Prevalence Of Nonalcoholic Steatohepatitis Research Articles

Prevalence and Correlates of Probable Nonalcoholic Steatohepatitis (NASH) in Pars Cohort Study.

Studies on the prevalence of nonalcoholic steatohepatitis (NASH) and the factors associated with its high prevalence among Iranian people are limited. This study evaluated the prevalence of NASH and its associated factors among Iranian adults using Pars Cohort Study (PCS) data. This cross-sectional study was conducted based on PCS, which includes 40-75-year-old adults from the Valashahr area. NASH was defined as alanine aminotransferase (ALT) higher than 40 U/L without evidence of hepatitis B or C infections. The prevalence of NASH and its associations with basic and demographic characteristics, socioeconomic characteristics, medical history, gastrointestinal symptoms, and laboratory tests were evaluated. Overall, 8734 patients, including 3917 men (44.8%), were enrolled in this study. The mean age of participants was 52.62 years (SD=9.68), and 605 individuals had NASH (6.9%). In the regression analysis, in contrast to female gender (OR=0.31, 95% CI=0.249‒0.386, P<0.001) and age (OR=0.951, 95% CI=0.941‒0.962, P<0.001), history of heart disease (OR=1.499, 95% CI=1.146‒1.962, P=0.003), history of diabetes (OR=1.523, 95% CI=1.162‒1.995, P=0.002), hypertension (OR=1.241, 95% CI=1.023‒1.506, P=0.029), being overweight or obese (OR=2.192, 95% CI=1.755‒2.737, P<0.001), being in the richest or second richest wealth index quantiles (OR=1.315, 95% CI=1.107‒1.156, P=0.002), and increased waist circumference (OR=1.409, 95% CI=1.107‒1.793, P<0.005) were independently associated with a higher risk of having NASH. In this study, we determined the prevalence of NASH and found male gender, younger age, history of heart disease, history of diabetes, hypertension, socioeconomic status, and obesity as possible factors associated with a higher risk of NASH among Iranians.

Association between triglyceride glucose-body mass index and the staging of non-alcoholic steatohepatitis and fibrosis in patients with non-alcoholic fatty liver disease

Objective The objective of this study was to thoroughly investigate the clinical value of triglyceride glucose-body mass index (TyG-BMI) in patients diagnosed with non-alcoholic fatty liver disease (NAFLD). Specifically, we aimed to determine its association with non-alcoholic steatohepatitis (NASH) and the progression of liver fibrosis. Methods The study included 393 patients diagnosed with NAFLD after liver biopsy. The patients were divided into two distinct cohorts: a training cohort (N = 320) and a validation cohort (N = 73). The training cohort was further divided into four groups based on TyG-BMI quartiles. The clinical characteristics of the patients in each group were compared in detail, and the association between TyG-BMI and NASH, NAFLD Activity Score (NAS) ≥ 4, at-risk NASH, significant fibrosis, advanced fibrosis, and cirrhosis was analyzed using multiple models. Additionally, we generated receiver operating characteristic (ROC) curves to evaluate the predictive ability of TyG-BMI for NASH and fibrosis staging in patients with NAFLD. Results Patients with higher TyG-BMI values had a significantly higher prevalence of NASH, NAS ≥ 4, at-risk NASH, significant fibrosis, advanced fibrosis, and cirrhosis (all p < .05). TyG-BMI was an independent predictor of these diseases in both unadjusted and adjusted models (all p < .05). ROC curve analysis further revealed the excellent performance of TyG-BMI in predicting NASH, NAS ≥ 4, at-risk NASH, significant fibrosis, advanced fibrosis, and cirrhosis. The validation cohort yielded analogous results. Furthermore, we constructed three multivariate models of TyG-BMI in conjunction with elastography metrics, which demonstrated elevated diagnostic AUC values of 0.782, 0.792, 0.794, 0.785, 0.834, and 0.845, respectively. Conclusion This study confirms a significant association between insulin resistance and NAFLD, including at-risk NASH and fibrosis staging, as assessed using the TyG-BMI index. TyG-BMI and its associated multivariate models can be valuable noninvasive indicators for NAFLD diagnosis, risk stratification, and disease course monitoring.

Resmetirom: A Systematic Review of the Revolutionizing Approach to Non-alcoholic Steatohepatitis Treatment Focusing on Efficacy, Safety, Cost-Effectiveness, and Impact on Quality of Life.

There has been a rise in the prevalence of non-alcoholic steatohepatitis (NASH), a subset of non-alcoholic fatty liver disease (NAFLD)with an ongoing increase in the prevalence of linked conditions such as obesity, type II diabetes mellitus, and metabolic syndrome. To date, there are no specific drugs that are approved for the treatment of NAFLD/NASH. With the recent discovery of association between subclinical hypothyroidism and NASH, various trials exploring treatment options for NASH using thyroid hormone derivatives led to the discovery of resmetirom (MGL-316) with high affinity to thyroid hormone receptors (THRs) targeting the liver. Following standardized guidelines, a systematic review was performed on the safety, efficacy, and other practical aspects of resmetirom in the treatment of NASH. Advanced search was carried out using the MeSH search strategyand appropriate keywords in major databases using various inclusion and exclusion criteria. The search was narrowed down to seven high-quality articles: four randomized control trials (RCTs), and three reviews to be included in the current study. The online database search yielded 62 articles, out of which six high-quality articles were selected to be included in the current systematic review after deleting duplicates and screening for irrelevant titles, and articles. Out of the three RCTs, two of them assessed the safetyand efficacy of resmetirom, while the remaining RCT assessed the impact on health-related quality of life with resmetirom on patients with NASH. resmetirom (MGL-316) is athyroid hormone derivative with high affinity to THRstargeting the liver and acts by improving mitochondrial oxidation, and lipophagy in the hepatic cell line. All the trials suggested in favor of resmetirom with a decrease in NASH fibrosis score by at least two points, along with reduction in hepatic fat content (minimum relative reduction of 20%), liver volume by 61%, improving secondary outcomes such as low-density lipoprotein-C, apolipoprotein-B, triglycerides, and hepatic enzymes with greater reduction in the study groups treated with higher doses of resmetirom with no significant increase in adverse events. Resmetirom was found to improve patient-reported outcomes, and thereby quality-adjusted life years (QALYs) in 12 weeks while being cost-effective compared to placebo at a willingness-to-pay threshold of US$100,000 up to a daily threshold of US$72.00, and an effective incremental cost-effectiveness ratio of US$53,925 per QALY gained. After carefully analyzing the available data by our team members, it could be concluded that resmetirom holds a strong potential to be implemented as a drug of choice in treating NAFLD/NASH in the coming years with proven efficacy, safety while being cost-effective, and also reducing secondary co-morbidities by improving cardiovascular risk factors. The results can be best achieved when combined withconventional approaches such as weight loss and dietary modifications. Long-term safety and sustainability of the achieved results are yet to be confirmed with large-scale clinical trials. However, resmetirom is still an investigational drug and could be expected to be available for clinical practice in the near future.

Liver biopsy in patients with gall stone disease and concomitant non-alcoholic fatty liver disease undergoing cholecystectomy: A prospective observational study

Objective: Gallstone disease (GSD) and non-alcoholic fatty liver disease (NAFLD) share common risk factors. NAFLD can progress to non-alcoholic steatohepatitis (NASH), which may lead to severe liver conditions. This study aimed to assess the prevalence of NASH and associated factors in patients with GSD and fatty liver undergoing cholecystectomy. Material and Methods: This prospective observational study was conducted from March 2021 to June 2023 and included 134 patients diagnosed with GSD and fatty liver based on preoperative ultrasound. Core liver biopsies were obtained during cholecystectomy. Preoperatively, clinical, anthropometric, demographic, biochemical variables, and FibroScan parameters were recorded. Results: NASH was found in 21 (15.67%) patients, while 50 (37.31%) patients had probable NASH, and 63 (47.01%) had non-NASH scores. Metabolic syndrome was present in 63.6% of the patients. Univariate analysis revealed significant differences in AST and ALT values between the NASH and nonNASH groups. In multivariate analysis, AST was statistically significant (p= 0.041). Mean controlled attenuation parameter in patients with non-NASH was 219.40 ± 60.44 dB/m, and in patients with NASH, it was 265.48 ± 63.47 dB/m (p= 0.006). Fibrosis was present in 33 of the 82 slides examined, with 17 patients having grade 2 and two patients with grade 3 fibrosis. Conclusion: The high prevalence of NASH among GSD patients highlights a significant public health issue, prompting consideration for liver biopsy in individuals with NAFLD and GSD undergoing laparoscopic cholecystectomy.

Global burden of adult non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) has been steadily increasing over the past decades and is expected to persist in the future.

At present, there is a dearth of comprehensive data at the global, national, and regional levels regarding the adult non-alcoholic fatty liver disease (NAFLD) prevalence. This cross-sectional study aims at ascertaining the prevalence of NAFLD and non-alcoholic steatohepatitis (NASH), utilizing body mass index (BMI) as a determining factor. Based on the NHANES database, sigmoidal fitting curves were generated to establish the relationship between BMI and the risk of NAFLD/NASH. Utilizing BMI data from the NCD Risk Factor Collaboration (NCD-RisC) database at both global and regional levels, the prevalence of NAFLD/NASH among adults was estimated from 1975 to 2016, encompassing global, regional, and national perspectives. Additionally, projections were made to forecast the prevalence of adult NAFLD/NASH from 2017 to 2030. In 2016, the global prevalence of NAFLD was 41.12% for males and 37.32% for females, while the global prevalence of NASH was 15.79% for males and 16.48% for females. The prevalence of NAFLD/NASH increased with higher BMI in both genders. Over the period from 1975 to 2016, there has been a gradual increase in the global prevalence of NAFLD/NASH in adults, and this trend is expected to continue between 2017 and 2030. In males, the prevalence of adult NAFLD/NASH was found to be highest in High-income Western countries, while it was highest in Central Asia, Middle East, and North African countries after 1995. The prevalence of adult NAFLD/NASH has been observed to increase annually, with significant variations in burden across different countries and regions.

Lactic acid-fermented Sake lees protect against nonalcoholic steatohepatitis in mice

Background: Nonalcoholic steatohepatitis (NASH) is a common disease that may lead to hepatocellular carcinoma (HCC) through fatty liver and cirrhosis. Although the prevalence of NASH is increasing worldwide, there is no cure established thus far. Sake lees are a by-product of sake refining, with a known liver-protecting effect. Lactic acid-fermented sake lees (FSL) are a food produced by lactic acid fermentation and dealcoholization of sake lees. This product is commercially available in Japan. Although FSL has been associated with numerous functions, thus far, studies have not investigated its hepatoprotective effect. Objectives: The objectives of this study are to evaluate the hepatoprotective effects of lactic acid-fermented sake lees (FSL) in a mouse model of NASH-HCC, to assess the impact of FSL supplementation on blood glucose levels in mice with NASH, to analyze the expression of inflammatory markers in FSL-fed mice compared to controls, and to determine the overall efficacy of FSL in inhibiting the progression of NASH. Methods: For this study, we established a mouse model of NASH-HCC. Mice were placed on a high-fat diet supplemented with FSL from 10 to 14 weeks of age. We assessed the diet's efficacy in halting NASH progression compared to a control group. Results: The group fed with FSL exhibited a significant suppression in blood glucose levels and a notable inhibition of NASH progression compared to the control group. Protein analysis revealed a reduction in the expression of inflammatory markers in the FSL-fed group compared to controls. Conclusion: Ingestion of FSL may exert anti-inflammatory and blood glucose-lowering effects and inhibit NASH progression. Keywords: anti-inflammation, blood glucose, fatty liver, Sake lees

Epidemiology of NAFLD – Focus on diabetes

There is increasing appreciation of the complex interaction between nonalcoholic fatty liver disease (NAFLD) with type 2 diabetes (T2D) and insulin resistance. Not only is the prevalence of NAFLD disease high among patients with T2D, the liver disease is also more progressive. Currently, the global prevalence of NAFLD in the general population (2016–2019) is 38 %. The prevalence of T2D among those with NAFLD is approximately 23 % while the prevalence of NAFLD among those with T2D can be as high as 70 %. The prevalence of nonalcoholic steatohepatitis (NASH) is approximately 7 % in the general population and 37 % among patients with T2D. Globally, the MENA and Latin America regions of the world appear to have the highest burden of both NAFLD and T2D. Compared to those with NAFLD but without T2D, those with NAFLD and T2D are at a much higher risk for disease progression to cirrhosis and for decompensated cirrhosis, hepatocellular carcinoma, and all-cause mortality. Given that highly effective new treatments are available for T2D, high risk NAFLD with T2D should be considered for these regimens. This requires implementation of risk stratification algorithms in the primary care and endocrinology practices to identify those patients at highest risk for adverse outcomes.

Prevalence of Nonalcoholic Steatohepatitis and Associated Fibrosis Stages Among US Adults Using Imaging-Based vs Biomarker-Based Noninvasive Tests.

Introduction: Nonalcoholic fatty liver disease (NAFLD) is believed to be the most common chronic liver disease worldwide. Therapies are under development for nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, such that the prevalence of NASH with liver fibrosis, which is likely to require treatment, may be of interest to healthcare decision makers. Noninvasive tests are used in initial screening for NASH, as well as in observational studies of NASH prevalence. However, existing evidence does not address how estimated prevalence varies with different noninvasive tests. This analysis estimated the prevalence of NASH among US adults and assessed variation with different noninvasive tests. Methods: A cross-sectional analysis was conducted using the 2017-March 2020 National Health and Nutrition Examination Survey cycle. Participants with presumed NAFLD (steatosis and without alternative causes of liver disease) were identified, among whom NASH was predicted based on FAST score, Fibrosis-4 (FIB-4), and AST-to-Platelet Ratio Index (APRI) cutoffs across 11 scenarios. Among NASH participants, fibrosis stages were explored based on distribution across the spectrum of liver-stiffness measurements. Results: Among participants with complete data for the analysis (N=6969), prevalence of presumed NAFLD was 25.6%. Within presumed NAFLD, prediction of NASH using imaging-based NIT cutoffs yielded estimated prevalence of 1.3%-4.8% (3.3 million-12.2 million) based on FAST score cutoffs from 0.35-0.67. Using biomarker-based NIT cutoffs yielded estimated prevalence of 0.4%-12.3% (1.0 million-14.5 million) based on FIB-4 cutoffs from 0.90-2.67, and 0.1%-1.9% (0.2-5.0 million) based on APRI cutoffs from 0.50-1.50. Conclusion: Prevalence of NASH among US adults was estimated to range from 1.3% to 4.8% when predicted using imaging-based noninvasive test values for participants with presumed NAFLD, generally aligning with estimates in the literature of prevalence of biopsy-confirmed NASH. Use of biomarker-based noninvasive test values for prediction of NASH yielded a wider range of estimates with FIB-4, and a considerably lower range of estimates with APRI.

Prevalence of Nonalcoholic Steatohepatitis and Associated Fibrosis Stages Among US Adults Using Imaging-Based vs Biomarker-Based Noninvasive Tests

Introduction: Nonalcoholic fatty liver disease (NAFLD) is believed to be the most common chronic liver disease worldwide. Therapies are under development for nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, such that the prevalence of NASH with liver fibrosis, which is likely to require treatment, may be of interest to healthcare decision makers. Noninvasive tests are used in initial screening for NASH, as well as in observational studies of NASH prevalence. However, existing evidence does not address how estimated prevalence varies with different noninvasive tests. This analysis estimated the prevalence of NASH among US adults and assessed variation with different noninvasive tests. Methods: A cross-sectional analysis was conducted using the 2017–March 2020 National Health and Nutrition Examination Survey cycle. Participants with presumed NAFLD (steatosis and without alternative causes of liver disease) were identified, among whom NASH was predicted based on FAST score, Fibrosis-4 (FIB-4), and AST-to-Platelet Ratio Index (APRI) cutoffs across 11 scenarios. Among NASH participants, fibrosis stages were explored based on distribution across the spectrum of liver-stiffness measurements. Results: Among participants with complete data for the analysis (N=6969), prevalence of presumed NAFLD was 25.6%. Within presumed NAFLD, prediction of NASH using imaging-based NIT cutoffs yielded estimated prevalence of 1.3%-4.8% (3.3 million-12.2 million) based on FAST score cutoffs from 0.35-0.67. Using biomarker-based NIT cutoffs yielded estimated prevalence of 0.4%-12.3% (1.0 million-14.5 million) based on FIB-4 cutoffs from 0.90-2.67, and 0.1%-1.9% (0.2-5.0 million) based on APRI cutoffs from 0.50-1.50. Conclusion: Prevalence of NASH among US adults was estimated to range from 1.3% to 4.8% when predicted using imaging-based noninvasive test values for participants with presumed NAFLD, generally aligning with estimates in the literature of prevalence of biopsy-confirmed NASH. Use of biomarker-based noninvasive test values for prediction of NASH yielded a wider range of estimates with FIB-4, and a considerably lower range of estimates with APRI.

Serologic Biomarkers for Hepatic Fibrosis in Obese Children with Nonalcoholic Steatohepatitis.

The prevalence of nonalcoholic steatohepatitis (NASH) is increasing with the increasing prevalence of childhood obesity. Although NASH has a high risk of progression to liver fibrosis and cirrhosis, few studies have reported noninvasive markers for predicting hepatic fibrosis in children. This study aimed to evaluate and compare the diagnostic accuracies of serologic biomarkers and scoring systems for hepatic fibrosis in obese children with NASH. A total of 96 children were diagnosed with NASH based on liver biopsy findings and divided into two groups according to the degree of liver fibrosis: mild (stage 0-1) or advanced (stage 2-4). Clinical and laboratory parameters and serum levels of hyaluronic acid and type IV collagen were measured. The aspartate aminotransferase/platelet ratio index (APRI) and fibrosis-4 (FIB-4) score were calculated. Among the noninvasive markers, only serum type IV collagen level and FIB-4 were significantly different between the two groups. The area under the receiver operating curve of each biomarker and scoring system was 0.80 (95% confidence interval [CI]: 0.70-0.90) for type IV collagen at an optimal cutoff of 148 ng/mL (sensitivity 69.8%, specificity 84.6%), followed by 0.69 (95% CI: 0.57-0.83) for APRI, 0.68 (95% CI: 0.56-0.80) for FIB-4, and 0.65 (95% CI: 0.53-0.77) for hyaluronic acid. Type IV collagen as a single noninvasive serologic biomarker for hepatic fibrosis and FIB-4 as a hepatic fibrosis score are beneficial in predicting advanced hepatic fibrosis and determining proper diagnosis and treatment strategies before fibrosis progresses in obese children with NASH.

A significant and persistent rise in the global burden of adolescent NAFLD and NASH estimated by BMI.

Currently, there is a lack of global or even country/regional level data on adolescent non-alcoholic fatty liver disease (NAFLD) prevalence. However, an evidenced dose-dependent relationship exists between body mass index (BMI) and the risk of NAFLD. We aim to estimate the global and regional prevalence of adolescent NAFLD and related non-alcoholic steatohepatitis (NASH) based on BMI. Sigmoidal fitting curves were generated between BMI and the risk of NAFLD/NASH using the data extracted from the NHANES database. With global and regional BMI data from the NCD-RisC database, adolescent NAFLD/NASH prevalence was estimated at the international, regional, and country levels from 1975 to 2016. The prevalence of adolescent NAFLD/NASH from 2017 to 2030 was also forecasted. The mean NAFLD prevalence was 15.31, and 12.68%, while the mean NASH prevalence was 2.50, and 2.47%, in boys, and girls aged 12-18, respectively. For both boys and girls, NAFLD/NASH prevalence increased with increasing BMI, and age. The global prevalence of adolescent NAFLD/NASH has gradually increased in the period from 1975 to 2016 and will maintain a similar trend between 2017 and 2030. High-income Western Countries had higher adolescent NAFLD/NASH whereas South Asia and Sub-Saharan Africa exhibited relatively lower adolescent NAFLD/NASH prevalence. The estimated annual percentage change (EAPC) of NAFLD prevalence in boys ranged from 0.72% (age 18) to 1.16% (age 12) while that in girls ranged from 0.69% (age 18) to 0.92% (age 12). EAPC of NASH prevalence in boys ranged from 1.65% (age 18) to 1.77% (age 12), and in girls from 1.48% (age 18) to 1.68% (age 12). The adolescent NAFLD/NASH prevalence increases year by year, and its burden varies significantly among different countries and regions. BMI is a precise predictor of NAFLD/NASH prevalence.

Higher consumption of animal organ meat is associated with a lower prevalence of nonalcoholic steatohepatitis.

Animal organ meat (offal) is a food with high nutrient density that is popular in different parts of the world, but its relationship with nonalcoholic steatohepatitis (NASH) is unclear. We aimed to examine whether daily animal organ meat consumption is associated with the presence of NASH in individuals with nonalcoholic fatty liver disease (NAFLD). A total of 136 Chinese adults with biopsy-proven NAFLD were included. Definite NASH was defined as NAFLD activity score ≥4 and at least one point for steatosis, ballooning, and lobular inflammation. Daily animal organ meat consumption was estimated using a self-administered validated food frequency questionnaire. Logistic regression analysis was performed to assess the association between animal organ meat intake and liver disease severity. The 136 participants (80.9% men) of the study had a mean ± standard deviation (SD) age of 39.0±12.5 years and body mass index of 27.4±3.6 kg/m2. Prevalence of definite NASH was 65.4%. Daily median organ meat consumption was 1.30 g/1,000 kcal. Animal organ meat consumption was inversely associated with the presence of NASH even after adjustment of demographics, lifestyle variables, metabolic and dietary factors, as well as liver fibrosis stage; adjusted-odds ratios (95% confidence intervals) for NASH were 0.15 (0.03, 0.69) for the highest tertile and 0.18 (0.05, 0.70) for the medium tertile, compared to the lowest (reference) tertile of animal organ meat intake (P value for trend =0.024). Our results suggest for the first time that higher animal organ meat consumption is associated with a lower prevalence of NASH in Chinese individuals with biopsy-proven NAFLD.

Sugar-Sweetened Beverages and Artificially Sweetened Beverages Consumption and the Risk of Nonalcoholic Fatty Liver (NAFLD) and Nonalcoholic Steatohepatitis (NASH).

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are fast becoming the most common chronic liver disease and are often preventable with healthy dietary habits and weight management. Sugar-sweetened beverage (SSB) consumption is associated with obesity and NAFLD. However, the impact of different types of SSBs, including artificially sweetened beverages (ASBs), is not clear after controlling for total sugar intake and total caloric intake. The aim of this study was to examine the association between the consumption of different SSBs and the risk of NAFLD and NASH in US adults. The representativeness of 3739 US adults aged ≥20 years old who had completed 24 h dietary recall interviews and measurements, including dietary, SSBs, smoking, physical activity, and liver stiffness measurements, were selected from the National Health and Nutrition Examination Survey 2017-2020 surveys. Chi-square tests, t-tests, and weighted logistic regression models were utilized for analyses. The prevalence of NASH was 20.5%, and that of NAFLD (defined without NASH) was 32.7% of US. adults. We observed a higher prevalence of NASH/NAFLD in men, Mexican-Americans, individuals with sugar intake from SSBs, light-moderate alcohol use, lower physical activity levels, higher energy intake, obesity, and medical comorbidities. Heavy sugar consumption through SSBs was significantly associated with NAFLD (aOR = 1.60, 95% CI = 1.05-2.45). In addition, the intake of ASBs only (compared to the non-SSB category) was significantly associated with NAFLD (aOR = 1.78, 95% CI = 1.04-3.05), after adjusting for demographic, risk behaviors, and body mass index. A higher sugar intake from SSBs and exclusive ASB intake are both associated with the risk of NAFLD.

Hepatitis C and Nonalcoholic Steatohepatitis in the 21st Century: Impact on Liver Disease and Liver Transplantation

Hepatitis C infection is a leading etiology of hepatic dysfunction and a major indication for liver transplantation due to the development of fibrosis, cirrhosis, and hepatocellular carcinoma. Nonalcoholic fatty liver disease (NAFLD) and, specifically, its subtype nonalcoholic steatohepatitis (NASH) is a rising cause of liver disease. It is predicted to surpass hepatitis C as a leading indication for transplant. The introduction of direct-acting antivirals (DAAs) decreased the prevalence of chronic hepatitis C infections, but the obesity epidemic and metabolic syndrome have increased the prevalence of NASH. Weight loss and dietary modifications are recommended NASH therapies, but unlike for hepatitis C, federally approved agents are lacking and currently under investigation. Clinical trials face many barriers in NASH treatment because of the difficulty of diagnosis and a lack of standardized and accurate clinical and histologic responses. Mortality and morbidity in NASH are heightened because of the presence of multiple comorbidities including cardiovascular disease, diabetes, and renal dysfunction. A liver transplant may be indicated, but a thorough screening of candidates, including a comprehensive cardiovascular assessment, is essential to ensuring successful outcomes pre- and post-transplant. Therapeutic agents for NASH are warranted before it becomes a significant and leading cause of morbidity and mortality worldwide.

1852-PUB: The Effect of Lactic Acid Fermented Sake Lees in a NASH-HCC Mouse Model

Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by fatty liver and cirrhosis that van lead to hepatocellular carcinoma. Although NASH prevalence is increasing worldwide, no cure has yet been established. Sake-lees, which are a by-product of sake refinement, have liver-protecting properties. Lactic acid fermented sake lees (FSL) is a food made by lactic acid fermentation of lees, which are then dealcoholized. Although FSL is regarded as a pro-health supplement, whether it has hepatoprotective effects remains unclear. To address this, we used a murine model of NASH to determine whether FSL could suppress progression of the disease. FSL supplementation significantly suppressed the increase in blood glucose impeded the progression of NASH. Protein analysis revealed that FSL also attenuated the increased expression of inflammatory markers. We infer that dietary FSL has anti-inflammatory and anti-hyperglycemic effects that contribute to the inhibition of NASH progression. Disclosure H. Suzuki: None. K. Watanabe: None. S. Arumugam: None. M. Afrin: None. Y. Matsubayashi: None. H. Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. Funding Japan Society for the Promotion of Science (22K17772)

Predictors of Nonalcoholic Steatohepatitis Severity in Obese Patients Undergoing Bariatric Surgery: A Cross-Sectional Study

Background: Nonalcoholic steatohepatitis (NASH) currently affects 3–5% of the general population and 10–50% of patients with obesity. Our aim was to determine the predictors of severity of NASH in patients with obesity undergoing sleeve gastrectomy. Methods: We conducted a retrospective study in patients with obesity who underwent sleeve gastrectomy from 2013 to 2016. Liver biopsy at the time of the surgery showed a histological grade of NASH in all the patients. Patients were stratified into two groups, mild and moderate-severe (MS) NASH. Predictors were evaluated with multivariate logistic regression. Results: We included 193 patients. Of these, 139 had mild, 22 moderate, and 36 severe NASH. Majority of patients were female (54.8%) and the mean body mass index was 40.30 ± 2.19 kg/m2. In the adjusted regression model, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (prevalence ratios [PR]: 1.06, confidence interval [95% CI]: 1.02–1.10) and alanine aminotransferase (ALT) (PR: 1.01, 95% CI: 1.00–1.01) were factors associated with MS NASH. Conclusions: Despite the high prevalence of NASH in the obese population, most patients presented mild severity. A higher severity of NASH among patients with obesity can be predicted by clinical abnormalities such as higher HOMA-IR and ALT levels. Higher HOMA-IR levels are potential predictors of MS NASH regardless of insulin resistance status and in patients without metabolic syndrome.

Analysis of clinicopathological characteristics of non-alcoholic fatty liver disease

Objective: To investigate the clinical and pathologic characteristics of obese adults with nonalcoholic fatty liver disease (NAFLD) and to aid the diagnosis of nonalcoholic steatohepatitis (NASH). Methods: A total of 262 patients eligible for inclusion who received volume reduction metabolism surgery and liver biopsy in the First Affiliated Hospital of Nanjing Medical University from June 2018 to September 2019 were selected. HE staining, reticular fiber staining and Masson staining were performed. Statistical analysis was performed using SPSS 20.0. Results: The patients ranged in age from 18 to 66 years. Among the 262 cases, 65 cases (65/262, 24.8%) were male and 197 cases (197/262, 75.2%) were female. Sixty-one cases (61/262, 23.3%) were non-NAFLD, 201 cases (201/262, 76.7%) were NAFLD including 27 cases (27/201, 13.4%) of nonalcoholic fatty live (NAFL) and 174 cases (174/201, 86.6%) of NASH. The main lesions of NAFLD were in hepatic acinus zone 3. There were significant differences in age, alanine aminotransferase (ALT), glutamic oxaloacetic transaminase (AST), body mass index (BMI), fasting blood-glucose (FPG) and apolipoprotein A (APOA) levels among the non-NAFLD group, NAFL group and NASH group (P<0.05). Patients with BMI≥35 m/kg2 combined with type 2 diabetes had a higher prevalence of NASH. Multiple logistic regression showed that ALT and APOA were independent predictors of NASH (P<0.001, OR=1.05, 95%CI: 1.020-1.082; P=0.027, OR=0.916, 95%CI: 0.878-0.941). Total cholesterol (CHO) and high-density lipoprotein (HDL) were independent predictors of lobular inflammation (P=0.043, 95%CI: 0.010-0.634; P=0.024, 95%CI:-3.068--0.216). AST and HDL were independent predictors of fibrosis stage (P=0.029, 95%CI: 0.001-0.021; P<0.001, 95%CI:-2.670--0.645). Conclusions: Biochemical indicators of NAFLD are closely related to its pathology. The histological lesions of NAFLD are mainly present in hepatic acinar area 3. The diagnosis of NASH is supported by extensive steatosis and high levels of CHO, ALT, AST and BMI, low levels of HDL and ApoA in biochemical markers, but pathological examination is still the gold standard for it.

Discovery of the First-in-Class Intestinal Restricted FXR and FABP1 Dual Modulator ZLY28 for the Treatment of Nonalcoholic Fatty Liver Disease.

The prevalence of nonalcoholic steatohepatitis (NASH) is increasing rapidly worldwide, and NASH has become a serious problem for human health. Recently, the selective activation of the intestinal farnesoid X receptor (FXR) was considered as a more promising strategy for the treatment of NASH with lesser side effects due to reduced systemic exposure. Moreover, the inhibition of intestinal fatty acid binding protein 1 (FABP1) alleviated obesity and NASH by reducing dietary fatty acid uptake. In this study, the first-in-class intestinal restricted FXR and FABP1 dual-target modulator ZLY28 was discovered by comprehensive multiparameter optimization studies. The reduced systemic exposure of ZLY28 might provide better safety by decreasing the on- and off-target side effects in vivo. In NASH mice, ZLY28 exerted robust anti-NASH effects by inhibiting FABP1 and activating the FXR-FGF15 signaling pathway in the ileum. With the above attractive efficacy and preliminary safety profiles, ZLY28 is worthy of further evaluation as a novel anti-NASH agent.

HILPDA promotes NASH-driven HCC development by restraining intracellular fatty acid flux in hypoxia

The prevalence of non-alcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) is rising rapidly, yet its underlying mechanisms remain unclear. Herein, we aim to determine the role of hypoxia-inducible lipid droplet associated protein (HILPDA)/hypoxia-inducible gene 2 (HIG2), a selective inhibitor of intracellular lipolysis, in NASH-driven HCC. The clinical significance of HILPDA was assessed in human NASH-driven HCC specimens by immunohistochemistry and transcriptomics analyses. The oncogenic effect of HILPDA was assessed in human HCC cells and in 3D epithelial spheroids upon exposure to free fatty acids and either normoxia or hypoxia. Lipidomics profiling of wild-type and HILPDA knockout HCC cells was assessed via shotgun and targeted approaches. Wild-type (Hilpdafl/fl) and hepatocyte-specific Hilpda knockout (HilpdaΔHep) mice were fed a Western diet and high sugar in drinking water while receiving carbon tetrachloride to induce NASH-driven HCC. In patients with NASH-driven HCC, upregulated HILPDA expression is strongly associated with poor survival. In oxygen-deprived and lipid-loaded culture conditions, HILPDA promotes viability of human hepatoma cells and growth of 3D epithelial spheroids. Lack of HILPDA triggered flux of polyunsaturated fatty acids to membrane phospholipids and of saturated fatty acids to ceramide synthesis, exacerbating lipid peroxidation and apoptosis in hypoxia. The apoptosis induced by HILPDA deficiency was reversed by pharmacological inhibition of ceramide synthesis. In our experimental mouse model of NASH-driven HCC, HilpdaΔHep exhibited reduced hepatic steatosis and tumorigenesis but increased oxidative stress in the liver. Single-cell analysis supports a dual role of hepatic HILPDA in protecting HCC cells and facilitating the establishment of a pro-tumorigenic immune microenvironment in NASH. Hepatic HILPDA is a pivotal oncometabolic factor in the NASH liver microenvironment and represents a potential novel therapeutic target. Non-alcoholic steatohepatitis (NASH, chronic metabolic liver disease caused by buildup of fat, inflammation and damage in the liver) is emerging as the leading risk factor and the fastest growing cause of hepatocellular carcinoma (HCC), the most common form of liver cancer. While curative therapeutic options exist for HCC, it frequently presents at a late stage when such options are no longer effective and only systemic therapies are available. However, systemic therapies are still associated with poor efficacy and some side effects. In addition, no approved drugs are available for NASH. Therefore, understanding the underlying metabolic alterations occurring during NASH-driven HCC is key to identifying new cancer treatments that target the unique metabolic needs of cancer cells.

Mouse strain-dependent variation in metabolic associated fatty liver disease (MAFLD): a comprehensive resource tool for pre-clinical studies

Non-alcoholic steatohepatitis (NASH), characterized as the joint presence of steatosis, hepatocellular ballooning and lobular inflammation, and liver fibrosis are strong contributors to liver-related and overall mortality. Despite the high global prevalence of NASH and the substantial healthcare burden, there are currently no FDA-approved therapies for preventing or reversing NASH and/or liver fibrosis. Importantly, despite nearly 200 pharmacotherapies in different phases of pre-clinical and clinical assessment, most therapeutic approaches that succeed from pre-clinical rodent models to the clinical stage fail in subsequent Phase I-III trials. In this respect, one major weakness is the lack of adequate mouse models of NASH that also show metabolic comorbidities commonly observed in NASH patients, including obesity, type 2 diabetes and dyslipidaemia. This study provides an in-depth comparison of NASH pathology and deep metabolic profiling in eight common inbred mouse strains (A/J, BALB/c, C3H/HeJ, C57BL/6J, CBA/CaH, DBA/2J, FVB/N and NOD/ShiLtJ) fed a western-style diet enriched in fat, sucrose, fructose and cholesterol for eight months. Combined analysis of histopathology and hepatic lipid metabolism, as well as measures of obesity, glycaemic control and insulin sensitivity, dyslipidaemia, adipose tissue lipolysis, systemic inflammation and whole-body energy metabolism points to the FVB/N mouse strain as the most adequate diet-induced mouse model for the recapitulation of metabolic (dysfunction) associated fatty liver disease (MAFLD) and NASH. With efforts in the pharmaceutical industry now focussed on developing multi-faceted therapies; that is, therapies that improve NASH and/or liver fibrosis, and concomitantly treat other metabolic comorbidities, this mouse model is ideally suited for such pre-clinical use.