Factors For Chronic Liver Disease Research Articles

Stiffness-induced modulation of ERG transcription factor in chronic liver disease

Chronic liver disease (CLD) is characterised by liver sinusoidal endothelial cells (LSECs) dysfunction. Mechanical forces and inflammation are among the leading factors. ETS-related gene (ERG) is an endothelial-specific transcription factor, involved in maintaining cell quiescence and homeostasis. Our study aimed to understand the expression and modulation of ERG in CLD. ERG expression was characterised and correlated to clinical data in human liver cirrhosis at different disease stages. ERG dynamics in response to stiffness and inflammation were investigated in primary healthy and cirrhotic rat LSEC and in human umbilical vein endothelial cells (HUVECs). ERG is markedly downregulated in cirrhosis independently of disease stage or aetiology and its expression is modulated by substrate stiffness in ECs. Inflammation downregulates ERG in cells on physiological stiffness, but not on high stiffness, suggesting a complementary role of inflammation and stiffness in suppressing ERG. This study outlines ERG as an LSEC inflammation and stiffness-responsive transcription factor in cirrhosis.

Impact of fine particulate matter on liver injury: evidence from human, mice and cells

BackgroundA recently discovered risk factor for chronic liver disease is ambient fine particulate matter (PM2.5). Our research aims to elucidate the effects of PM2.5 on liver injury and the potential molecular mechanisms. Methods and resultsA population-based longitudinal study involving 102,918 participants from 15 Chinese cities, using linear mixed-effect models, found that abnormal alterations in liver function were significantly associated with long-term exposure to PM2.5. The serum levels of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, direct bilirubin, and triglyceride increased by 2.05%, 2.04%, 0.58%, 2.99%, and 1.46% with each 10 µg/m3 increase in PM2.5. In contrast, the serum levels of total protein, albumin, and prealbumin decreased by 0.27%, 0.48%, and 2.42%, respectively. Mice underwent chronic inhalation exposure to PM2.5 experienced hepatic inflammation, steatosis and fibrosis. In vitro experiments found that hepatocytes experienced an inflammatory response and lipid metabolic dysregulation due to PM2.5, which also activated hepatic stellate cells. The down-regulation and mis-localization of polarity protein Par3 mediated PM2.5-induced liver injury. ConclusionsPM2.5 exposure induced liver injury, mainly characterized by steatosis and fibrosis. The down-regulation and mis-localization of Par3 were important mechanisms of liver injury induced by PM2.5.

The Current Status of the Liver Liquid Biopsy in MASH Related HCC: Overview and Future Directions.

Metabolic dysfunction-associated steatohepatitis (MASH) is one of the major risk factors for chronic liver disease and hepatocellular carcinoma (HCC). The incidence of MASH in Western countries continues to rise, driving HCC as the third cause of cancer-related death worldwide. HCC has become a major global health challenge, partly from the obesity epidemic promoting metabolic cellular disturbances but also from the paucity of biomarkers for its early detection. Over 50% of HCC cases are clinically present at a late stage, where curative measures are no longer beneficial. Currently, there is a paucity of both specific and sensitive biological markers for the early-stage detection of HCC. The search for biological markers in the diagnosis of early HCC in high-risk populations is intense. We described the potential role of surrogates for a liver biopsy in the screening and monitoring of patients at risk for nesting HCC.

Persistent organic pollutants associate with liver disease in a Finnish general population sample.

Persistent organic pollutants (POPs) have multiple adverse effects on human health. Recent studies show a possible association with liver disease, but population-based data are scarce. In this population-based study, we studied the associations between POPs and biomarkers of liver disease and incident liver disease. This study consisted of 2789 adults that participated in the environmental toxin subset of the Finnish health-examination survey, FINRISK 2007. Toxins were measured from serum samples, and standard liver tests and dynamic aspartate aminotransferase-alanine aminotransferase ratio (dAAR) were measured as biomarkers of liver function. Associations between POPs and the biomarkers were then analysed using linear regression. Associations between POPs and incident liver disease (n = 36) were analysed by Cox regression. Organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs) and several perfluorinated alkyl substances exhibited statistically significant positive associations with several biomarkers of liver injury (betacoefficient per SD 0.04-0.14, p < 0.05). These associations were stronger in subgroups of individuals with obesity or non-alcoholic fatty liver disease. OCPs, PCBs and perfluoro-octanoic acid also had significant positive associations with dAAR, which can be used to predict risk of incident severe liver outcomes (beta coefficient per SD 0.05-0.08, p < 0.05). OCPs and PCBs were also significantly and positively associated with incident liver disease (hazard ratio per SD 1.82 95% CI 1.21-2.73, p < 0.01 and hazard ratio per SD 1.69, 95% CI 1.07-2.68, p < 0.05 respectively). Several POPs show positive associations with markers of liver injury and incident liver disease, suggesting that environmental toxins are important risk factors for chronic liver disease.

Non-alcoholic fatty liver disease is characterised by a reduced polyunsaturated fatty acid transport via free fatty acids and high-density lipoproteins (HDL)

Background and objectivesNon-alcoholic fatty liver disease (NAFLD) develops due to impaired hepatic lipid fluxes and is a risk factor for chronic liver disease and atherosclerosis. Lipidomic studies consistently reported characteristic hepatic/VLDL “lipid signatures” in NAFLD; whole plasma traits are more debated. Surprisingly, the HDL lipid composition by mass spectrometry has not been characterised across the NAFLD spectrum, despite HDL being a possible source of hepatic lipids delivered from peripheral tissues alongside free fatty acids (FFA). This study characterises the HDL lipidomic signature in NAFLD, and its correlation with metabolic and liver disease markers. MethodsWe used liquid chromatography-mass spectrometry to determine the whole serum and HDL lipidomic profile in 89 biopsy-proven NAFLD patients and 20 sex and age-matched controls. ResultsIn the whole serum of NAFLD versus controls, we report a depletion in polyunsaturated (PUFA) phospholipids (PL) and FFA; with PUFA PL being also lower in HDL, and negatively correlated with BMI, insulin resistance, triglycerides, and hepatocyte ballooning. In the HDL of the NAFLD group we also describe higher saturated ceramides, which positively correlate with insulin resistance and transaminases. ConclusionNAFLD features lower serum lipid species containing polyunsaturated fatty acids; the most affected lipid fractions are FFA and (HDL) phospholipids; our data suggest a possible defect in the transfer of PUFA from peripheral tissues to the liver in NAFLD. Mechanistic studies are required to explore the biological implications of our findings addressing if HDL composition can influence liver metabolism and damage, thus contributing to NAFLD pathophysiology.

The Role of LINC01564, RAMS11, CBX4 and TOP2A in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common histologic type of primary liver cancers worldwide. Hepatitis C virus (HCV) infection remains a major risk factor for chronic liver disease, cirrhosis, and HCC. To understand the molecular pathogenesis of HCC in chronic HCV infection, many molecular markers are extensively studied, including long noncoding RNAs (lncRNA). To evaluate the expression levels of lncRNAs (LINC01564, RAMS11), CBX4, and TOP2A in patients with chronic HCV infection and patients with HCC on top of chronic HCV infection and correlate these levels with the clinicopathological features of HCC. One hundred and fifty subjects were enrolled in this study and divided into three groups: group I included 50 patients with HCC on top of chronic hepatitis C (CHC), group II included 50 patients with CHC only, and group III included 50 healthy individuals as a control group. LncRNAs relative expression level was determined by RT-PCR. lncRNA (LINC01564, RAMS11), CBX4, and TOP2A relative expression levels were upregulated in both patient groups compared to controls (p &lt; 0.001*), with the highest levels in the HCC group compared with the CHC group. Additionally, these levels were significantly positively correlated with the clinicopathological features of HCC. The lncRNA (LINC01564, RAMS11), CBX4, and TOP2A relative expression levels were upregulated in CHC patients-in particular, patients with HCC. Thus, these circulatory lncRNAs may be able to serve as promising noninvasive diagnostic markers for HCC associated with viral C hepatitis.

LiverScreen project: study protocol for screening for liver fibrosis in the general population in European countries

BackgroundThe development of liver cirrhosis is usually an asymptomatic process until late stages when complications occur. The potential reversibility of the disease is dependent on early diagnosis of liver fibrosis and timely targeted treatment. Recently, the use of non-invasive tools has been suggested for screening of liver fibrosis, especially in subjects with risk factors for chronic liver disease. Nevertheless, large population-based studies with cost-effectiveness analyses are still lacking to support the widespread use of such tools. The aim of this study is to investigate whether non-invasive liver stiffness measurement in the general population is useful to identify subjects with asymptomatic, advanced chronic liver disease.MethodsThis study aims to include 30,000 subjects from eight European countries. Subjects from the general population aged ≥ 40 years without known liver disease will be invited to participate in the study either through phone calls/letters or through their primary care center. In the first study visit, subjects will undergo bloodwork as well as hepatic fat quantification and liver stiffness measurement (LSM) by vibration-controlled transient elastography. If LSM is ≥ 8 kPa and/or if ALT levels are ≥1.5 x upper limit of normal, subjects will be referred to hospital for further evaluation and consideration of liver biopsy. The primary outcome is the percentage of subjects with LSM ≥ 8kPa. In addition, a health economic evaluation will be performed to assess the cost-effectiveness and budget impact of such an intervention. The project is funded by the European Commission H2020 program.DiscussionThis study comes at an especially important time, as the burden of chronic liver diseases is expected to increase in the coming years. There is consequently an urgent need to change our current approach, from diagnosing the disease late when the impact of interventions may be limited to diagnosing the disease earlier, when the patient is asymptomatic and free of complications, and the disease potentially reversible. Ultimately, the LiverScreen study will serve as a basis from which diagnostic pathways can be developed and adapted to the specific socio-economic and healthcare conditions in each country.Trial registrationThis study is registered on Clinicaltrials.gov (NCT03789825).

The Non-Invasive Ultrasound-Based Assessment of Liver Viscosity in a Healthy Cohort.

Liver fibrosis is the most significant prognostic factor in chronic liver disease (CLD). Clinical practice guidelines recommend the use of non-invasive techniques, such as two-dimensional shear-wave elastography (2D-SWE), to assess liver stiffness as a marker of fibrosis. Several other factors influence liver stiffness in addition to liver fibrosis. It is presumed that changes due to necro-inflammation modify the propagation of shear waves (dispersion). Therefore, new imaging techniques that investigate the dispersion properties of shear waves have been developed, which can serve as an indirect method of measuring liver viscosity (Vi PLUS). Defining the reference values in healthy subjects among different age groups and genders and analyzing the factors that influence these values is essential. However, published data on liver viscosity are still limited. This is the first study that aimed to assess the normal range of liver viscosity values in subjects with healthy livers and analyze the factors that influence them. One hundred and thirty-one consecutive subjects with healthy livers were enrolled in this prospective study. The results showed that Vi PLUS is a highly feasible method. Liver stiffness, age and BMI influenced the liver viscosity values. The mean liver viscosity by Vi PLUS in subjects with healthy livers was 1.59 Pa·s.

Automated CNN-Based Analysis Versus Manual Analysis for MR Elastography in Nonalcoholic Fatty Liver Disease: Intermethod Agreement and Fibrosis Stage Discriminative Performance.

BACKGROUND. Histologic fibrosis stage is the most important prognostic factor in chronic liver disease. MR elastography (MRE) is the most accurate noninvasive method for detecting and staging liver fibrosis. Although accurate, manual ROI-based MRE analysis is complex, time-consuming, requires specialized readers, and is prone to methodologic variability and suboptimal interreader agreement. OBJECTIVE. The purpose of this study was to develop an automated convolutional neural network (CNN)-based method for liver MRE analysis, evaluate its agreement with manual ROI-based analysis, and assess its performance for classifying dichotomized fibrosis stages using histology as the reference standard. METHODS. In this retrospective cross-sectional study, 675 participants who underwent MRE using different MRI systems and field strengths at 28 imaging sites from five multicenter international clinical trials of nonalcoholic steatohepatitis were included for algorithm development and internal testing of agreement between automated CNN-based and manual ROI-based analyses. Eighty-one patients (52 women, 29 men; mean age, 54 years) who underwent MRE using a single 3-T system and liver biopsy for clinical purposes at a single institution were included for external testing of agreement between the two analysis methods and assessment of fibrosis stage discriminative performance. Agreement was evaluated using intraclass correlation coefficients (ICCs). Bootstrapping was used to compute 95% CIs. Discriminative performance of each method for dichotomized histologic fibrosis stage was evaluated by AUC and compared using bootstrapping. RESULTS. Mean CNN- and manual ROI-based stiffness measurements ranged from 3.21 to 3.34 kPa in trial participants and from 3.21 to 3.30 kPa in clinical patients. ICC for CNN- and manual ROI-based measurements was 0.98 (95% CI, 0.97-0.98) in trial participants and 0.99 (95% CI, 0.98-0.99) in clinical patients. AUCs for classification of dichotomized fibrosis stage ranged from 0.89 to 0.93 for CNN-based analysis and 0.87 to 0.93 for manual ROI-based analysis (p = .23-.75). CONCLUSION. Stiffness measurements using the automated CNN-based method agreed strongly with manual ROI-based analysis across MRI systems and field strengths, with excellent discriminative performance for histology-determined dichotomized fibrosis stages in external testing. CLINICAL IMPACT. Given the high incidence of chronic liver disease worldwide, it is important that noninvasive tools to assess fibrosis are applied reliably across different settings. CNN-based analysis is feasible and may reduce reliance on expert image analysts.

Therapeutic potential of macrophage colony-stimulating factor in chronic liver disease.

ABSTRACTResident and recruited macrophages control the development and proliferation of the liver. We have previously shown in multiple species that treatment with a macrophage colony stimulating factor (CSF1)-Fc fusion protein initiated hepatocyte proliferation and promoted repair in models of acute hepatic injury in mice. Here, we investigated the impact of CSF1-Fc on resolution of advanced fibrosis and liver regeneration, using a non-resolving toxin-induced model of chronic liver injury and fibrosis in C57BL/6J mice. Co-administration of CSF1-Fc with exposure to thioacetamide (TAA) exacerbated inflammation consistent with monocyte contributions to initiation of pathology. After removal of TAA, either acute or chronic CSF1-Fc treatment promoted liver growth, prevented progression and promoted resolution of fibrosis. Acute CSF1-Fc treatment was also anti-fibrotic and pro-regenerative in a model of partial hepatectomy in mice with established fibrosis. The beneficial impacts of CSF1-Fc treatment were associated with monocyte-macrophage recruitment and increased expression of remodelling enzymes and growth factors. These studies indicate that CSF1-dependent macrophages contribute to both initiation and resolution of fibrotic injury and that CSF1-Fc has therapeutic potential in human liver disease.

Performance of routine risk scores for predicting cirrhosis-related morbidity in the community

Models predicting an individual's 10-year risk of cirrhosis complications have not been developed for a community setting. Our objectives were to assess the performance of existing risk scores - both with and without genetic data - for predicting cirrhosis complications in the community. We used a 2-stage study design. In stage 1, a systematic review was conducted to identify risk scores derived from routine liver blood tests that have demonstrated prior ability to predict cirrhosis-related complication events. Risk scores identified from stage 1 were tested in a UK Biobank subgroup, comprising participants with a risk factor for chronic liver disease (stage 2). Cirrhosis complications were defined as hospitalisation for liver cirrhosis or presentation with hepatocellular carcinoma. Discrimination of risk scores with and without genetic data was assessed using the Wolbers C-index, Harrell's adequacy index, and cumulative incidence curves. Twenty risk scores were identified from the stage-1 systematic review. For stage-2, 197,509 UK biobank participants were selected. The cumulative incidence of cirrhosis complications at 10 years was 0.58%; 95% CI 0.54-0.61 (1,110 events). The top performing risk scores were aspartate aminotransferase-to-platelet ratio index (APRI: C-index 0.804; 95% CI 0.788-0.820) and fibrosis-4 index (FIB-4: C-index 0.780; 95% CI 0.764-0.795). The 10-year cumulative incidences of cirrhosis complications for participants with an APRI score exceeding the 90th, 95th and 99th percentile were 3.30%, 5.42% and 14.83%, respectively. Inclusion of established genetic risk loci associated with cirrhosis added <5% of new prognostic information to the APRI score and improved the C-index only minimally (i.e. from 0.804 to 0.809). Accessible risk scores derived from routine blood tests (particularly APRI and FIB-4) can be repurposed to estimate 10-year risk of cirrhosis morbidity in the community. Genetic data improves performance only minimally. New approaches are needed in community settings to reduce the late diagnosis of chronic liver disease. Thus, in a community cohort, we assessed the ability of 20 routine risk scores to predict 10-year risk of cirrhosis-related complications. We show that 2 routine risk scores in particular - "APRI" and "FIB-4" - could be repurposed to estimate an individual's 10-year risk of cirrhosis-related morbidity. Adding genetic risk factor information to these scores only modestly improved performance.

Low Accuracy of FIB-4 and NAFLD Fibrosis Scores for Screening for Liver Fibrosis in the Population

Fibrosis-4 (FIB-4) and the nonalcoholic fatty liver disease fibrosis score (NFS) are the 2 most popular noninvasive blood-based serum tests proposed for widespread fibrosis screening. We therefore aimed to describe the accuracy of FIB-4 and NFS to detect elevated liver stiffness as an indicator of hepatic fibrosis in low-prevalence populations. This study included a total of 5129 patients with concomitant measurement of FIB-4, NFS, and liver stiffness measurement (LSM) by Fibroscan (Echosens, France) from 5 independent population-based cohorts from Spain, Hong Kong, Denmark, England, and France; 3979 participants from the general population and 1150 from at-risk cohorts due to alcohol, diabetes, or obesity. We correlated LSM with FIB-4 and NFS, and calculated pre- and post-test predictive values of FIB-4 and NFS to detect elevated LSM at 8 kPa and 12 kPa cutoffs. The mean age was 53 ± 12 years, the mean body mass index was 27 ± 5 kg/m2, and 2439 (57%) were women. One in 10 patients (552; 11%) had liver stiffness ≥8 kPa, but 239 of those (43%) had a normal FIB-4, and 171 (31%) had normal NFS. The proportion of false-negatives was higher in at-risk patients than the general population. FIB-4 was false-negative in 11% of diabetic subjects, compared with 2.5% false-negatives with NFS. Waist circumference outperformed FIB-4 and NFS for detecting LSM ≥8 kPa in the general population. Almost one-third (28%-29%) of elevated FIB-4/NFS were false-positive in both the general population and at-risk cohorts. FIB-4 and NFS are suboptimal for screening purposes due to a high risk of overdiagnosis and a non-negligible percentage of false-negatives, especially in patients with risk factors for chronic liver disease. Waist circumference emerged as a potential first step to identify patients at risk for liver fibrosis in the general population.

Translational Control in Liver Disease

Chronic liver disease is one of the biggest threats to public health worldwide. Worryingly, the incidence of liver disease is dramatically rising due to the aging of the population and the global epidemics of obesity. Both are major risk factors for chronic liver disease and adverse prognostic factors, causing an increase in mortality rate. It is of great concern that 80–95% of obese people have non-alcoholic fatty liver disease, the major precursor for liver failure and a global health challenge. Currently, the only curative treatment for advanced chronic liver disease is liver transplantation, which is, however, hampered by high treatment costs and the scarcity of donor organs. New strategies are therefore urgently needed to prevent and reverse chronic liver disease. And for that it is essential to understand better the molecular mechanisms underlying human disease. This review focuses on the abnormalities in the regulation of translation by RNA-binding proteins during chronic liver disease and their pathological impact on portal hypertension, fibrosis, steatosis, neovascularization, and cancer development.

Risk factors for chronic liver disease in population of Central India: a case-control study from rural India

BackgroundChronic liver disease (CLD) is one of the leading causes of morbidity and mortality in today’s world. Common risk factors for CLD are alcohol, chronic hepatitis B, chronic hepatitis C, non-alcoholic steatohepatitis (NASH), malnutrition, toxins, and some tropical infections. This case-control study was carried out to determine the risk factors of domestic CLD in a resource-constrained setting in central rural India. A hospital-based matched case-control study was carried out among eligible CLD cases from November 2015 to October 2017. A total of 200 cases and 200 age- and gender-matched community controls were selected using consecutive sampling from tertiary care hospitals from central rural India. Information on socio-demographic, etiological was collected through using a pretested structured questionnaire after obtaining informed written consent. Univariate and multivariate analyses were carried out to find the risk factors associated with CLD.ResultsThe median age of study participant was 58.5 years among the cases. There were 75% male and remaining 25% were female in each case and control group. On multivariate analysis, we found less education, poor socioeconomic status, diabetes mellitus, increased body mass index (BMI), alcohol consumption, and tobacco chewing were significant risk factors for CLD in comparison to controls. However, amount of alcohol, smoking, and occupation were not found to be statistically significant association with CLD.ConclusionsThe findings showed that in patients with CLD when compared to controls, high alcohol intake, diabetes mellitus, tobacco chewing, central obesity, low education, and low-income group are significant risk factors in our rural population. An initiative needs to be taken to reduce alcohol, and tobacco chewing habits at various levels through awareness campaigns, strict control, and legislation to limit further abuse. Control of blood glucose and reduction of obesity may be important in preventing CLD in our rural community.

Alcohol consumption in patients with nonalcoholic fatty liver disease: yes, or no?

Excessive alcohol intake is an established risk factor for chronic liver disease. At the same time, moderate alcohol intake appears to reduce cardiovascular morbidity. Accordingly, recommendations for alcohol intake in patients with nonalcoholic fatty liver disease (NAFLD), who are at increased risk for liver-related and cardiovascular events, are a point of debate. Some studies have shown beneficial effects of alcohol on cardiovascular and overall mortality in this specific subset of patients. Nonetheless, even light alcohol intake appears to aggravate liver disease and increase the risk of hepatocellular cancer. Therefore, patients with nonalcoholic steatohepatitis or advanced fibrosis should be advised against consuming alcohol. On the other hand, only light alcohol consumption (<10 g/day) might be permitted in patients without significant hepatic fibrosis, provided that they are carefully followed-up. As the research field focusing on NAFLD keeps widening, more prospective studies regarding this specific subject are expected, and may provide a basis for less ambiguous recommendations.

Low incidence of HCC in chronic hepatitis C patients with pretreatment liver stiffness measurements below 17.5 kilopascal who achieve SVR following DAAs

To evaluate the ability of pretreatment liver stiffness measurements (pLSM) to predict hepatocellular carcinoma (HCC), incident decompensation and all-cause mortality in chronic hepatitis C (CHC) patients who achieved sustained virological response (SVR) after treatment with direct-acting antivirals (DAAs). 773 CHC patients with SVR after DAA treatment and no prior liver complications were identified retrospectively. Optimized cut-off of 17.5 kPa for incident HCC was selected by maximum Youden's index. Patients were grouped by pLSM: <10 kPa [reference], 10-17.4 kPa and ≥17.5 kPa. Primary outcomes were incident hepatocellular carcinoma and secondary outcomes were incident decompensated cirrhosis and all-cause mortality, analyzed using cox-regression. Median follow-up was 36 months and 43.5% (336) had cirrhosis (LSM>12.5 kPa). The median pLSM was 11.6 kPa (IQR 6.7-17.8, range 2.5-75) and pLSM of <10 kPa, 10-17.4 kPa and 17.5-75 kPa was seen in 41.5%, 32.2% and 26.3%. During a median follow-up time of 36 months, 11 (1.4%) developed HCC, 14 (1.5%) developed decompensated cirrhosis, and 38 (4.9%) patients died. A pLSM of 17.5 kPa identified patients with a high risk of HCC with a negative predictive value of 98.9% and incidence rate of HCC in the 17.5-75 kPa group of 1.40/100 person years compared to 0.14/100 person years and 0.12/100 person years in the 10-17.4 kPa and <10 kPa groups, p<0.001. Pretreatment LSM predicts risk of HCC, decompensation and all-cause mortality in patients with SVR after DAA treatment. Patients with a pLSM <17.5 kPa and no other risk factors for chronic liver disease appear not to benefit from HCC surveillance for the first 3 years after treatment. Longer follow-up is needed to clarify if they can be safely excluded from post treatment HCC screening hereafter.

Association between behavioural risk factors for chronic liver disease and transient elastography measurements across the UK: a cross-sectional study

ObjectiveChronic liver disease (CLD) is a largely preventable condition with increasing burden on National Health Service resources. We aimed to determine the prevalence of behavioural risk factors for CLD and...

Hepatocellular Carcinoma in Hispanic Patients: Trends and Outcomes in a Large United States Cohort

Hepatocellular carcinoma (HCC) has a strong racial and ethnic association, with Hispanic patients having a higher incidence and mortality. However, there are limited data regarding clinical features and outcomes. This study includes Hispanic and non‐Hispanic White patients with HCC diagnosed between January 2000 and June 2014 from five United States academic medical centers. The chi‐square test for categorical variables and analysis of variance for continuous variables were used for statistical analysis, with two‐tailed P < 0.05 considered statistically significant. Of 5,327 patients, 4,217 met inclusion criteria, of whom 12.3% were Hispanic patients. Compared to their non‐Hispanic White counterparts, Hispanic patients were older at age of diagnosis (mean ± SD, 64.2 ± 10.9 vs. 61.9 ± 10.5 years; P < 0.0001), with higher body mass index (29.6 ± 6.5 vs. 28.8 ± 5.9 kg/m2; P = 0.01), and were more likely to have diabetes and hypertension. Hispanic patients had significantly more nonalcoholic fatty liver disease and alcohol‐related liver disease (both P < 0.0001). Hispanic patients presented with larger tumors, more advanced stage disease, and increased rates of macrovascular invasion and extrahepatic spread. HCCs in Hispanic patients were less likely to be within Milan criteria (26% vs. 38%; P < 0.0001) and were less likely to be treated with resection (9% vs. 13%; P = 0.03) or transplantation (8% vs. 19%; P < 0.0001). Hispanic patients had a median overall survival of 1.4 years (95% confidence interval [CI], 1.22‐1.56), which was similar to that of non‐Hispanic White patients (1.3 years; 95% CI, 1.26‐1.41; P = 0.07). Conclusion: Hispanic patients with HCC were more likely to have metabolic risk factors for chronic liver disease, including obesity. Despite diagnosis at more advanced stages with less curative intervention than non‐Hispanic White patients, median overall survival was similar between groups.

Post-transplant diabetes mellitus and preexisting liver disease - a bidirectional relationship affecting treatment and management.

Liver cirrhosis and diabetes mellitus (DM) are both common conditions with significant socioeconomic burden and impact on morbidity and mortality. A bidirectional relationship exists between DM and liver cirrhosis regarding both etiology and disease-related complications. Type 2 DM (T2DM) is a well-recognized risk factor for chronic liver disease and vice-versa, DM may develop as a complication of cirrhosis, irrespective of its etiology. Liver transplantation (LT) represents an important treatment option for patients with end-stage liver disease due to non-alcoholic fatty liver disease (NAFLD), which represents a hepatic manifestation of metabolic syndrome and a common complication of T2DM. The metabolic risk factors including immunosuppressive drugs, can contribute to persistent or de novo development of DM and NAFLD after LT. T2DM, obesity, cardiovascular morbidities and renal impairment, frequently associated with metabolic syndrome and NAFLD, may have negative impact on short and long-term outcomes following LT. The treatment of DM in the context of chronic liver disease and post-transplant is challenging, but new emerging therapies such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium–glucose cotransporter 2 inhibitors (SGLT2i) targeting multiple mechanisms in the shared pathophysiology of disorders such as oxidative stress and chronic inflammation are a promising tool in future patient management.

Integration of miRNA-regulatory networks in hepatic stellate cells identifies TIMP3 as a key factor in chronic liver disease.

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. 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. 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. 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.