3 and F = 4 respectively). Optimal cut‐off values of ElastPQ for individual fibrosis stages were lower than those of F‐TE. Conclusions: ElastPQ shows an excellent correlation with F‐TE in patients with NAFLD, which was better for lower LSM. The optimal cut‐off values of ElastPQ are lower than those of F‐TE for individual stages of fibrosis. ElastPQ has similar diagnostic accuracy to F‐TE for all stages of fibrosis. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) infection and nonalcoholic fatty liver disease (NAFLD) are two major causes of chronic liver disease (CLD) that can cause liver cirrhosis and hepatocellular carcinoma (HCC). It is a trend to superimpose NAFLD on chronic HBV infection in Asia. This review presents the epidemiology of concurrent NAFLD in chronic hepatitis B (CHB) patients and focuses on the impact of concurrent NAFLD on the outcome of CHB patients in Asia. Although CHB patients tend to have a lower prevalence and incidence of NAFLD than the general population, concurrent NAFLD among CHB patients is still common and has an upward trend over time. Concurrent NAFLD can promote hepatitis B surface antigen (HBsAg) seroclearance and might inhibit HBV replication but exacerbate liver fibrosis. The impacts of concurrent NAFLD on HCC risk, all-cause mortality and antiviral treatment response in CHB patients remain controversial. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, affecting approximately 25% of the world's population. Recently, because of the sedentary lifestyle and overnutrition resulting from urbanisation, the burden of NAFLD has rapidly increased in many Asian countries. Currently, the prevalence of NAFLD in Asia is approximately 30%, as is the case in many Western countries. In Asia, the prevalence and presentation of NAFLD vary widely across regions because of the substantial diversity in race, socioeconomic status and living environment. Furthermore, the dual aetiology of fatty liver, particularly with viral hepatitis in Asia, makes it complex and challenging to manage. Because Asians are likely to have central adiposity and insulin resistance, approximately 7%-20% of non-obese Asians with body mass indexes of less than 25 kg/m² are estimated to have NAFLD. Accumulating evidence indicates that NAFLD is associated with various extrahepatic comorbidities such as cardiovascular disease, chronic kidney disease, malignancy, in addition to liver-specific complications. Therefore, NAFLD should be managed as a multisystem disease in conjunction with metabolic syndrome. Lifestyle modification remains the basis of NAFLD management, but few patients can achieve adequate weight loss and maintain it long term. While various pharmacological agents are in phase 3 trials for steatohepatitis, Asian patients are underrepresented in most trials. This article reviews the epidemiological trends, clinical features, optimal assessment and current management practices for NAFLD in Asia. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) infection and nonalcoholic fatty liver disease (NAFLD) are two major causes of chronic liver disease (CLD) that can cause liver cirrhosis and hepatocellular carcinoma (HCC). It is a trend to superimpose NAFLD on chronic HBV infection in Asia. This review presents the epidemiology of concurrent NAFLD in chronic hepatitis B (CHB) patients and focuses on the impact of concurrent NAFLD on the outcome of CHB patients in Asia. Although CHB patients tend to have a lower prevalence and incidence of NAFLD than the general population, concurrent NAFLD among CHB patients is still common and has an upward trend over time. Concurrent NAFLD can promote hepatitis B surface antigen (HBsAg) seroclearance and might inhibit HBV replication but exacerbate liver fibrosis. The impacts of concurrent NAFLD on HCC risk, all‐cause mortality and antiviral treatment response in CHB patients remain controversial. [ABSTRACT FROM AUTHOR]

Non‐alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, affecting approximately 25% of the world's population. Recently, because of the sedentary lifestyle and overnutrition resulting from urbanisation, the burden of NAFLD has rapidly increased in many Asian countries. Currently, the prevalence of NAFLD in Asia is approximately 30%, as is the case in many Western countries. In Asia, the prevalence and presentation of NAFLD vary widely across regions because of the substantial diversity in race, socioeconomic status and living environment. Furthermore, the dual aetiology of fatty liver, particularly with viral hepatitis in Asia, makes it complex and challenging to manage. Because Asians are likely to have central adiposity and insulin resistance, approximately 7%‐20% of non‐obese Asians with body mass indexes of less than 25 kg/m2 are estimated to have NAFLD. Accumulating evidence indicates that NAFLD is associated with various extrahepatic comorbidities such as cardiovascular disease, chronic kidney disease, malignancy, in addition to liver‐specific complications. Therefore, NAFLD should be managed as a multisystem disease in conjunction with metabolic syndrome. Lifestyle modification remains the basis of NAFLD management, but few patients can achieve adequate weight loss and maintain it long term. While various pharmacological agents are in phase 3 trials for steatohepatitis, Asian patients are underrepresented in most trials. This article reviews the epidemiological trends, clinical features, optimal assessment and current management practices for NAFLD in Asia. [ABSTRACT FROM AUTHOR]

Background and Aims: Leukocyte infiltration is a hallmark of hepatic inflammation. The Junctional Adhesion Molecule A (JAM‐A) is a crucial regulator of leukocyte extravasation and is upregulated in human viral fibrosis. Reduced shear stress within hepatic sinusoids and the specific phenotype of liver sinusoidal endothelial cells (LSEC) cumulate in differing adhesion characteristics during liver fibrosis. The aim of this study was to define the functional role of cell‐specific adhesion molecule JAM‐A during hepatic fibrogenesis. Methods: Complete, conditional (intestinal epithelial; endothelial) and bone marrow chimeric Jam‐a knockout animals and corresponding C57Bl/6 wild‐type animals were treated with carbon tetrachloride (CCl4, 6 weeks). For functional analyses of JAM‐A, comprehensive in vivo studies, co‐culture models and flow‐based adhesion assays were performed. Results: Complete and bone marrow‐derived Jam‐a−/− animals showed aggravated fibrosis with increased non‐sinusoidal, perivascular accumulation of CD11b+F4/80+ monocyte‐derived macrophages in contrast to wild‐type mice. Despite being associated with disturbed epithelial barrier function, an intestinal epithelial Jam‐a knockout did not affect fibrogenesis. In endothelial‐specific Jam‐a−/− animals, liver fibrosis was aggravated alongside sinusoid capillarization and hepatic stellate cell (HSC) activation. HSC activation is induced via Jam‐a−/− LSEC‐derived secretion of soluble factors. Sinusoid CD31 expression and hedgehog gene signalling were increased, but leukocyte infiltration and adhesion to LSECs remained unaffected. Conclusions: Our models decipher cell‐specific JAM‐A to exert crucial functions during hepatic fibrogenesis. JAM‐A on bone marrow‐derived cells regulates non‐sinusoidal vascular immune cell recruitment, while endothelial JAM‐A controls liver sinusoid capillarization and HSC quiescence. [ABSTRACT FROM AUTHOR]

Background & Aims: The evaluation of the stage of liver fibrosis is essential in patients with chronic liver disease. However, due to the low quality of ultrasound images, the non‐invasive diagnosis of liver fibrosis based on ultrasound images is still an outstanding question. This study aimed to investigate the diagnostic accuracy of a deep learning‐based method in ultrasound images for liver fibrosis staging in multicentre patients. Methods: In this study, we proposed a novel deep learning‐based approach, named multi‐scale texture network (MSTNet), to assess liver fibrosis, which extracted multi‐scale texture features from constructed image pyramid patches. Its diagnostic accuracy was investigated by comparing it with APRI, FIB‐4, Forns and sonographers. Data of 508 patients who underwent liver biopsy were included from 4 hospitals. The area‐under‐the ROC curve (AUC) was determined by receiver operating characteristics (ROC) curves for significant fibrosis (≥F2) and cirrhosis (F4). Results: The AUCs (95% confidence interval) of MSTNet were 0.92 (0.87‐0.96) for ≥F2 and 0.89 (0.83‐0.95) for F4 on the validation group, which significantly outperformed APRI, FIB‐4 and Forns. The sensitivity and specificity of MSTNet (85.1% (74.5%‐92.0%) and 87.6% (78.0%‐93.6%)) were better than those of three sonographers in assessing ≥F2. Conclusions: The proposed MSTNet is a promising ultrasound image‐based method for the non‐invasive grading of liver fibrosis in patients with chronic HBV infection. [ABSTRACT FROM AUTHOR]

Background and Aims: While biopsy is the gold standard for liver fibrosis staging, it poses significant risks. Noninvasive assessment of liver fibrosis is a growing field. Recently, deep learning (DL) technology has revolutionized medical image analysis. This technology has the potential to enhance noninvasive fibrosis assessment. We systematically examined the application of DL in noninvasive liver fibrosis imaging. Methods: Embase, MEDLINE, Web of Science, and IEEE Xplore databases were used to identify studies that reported on the accuracy of DL for classification of liver fibrosis on noninvasive imaging. The search keywords were "liver or hepatic," "fibrosis or cirrhosis," and "neural or DL networks." Risk of bias and applicability were evaluated using the QUADAS‐2 tool. Results: Sixteen studies were retrieved. Imaging modalities included ultrasound (n = 10), computed tomography (n = 3), and magnetic resonance imaging (n = 3). The studies analyzed a total of 40 405 radiological images from 15 853 patients. All but two of the studies were retrospective. In most studies the "ground truth" reference was the METAVIR score for pathological staging (n = 9.56%). The majority of the studies reported an accuracy >85% when compared to histopathology. Fourteen studies (87.5%) had a high risk of bias and concerns regarding applicability. Conclusions: Deep learning has the potential to play an emerging role in liver fibrosis classification. Yet, it is still limited by a relatively small number of retrospective studies. Clinicians should facilitate the use of this technology by sharing databases and standardized reports. This may optimize the noninvasive evaluation of liver fibrosis on a large scale. [ABSTRACT FROM AUTHOR]

Hepatic fibrosis is a common pathological process involving persistent liver injury with various etiologies and subsequent inflammatory responses that occur in chronic liver diseases. If left untreated, liver fibrosis can progress to liver cirrhosis, hepatocellular carcinoma and eventually, liver failure. Unfortunately, to date, there is no effective treatment for liver fibrosis, with the exception of liver transplantation. Although the pathophysiology of liver fibrosis is multifactorial and includes the activation of hepatic stellate cells, which are known to drive liver fibrogenesis, hepatic macrophages have emerged as central players in the development of liver fibrosis and regression. Hepatic macrophages, which consist of resident macrophages (Kupffer cells) and monocyte‐derived macrophages, have been shown to play an intricate role in the initiation of inflammatory responses to liver injury, progression of fibrosis, and promotion of fibrosis resolution. These features have made hepatic macrophages uniquely attractive therapeutic targets in the fight against hepatic fibrosis. In this review, we synthesised the literature to highlight the functions and regulation of heterogeneity in hepatic macrophages. Furthermore, using the existing findings, we attempt to offer insights into the molecular mechanisms underlying the phenotypic switch from fibrogenic macrophages to restorative macrophages, the regulation of heterogeneity, and modes of action for hepatic macrophages. A better understanding of these mechanisms may guide the development of novel anti‐fibrotic therapies (eg macrophage subset‐targeted treatments) to combat liver fibrosis in the future. [ABSTRACT FROM AUTHOR]

Background: Liver fibrosis is pathologically important in the liver cirrhosis progression. The epithelial–mesenchymal transition (EMT) is crucial for organ fibrosis. Macrophage‐stimulating protein (MSP) and its receptor tyrosine kinase, RON, promote cellular EMT. However, their role in liver fibrosis is unclear. Here, we clarify the biological profile, potential mechanisms and therapeutic targets of the MSP‐RON pathway in liver fibrosis. Materials and methods: Macrophage‐stimulating protein expression and its correlation with clinicopathological characteristics of cirrhosis were evaluated in 57 clinical cases and a control group. The effect of MSP‐RON pathway in liver fibrosis was determined in vitro and in vivo. The therapeutic effects of MSP or RON inhibition on liver fibrosis were evaluated in a mouse liver fibrosis model. Results: Macrophage‐stimulating protein is upregulated in liver cirrhosis, which was associated with poor patient prognosis. The MSP‐RON pathway promoted hepatocytes EMT. MSP‐RON‐induced EMT depends on the transforming growth factor beta (TGF‐β) pathway and is regulated by TGF‐β inhibitors. In animal models, an MSP blocking antibody and a small molecule inhibitor of RON, BMS‐777607, both inhibited liver fibrosis progression. Conclusion: Our study revealed that MSP is an important biomarker in liver cirrhosis progression and can be used to prognose patients. The MSP‐RON pathway promotes the EMT of hepatocytes and the progress of fibrosis via a TGF‐β related pathway. Consequently, we identified a new treatment strategy for liver cirrhosis through targeted inhibition of MSP/RON. This research increases the understanding of EMT‐modulated liver fibrosis and provides new insights into biomarkers and therapeutic targets of liver fibrosis. [ABSTRACT FROM AUTHOR]

Background: Impact of SARS‐CoV‐2 infection upon hospitalization, intensive care unit (ICU) admissions and mortality in persons with hepatitis C virus (HCV) infection is unknown. Methods: We used the Electronically Retrieved Cohort of HCV infected Veterans (ERCHIVES) database to determine the impact of HCV infection upon the rates of acute care hospitalization, ICU admission and all‐cause mortality. We identified Veterans with chronic HCV infection and propensity score matched controls without HCV in ERCHIVES. We excluded those with HIV or hepatitis B virus coinfection. Results: We identified 975 HCV+ and 975 propensity score matched HCV− persons with SARS‐CoV‐2 infection. Mean FIB‐4 score (±SD) was higher in those with HCV (1.9 ± 2.1 vs 1.2 ± 0.9; P <.0001) and a larger proportion of those with HCV had cirrhosis (8.1% vs 1.4%; P <.0001). A larger proportion of HCV+ were hospitalized compared to HCV‐ (24.0% vs 18.3%; P =.002); however, those requiring ICU care and mortality were also similar in both groups (6.6% vs 6.5%; P =.9). Among those with FIB‐4 score of 1.45‐3.25, hospitalization rate/1000‐person‐years was 41.4 among HCV+ and 20.2 among HCV−, while among those with a FIB‐4 > 3.25, the rate‐ was 9.4 and 0.6 (P <.0001). There was no difference in all‐cause mortality by age, gender, FIB‐4 score, number of comorbidities or treatment with remdesivir and/or systemic corticosteroids. Conclusions: HCV+ persons with SARS‐CoV‐2 infection are more likely to be admitted to a hospital. The hospitalization rate also increased with higher FIB‐4 score. However, admission to an ICU and mortality are not different between those with and without HCV infection. [ABSTRACT FROM AUTHOR]

Background and aims: Alcohol and metabolic syndrome (MS) coexist frequently as cofactors of liver disease. Previous studies suggest a deleterious effect of MS in advanced alcohol‐related liver disease (ArLD). However, it is unknow whether MS can increase the risk of liver fibrosis in early stages of ArLD. The aim of this study was to investigate the effect of MS on liver fibrosis in subjects with alcohol consumption from a population‐based cohort. Methods: The number of subjects include 1760(58%) of 3014 who were randomly selected from the community consumed alcohol and were classified as current drinkers, divided in moderate (n = 1222) or high‐risk drinkers (n = 275) (>21 units/week men, >14 units/week women for high‐risk drinkers), or former drinkers (n = 263). Liver fibrosis was estimated by measuring liver stiffness(LS) with transient elastography (TE). Results: Prevalence of significant LS using cutoff values of TE of 8 and 9.1kPa was increased in high‐risk compared with moderate or former drinkers and lifetime abstainers. In subjects with alcohol consumption, LS was associated with male gender, AST, ALT, years of consumption, and MS. In high‐risk drinkers, MS and intensity of consumption were the only factors associated with significant LS (OR 3.7 and 4.6 for LS ≥ 8 kPa and 3.9 and 9.2 kPa for LS ≥ 9.1 kPa, respectively). Presence of significant liver fibrosis in the liver biopsy was higher among high‐risk as compared with moderate or former drinkers. Conclusion: MS increases the risk of liver fibrosis in subjects with alcohol consumption. Among high‐risk drinkers, only MS and consumption of high amount of alcohol are associated with risk of liver fibrosis. [ABSTRACT FROM AUTHOR]

Background & Aims: Inhalation of welding fume may cause pulmonary disease known as welder's lung. At our centre we came across a number of welders with systemic iron overload and prolonged occupational history and we aimed at characterizing this novel clinical form of iron overload. Methods: After exclusion of other known causes of iron overload, 20 welders were fully evaluated for working history, hepatic, metabolic and iron status. MRI iron assessment was performed in 19 patients and liver biopsy in 12. We included 40 HFE‐HH patients and 24 healthy controls for comparison. Results: 75% of patients showed lung HRCT alterations; 90% had s‐FERR > 1000 ng/mL and 60% had TSAT > 45%. Liver iron overload was mild in 8 and moderate‐severe in 12. The median iron removed was 7.8 g. Welders showed significantly lower TSAT and higher SIS and SIS/TIS ratio than HFE‐HH patients. Serum hepcidin was significantly higher in welders than in HFE‐HH patients and healthy controls. At liver biopsy, 50% showed liver fibrosis that was mild in four, and moderate‐severe in two. Liver staging correlated with liver iron overload. Conclusions: Welders with prolonged fume exposure can develop severe liver iron overload. The mechanism of liver iron accumulation is quite different to that of HFE‐HH suggesting that reticuloendothelial cells may be the initial site of deposition. We recommend routine measurement of serum iron indices in welders to provide adequate diagnosis and therapy, and the inclusion of prolonged welding fume exposure in the list of acquired causes of hyperferritinemia and iron overload. [ABSTRACT FROM AUTHOR]

The prevalence of non alcoholic fatty liver disease (NAFLD) has increased to 25% in the general population and could double by 2030. Liver fibrosis is the main indicator of morbidity and mortality and recent estimations suggest a substantial number of individuals with undiagnosed advanced liver disease. Strategies to monitor advanced fibrosis are essential for early detection, referral, diagnosis and treatment in primary care and endocrine units, where NAFLD and consequently liver fibrosis are more prevalent. Blood‐based non‐invasive methods could be used to stratify patients according to the risk of the progression of fibrosis and combined with imaging techniques to improve stratification. Powerful new diagnostic tools such as MRE and PDFF are emerging and might prevent the need for liver biopsy in the near future. The current therapeutic landscape of NAFLD is rapidly evolving with an increasing number of molecules that treat key factors involved in its progression, but that still have a limited or no ability to effectively reverse fibrosis. Management of this disease will probably require a combination of sequential and personalized treatments as a result of its complex and dynamic pathophysiology. Lifestyle interventions are still the most effective therapeutic option and should be better integrated into patient management together with specific programs of bariatric endoscopy/surgery for morbidly obese patients. [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatic stellate cells (HSCs) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC). Tribbles homolog 2 (TRIB2) is an oncogene implicated in a variety of cancers, including liver cancer. However, the biological function and regulatory mechanism of TRIB2 in HSCs are poorly understood. In addition, little is known about its role in liver fibrosis progression to HCC. Here, we revealed the clinical significance of TRIB2 in liver fibrosis and HCC development. Methods: We investigated TRIB2 promoting liver fibrosis in vitro and in vivo. In mouse model of liver fibrosis and HCC, we measured hepatic fibrosis and HCC level through knockdown TRIB2 with shRNA. In addition, we performed western blotting, real‐time quantitative PCR, immunofluorescence and co‐immunoprecipitation assay to study TRIB2 function in LX‐2 cells. Results: TRIB2 expression was strongly upregulated in human fibrotic liver tissues and HCC tissues. TRIB2 colocalized with α‐smooth muscle actin (α‐SMA) in fibrotic and HCC liver tissues. Knockdown of TRIB2 inhibited HSC activation and liver fibrosis in vitro and in vivo. TRIB2 promoted Yes‐associated protein (YAP) stabilization, nuclear localization, and subsequent fibrotic gene expression independent of the MST‐LATS phosphorylation cascade in HSCs. TRIB2 interacted with YAP to recruit phosphatase 1A (PP1A), promoting PP1A‐mediated YAP dephosphorylation. TRIB2 knockdown potently attenuated the development of fibrosis‐associated liver cancer. Conclusions: TRIB2 is an attractive target for hepatic fibrosis and fibrosis‐associated liver cancer treatment. [ABSTRACT FROM AUTHOR]

Background & Aims: Chronic hepatitis B virus (HBV) infection accounts for 30%‐50% of cirrhosis related deaths in sub‐Saharan Africa (SSA). Since HBV‐related cirrhosis is an indication for immediate antiviral therapy and cancer surveillance, we aimed to estimate the prevalence of cirrhosis among treatment‐naïve patients with chronic HBV infection in SSA. Methods: We performed a systematic review of published articles which evaluated liver fibrosis stage among treatment‐naïve HBV‐infected individuals who presented to care in SSA. Our primary outcome was the prevalence of cirrhosis in HBsAg‐positive persons, which was estimated using random‐effects meta‐analysis. Risk factors for cirrhosis were explored using subgroup‐analyses and multivariable meta‐regression. Results: Of 2129 articles identified, 17 met our eligibility criteria. The studies described 22 cohorts from 13 countries, including 13 cohorts (3204 patients) with chronic HBV mono‐infection and nine cohorts (688 patients) with HIV/HBV‐coinfection. Liver fibrosis was assessed using transient elastography (10 cohorts), APRI score (11 cohorts), and Fibrotest (one cohort). The pooled prevalence of cirrhosis was 4.1% (95% confidence interval [CI] 2.6‐6.4) among studies from primary care facilities or general population, compared to 12.7% (95% CI 8.6‐18.3) in studies performed in referral or tertiary care facilities (adjusted odds ratio 0.29, 95% CI 0.15‐0.56). We found no association between cirrhosis and age, gender, fibrosis test used or HIV‐coinfection. Conclusions: Depending on the setting, between 4% and 13% of HBV‐infected individuals in SSA have cirrhosis and need immediate antiviral therapy. These estimates should be considered when planning HBV treatment strategies and resource allocation. [ABSTRACT FROM AUTHOR]

Background and Aims: Liver stiffness measurements (LSM), commonly performed by transient elastography (TE) or two‐dimensional shear wave elastography (2D‐SWE), are used to quantify liver fibrosis. Active hepatitis, a hallmark of autoimmune hepatitis (AIH), could bias LSM. This bias might be overcome by measurement spleen 2D‐SWE. Here, we compare liver and spleen 2D‐SWE to TE and liver biopsy (LB) in prospectively recruited patients with AIH. Methods: We analysed liver and spleen 2D‐SWE in relation to liver TE in 90 patients treated ≥ 6 months for AIH. Liver and spleen 2D‐SWE were also compared to LB in 63 individuals with AIH. Finally, we evaluated these tools in 220 patients with AIH and during 18 months follow‐up. Results: Liver 2D‐SWE correlated with surrogate markers of active hepatitis (ALT and IgG, both P <.001) but there was no link between spleen 2D‐SWE and ALT. Liver 2D‐SWE, but not spleen 2D‐SWE, was associated with histopathological inflammatory score (P <.01). When compared to LB, the optimal cut‐offs for detecting cirrhosis by liver and spleen 2D‐SWE were 16.1 kPa (AUROC 0.93) and 29.8 kPa (AUROC 0.95), respectively. In patients with active hepatitis the combined diagnostic approach including liver and spleen 2D‐SWE had significantly better AUROC for detecting cirrhosis than liver 2D‐SWE alone. Conclusions: Liver and spleen 2D‐SWE are reliable complementary methods for the diagnosis of advanced fibrosis in AIH. Spleen 2D‐SWE seems to be less biased by inflammation and could facilitate fibrosis assessment in therapy‐naïve patients or in the presence of active hepatitis. [ABSTRACT FROM AUTHOR]

Background: Rate of SARS‐CoV‐2 infection and impact of liver fibrosis stage upon infection rates in persons with hepatitis C virus (HCV) infection are unknown. Methods: We retrospectively analysed the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), a well‐established database of HCV‐infected Veterans in care. We excluded those with missing FIB‐4 score and those with HIV or hepatitis B virus co‐infection. We determined the number of persons tested, proportion who tested positive for SARS‐CoV‐2 and the infection rate by age and liver fibrosis stage. Results: Among 172,235 persons with HCV, 14,305 (8.3%) were tested for SARS‐CoV‐2 infection and 892 (6.2%) tested positive. Those with SARS‐CoV‐2 infection were older, more likely to be Black (55.2% vs 37.8%), obese (body mass index >30 kg/m2 36.2% vs 29.7%) and have diabetes or stroke (P <.0001 for all comparisons). Mean FIB‐4 scores and proportion of persons with cirrhosis (based on a FIB‐4 > 3.25) were similar in both groups. Incidence rate/1,000 tested persons was much higher among Blacks (88.4; 95% CI 81.1, 96.2) vs Whites (37.5; 95% CI 33.1, 42.4) but similar among those with cirrhosis (FIB‐4 > 3.25). The rates were also similar among those who were untreated for HCV vs those treated with or without attaining a sustained virologic response. Conclusions: Testing rates among persons with HCV are very low. Persons with infection are more likely to be Black, have a higher body mass index and diabetes or stroke. The degree of liver fibrosis does not appear to have an impact on infection rate. [ABSTRACT FROM AUTHOR]

Background & Aim : Low‐grade albuminuria, as an early marker of endothelial dysfunction and kidney damage, has been recognized as a risk factor for metabolic disorders. Epidemiological studies manifesting the association of low‐grade albuminuria with the risk of incident NAFLD and fibrosis were not available. We aimed to investigate the association of low‐grade albuminuria with incident NAFLD and fibrosis by glycaemia status. Methods: A prospective population‐based study was performed in 3308 participants without NAFLD at recruitment. Baseline urinary albumin excretion was obtained by a first‐voided early morning spot urine sample. At follow‐up visit, incident NAFLD was diagnosed by hepatic ultrasound after excluding alcohol abuse and other cause of hepatic diseases. Fatty liver index (FLI) was employed to reflect liver fat content. Liver fibrosis was evaluated by NAFLD fibrosis score (NFS), fibrosis‐4 score (FIB‐4) and Hepamet fibrosis score (HFS) respectively. Results: After 4.3 years of follow‐up, 622 (18.8%) were detected as incident NAFLD. Participants with low‐grade albuminuria imposed a 40.4% [1.404 (1.112‐1.772)] greater risk on incident NAFLD, and 52.0% [1.520 (1.141‐2.026)], 87.4% [1.874 (1.291‐2.720)] and 40.4% [1.404 (1.038‐1.898)] higher risks on newly onset higher values of FLI, NFS and FIB‐4 respectively. The effect of low‐grade albuminuria was stronger in the subgroup of non‐diabetic population. Conclusions: Low‐grade albuminuria was independently associated with incident NAFLD and a higher probability of fibrosis, especially among non‐diabetic individuals. [ABSTRACT FROM AUTHOR]

With advances in genome and transcriptome research technology, the function and mechanism of lncRNAs in physiological and pathological states have been gradually revealed. Nuclear Enriched Abundant Transcript 1 (NEAT1, a long non‐coding RNA), a vital component of paraspeckles, plays an indispensable role in the formation and integrity of paraspeckles. Throughout the research history, NEAT1 is mostly aberrantly upregulated in various cancers, and high expression of NEAT1 often contributes to poor prognosis of patients. Notably, the role and mechanism of NEAT1 in liver diseases have been increasingly reported. NEAT1 accelerates the progression of non‐alcoholic fatty liver disease (NAFLD), liver fibrosis and hepatocellular carcinoma, while exerting a protective role in the pathogenesis of acute‐on‐chronic liver failure by inhibiting the inflammatory response. In this review, we will elaborate on relevant studies on the different casting of NEAT1 in liver diseases, especially focusing on its regulatory mechanisms and new opportunities for alcoholic liver disease. [ABSTRACT FROM AUTHOR]

Background & Aims: Lifestyle modification is the cornerstone for the management of non‐alcoholic fatty liver disease (NAFLD). We aim to understand lifestyle habits of NAFLD patients, compare across Asian regions and identify area of deficiency. Methods: In the multi‐centre controlled attenuation parameter (CAP)‐Asia study, we collected clinical data and lifestyle habit data of NAFLD patients from Singapore, mainland China, Hong Kong, Taiwan and Malaysia. Physical activity was assessed using the International Physical Activity Questionnaire. Results: A total of 555 patients were included in the final analysis (mean age 54.5 ± 11.2 years, 54.1% men and median liver stiffness 6.7 kPa). More patients from mainland China (27.4%) and Taipei (25.0%) were smokers. Modest drinking was more common in Taiwan (25.0%) and Hong Kong (18.2%); only 1.3% had binge drinking. Majority of patients drank coffee (64.0%) and tea (80.2%), with varying amounts and durations in different regions. Soft drinks consumption was most common in Singapore (62.2%) and Malaysia (57.7%). Only 29.7% of patients met the Physical Activity Guidelines Recommendations, with no major differences across regions. Patients with liver stiffness <10 kPa were more likely to report any vigorous activity, and sitting time was an independent factor associated with high CAP. Tea and coffee consumption were independently associated with high CAP and liver stiffness, respectively. Conclusions: Despite some heterogeneity, unhealthy lifestyle and physical inactivity are common across Asian regions. Patients with liver stiffness <10 kPa were more likely to report any vigorous activity. Healthcare providers may use the comparative data to identify areas of deficiency. [ABSTRACT FROM AUTHOR]

Background & Aims: Liver fibrosis assessed by liver biopsy is predictive of clinical liver events in patients with nonalcoholic fatty liver disease (NAFLD). Magnetic resonance elastography (MRE) correlates with liver biopsy in assessing liver fibrosis. However, data assessing the relationship between MRE and clinical liver events are lacking. We investigated the association between MRE and clinical liver events/death and identified the cut‐off to predict clinical liver events in NAFLD patients. Methods: We conducted a multicenter retrospective study of NAFLD patients who underwent MRE between 2016 and 2019. Clinical liver events were defined as decompensation events and death. We categorized patients into noncirrhosis, compensated cirrhosis and decompensated cirrhosis. Fisher's exact test was used to test association strength. Receiver operative curve methods were used to determine the optimal cut‐off of MRE liver stiffness and to maximize the accuracy for classifying noncirrhosis, compensated cirrhosis and decompensated cirrhosis. Logistic regression modelling was used to predict decompensation. Results: The study included 320 NAFLD patients who underwent MRE. The best threshold for distinguishing cirrhosis from noncirrhosis was 4.39 kPa (AUROC 0.92) and from decompensated cirrhosis was 6.48 kPa (AUROC 0.71). Odds of decompensation increased as liver stiffness increased (OR 3.28) (P <.001). Increased liver stiffness was associated with ascites, hepatic encephalopathy, oesophageal variceal bleeding and mortality (median 7.10, 10.15 and 10.15 kPa respectively). Conclusion: In NAFLD patients, liver stiffness measured by MRE with a cut‐off of ≥6.48 kPa is associated with decompensation and mortality, and specific MRE cut‐offs are predictive of individual clinical liver events. [ABSTRACT FROM AUTHOR]

Background and Aims: To date, no study has explored the potential role of ElastPQ, a novel point‐SWE technique, in the assessment of clinically significant portal hypertension. The aim of our study was to determine a liver stiffness (LS) cut‐off value measured by ElastPQ and laboratory parameters that could help to identify those patients who can safely avoid screening endoscopy. Methods: Data were collected on 1422 patients who underwent ElastPQ measurement from January 2013 to January 2016 in our Department. Inclusion criteria were a LS value of ≥7 kPa, an upper gastrointestinal endoscopy within 12 months and a diagnosis of compensated chronic liver disease. Exclusion criteria were history of decompensated liver disease, evidence of porto‐spleno‐mesenteric vein thrombosis and non‐cirrhotic portal hypertension. Varices were graded as low‐risk varices (grade <2) or varices needing treatment (VNT, grade ≥2). Results: The study included 195 patients (120 [61%] HCV, 171 [88%] Child‐Pugh A). Varices were present in 35% cases, with 10% prevalence of VNT. According to ROC curve analysis, LS measurement and platelet count were evaluated as predictors of VNT. Overall, 75/195 (38%) met the 'BAVElastPQ' criteria (that is, LS < 12 kPa and platelet count >150 000/μL). Within this group, 11/75 (15%) had any grade of varices and only 1/75 (1%) had VNT. The BAVElastPQ criteria gave sensitivity of 0.95, specificity of 0.42, positive predictive value of 0.15 and negative predictive value of 0.99. Conclusions: The BAVElastPQ criteria correctly identified 99% of patients without VNT. By applying such criteria, we could have potentially avoided 38% of surveillance endoscopies in our cohort. [ABSTRACT FROM AUTHOR]

Background & Aims: Activation of hepatic stellate cells (HSC) is a critical process involved in liver fibrosis. Several miRNAs are implicated in gene regulation during this process but their exact and respective contribution is still incompletely understood. Here we propose an integrative approach of miRNA‐regulatory networks to predict new targets. Methods: miRNA regulatory networks in activated HSCs were built using lists of validated miRNAs and the CyTargetLinker tool. The resulting graphs were filtered according to public transcriptomic data and the reduced graphs were analysed through GO annotation. A miRNA network regulating the expression of TIMP3 was further studied in human liver samples, isolated hepatic cells and mouse model of liver fibrosis. Results: Within the up‐regulated miRNAs, we identified a subnetwork of five miRNAs (miR‐21‐5p, miR‐222‐3p, miR‐221‐3p miR‐181b‐5p and miR‐17‐5p) that target TIMP3. We demonstrated that TIMP3 expression is inversely associated with inflammatory activity and IL1‐ß expression in vivo. We further showed that IL1‐ß inhibits TIMP3 expression in HSC‐derived LX‐2 cells. Using data from The Cancer Genome Atlas (TCGA), we showed that, in hepatocellular carcinoma (HCC), TIMP3 expression is associated with survival (P <.001), while miR‐221 (P <.05), miR‐222 (P <.01) and miR‐181b (P <.01) are markers for a poor prognosis. Conclusions: Several miRNAs targeting TIMP3 are up‐regulated in activated HSCs and down‐regulation of TIMP3 expression is associated with inflammatory activity in liver fibrosis and poor prognosis in HCC. The regulatory network including specific miRNAs and TIMP3 is therefore central for the evolution of chronic liver disease. [ABSTRACT FROM AUTHOR]

Background & Aims: Non‐alcoholic steatohepatitis (NASH) is a major cause of chronic liver disease. The precise role of NK cells in the progression of NASH has yet to be elucidated. Methods: Using methionine‐ and choline‐deficient diets (MCD)‐induced NASH model, the role of NK cells was identified in WT mice compared with conventional NK cell–deficient Nfil3−/− mice. Results: After 8 weeks of MCD treatment, NASH was induced as shown by the significant macrovesicular steatosis, necro‐inflammation and fibrosis in the liver of WT B6 mice. In MCD‐treated WT B6 mice, the number of NK cells was markedly increased in the liver, but decreased in the spleen. Intrahepatic NK cells exhibited high levels of activation, as evidenced by the expression of CD107a and cytokine production of IFN‐γ, TGF‐β and IL‐10. Lower expression levels of Ki67 indicated a reduction in the proliferation of intrahepatic NK cells after MCD treatment. Increased expression of CXCL10 in the liver early after MCD treatment led to the increased recruitment of CXCR3+ NK cells into the liver. The MCD‐treated Nfil3−/− mice showed similar levels of TG and macrovesicular steatosis, thus more inflammatory infiltration and increased collagen deposition in the liver. Furthermore, the depletion of NK cells during MCD‐induced NASH caused a significant increase in the infiltration of monocyte‐derived macrophages (MoMFs) particularly Ly6Clo subsets towards M2. Conclusions: Intrahepatic NK cells, recruited through CXCL10‐CXCR3 interaction, play a protective role against the fibrosis progression in NASH, which provide us with a better understanding of the immunopathogenesis of NASH. [ABSTRACT FROM AUTHOR]

In liver cirrhosis, renin‐angiotensin system (RAS) activation sustains renal sodium retention and hepatic fibrogenesis. New information has recently enlivened the traditional concept of RAS. For instance, renin and prorenin bind their ubiquitous receptors, resulting in the local production of angiotensin (Ang) II; increased serum calcium and calcimimetic agents, through stimulation of extracellular calcium‐sensing receptors (CaSR), blunt renin production and lead to natriuretic effects in human and experimental cirrhosis. Alongside systemic production, there is Ang II tissue production within various organs through RAS enzymes different from angiotensin‐converting enzyme (ACE), that is chymase, tissue plasminogen activator and several cathepsins. In experimental cirrhosis, inhibition of chymase leads to natriuretic and hepatic antifibrotic effects, without changes in systemic haemodynamics. In the kidney, local RAS coordinates proximal and distal tubular sodium reabsorption. However, renalase, whose plasma and tissue levels are severely altered in experimental cirrhosis, degrades systemic and renal tubule catecholamines, antagonizing the effects of renal RAS. Angiotensinogen‐derived natriuretic and vasodilating peptides (Ang1‐9, Ang1‐7, Ang3‐8) and their receptors have been described. Receptor agonists or antagonists are available to affect portal hypertension and sodium retention in cirrhosis. ACE2‐dependent generation of Ang1‐7 may inhibit experimental liver fibrosis. inhibition of Ang1‐7 clearance by means of neprilysin blockade has portal hypotensive and natriuretic effects. Ang1‐12, whose production renin does not regulate, is converted to several different angiotensin peptides via chymase. Finally, Ang II behaves as either an antinatriuretic or a natriuretic agent, based on the tissue content of AT1R and AT2R receptors, their ratio being prone to pharmacological modulation. [ABSTRACT FROM AUTHOR]

Background & Aims: We examined the diagnostic performance of plasma N‐terminal propeptide of type III procollagen (PIIINP) levels, aspartate aminotransferase to platelet ratio index (APRI) and Fibrosis‐4 (FIB‐4) score for predicting non‐alcoholic steatohepatitis (NASH) and liver fibrosis stage in children/adolescents with non‐alcoholic fatty liver disease (NAFLD). Methods: We enrolled 204 children/adolescents with biopsy‐proven NAFLD at the "Bambino Gesù" Children's Hospital. We measured plasma PIIINP levels using a commercially available enzyme‐linked immunosorbent assay kit and calculated APRI and FIB‐4 scores using standard methods. Results: Children with NASH had higher plasma PIIINP levels, APRI and FIB‐4 scores compared with those without NASH (all P < .001). However, PIIINP levels had much better diagnostic performance and accuracy than APRI and FIB‐4 scores for predicting liver fibrosis stage. PIIINP levels correlated with the total NAFLD activity score (NAS) and its constituent components (P < .0001). The risk of either NASH or F ≥ 2 fibrosis progressively increased with increasing PIIINP levels (P < .0001), independent of age, gender, adiposity measures, insulin resistance, NAS score and the patatin‐like phospholipase domain‐containing protein‐3 rs738409 polymorphism. For every 3.6 ng/mL increase in PIIINP levels, the likelihood of having F ≥ 2 fibrosis increased by ~14‐fold (adjusted‐odds ratio 14.1, 95% CI 5.50‐35.8, P < .0001) after adjustment for the aforementioned risk factors. The area under the receiver operating characteristics curve was 0.921 (95% CI 0.87‐0.97) for F ≥ 2 fibrosis, and 0.993 (95% CI 0.98‐1.0) for F3 fibrosis respectively. Conclusions: Unlike APRI and FIB‐4 scores, plasma PIIINP levels are a promising, non‐invasive biomarker for diagnosing liver fibrosis stage in children/adolescents with biopsy‐proven NAFLD. [ABSTRACT FROM AUTHOR]