Nonalcoholic Steatohepatitis Patient Research Articles

Derlin-1 promotes diet-induced non-alcoholic fatty liver disease via increasing RIPK3-mediated necroptosis

Background & aimsUnrestricted endoplasmic reticulum (ER) stress and the continuous activation of ER associated protein degradation (ERAD) pathway might lead to the aggravation of non-alcoholic steatohepatitis (NASH). Derlin-1 has been considered to be an integral part of the ERAD pathway, which is involved in the regulation of the transport and excretion of protein degradation products within ER. However, the regulatory role and mechanism of Derlin-1 in NASH remains unclear. MethodsThe expression of Derlin-1 was firstly detected in the liver of normal and NASH animal model and patient. Then, western diet (WD)-induced NASH mice were administrated with the lentivirus-mediated Derlin-1 knockdown or overexpression. Finally, RIPK3 knockout mice were used to explore the mechanism. The liver injury, hepatic steatosis, inflammation, and fibrosis as well as ER stress signal pathway were evaluated. ResultsThe levels of Derlin-1 were significantly elevated in the liver of WD-fed mice and NASH patients when compared to the control group. Furthermore, Derlin-1 knockdown attenuated WD-induced liver injury, lipid accumulation, inflammatory response, and fibrosis. Conversely, overexpression of Derlin-1 presented the completely opposite results. Mechanistically, Derlin-1 enhanced ER stress pathways and led to necroptosis, and RIPK3 knockout dramatically reduced Derlin-1 expression and reversed the progression of NASH aggravated by Derlin-1. ConclusionsNotably, Derlin-1 is a critical modulator in NASH. It may accelerate the progression of NASH by regulating the activation of the ERAD pathway and further aggravating the ER stress, which might be involved in RIPK3-mediated necroptosis. Therefore, targeting Derlin-1 as a novel intervention point holds the potential to delay or even reverse NASH.

Sonic hedgehog-heat shock protein 90β axis promotes the development of nonalcoholic steatohepatitis in mice

Sonic hedgehog (SHH) and heat shock protein 90β (HSP90β) have been implicated in nonalcoholic steatohepatitis (NASH) but their molecular mechanisms of action remain elusive. We find that HSP90β is a key SHH downstream molecule for promoting NASH process. In hepatocytes, SHH reduces HSP90β ubiquitylation through deubiquitylase USP31, thus preventing HSP90β degradation and promoting hepatic lipid synthesis. HSP90β significantly increases in NASH mouse model, leading to secretion of exosomes enriched with miR-28-5p. miR-28-5p directly targetes and decreases Rap1b levels, which in turn promotes NF-κB transcriptional activity in macrophages and stimulates the expression of inflammatory factors. Genetic deletion, pharmacological inhibition of the SHH-HSP90β axis, or delivery of miR-28-5p to macrophages in the male mice liver, impairs NASH symptomatic development. Importantly, there is a markedly higher abundance of miR-28-5p in NASH patient sera. Taken together, the SHH-HSP90β-miR-28-5p axis offers promising therapeutic targets against NASH, and serum miR-28-5p may serve as a NASH diagnostic biomarker.

Lifestyle interventions for patients with non-alcoholic steato-hepatitis-Design, rationale and protocol of the study "target group-specific optimisation of lifestyle interventions for behavior change in non-alcoholic steato-hepatitis (OPTI-NASH)".

Non-alcoholic steato-hepatitis (NASH) is the inflammatory, progressive form of non-alcoholic fatty liver disease (NAFLD). A delayed diagnose interval is typical for the majority of the patients because of the asymptomatic natural course. However, serious sequelae may develop such as cirrhosis or hepatocellular carcinoma. NASH is also associated with an increased risk of metabolic diseases. Obesity developed due to a lack of exercise or a disadvantageous diet often leads to NAFLD or NASH, thereby interventions including enhanced physical activity and calorie reduction form the actual gold standard of treatment. To date, patients rarely use these. The project aims to model lifestyle interventions based on the preferences of the NASH patients. Based on a systematic review and focus group discussions, two discrete choice experiments (DCE) will be designed, one on aspects influencing successful uptake of lifestyle interventions and one to analyses parameters contributing to long-term participation. An online survey will be used to elicit patient's preferences on program design and on motivational aspects in a cross-sectional design. The recruitment will take place in nine certified specialist practices and hospital outpatient clinics aiming to reach a sample size of n = 500 which is also required for the DCE design. The results will provide an overview of the NASH patient's preferences regarding the successful uptake and long-term implementation of lifestyle interventions. Recommendations for optimized lifestyle change programs will be derived and an intervention manual will be developed to facilitate target group-specific inclusion in programs in practice.

Discovery of novel AdipoRon analogues as potent anti-inflammatory agents against nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) is a rising public health burden, and there is a lack of effective therapeutic drugs in clinical practice. Sustained hepatic inflammation is considered as the key histopathological feature and dangerous fact for NASH. Different causes vary from one NASH patient to another, while sustained hepatic inflammation affects all NASH patients. AdipoRon is the first small-molecule AdipoR agonist, exerting antidiabetic and anti-inflammatory effect. In order to find novel AdipoRon analogues with more potent anti-inflammatory activity, we designed, synthesized and biologically evaluated 32 analogues. Among them, Q7 exerted potent anti-inflammatory activity and less cytotoxicity. Q7 could dose-dependently stimulate the increasing of AMPK phosphorylation, the widely recognized downstream effector of AdipoR1 activation. In NASH model mice, Q7 showed significant anti-inflammatory, anti-fibrotic and lipid-lowering effect in mice liver, and was superior to AdipoRon. Together, Q7 holds promise for developing anti-inflammatory and anti-NASH agents.

Predictors of patient survival following liver transplant in non-alcoholic steatohepatitis: A systematic review and meta-analysis.

SummaryBackgroundNon-alcoholic steatohepatitis (NASH) is the second-leading indication for liver transplantation (LT) worldwide and is projected to become the leading indication. Our study aimed to determine clinical variables that predict post-LT survival in NASH.MethodsA systematic review and meta-analysis was performed. On June 18, 2020 and April 28, 2022, Ovid MEDLINE ALL, Ovid Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials were searched. No date limits were applied. Inclusion criteria specified the type of study and our study's population/comparison and outcome/timepoints. Pediatric, animal, retransplantation-only, and studies classifying cryptogenic cirrhosis patients with body mass index (BMI) <30 as NASH were excluded. Studies with duplicate cohorts and missing information were excluded from the meta-analysis. Studies were appraised using the Newcastle–Ottawa Scale. This study was preregistered in PROSPERO (CRD42020196915).FindingsOut of 8583 studies identified, 25 studies were included in the systematic review, while 5 studies were included in the meta-analysis. Our quantitative review suggested that the following variables were predictive of post-LT NASH patient survival: recipient age, functional status, pre-LT hepatoma, model for end-stage liver disease (MELD) score, diabetes mellitus (DM), pre-LT dialysis, hepatic encephalopathy, portal vein thrombosis, hospitalization/ICU at LT, and year of LT. Predictors of graft survival included recipient age, BMI, pre-LT dialysis, and DM. Our pooled meta-analyses included five predictors of patient survival. Increased patient mortality was associated with older recipient age (HR=2·07, 95%CI: 1·71-2·50, I2=0, τ2=0, p=0·40) and pretransplant DM (HR=1·18, 95%CI: 1·08-1·28, I2=0, τ2=0, p=0·76).InterpretationOur systematic review and meta-analysis aimed to synthesise predictive variables of mortality in LT NASH patients. Clinically, this might help to identify modifiable risk factors that can be optimized in the post-transplant setting to improve patient outcomes and optimises decision making in the resource-limited LT setting.FundingToronto General and Western Hospital Foundation.

Assessment of drug-drug interaction potential with EDP-305, a farnesoid X receptor agonist, in healthy subjects.

EDP‐305 is a farnesoid X receptor (FXR) agonist that selectively activates FXR and is a potential treatment for patients with nonalcoholic steatohepatitis (NASH) with liver fibrosis. Results from preclinical studies indicate that CYP3A4 is the primary enzyme involved in EDP‐305 metabolism and that EDP‐305 has low potential to inhibit or induce cytochrome (CYP) isoenzymes and drug transporters. Four studies were conducted in healthy volunteers to evaluate the drug–drug interaction (DDI) potential of EDP‐305 co‐administered with drugs known to be substrates for drug metabolizing enzymes or transporters, and to assess the effect of inhibitors and inducers of CYP3A4 on EDP‐305. Results suggest caution when substrates of CYP3A4 are administered concomitantly with EDP‐305. A potential for increased exposure is apparent when CYP1A2 substrates with a narrow therapeutic index are administered with EDP‐305. In contrast, substrates of drug transporters can be administered concomitantly with EDP‐305 with a low potential for interactions. Coadministration of EDP‐305 and a combined OC had no relevant effects on plasma concentrations of the combined OC. Co‐administration of EDP‐305 with strong or moderate inhibitors and inducers of CYP3A4 is not recommended. These results indicate low overall likelihood of interaction of EDP‐305 and other substrates through CYP mediated interactions. The interaction potential of EDP‐305 with drug transporters was low and of unlikely clinical significance. The EDP‐305 DDI profile allows for convenient administration in patients with NASH and other patient populations with comorbidities, with minimal dose modification of concomitant medications.

Identification and New Indication of Melanin-Concentrating Hormone Receptor 1 (MCHR1) Antagonist Derived from Machine Learning and Transcriptome-Based Drug Repositioning Approaches.

Melanin-concentrating hormone receptor 1 (MCHR1) has been a target for appetite suppressants, which are helpful in treating obesity. However, it is challenging to develop an MCHR1 antagonist because its binding site is similar to that of the human Ether-à-go-go-Related Gene (hERG) channel, whose inhibition may cause cardiotoxicity. Most drugs developed as MCHR1 antagonists have failed in clinical development due to cardiotoxicity caused by hERG inhibition. Machine learning-based prediction models can overcome these difficulties and provide new opportunities for drug discovery. In this study, we identified KRX-104130 with potent MCHR1 antagonistic activity and no cardiotoxicity through virtual screening using two MCHR1 binding affinity prediction models and an hERG-induced cardiotoxicity prediction model. In addition, we explored other possibilities for expanding the new indications for KRX-104130 using a transcriptome-based drug repositioning approach. KRX-104130 increased the expression of low-density lipoprotein receptor (LDLR), which induced cholesterol reduction in the gene expression analysis. This was confirmed by comparison with gene expression in a nonalcoholic steatohepatitis (NASH) patient group. In a NASH mouse model, the administration of KRX-104130 showed a protective effect by reducing hepatic lipid accumulation, liver injury, and histopathological changes, indicating a promising prospect for the therapeutic effect of NASH as a new indication for MCHR1 antagonists.

Single-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis

Fibrosis is characterized by the excessive production of collagen and other extracellular matrix (ECM) components and represents a leading cause of morbidity and mortality worldwide. Previous studies of nonalcoholic steatohepatitis (NASH) with fibrosis were largely restricted to bulk transcriptome profiles. Thus, our understanding of this disease is limited by an incomplete characterization of liver cell types in general and hepatic stellate cells (HSCs) in particular, given that activated HSCs are the major hepatic fibrogenic cell population. To help fill this gap, we profiled 17,810 non-parenchymal cells derived from six healthy human livers. In conjunction with public single-cell data of fibrotic/cirrhotic human livers, these profiles enable the identification of potential intercellular signaling axes (e.g., ITGAV–LAMC1, TNFRSF11B–VWF and NOTCH2–DLL4) and master regulators (e.g., RUNX1 and CREB3L1) responsible for the activation of HSCs during fibrogenesis. Bulk RNA-seq data of NASH patient livers and rodent models for liver fibrosis of diverse etiologies allowed us to evaluate the translatability of candidate therapeutic targets for NASH-related fibrosis. We identified 61 liver fibrosis-associated genes (e.g., AEBP1, PRRX1 and LARP6) that may serve as a repertoire of translatable drug target candidates. Consistent with the above regulon results, gene regulatory network analysis allowed the identification of CREB3L1 as a master regulator of many of the 61 genes. Together, this study highlights potential cell–cell interactions and master regulators that underlie HSC activation and reveals genes that may represent prospective hallmark signatures for liver fibrosis.

The efficacy of novel metabolic targeted agents and natural plant drugs for nonalcoholic fatty liver disease treatment: A PRISMA-compliant network meta-analysis of randomized controlled trials.

Background:Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease characterized by excess accumulation of fat in hepatocytes. Because no drug has been approved for NAFLD treatment, this work analyzed the effects of agents resulting from 2 research hotspots, metabolic target agents, and natural plant drugs, on NAFLD with network meta-analysis.Methods:Public databases were searched through August 14, 2020. Randomized controlled trials that compared obeticholic acid, elafibranor, cenicriviroc, selonsertib, curcumin, silymarin, and resveratrol to placebo were included. Liver pathology improvement, hepatic biochemical indicators, and lipid metabolism indicators were analyzed.Results:Thirty-five studies were included in the meta-analysis. Obeticholic acid was found to significantly increase the frequency of liver biopsy improvement compared to placebo (OR: 2.10; 95% CI: 1.60, 2.77). The ranking results among the hepatic biochemical indicators showed that obeticholic acid (94.9%) and elafibranor (86.3%) have a relative advantage in reducing alanine aminotransferase (ALT) levels, and obeticholic acid also had an advantage (95.4%) in reducing aspartate aminotransferase (AST) levels. Considering lipid metabolic indicators, elafibranor (expSMD: 0.01; 95% CI: 0.00, 0.05; SUCRA: 100%), and obeticholic acid (expSMD: 0.48; 95% CI: 0.28,0.84; SUCRA: 75.6%) significantly reduced triglyceride (TG) levels compared with placebo; moreover, obeticholic acid, but not elafibranor, caused a serious increase in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels and a decrease in high-density lipoprotein cholesterol (HDL-C) levels.Conclusions:Novel metabolic targeted agents generally have better effects than natural plant drugs, especially obeticholic acid, and elafibranor. However, obeticholic acid showed serious adverse effects such as increasing LDL-C levels and decreasing HDL-C levels. Curcumin showed potential advantages for NAFLD but lacked statistical significance.

Beneficial effect of omarigliptin on diabetic patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis

BackgroundDipeptidyl peptidase 4 (DPP4) is a serine exopeptidase able to inactivate various oligopeptides, and also a hepatokine. Hepatocyte-specific overexpression of DPP4 is associated with hepatic insulin resistance and liver steatosis.MethodWe examined whether weekly DPP4 inhibitor omarigliptin (OMG) can improve liver function as well as levels of inflammation and insulin resistance in type 2 diabetic patients with non-alcoholic fatty liver disease (NAFLD). Further, we investigated the effects of OMG in a diabetic patient with biopsy-confirmed nonalcoholic steatohepatitis (NASH).ResultsIn NAFLD patients, OMG significantly decreased levels of aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hsCRP), while no significant change was seen in hemoglobin A1c or body mass index. In the NASH patient, liver function improved markedly, and levels of the hepatic fibrosis marker FIB-4 decreased in parallel with HOMA-IR and hsCRP. Slight but clear improvements in intrahepatic fat deposition and fibrosis appeared to be seen on diagnostic ultrasonography.ConclusionWeekly administration of the DPP4 inhibitor OMG in ameliorating hepatic insulin resistance may cause beneficial effects in liver with NAFLD/NASH.

The association between obstructive sleep apnea and non-alcoholic steatohepatitis: a retrospective nationwide inpatient sample analysis.

Aim of the studyThe primary purpose of this study was to assess the association of obstructive sleep apnea (OSA) and non-alcoholic steatohepatitis (NASH) from a large national inpatient sample database.Material and methodsWe conducted a retrospective analysis using the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample. OSA and NASH patients were identified using the ICD-10-CM code G47.33 and K75.81. Non-NASH patients (control) were randomly selected and matched by age and gender to each NASH patient in a 4 : 1 ratio. Weighted logistic regression models were used to calculate the association between OSA and NASH in addition to different comorbidities.ResultsA total of 54,169 participants were included in our analysis; 10,740 cases of NASH were matched to 43,429 controls (non-NASH). NASH was significantly higher in the white population (82.12% vs. 76.64%, p < 0.001). The prevalence of OSA among NASH patients was significantly higher compared to the control group (15.8% vs. 8.9%, adjusted OR: 1.34, 95% CI: 1.14-1.56, p = 0.0003). The prevalence of celiac disease and Crohn’s disease was significantly higher in patients with NASH (0.7% vs. 0.2%, p < 0.0002 and 1.28% vs. 0.76%, p < 0.0001). Multiple comorbidities were significantly elevated in the NASH group compared to the non-NASH group, including diabetes mellitus (DM; 36% vs. 17.6%, p < 0.0001), obesity (36.4% vs. 18.2%, p < 0.0001) and metabolic syndrome (0.86% vs. 0.06%, p < 0.0001). The mortality rate was significantly higher in the NASH group (3.8% vs. 2%, p < 0.0001).ConclusionsThis is the first study using the ICD-10-CM code with a specific search code for NASH. Our large population database results emphasize that there is a significant association between OSA and NASH.

Human translatability of the GAN diet-induced obese mouse model of non-alcoholic steatohepatitis

BackgroundAnimal models of non-alcoholic steatohepatitis (NASH) are important tools in preclinical research and drug discovery. Gubra-Amylin NASH (GAN) diet-induced obese (DIO) mice represent a model of fibrosing NASH. The present study directly assessed the clinical translatability of the model by head-to-head comparison of liver biopsy histological and transcriptome changes in GAN DIO-NASH mouse and human NASH patients.MethodsC57Bl/6 J mice were fed chow or the GAN diet rich in saturated fat (40%), fructose (22%) and cholesterol (2%) for ≥38 weeks. Metabolic parameters as well as plasma and liver biomarkers were assessed. Liver biopsy histology and transcriptome signatures were compared to samples from human lean individuals and patients diagnosed with NASH.ResultsLiver lesions in GAN DIO-NASH mice showed similar morphological characteristics compared to the NASH patient validation set, including macrosteatosis, lobular inflammation, hepatocyte ballooning degeneration and periportal/perisinusoidal fibrosis. Histomorphometric analysis indicated comparable increases in markers of hepatic lipid accumulation, inflammation and collagen deposition in GAN DIO-NASH mice and NASH patient samples. Liver biopsies from GAN DIO-NASH mice and NASH patients showed comparable dynamics in several gene expression pathways involved in NASH pathogenesis. Consistent with the clinical features of NASH, GAN DIO-NASH mice demonstrated key components of the metabolic syndrome, including obesity and impaired glucose tolerance.ConclusionsThe GAN DIO-NASH mouse model demonstrates good clinical translatability with respect to the histopathological, transcriptional and metabolic aspects of the human disease, highlighting the suitability of the GAN DIO-NASH mouse model for identifying therapeutic targets and characterizing novel drug therapies for NASH.

PB1 PATIENT-REPORTED CONCERN, UNDERSTANDING AND LIFESTYLE MANAGMENT OF NON ALCOHOLIC STEATOHEPATATIS PATIENTS: A 12-COUNTRY REAL WORLD STUDY

There is currently a lack of real-world evidence regarding non-alcoholic steatohepatitis (NASH) patient perceptions and experience of their condition. This study investigated differences between patients with advanced fibrosis (AF-NASH; fibrosis stage 3-4) and early fibrosis (EF-NASH; fibrosis stage 0-2) regarding concerns about NASH, degree of knowledge, associated impact and motivation to change lifestyle.

PDB93 NAFLD SIMULATOR: A WEB-BASED SIMULATION TOOL TO PREDICT LONG-TERM OUTCOMES OF NON-ALCOHOLIC FATTY LIVER DISEASE

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide, with an estimated prevalence of 25-40%. Non-alcoholic steatohepatitis (NASH), an aggressive form of NAFLD, is projected to become the leading indication of liver transplantation in the US by 2020. Potential drugs for NAFLD/NASH treatment are in early stages of development; however, long-term outcomes of these treatments will not be known for decades. Our aim was to predict long-term outcomes of NAFLD/NASH and develop an interactive platform for patients and providers. We developed a microsimulation model to simulate the life course of NAFLD patients as they progressed through the different stages of the natural history. The model parameters were derived from published observational studies and clinical trials. Unknown model parameters were estimated through calibration process using simulated annealing algorithm to match the model-predicted survival to the survival of a large observational study up to 40 years. We generated NASH patient profiles and used their outcomes to develop an interactive, web-based tool, NAFLD Simulator. NAFLD Simulator can predict survival, mortality due to liver, non-liver, and background causes, risk of hepatocellular carcinoma and cirrhosis. NAFLD simulator could generate long-term outcomes of patients having fibrosis stages F1, F2, F3, and F4. For instance, for a 50-year-old female, the 20-year survival in patients with NASH F1, F2, F3, and F4 was 73.9%, 66%, 52.6%, and 30.8%, respectively. The 20-year non-liver-related mortality in these patients was 7.5%, 13.6%, 22.1%, and 26.6%, respectively; and the corresponding liver-related mortality was 1.5%, 4.4%, 11.2%, and 32.4%. If a patient progressed from F3 to F4 stage, the 20-year risk of developing hepatocellular carcinoma increased from from 4.3% to 11.4%. NAFLD Simulator provides a novel platform to disseminate the long-term risk associated with NAFLD and NASH to patients and providers.

Effect of Weight Reduction on Histological Activity and Fibrosis of Lean Nonalcoholic Steatohepatitis Patient.

Background and ObjectivesWeight reduction has evidenced benefit on attenuation of histological activity and fibrosis of nonalcoholic steatohepatitis (NASH), but there is scarcity of data for lean NASH subgroup. We have designed this study to compare the effects of weight reduction on histological activity and fibrosis of lean and non-lean NASH.MethodsWe have included 20 lean and 20 non-lean histologically proven NASH patients. BMI < 25 kg/m2 was defined as non-lean. Informed consent was taken from each subject. All methods were carried out in accordance with the Declaration of Helsinki. Moderate exercise along with dietary restriction was advised for both groups for weight reduction. After 1 year, 16 non-lean and 15 lean had completed second liver biopsy.ResultsAge, sex, alanine transaminase (ALT), aspartate aminotransferase (AST), gamma-glutamyltrasferase (GGT), Homeostasis model assessment insulin resistance (HOMA-IR), triglyceride and high density lipoprotein (HDL) was similar in both groups. Steatosis, ballooning, lobular inflammation, nonalcoholic fatty liver disease activity score (NAS) and fibrosis was similar in the two groups. In lean/non-lean group, any amount of weight reduction, ≥ 5% weight reduction and ≥ 7% weight reduction was found in respectively 8/11, 5/6 and 2/6 patients. In both lean and non-lean groups, weight reduction of any amount was associated with significant reduction of steatosis, ballooning and NAS, except lobular inflammation and fibrosis. In both groups, weight reduction of ≥ 5% was associated with significant reduction in NAS only. However, significant improvement in NAS was noted with ≥ 7% weight reduction in non-lean group only.ConclusionSmaller amount of weight reduction had the good benefit of improvement in all the segments of histological activity in both lean and non-lean NASH.

990 The Association of Obstructive Sleep Apnea and Nonalcoholic Steatohepatitis: A Nationwide Inpatient Sample Analysis

INTRODUCTION: Obstructive sleep apnea (OSA) has been suggested to be a potential contributing factor for nonalcoholic steatohepatitis (NASH). The oxidative stress caused by chronic intermittent hypoxia is known to play a vital role in the pathogenesis of NASH. There is conflicting data in the literature regarding the association of OSA and NASH. The primary purpose of this study was to determine the association of OSA and NASH from a large national inpatient sample database. METHODS: We conducted a retrospective analysis using the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (HCUP-NIS). NASH patients were identified by ICD-10-CM code K75.81. Non-NASH patients (control) were randomly selected and matched to each NASH patient 4:1 by age and gender. Weighted logistic regression models were used to calculate the association between OSA and NASH for different comorbidities. RESULTS: A total of 54,169 patients were included in our analysis, 10,740 cases of NASH were matched to 43,429 controls (non-NASH). NASH was significantly higher in the white population (82.12% vs. 76.64%, P &lt; 0.001). The prevalence of NASH among OSA patients was significantly higher compared to the non-OSA group (15.8% vs. 8.9%; adjusted OR: 1.34, 95% CI: 1.14–1.56, P = 0.0003). Celiac disease and Crohn’s disease were significantly higher in patients with NASH (0.7% vs. 0.2%, P &lt; 0.0002 and 1.28% vs. 0.76%, P &lt; 0.0001). Multiple comorbidities were significantly elevated in the NASH group compared to the non-NASH group including diabetes mellitus (36.0% vs. 17.6%, P &lt; 0.0001), obesity (36.4% vs. 18.2%, P &lt; 0.0001) and metabolic syndrome (0.86% vs. 0.06%, P &lt; 0.0001). Mortality rate was significantly higher in the NASH group (3.8% vs. 2.0%, P &lt; 0.0001). CONCLUSION: This is the first study using ICD-10-CM code with a specific search code for NASH. Our large population database results emphasize that there is a significant association between OSA and NASH. This important association should prompt physicians to evaluate for the presence of NASH in OSA patients. Additional studies are needed to evaluate this association and the effect of OSA treatment on NASH.

THU-313-Differences between non-alcoholic steatohepatitis patient characterisation and management approaches: A multinational real-world study

THU-313-Differences between non-alcoholic steatohepatitis patient characterisation and management approaches: A multinational real-world study

The OMICs Window into Nonalcoholic Fatty Liver Disease (NAFLD).

Nonalcoholic fatty liver disease (NAFLD) is a common cause of hepatic abnormalities worldwide. Nonalcoholic steatohepatitis (NASH) is part of the spectrum of NAFLD and leads to progressive liver disease, such as cirrhosis and hepatocellular carcinoma. In NASH patient, fibrosis represents the major predictor of liver-related mortality; therefore, it is important to have an early and accurate diagnosis of NASH. The current gold standard for the diagnosis of NASH is still liver biopsy. The development of biomarkers able to predict disease severity, prognosis, as well as response to therapy without the need for a biopsy is the focus of most up-to-date genomic, transcriptomic, proteomic, and metabolomic research. In the future, patients might be diagnosed and treated according to their molecular signatures. In this short review, we discuss how information from genomics, proteomics, and metabolomics contribute to the understanding of NAFLD pathogenesis.

International Liver Transplantation Consensus Statement on End-stage Liver Disease Due to Nonalcoholic Steatohepatitis and Liver Transplantation.

Nonalcoholic steatohepatitis (NASH)-related cirrhosis has become one of the most common indications for liver transplantation (LT), particularly in candidates older than 65 years. Typically, NASH candidates have concurrent obesity, metabolic, and cardiovascular risks, which directly impact patient evaluation and selection, waitlist morbidity and mortality, and eventually posttransplant outcomes. The purpose of these guidelines is to highlight specific features commonly observed in NASH candidates and strategies to optimize pretransplant evaluation and waitlist survival. More specifically, the working group addressed the following clinically relevant questions providing recommendations based on the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system supported by rigorous systematic reviews and consensus: (1) Is the outcome after LT similar to that of other etiologies of liver disease? (2) Is the natural history of NASH-related cirrhosis different from other etiologies of end-stage liver disease? (3) How should cardiovascular risk be assessed in the candidate for LT? Should the assessment differ from that done in other etiologies? (4) How should comorbidities (hypertension, diabetes, dyslipidemia, obesity, renal dysfunction, etc.) be treated in the candidate for LT? Should treatment and monitoring of these comorbidities differ from that applied in other etiologies? (5) What are the therapeutic strategies recommended to improve the cardiovascular and nutritional status of a NASH patient in the waiting list for LT? (6) Is there any circumstance where obesity should contraindicate LT? (7) What is the optimal time for bariatric surgery: before, during, or after LT? (8) How relevant is donor steatosis for LT in NASH patients?

Glucagon like Peptide-1(GLP-1) a Novel Therapeutic Strategy in Non-Alcoholic Fatty Liver Disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is a main cause of liver disease and its global prevalence is estimated to be 24%. At present no approved medicines are available for NAFLD treatment. Glucagon-like peptide-1 (GLP-1) is a significant regulator of energy balance, show potential efficacy in the management of NAFLD. GLP-1 and GLP-1 receptor agonist (GLP-1RAs) are attractive options for the treatment of type 2 diabetes (T2D) since they efficiently reduce weight, HbA1C and blood glucose without having a risk of hypoglycaemia. This incretin hormone by normalizing of insulin resistance (IR), oxidative stress, lipid accumulation, lipotoxicity, and liver cell apoptosis is proposed for the management of NAFLD and nonalcoholic steatohepatitis (NASH) patient. Hence, the aim of this review was to discuss the useful effects of GLP-1, GLP-1 receptor agonist (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) on NAFLD. In this paper we provided a new finding which highlighted the role of GLP-1 and GLP-1RAs in the treatment of NAFLD.