Development Of End-stage Liver Disease Research Articles

Conserved long noncoding RNA TILAM promotes liver fibrosis through interaction with PML in HSCs.

Fibrosis is the common end point for all forms of chronic liver injury, and the progression of fibrosis leads to the development of end-stage liver disease. Activation of HSCs and their transdifferentiation into myofibroblasts results in the accumulation of extracellular matrix proteins that form the fibrotic scar. Long noncoding RNAs regulate the activity of HSCs and provide targets for fibrotic therapies. We identified long noncoding RNA TILAM located near COL1A1 , expressed in HSCs, and induced with liver fibrosis in humans and mice. Loss-of-function studies in human HSCs and human liver organoids revealed that TILAM regulates the expression of COL1A1 and other extracellular matrix genes. To determine the role of TILAM in vivo, we annotated the mouse ortholog ( Tilam ), generated Tilam- deficient green fluorescent protein-reporter mice, and challenged these mice in 2 different models of liver fibrosis. Single-cell data and analysis of single-data and analysis of Tilam-deficient reporter mice revealed that Tilam is induced in murine HSCs with the development of fibrosis in vivo. Tilam -deficient reporter mice revealed that Tilam is induced in murine HSCs with the development of fibrosis in vivo. Furthermore, loss of Tilam expression attenuated the development of fibrosis in the setting of in vivo liver injury. Finally, we found that TILAM interacts with promyelocytic leukemia nuclear body scaffold protein to regulate a feedback loop by which TGF-β2 reinforces TILAM expression and nuclear localization of promyelocytic leukemia nuclear body scaffold protein to promote the fibrotic activity of HSCs. TILAM is activated in HSCs with liver injury and interacts with promyelocytic leukemia nuclear body scaffold protein to drive the development of fibrosis. Depletion of TILAM may serve as a therapeutic approach to combat the development of end-stage liver disease.

Is there a connection between neurocognitive profile in treatment naïve non-cirrhotic HCV patients and level of systemic inflammation?

Hepatitis C virus (HCV) infection is a progressive, systemic disease which leads to the development of end-stage liver disease. In 70% of patients, HCV infection is followed by the development of extrahepatic manifestations (EHM). A common EHM is HCV associated neurocognitive disorder (HCV-AND), characterized by neuropsychological changes in attention, working memory, psychomotor speed, executive function, verbal learning, and recall. The aim of this study is to examine the correlation between the neurocognitive profile and routine, available laboratory parameters of inflammation, liver function tests, grade of liver fibrosis, and clinical and laboratory parameters of mixed cryoglobulinemia in treatment naïve non-cirrhotic HCV patients. This is a single-center exploratory study in which we examined 38 HCV + treatment naïve patients. The complete blood count and hematological parameters of systemic inflammation, liver function tests, biopsy confirmed grade of liver fibrosis, and clinical and laboratory parameters of mixed cryoglobulinemia caused by chronic HCV infection were observed. In the study, we used a battery of neuropsychological tests assessing multiple cognitive domains: executive functions, verbal fluency, delayed memory, working memory and learning, and one measure for visuo-constructive performance. Before the Bonferroni correction for multiple comparisons, the results show significant correlations between the scores in the neurocognitive variables and the single measures of inflammation, liver function parameters, and mixed cryoglobulinemia. It has not found a statistically significant correlation between systemic inflammation and neurocognitive variables. After the Bonferroni adjustment, no correlations remained significant. Certainly, the obtained results can be a recommendation for additional validation through future research.

A Markov model of fibrosis development in nonalcoholic fatty liver disease predicts fibrosis progression in clinical cohorts.

Disease progression in nonalcoholic steatohepatitis (NASH) is highly heterogenous and remains poorly understood. Fibrosis stage is currently the best predictor for development of end-stage liver disease and mortality. Better understanding and quantifying the impact of factors affecting NASH and fibrosis is essential to inform a clinical study design. We developed a population Markov model to describe the transition probability between fibrosis stages and mortality using a unique clinical nonalcoholic fatty liver disease cohort with serial biopsies over 3 decades. We evaluated covariate effects on all model parameters and performed clinical trial simulations to predict the fibrosis progression rate for external clinical cohorts. All parameters were estimated with good precision. Age and diagnosis of type 2 diabetes (T2D) were found to be significant predictors in the model. Increase in hepatic steatosis between visits was the most important predictor for progression of fibrosis. Fibrosis progression rate (FPR) was twofold higher for fibrosis stages 0 and 1 (F0-1) compared to fibrosis stage 2 and 3 (F2-3). A twofold increase in FPR was observed for T2D. A two-point steatosis worsening increased the FPR 11-fold. Predicted fibrosis progression was in good agreement with data from external clinical cohorts. Our fibrosis progression model shows that patient selection, particularly initial fibrosis stage distribution, can significantly impact fibrosis progression and as such the window for assessing drug efficacy in clinical trials. Our work highlights the increase in hepatic steatosis as the most important factor in increasing FPR, emphasizing the importance of well-defined lifestyle advise for reducing variability in NASH progression during clinical trials.

Stress mechanism involved in the progression of alcoholic liver disease and the therapeutic efficacy of nanoparticles.

Alcoholic liver disease (ALD) poses a significant threat to human health, with excessive alcohol intake disrupting the immunotolerant environment of the liver and initiating a cascade of pathological events. This progressive disease unfolds through fat deposition, proinflammatory cytokine upregulation, activation of hepatic stellate cells, and eventual development of end-stage liver disease, known as hepatocellular carcinoma (HCC). ALD is intricately intertwined with stress mechanisms such as oxidative stress mediated by reactive oxygen species, endoplasmic reticulum stress, and alcohol-induced gut dysbiosis, culminating in increased inflammation. While the initial stages of ALD can be reversible with diligent care and abstinence, further progression necessitates alternative treatment approaches. Herbal medicines have shown promise, albeit limited by their poor water solubility and subsequent lack of extensive exploration. Consequently, researchers have embarked on a quest to overcome these challenges by delving into the potential of nanoparticle-mediated therapy. Nanoparticle-based treatments are being explored for liver diseases that share similar mechanisms with alcoholic liver disease. It underscores the potential of these innovative approaches to counteract the complex pathogenesis of ALD, providing new avenues for therapeutic intervention. Nevertheless, further investigations are imperative to fully unravel the therapeutic potential and unlock the promise of nanoparticle-mediated therapy specifically tailored for ALD treatment.

Insights of mitochondrial involvement in alcoholic fatty liver disease.

Alcoholic liver disease (ALD) is a global concern affecting most of the population and leading to the development of end-stage liver disease. Metabolic alterations due to increased alcohol consumption surge the hepatic accumulation of lipids and develop into a severe form of alcoholic steatohepatitis (ASH), depending on age and the consumption rate. The mitochondria in the hepatocyte actively regulate metabolic homeostasis and are disrupted in ALD pathogenesis. The increased NADH upon ethanol metabolism inhibits the mitochondrial oxidation of fatty acids, alters oxidative phosphorylation, and favors de novo lipogenesis. The higher mitochondrial respiration in early ALD increases free radical generation, whereas mitochondrial respiration is uncoupled in chronic ALD, affecting the cellular energy status. The defective glutathione importer due to excessive cholesterol loading and low adenosine triphosphate accounts for additional oxidative stress leading to hepatocyte apoptosis. The defective mitochondrial transcription machinery and sirtuins function in ALD affect mitochondrial function and biogenesis. The metabolites of ethanol metabolism epigenetically alter the gene expression profile of hepatic cell populations by modulating the promoters and sirtuins, aiding hepatic fibrosis and inflammation. The defect in mitophagy increases the accumulation of megamitochondria in hepatocytes and attracts immune cells by releasing mitochondrial damage-associated molecular patterns to initiate hepatic inflammation and ASH progression. Thus, maintaining mitochondrial lipid homeostasis and antioxidant capacity pharmacologically could provide a better outcome for ALD management.

Progression of non-alcoholic fatty liver disease and long-term outcomes: A nationwide paired liver biopsy cohort study

More data are needed regarding the long-term impact of the histological progression of non-alcoholic fatty liver disease (NAFLD) on long-term outcomes, including end-stage liver disease (ESLD) and mortality. We included Swedish adults with biopsy-confirmed non-cirrhotic NAFLD and ≥2 liver biopsies >6 months apart (1969-2017; n= 718). NAFLD was categorized at initial biopsy as simple steatosis, non-fibrotic steatohepatitis (NASH), or non-cirrhotic fibrosis. NAFLD progression was defined by histological changes between biopsies (i.e. incident NASH, incident fibrosis, fibrosis progression, cirrhosis). Using Cox regression, we estimated multivariable adjusted hazard ratios (aHRs) and 95% CIs for incident ESLD (i.e. hospitalization for decompensated cirrhosis, hepatocellular carcinoma or liver transplantation) and mortality, according to NAFLD progression vs. stable/regressed disease. At initial biopsy, 497 patients (69.2%) had simple steatosis, 90 (12.5%) had non-fibrotic NASH, and 131 (18.2%) had non-cirrhotic fibrosis. Over a median of 3.4 years between biopsies, 30.4% (218/718) experienced NAFLD progression, including 12.5% (62/497) with incident non-fibrotic NASH, 24.0% (141/587) with incident fibrosis, and 5.6% (40/718) with cirrhosis. Compared to stable/regressed disease, NAFLD progression was associated with significantly higher rates of developing incident ESLD (23.8 vs. 11.4/1,000 person-years [PY]; difference= 12.4/1,000 PY; aHR 1.65, 95% CI 1.17-2.32). While the highest ESLD incidence occurred with progression to cirrhosis (difference vs. stable/regressed disease= 56.3/1,000 PY), significant excess risk was also found with earlier transitions, including from simple steatosis to incident fibrosis (difference vs. stable/regressed disease= 18.9/1,000 PY). In contrast, all-cause mortality rates did not appear to differ when NAFLD progression was compared to stable/regressed disease (difference= 4.7/1,000 PY; aHR 0.99, 95% CI 0.78-1.24). In a nationwide, real-world cohort of patients with paired NAFLD biopsies, histological disease progression contributed to significantly higher rates of developing incident ESLD, but did not appear to impact all-cause mortality. Currently, data are scarce regarding the long-term impact of histological progression or regression of non-alcoholic fatty liver disease (NAFLD) on subsequent risk of adverse clinical outcomes, including the development of end-stage liver disease and mortality. This is particularly important because randomized-controlled trials of NAFLD therapeutics currently focus on short-term histological endpoints as presumed surrogates for those major clinical outcomes. Thus, the results from this study can help inform the optimal design of future NAFLD therapeutic trials, while also providing the necessary evidence base for public health policies focused on preventing the development and progression of NAFLD.

HIV-HBV Coinfection-Current Challenges for Virologic Monitoring.

HIV-HBV coinfected patients have higher rates of liver-related morbidity, hospitalizations, and mortality compared to HBV or HIV mono-infected ones. Clinical studies have shown an accelerated progression of liver fibrosis and an increased incidence of HCC, resulting from the combined action of HBV replication, immune-mediated hepatocytolysis, and HIV-induced immunosuppression and immunosenescence. Antiviral therapy based on dually active antiretrovirals is highly efficient, but late initiation, global disparities in accessibility, suboptimal regimens, and adherence issues may limit its impact on the development of end-stage liver disease. In this paper, we review the mechanisms of liver injuries in HIV-HBV coinfected patients and the novel biomarkers that can be used for treatment monitoring in HIV-HBV coinfected persons: markers that assess viral suppression, markers for liver fibrosis evaluation, and predictors of oncogenesis.

Use of serum Golgi protein 73 for screening chronic hepatitis B virus infection patients needing antiviral therapy in the community.

Use of serum Golgi protein 73 for screening chronic hepatitis B virus infection patients needing antiviral therapy in the community.

Repeated measurements of non-invasive fibrosis tests to monitor the progression of non-alcoholic fatty liver disease: A long-term follow-up study.

Background and AimsThe presence of advanced hepatic fibrosis is the prime marker for the prediction of liver‐related complications in non‐alcoholic fatty liver disease (NAFLD). Blood‐based non‐invasive tests (NITs) have been developed to evaluate fibrosis and identify patients at risk. Current guidelines propose monitoring the progression of NAFLD using repeated NITs at 2–3‐year intervals. The aim of this study was to evaluate the association of changes in NITs measured at two time points with the progression of NAFLD.MethodsWe retrospectively included NAFLD patients with NIT measurements in whom the baseline hepatic fibrosis stage had been assessed by biopsy or transient elastography (TE). Subjects underwent follow‐up visits at least 1 year from baseline to evaluate the progression of NAFLD. NAFLD progression was defined as the development of end‐stage liver disease or fibrosis progression according to repeat biopsy or TE. The following NITs were calculated at baseline and follow‐up: Fibrosis‐4 (FIB‐4), NAFLD fibrosis score (NFS), aspartate aminotransferase to platelet ratio index (APRI) and dynamic aspartate‐to‐alanine aminotransferase ratio (dAAR).ResultsOne hundred and thirty‐five patients were included with a mean follow‐up of 12.6 ± 8.5 years. During follow‐up, 41 patients (30%) were diagnosed with progressive NAFLD. Change in NIT scores during follow‐up was significantly associated with disease progression for all NITs tested except for NFS. However, the diagnostic precision was suboptimal with area under the receiver operating characteristics 0.56–0.64 and positive predictive values of 0.28–0.36 at sensitivity fixed at 90%.ConclusionsChange of FIB‐4, NFS, APRI, and dAAR scores is only weakly associated with disease progression in NAFLD. Our findings do not support repeated measurements of these NITs for monitoring the course of NAFLD.

Complications of End-Stage Liver Disease: Advances from a Clinical Viewpoint

Complications of End-Stage Liver Disease: Advances from a Clinical Viewpoint

A Tale of Two Viruses: Immunological Insights Into HCV/HIV Coinfection.

Nearly 2.3 million individuals worldwide are coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Odds of HCV infection are six times higher in people living with HIV (PLWH) compared to their HIV-negative counterparts, with the highest prevalence among people who inject drugs (PWID) and men who have sex with men (MSM). HIV coinfection has a detrimental impact on the natural history of HCV, including higher rates of HCV persistence following acute infection, higher viral loads, and accelerated progression of liver fibrosis and development of end-stage liver disease compared to HCV monoinfection. Similarly, it has been reported that HCV coinfection impacts HIV disease progression in PLWH receiving anti-retroviral therapies (ART) where HCV coinfection negatively affects the homeostasis of CD4+ T cell counts and facilitates HIV replication and viral reservoir persistence. While ART does not cure HIV, direct acting antivirals (DAA) can now achieve HCV cure in nearly 95% of coinfected individuals. However, little is known about how HCV cure and the subsequent resolution of liver inflammation influence systemic immune activation, immune reconstitution and the latent HIV reservoir. In this review, we will summarize the current knowledge regarding the pathogenesis of HIV/HCV coinfection, the effects of HCV coinfection on HIV disease progression in the context of ART, the impact of HIV on HCV-associated liver morbidity, and the consequences of DAA-mediated HCV cure on immune reconstitution and HIV reservoir persistence in coinfected patients.

Anti-HDV seroprevalence in patients with decompensated liver cirrhosis due to hepatitis B

Aim: Hepatitis B (HBV) and Hepatitis D (HDV) viruses are among the two important causes of end-stage liver disease today. In this study, we aimed to increase HDV awareness in people infected with HBV by examining the prevalence of HDV in patients with end-stage liver disease due to HBV and who were evaluated for liver transplantation.Materials and Methods: The study was designed as a retrospective single-center and cross-sectional. Patients with HBV decompensated liver cirrhosis were divided into two groups as anti-HDV positive and negative. Child-turcott pugh (CTP), Model for End-Stage Liver Disease (MELD) score, complications of liver cirrhosis, viral hepatitis serology, and platelet count variables were statistically compared between the groups.Results: A total of 147 patients with decompensated liver cirrhosis due to HBV were included in the study. Anti-HDV positivity was detected in 46 (31.3%) patients, and anti-HDV negative in 101 (68.7%) patients. The mean age of HDV positive patients (48.39±9.20) was statistically significantly lower than HDV negative (54.37±7.80) patients (p<0.001). Although MELD and CTP scores were slightly higher in the anti-HDV negative group, there was no statistically significant difference between the groups in terms of both scores (p=0.401; p=0.782, respectively). The platelet count was found to be significantly lower in the anti-HDV positive group than in the anti-HDV negative group (p=0.008).Conclusion: The rate of encountering HDV in end-stage liver disease due to HBV was found to be quite high. HDV is an important factor in the development of end-stage liver disease in HBV-infected individuals, especially at an early age, and taking precautions for this is of great importance.

Long-Term Follow-Up of a Portuguese Single-Centre Cohort of Persons with Haemophilia and Hepatitis C Virus Infection

Introduction: Persons with haemophilia (PWH) used to represent a population with a high prevalence of hepatitis C virus (HCV) infection due to the use of contaminated blood products. Although the goals of antiviral therapy are the same as the general population, long real-life follow-up data regarding their outcomes are still scarce. Our aim was to report the outcomes of HCV infection and the results of antiviral therapy in PWH. Methods: A retrospective analysis was performed in a single-centre cohort of PWH with positive HCV antibody. Outcomes registered were rate of spontaneous clearance of HCV, sustained virologic response (SVR) achievement, development of end-stage liver disease, and all-cause and liver-related mortality. Results: Out of 131 PWH, 73 (55.7%) had positive HCV antibody. During a median follow-up time of 22 years, 46 patients (63.9%) developed chronic hepatitis C, of which 16 (34.8%) developed cirrhosis. Treatment was pursued in 34 PWH. Most (n = 32) were first treated with interferon (IFN)-based regimens with SVR rates of 40.6%. Direct-acting antivirals were used in 14 IFN-experienced and 2 naïve patients, with an overall SVR rate of 100%. Overall, 17 patients (23.3%) died during the follow-up, only 4 related to liver disease. Of these, none had achieved SVR. Conclusions: We describe the outcomes of a cohort of Portuguese PWH and hepatitis C exposure after two decades of follow-up, with a lower mortality than previously described. Our response rates to HCV treatment were comparable to those in the general population and stress the importance of early treatment.

The Metabolic Sensor Adenosine Monophosphate-Activated Protein Kinase Regulates Apoptosis in Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH), occurring in a subset of patients with nonalcoholic fatty liver disease (NAFLD), is characterized by cellular inflammation and hepatic fibrosis. NASH may lead to the development of end-stage liver disease and its sequelae. Hepatocyte cell death contributes to inflammation and fibrosis in NASH. Although multiple modes of cell death occur in experimental models of NASH (i.e., apoptosis, necroptosis, and pyroptosis), apoptosis is the best characterized. Apoptosis is mediated by activation of a family of cysteine proteases termed caspases, which ultimately cleave a plethora of cellular substrates resulting in cellular demise. Caspases are classified as "initiators" (i.e., caspase-8, caspase-9) and "executioners" (i.e., caspase-3, caspase-7, caspase-6), the former being activated in molecular platforms assembled after engagement of death receptors or mitochondrial permeabilization, and the latter being cleaved and activated by initiator caspases, with the exception of caspase-6, which is often activated by caspase-3 rather than by initiator caspases. Although caspase-3 has been implicated in hepatocyte apoptosis and liver fibrosis in a mouse model of NASH (1), the involvement of caspase-6 was never reported until now.

Role of alcohol in pathogenesis of hepatitis B virus infection.

Hepatitis B virus (HBV) and alcohol abuse often contribute to the development of end-stage liver disease. Alcohol abuse not only causes rapid progression of liver disease in HBV infected patients but also allows HBV to persist chronically. Importantly, the mechanism by which alcohol promotes the progression of HBV-associated liver disease are not completely understood. Potential mechanisms include a suppressed immune response, oxidative stress, endoplasmic reticulum and Golgi apparatus stresses, and increased HBV replication. Certainly, more research is necessary to gain a better understanding of these mechanisms such that treatment(s) to prevent rapid liver disease progression in alcohol-abusing HBV patients could be developed. In this review, we discuss the aforementioned factors for the higher risk of liver diseases in alcohol-induced HBV pathogenies and suggest the areas for future studies in this field.

Established and emerging factors affecting the progression of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease affecting approximately 25% of the global population. Although a majority of NAFLD patients will never experience liver-related symptoms it is estimated that 5–10% will develop cirrhosis-related complications with risk of death or need for liver transplantation. NAFLD is closely associated with cardiovascular disease and components of the metabolic syndrome. However, NAFLD is not uncommon in lean individuals and may in these subjects represent a different entity with separate pathophysiological mechanisms involved implying a higher risk for development of end-stage liver disease. There is considerable fluctuation in the histopathological course of NAFLD that may partly be attributed to lifestyle factors and dietary composition. Nutrients such as fructose, monounsaturated fatty acids, and trans-fatty acids may aggravate NAFLD. Presence of type 2 diabetes mellitus seems to be the most important clinical predictor of liver-related morbidity and mortality in NAFLD. Apart from severity of the metabolic syndrome, genetic polymorphisms and environmental factors, such as moderate alcohol consumption, may explain the variation in histopathological and clinical outcome among NAFLD patients.

Acetaldehyde suppresses the display of HBV-MHC class I complexes on HBV-expressing hepatocytes.

Hepatitis B virus (HBV) infection and alcoholism are major public health problems worldwide, contributing to the development of end-stage liver disease. Alcohol intake affects HBV infection pathogenesis and treatment outcomes. HBV-specific cytotoxic T lymphocytes (CTLs) play an important role in HBV clearance. Many previous studies have focused on alcohol-induced impairments of the immune response. However, it is not clear whether alcohol alters the presentation of HBV peptide-major histocompatibility complex (MHC) class I complexes on infected hepatocytes resulting in escape of its recognition by CTLs. Hence, the focus of this study was to investigate the mechanisms by which ethanol metabolism affects the presentation of CTL epitope on HBV-infected hepatocytes. As demonstrated here, although continuous cell exposure to acetaldehyde-generating system (AGS) increased HBV load in HepG2.2.15 cells, it decreased the expression of HBV core peptide 18-27-human leukocyte antigen-A2complex (CTL epitope) on the cell surface. Moreover, we observed AGS-induced suppression of chymotrypsin- and trypsin-like proteasome activities necessary for peptide processing by proteasome as well as a decline in IFNγ-stimulated immunoproteasome (IPR) function and expression of PA28 activator and immunoproteasome subunits LMP7 and LMP2. Furthermore, IFNγ-induced activation of peptide-loading complex (PLC) components, such as transporter associated with antigen processing (TAP1) and tapasin, were suppressed by AGS. The attenuation of IPR and PLC activation was attributed to AGS-triggered impairment of IFNγ signaling in HepG2.2.15 cells. Collectively, all these downstream events reduced the display of HBV peptide-MHC class I complexes on the hepatocyte surface, which may suppress CTL activation and the recognition of CTL epitopes on HBV-expressing hepatocytes by immune cells, thereby leading to persistence of liver inflammation.NEW & NOTEWORTHY Our study shows that in HBV-expressing HepG2.2.15 cells, acetaldehyde alters HBV peptide processing by suppressing chymotrypsin- and trypsin-like proteasome activities and decreases IFNγ-stimulated immunoproteasome function and expression of PA28 activator and immunoproteasome subunits. It also suppresses IFNγ-induced activation of peptide-loading complex (PLC) components due to impairment of IFNγ signaling via the JAK-STAT1 pathway. These acetaldehyde-induced dysfunctions reduced the display of HBV peptide-MHC class I complexes on the hepatocyte surface, thereby leading to persistence of HBV infection.

HCV infection causes cirrhosis in human by step-wise regulation of host genes involved in cellular functioning and defense during fibrosis: Identification of bio-markers

Chronic Hepatitis C Viral (HCV) infection is a leading health problem worldwide and resulted in fibrotic scar formation, and finally liver-cirrhosis. Although contemporary therapies can partially reverse this destructive process, the rehabilitation is too slow and unsuitable for all chronic infections. The current study elucidates the mechanism of disease progression from early (F1) to moderate (F2, F3), and to severe fibrosis (F4)/cirrhosis in HCV genotype 3a infected patients to find out new candidates as potential disease progression markers and antiviral therapeutic agents. A total of 550 genes were found differentially regulated in the four fibrosis stages and grouped in 22 classes according to their biological functions. Gene set enrichment (GSEA) and Ingenuity pathway analysis (IPA) were used to identify the regulation of crucial biological functions and pathways involved in HCV progression. HCV differentially regulated the expression of genes involved in apoptosis, cell structure, signal transduction, proliferation, metabolism, cytokine signaling, immune response, cell adhesion and maintenance, and post translational modifications by pathway analysis. There was an increasing trend of proliferative and cell growth related genes and shutting down of immune response as the disease progress mild to moderate to advanced stage cirrhosis. The myriad of changes in gene expression showed more chances of developing liver cancer in patients infected with HCV genotype 3a in a systematic manner. The identified gene set can act as disease markers for prediction, whether the fibrosis lead to cirrhosis and its association with end stage liver disease development.

Alagille Syndrome and the Liver: Current Insights.

Alagille syndrome (ALGS) is an autosomal dominant disorder, with multisystem involvement, which usually occurs due to Notch signaling pathway defects, mostly due to JAG1 mutation (ALGS type 1), but rarely due to neurogenic locus notch homolog protein (NOTCH2) mutation (ALGS type 2). It was suspected in cases having at least three out of five major clinical criteria: cholestasis with a paucity of the bile duct, congenital cardiac defects, ocular posterior embryotoxon, typical facial features, and skeletal malformation. Till date, no early predictive marker for hepatic outcome in ALGS has found. No genotypic or, phenotype features or correlation could predict the development of endstage liver disease, which poses a unique management challenge. Cases with progressive liver damage, unremitting cholestasis and intractable pruritus often depend on liver transplantation as last resort. The cardiac, and renal status should be well accessed before liver transplant for the better post-transplantation outcome. Most of the clinical manifestations usually improve the following transplant, except any change in stature. The post liver transplantation outcome was usually comparable with other conditions which require liver transplantation as a last resort, but in this disease the effect of long term immunosuppression on other affected systems not evaluated well till date. Therefore long term post transplant prospective study is required to address these issues.How to cite this article: Singh SP, Pati GK. Alagille Syndrome and the Liver: Current Insights. Euroasian J Hepatogastroenterol, 2018;8(2):140-147

Recent research trends and updates on nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD), together with metabolic syndrome and obesity, has shown a rapid increase in prevalence worldwide and is emerging as a major cause of chronic liver disease and liver transplantation. Among the various phenotypes of NAFLD, nonalcoholic steatohepatitis (NASH) is highly likely to progress to development of end-stage liver disease and cardiometabolic disease, resulting in liver-related and non-liver–related mortality. Nonetheless, there is no standardized pharmacotherapy against NASH and many drugs are under development in ongoing clinical trials. To develop a successful anti-NASH drug, it is necessary to select an appropriate target population and treatment outcomes depending on whether the mode of action is anti-metabolic, anti-inflammatory or anti-fibrotic. Recently, innovative surrogate markers have been investigated to replace hard outcomes such as liver histology and mortality and reduce the clinical trial duration. Currently, several drugs with fast track designation are being tested in phase III clinical trials, and many other drugs have moved into phase II clinical trials. Both lean NAFLD and typical obese NAFLD have been extensively studied and genetic variants such as PNPLA3 and TM6SF2 have been identified as significant risk factors for lean NAFLD. In the near future, noninvasive biomarkers and effective targeted therapies for NASH and associated fibrosis are required to develop precision medicine and tailored therapy according to various phenotypes of NAFLD.