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To standardize the effective prevention, surveillance, and diagnosis of primary liver cancer, the Chinese Society of Hepatology, Chinese Medical Association, invited clinical experts and methodologists to develop the Consensus on the Secondary Prevention of Primary Liver Cancer, which was based on the clinical and scientific advances on hepatocellular carcinoma. The purpose is to provide a current basis for the prevention, surveillance, and early diagnosis of primary liver cancer in patients with chronic liver diseases.

BACKGROUND Despite substantial attention paid to the epidemic of nonalcoholic fatty liver disease (NAFLD) in adults, data on the burden and sexual dimorphism of NAFLD in Asian children have not yet been synthesized. METHODS We conducted a literature search of 735 references up to April 2021. Pooled analyses, stratified analyses and meta-regression were all performed. RESULTS Thirty-three study populations were finally included. Nine of them comprising 20 595 children showed an overall NAFLD prevalence of 5.53% (95% CI 3.46%-8.72%), in which, 36.64% (95% CI, 27.99%-46.26%) NAFLD subjects had elevated levels of ALT. The prevalence rate of NAFLD increased about 1.6-fold from 2004 to 2010 to the last decade. Male predominant trends were observed in paediatric NAFLD (boys: 8.18%, 95% CI 4.93%-13.26%; girls: 3.60%, 95% CI 1.60%-7.87%). Moreover, meta-analysis showed that after 10 years of age, boys were more prone to have NAFLD than girls (OR = 1.75; P = .0012). In addition, the pooled prevalence of NAFLD increased sequentially in normal-weight (1.49%, 95% CI 0.88%-2.51%, n = 2610), overweight (16.72%, 95% CI 7.07%-34.65%, n = 1265) and obese children (50.13%, 95% CI 41.99%-58.27%, n = 6434 individuals). After full covariate adjustment, the multivariate meta-regression also showed that boy percentage (P = .0396) and body mass index (P

Although concomitant nonalcoholic steatohepatitis (NASH) is common in chronic hepatitis B (CHB), the impact of viral factors on NASH and the outcome of CHB patients concomitant with NASH remain unclear. We aimed to investigate the outcomes of NASH in CHB patients receiving antiviral treatment.In the post-hoc analysis of a multicenter trial, naïve CHB patients receiving 72-week entecavir treatment were enrolled. We evaluated the biochemical, viral and histopathological responses of these patients. The histopathological features of NASH were also evaluated, using paired liver biopsies at baseline and week 72.A total of 1000 CHB patients were finally enrolled for analysis, with 18.2% of whom fulfilling the criteria of NASH. A total of 727 patients completed entecavir antiviral treatment and received the second biopsy. Serum HBeAg loss, HBeAg seroconversion and HBV-DNA undetectable rates were similar between patients with or without NASH (P0.05). Among patients with NASH, the hepatic steatosis, ballooning, lobular inflammation scores and fibrosis stages all improved during follow-up (all P0.001), 46% (63/136) achieved NASH resolution. Patients with baseline body mass index (BMI) ≥ 23 kg/mLower BMI and weight reduction but not virologic factors determine NASH resolution in CHB. The value of weight management in CHB patients during antiviral treatment deserves further evaluation.

Background This study aimed to assess the association between metabolic syndrome (MetS) and severity of nonalcoholic fatty liver disease (NAFLD), and to discuss the pathological relevance of the diagnostic criteria in metabolic (dysfunction) associated fatty liver disease (MAFLD). Methods This was a multicenter, cross-sectional study. Patients with NAFLD confirmed by liver biopsy were enrolled between July 2016 and December 2018 from 14 centers across the mainland of China. Anthropometric and metabolic parameters were collected to assess the pathological relevance. Results Of 246 enrolled patients with NAFLD, 150 (61.0%) had the comorbidity of MetS. With the increase of metabolic components, the proportions of nonalcoholic steatohepatitis (NASH) and significant fibrosis were notably increased. The comorbid three metabolic components significantly increased the proportion of NASH, and further increase of metabolic components did not increase the proportion of NASH. However, the increase of metabolic components was parallel to the increase of the proportion of liver fibrosis. Among the 246 patients, 239 (97.2%) met the diagnostic criteria of MAFLD. Although non-MAFLD patients had less NASH, they present with similar proportion of significant fibrosis and cirrhosis. In the diagnostic criteria of MAFLD, BMI ≥ 23 kg/m2 was related to NASH (Mantel-Haenszel Common Estimate OR: 2.975; 95% CI: 1.037–8.538; P = 0.043), and T2DM was related to significant fibrosis (Mantel-Haenszel Common Estimate OR: 2.531; 95% CI: 1.388–4.613; P = 0.002). The homeostasis model assessment of insulin resistance (HOMA-IR) ≥ 2.5 was the most significant factor for NASH (OR: 4.100; 95% CI: 1.772–9.487; P = 0.001) and significant factor for liver fibrosis (OR: 2.947; 95% CI: 1.398–6.210; P = 0.004) after the adjustments of the BMI and diabetes. Conclusions Metabolic dysregulations are important risk factors in NAFLD progression. The insulin resistance status may play a predominant role in the progression in MAFLD patients.

BACKGROUND The association between PPARGC1A rs8192678 and nonalcoholic fatty liver disease (NAFLD) requires further confirmation. In addition, it is still unknown whether PPARGC1A rs8192678 is associated with hepatic histological features in NAFLD in the Chinese population. AIM To investigate the interaction between PPARGC1A rs8192678 and nonalcoholic steatohepatitis (NASH), and whether this polymorphism is associated with hepatic histological features. METHODS Fifty-nine patients with liver biopsy-proven NAFLD and 93 healthy controls were recruited to a cohort representing the Chinese Han population. The SAF (steatosis, activity, and fibrosis) scoring system was used for hepatic histopathological evaluation. The polymorphisms of PPARGC1A rs8192678 and patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 were genotyped. The intrahepatic mRNA expression of PPARGC1A was evaluated by real-time polymerase chain reaction. RESULTS Thirty-seven patients with NAFLD had NASH, of which 12 were nonobese. The PPARGC1A rs8192678 risk A allele (carrying GA and AA genotypes) had the lowest P value in the dominant model; the odds ratio (OR) for NAFLD was 2.321 [95% confidence interval (CI): 1.121-4.806]. After adjusting for age, sex, and the PNPLA3 rs738409 risk G allele, the PPARGC1A rs8192678 A allele was a risk factor for NAFLD (OR 2.202, 95%CI: 1.030-4.705, P = 0.042). The genetic analysis showed that patients with NAFLD, moderate-to-severe steatosis (S2-3), and Activity 2-4 (A ≥ 2) were more likely to carry A in PPARGC1A rs8192678 (OR 5.000, 95%CI: 1.343-18.620, P = 0.012; and OR 4.071, 95%CI: 1.076-15.402, P = 0.031). The multivariate logistic regression analysis showed that PPARGC1A rs8192678 risk A allele was also independently associated with S2-3, A ≥ 2, and NASH (OR 6.190, 95%CI: 1.508-25.410, P = 0.011; OR 4.506, 95%CI 1.070-18.978, P = 0.040; and OR 6.337, 95%CI: 1.135-35.392, P = 0.035, respectively) after adjusting for age, sex, body mass index, and PNPLA3 rs738409 risk G allele. The results also showed that this polymorphism was associated with nonobese NASH (OR 22.000, 95%CI: 1.540-314.292, P = 0.021). The intrahepatic expression of PPARGC1A mRNA was significantly lower in the group of patients who carried the risk A allele (P = 0.014). CONCLUSION The PPARGC1A rs8192678 risk A allele is associated with NAFLD, and with S2-3, A ≥ 2 and NASH in NAFLD patients, independent of PNPLA3 rs738409, and may be associated with nonobese NASH.

Background Health Related Quality of Life (HRQL) is a multi-dimensional construct that can comprehensively evaluate the patient’s health status, including physical, emotional, mental and social well-being. In this study, we aimed to evaluate the impact of non-alcoholic fatty liver disease (NAFLD) on HRQL in a Chinese population. Methods In this national multicenter cross-sectional survey, patients with NAFLD were enrolled. Chronic Liver Disease Questionnaire (CLDQ)-NAFLD was used to qualify HRQL. Univariate and multivariate analysis were used to identify independent risk factors of HRQL. Results A total of 5181 patients with NAFLD from 90 centers were enrolled in this study (mean age, 43.8 ± 13.3 years; male, 65.8%). The overall CLDQ score was 5.66 ± 0.89. Multivariate logistic regression analysis showed that body mass index (BMI: HR, 1.642; 95% CI, 1.330–2.026), alanine transaminase (ALT: HR, 1.006; 95% CI, 1.001–1.011), triglyceride (HR, 1.184; 95% CI, 1.074–1.305), disease severity (HR, 3.203; 95% CI, 1.418–7.232) and cardiovascular disease (HR, 4.305; 95% CI, 2.074–8.939) were independent risk factors for overall CLDQ score. In the logistic analyses of individual domain, BMI and triglyceride were independent risk factors of all domains. ALT, disease severity, diabetes, depression and cardiovascular disease were influencing factors for the CLDQ score of several domains. Conclusions This national multicenter cross-sectional survey in China indicated that the HRQL in patients with NAFLD was impaired. HRQL was found to be significantly associated with sociodemographic and clinical factors. Attention should be paid to the optimally managing care of patients with NAFLD to improve their HRQL.

Background and Aims Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic disorders. This study aimed to explore the role of metabolic disorders in screening advanced fibrosis in NAFLD patients. Methods A total of 246 histologically-proven NAFLD patients were enrolled across 14 centers. We compared the severity of fibrosis in patients with different components of metabolic disorders. Based on standard noninvasive tests and metabolic disorders, we developed new algorithms to identify advanced fibrosis. Results Metabolic syndrome (MetS) was frequent in NAFLD patients (133/246, 54%). Patients with MetS had a higher proportion of significant fibrosis (p=0.014) and higher LSM values (9.2 kPa, vs. 7.4 kPa, p=0.002) than those without MetS. Patients with more metabolic disorders had higher fibrosis stages (p=0.017). Reduced high-density lipoprotein cholesterol (odds ratio [OR]: 2.241, 95% confidence interval [CI]: 1.004–5.002, p=0.049) and raised fasting glucose (OR: 4.500, 95% CI: 2.083–9.725, p

Background/Aims Nonalcoholic fatty liver disease (NAFLD) is closely related to gut-microbiome. There is a paucity of research on which strains of gut microbiota affect the progression of NAFLD. This study explored the NAFLD-associated microbiome in humans and the role of Lactobacillus in the progression of NAFLD in mice. Methods The gut microbiome was analyzed via next-generation sequencing in healthy people (n=37) and NAFLD patients with elevated liver enzymes (n=57). Six-week-old male C57BL/6J mice were separated into six groups (n=10 per group; normal, Western, and four Western diet + strains [109 colony-forming units/g for 8 weeks; L. acidophilus, L. fermentum, L. paracasei, and L. plantarum]). Liver/body weight ratio, liver pathology, serum analysis, and metagenomics in the mice were examined. Results Compared to healthy subjects (1.6±4.3), NAFLD patients showed an elevated Firmicutes/Bacteroidetes ratio (25.0±29.0) and a reduced composition of Akkermansia and L. murinus (P

Background and Aims Butyric acid is an intestinal microbiota-produced short-chain fatty acid, which exerts salutary effects on alleviating nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanism of butyrate on regulating hepatic lipid metabolism is largely unexplored. Methods A mouse model of NAFLD was induced with high-fat diet feeding, and sodium butyrate (NaB) intervention was initiated at the eighth week and lasted for 8 weeks. Hepatic steatosis was evaluated and metabolic pathways concerning lipid homeostasis were analyzed. Results Here, we report that administration of NaB by gavage once daily for 8 weeks causes an augmentation of insulin-induced gene (Insig) activity and inhibition of lipogenic gene in mice fed with high-fat diet. Mechanistically, NaB is sufficient to enhance the interaction between Insig and its upstream kinase AMP-activated protein kinase (AMPK). The stimulatory effects of NaB on Insig-1 activity are abolished in AMPKα1/α2 double knockout (AMPK−/−) mouse primary hepatocytes. Moreover, AMPK activation by NaB is mediated by LKB1, as evidenced by the observations showing NaB-mediated induction of phosphorylation of AMPK, and its downstream target acetyl-CoA carboxylase is diminished in LKB1–/– mouse embryonic fibroblasts. Conclusions These studies indicate that NaB serves as a negative regulator of hepatic lipogenesis in NAFLD and that NaB attenuates hepatic steatosis and improves lipid profile and liver function largely through the activation of LKB1-AMPK-Insig signaling pathway. Therefore, NaB has therapeutic potential for treating NAFLD and related metabolic diseases., Graphical abstract

The aim of the present study was to explore the dynamic relationship between Notch and non-alcoholic fatty liver disease (NAFLD), both in vitro and in vivo. The LX2, Huh7 and MIHA hepatic cell lines were used to establish a cell steatosis model induced by palmitic acid (PA) at different concentrations (0.1, 0.25 and 0.5 mM). Cell proliferation and migration were assessed using a 5-bromo-2′-deoxyuridine kit and a wound healing assay. The dosage of 0.25 mM PA for 36–48 h treatment was chosen for subsequent experiments. Steatotic cells were identified by Oil Red O staining. Feeding mice a methionine-choline-deficient (MCD) diet is known induce a model of NAFLD, compared with a methionine-choline-sufficient (MCS) diet. Therefore, Notch family mRNA expression was evaluated in the liver of MCD-fed mice at varying time points (days 5, 10, 21 and 70) using reverse transcription-quantitative PCR. Notch expression levels were also assessed in cell lines at 12, 24, 36 and 48 h after PA treatment. Notch signaling molecules changed in the PA or MCD model over time. In vitro, the mRNA levels of Notch1, −2 and −4 increased in all cell lines after 12-h PA treatment. At 24 h, these genes were upregulated only in LX2 cells, while showing a ‘down-up’ pattern in MIHA cells (i.e. these genes were downregulated at 24 h but upregulated at 36 h). However, expression of Notch1, −2, −3 and −4 mRNA rose significantly in the early stage (day 10) of NAFLD. At week 3, the levels of Notch1 and −2 were higher in the MCD group than in the MCS group, while the reverse was observed for Notch3 and −4. Expression of these four genes increased again in the late stage (day 70) of NAFLD. Therefore, these results indicated that Notch family members Notch1-4 were involved in the development of NAFLD and played an important role in steatosis in this model.

Background and aims Hepatic macrophages can be activated by many factors such as gut-derived bacterial components and factors released from damaged hepatocytes. Macrophage polarization toward a proinflammatory phenotype (M1) represents an important event in the disease progression of nonalcoholic fatty liver disease (NAFLD). However, the underlying molecular mechanisms remain incompletely understood. Exosomes have been identified as important mediators for cell-cell communication by transferring various biological components such as microRNAs (miRs), proteins, and lipids. The role of exosomes in crosstalk between hepatocytes and macrophages in disease progression of NAFLD is yet to be explored. Approach and results In the present study, we reported that lipotoxic injury-induced release of hepatocyte exosomes enriched with miR-192-5p played a critical role in the activation of M1 macrophages and hepatic inflammation. Serum miR-192-5p levels in patients with NAFLD positively correlated with hepatic inflammatory activity score and disease progression. Similarly, the serum miR-192-5p level and the number of M1 macrophages, as well as the expression levels of the hepatic proinflammatory mediators, were correlated with disease progression in high-fat high-cholesterol diet-fed rat models. Lipotoxic hepatocytes released more miR-192-5p-enriched exosomes than controls, which induced M1 macrophage (cluster of differentiation 11b-positive [CD11b+ ]/CD86+ ) activation and increase of inducible nitric oxide synthase, interleukin 6, and tumor necrosis factor alpha expression. Furthermore, hepatocyte-derived exosomal miR-192-5p inhibited the protein expression of the rapamycin-insensitive companion of mammalian target of rapamycin (Rictor), which further inhibited the phosphorylation levels of Akt and forkhead box transcription factor O1 (FoxO1) and resulted in activation of FoxO1 and subsequent induction of the inflammatory response. Conclusions Hepatocyte-derived exosomal miR-192-5p plays a critical role in the activation of proinflammatory macrophages and disease progression of NAFLD through modulating Rictor/Akt/FoxO1 signaling. Serum exosomal miR-192-5p represents a potential noninvasive biomarker and therapeutic target for nonalcoholic steatohepatitis.

Folic acid attenuates high-fat diet-induced steatohepatitis via deacetylase SIRT1-dependent restoration of PPARα

BACKGROUND Gamma-glutamyl transferase (GGT) is associated with the risk of cardiovascular disease (CVD) in the general population. AIM To identify the association of baseline GGT level and QRISK2 score among patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD). METHODS This was a retrospective study involving 1535 biopsy-proven NAFLD patients from 10 Asian centers in 8 countries using data collected by the Gut and Obesity in Asia (referred to as "GO ASIA") workgroup. All patients with available baseline GGT levels and all 16 variables for the QRISK2 calculation (QRISK2-2017; developed by researchers at the United Kingdom National Health Service; https://qrisk.org/2017/; 10-year cardiovascular risk estimation) were included and compared to healthy controls with the same age, sex, and ethnicity. Relative risk was reported. QRISK2 score > 10% was defined as the high-CVD-risk group. Fibrosis stages 3 and 4 (F3 and F4) were considered advanced fibrosis. RESULTS A total of 1122 patients (73%) had complete data and were included in the final analysis; 314 (28%) had advanced fibrosis. The median age (interquartile range [IQR]) of the study population was 53 (44-60) years, 532 (47.4%) were females, and 492 (43.9%) were of Chinese ethnicity. The median 10-year CVD risk (IQR) was 5.9% (2.6-10.9), and the median relative risk of CVD over 10 years (IQR) was 1.65 (1.13-2.2) compared to healthy individuals with the same age, sex, and ethnicity. The high-CVD-risk group was significantly older than the low-risk group (median [IQR]: 63 [59-67] vs 49 [41-55] years; P < 0.001). Higher fibrosis stages in biopsy-proven NAFLD patients brought a significantly higher CVD risk (P < 0.001). Median GGT level was not different between the two groups (GGT [U/L]: Median [IQR], high risk 60 [37-113] vs low risk 66 [38-103], P = 0.56). There was no correlation between baseline GGT level and 10-year CVD risk based on the QRISK2 score (r = 0.02). CONCLUSION The CVD risk of NAFLD patients is higher than that of healthy individuals. Baseline GGT level cannot predict CVD risk in NAFLD patients. However, advanced fibrosis is a predictor of a high CVD risk.

BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic diseases in the world. Nowadays, the percentage of non-obese or lean patients with NAFLD is increasing. NAFLD in non-obese populations, especially the lean subgroup with a normal waist circumference (WC), might lead to more problems than obese individuals, as these individuals may not visit clinics for NAFLD diagnosis or ignore the diagnosis of NAFLD. If the precise characteristics of these populations, especially the lean subgroup, are identified, the clinicians would be able to provide more appropriate advice and treatment to these populations. AIM To investigate the prevalence, clinical characteristics, risk factors, and possible indicators for NAFLD in lean Chinese adults with a normal WC. METHODS People without diabetes mellitus or significant alcohol consumption who underwent routine health examinations were included. Their fatty liver index (FLI), abdominal ultrasonography results, and controlled attenuation parameter were all assessed. Genotyping for single-nucleotide polymorphisms associated with NAFLD was performed in another small group consisting of biopsy-proven NAFLD subjects and healthy controls. RESULTS A total of 2715 subjects who underwent routine health examinations were included in the study. Among 810 lean participants with a normal WC, 142 (17.5%) fulfilled the diagnostic criteria for NAFLD. Waist-height ratio, hemoglobin, platelets, and triglycerides were significant factors associated with the presence of NAFLD in these participants. The appropriate cut-off value of the FLI score in screening for NAFLD in the lean subjects with a normal WC was 25.15, which had a 77.8% sensitivity and 75.9% specificity. There was no significant difference in the single-nucleotide polymorphisms in the SIRT1, APOC3, PNPLA3, AGTR1, and PPARGC1A genes between lean subjects with and without NAFLD (P < 0.05). CONCLUSION NAFLD is not uncommon in lean Chinese adults even with a normal WC. Metabolic factors, rather than genetic factors, may play important roles in the development of NAFLD in this population. A lower cut-off value of the FLI score in screening for NAFLD should be used for lean Chinese adults with a normal WC.

Background and aims STAT3, a member of the signal transducer and activator of transcription (STAT) family, is strongly associated with liver injury, inflammation, regeneration, and hepatocellular carcinoma development. However, the signals that regulate STAT3 activity are not completely understood. Approach and results Here we characterize CREB/ATF bZIP transcription factor CREBZF as a critical regulator of STAT3 in the hepatocyte to repress liver regeneration. We show that CREBZF deficiency stimulates the expression of the cyclin gene family and enhances liver regeneration after partial hepatectomy. Flow cytometry analysis reveals that CREBZF regulates cell cycle progression during liver regeneration in a hepatocyte-autonomous manner. Similar results were observed in another model of liver regeneration induced by intraperitoneal injection of carbon tetrachloride (CCl4 ). Mechanistically, CREBZF potently associates with the linker domain of STAT3 and represses its dimerization and transcriptional activity in vivo and in vitro. Importantly, hepatectomy-induced hyperactivation of cyclin D1 and liver regeneration in CREBZF liver-specific knockout mice was reversed by selective STAT3 inhibitor cucurbitacin I. In contrast, adeno-associated virus-mediated overexpression of CREBZF in the liver inhibits the expression of the cyclin gene family and attenuates liver regeneration in CCl4 -treated mice. Conclusions These results characterize CREBZF as a coregulator of STAT3 to inhibit regenerative capacity, which may represent an essential cellular signal to maintain liver mass homeostasis. Therapeutic approaches to inhibit CREBZF may benefit the compromised liver during liver transplantation.

Introduction: Multiple studies have revealed a strong relationship between the development of nephropathy and hepatitis B virus (HBV) infection. The underlying pathogenesis of hepatitis B-related glomerulonephritis (HBV-GN) involves immune complexes, which can be isolated from kidney tissues. Clearance of HBV antigenemia improves renal impairment and proteinuria in HBV-GN patients.Areas covered: In this review, we present our current understanding of the epidemiology, pathogenesis, pathology, diagnosis, and treatment of HBV-GN. We discuss the advantages and disadvantages of oral nucleoside/nucleotide analogs (NAs), and the main pharmaceutical treatment for hepatis B.Expert opinion: Currently, antiviral agents are the main HBV-GN therapeutic agents. Although no randomized controlled clinical trials have compared the efficacy of interferon (IFN) and NA, we suggest IFN treatment for pediatric patients (IFN-α in patients ≥1 year; pegIFN-α in patients ≥3 years) considering treatment duration and absence of resistance. Novel NAs have brought about promising treatment options involving high efficacy viral suppression and low resistance rates. NAs with a high barrier to resistance (e.g. entecavir) are recommended as first-line therapy of HBV-GN. Immunosuppression monotherapy, such as corticosteroids, is of little benefit and potentially harmful to HBV-GN patients due to the possibility of viral reactivation.

BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is now regarded as the hepatic manifestation of metabolic syndrome (MetS). Recent research has suggested that serum creatinine (SCr) may be an indicator of MetS and its related diseases. We aimed to investigate the association between SCr and NAFLD in Chinese adults. METHODS A cross-sectional sample of 8862 subjects aged 40 years or older (40-73 years) from China were analysed in this study. The anthropometric measurements, laboratory tests, and hepatic ultrasonography were conducted. NAFLD presence was defined by hepatic ultrasound in the absence of other liver diseases. RESULTS NAFLD subjects had higher SCr than those without NAFLD (66.8 μmol/L vs. 65.6 μmol/L, p

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that is increasingly prevalent worldwide. Liver inflammation is an important contributor to disease progression from nonalcoholic fatty liver (NAFL) to NASH, but there is a lack of efficient therapies. In the current study we evaluated the therapeutic potential of givinostat, a histone deacetylase (HDAC) inhibitor, in the treatment of NASH in vivo and in vitro. Liver inflammation was induced in mice by feeding a methionine- and choline-deficient diet (MCD) or a fructose, palmitate, cholesterol diet (FPC). The mice were treated with givoinostat (10 mg·kg(−1)·d(−1), ip) for 8 or 10 weeks. At the end of the experiment, the livers were harvested for analysis. We showed that givoinostat administration significantly alleviated inflammation and attenuated hepatic fibrosis in MCD-induced NASH mice. RNA-seq analysis of liver tissues form MCD-fed mice revealed that givinostat potently blocked expression of inflammation-related genes and regulated a broad set of lipid metabolism-related genes. In human hepatocellular carcinoma cell line HepG2 and human derived fetal hepatocyte cell line L02, givinostat significantly decreased palmitic acid-induced intracellular lipid accumulation. The benefit of givinostat was further confirmed in FPC-induced NASH mice. Givinostat administration significantly attenuated hepatic steatosis, inflammation as well as liver injury in this mouse model. In conclusion, givinostat is efficacious in reversing diet-induced NASH, and may serve as a therapeutic agent for the treatment of human NASH.

OBJECTIVES The accelerated shedding of extracellular domains of syndecan-4 (SDC4) is associated with central obesity and insulin resistance, while the association between serum SDC4 and nonalcoholic fatty liver disease (NAFLD) is unknown. We aimed to examine the association between SDC4 and NAFLD. METHODS Adults undergoing a health examination from 1 June 2019 to 31 December 2019 were enrolled. A diagnosis of NAFLD was made with an abdominal ultrasound. Logistic regression models and the receiver operating characteristic (ROC) curves were used to evaluate the role of SDC4 in predicting NAFLD. RESULTS In total, 533 eligible participants were finally enrolled, among them 157 (29.46%) had NAFLD. The proportion of patients with NAFLD increased with the increasing quartiles of serum SDC4. With the increase of serum SDC4 levels, metabolic features including waist circumference, serum triglyceride, total cholesterol, fasting blood glucose, fasting insulin and homeostasis model assessment of insulin resistance were significantly increased. SDC4 was an independent factor for NAFLD (odds ratio 1.963, 95% confidence interval [CI] 1.628-2.367, P

Over the past 2 decades, nonalcoholic fatty liver disease (NAFLD) has grown from a relatively unknown disease to the most common cause of chronic liver disease in the world. In fact, 25% of the world's population is currently thought to have NAFLD. Nonalcoholic steatohepatitis (NASH) is the subtype of NAFLD that can progress to cirrhosis, hepatocellular carcinoma (HCC), and death. NAFLD and NASH are not only found in adults-there is also a high prevalence of these diseases in children and adolescents. Because of the close association of NAFLD with type 2 diabetes (T2DM) and obesity, the latest models predict that the prevalence of NAFLD and NASH will increase, causing a tremendous clinical and economic burden and poor patient-reported outcomes. Nonetheless, there is no accurate noninvasive method to detect NASH, and treatment of this disease is limited to lifestyle modifications. To examine the state of NAFLD among different regions and understand the global trajectory of this disease, an international group of experts came together during the 2017 American Association for the Study of Liver Diseases Global NAFLD Forum. We provide a summary of this forum and an assessment of the current state of NAFLD and NASH worldwide.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is rising exponentially worldwide. The spectrum of NAFLD includes non-alcoholic fatty liver, non-alcoholic steatohepatitis, liver cirrhosis, and even hepatocellular carcinoma. Evidence shows that microbial metabolites play pivotal roles in the onset and progression of NAFLD. In this review, we discuss how microbe-derived metabolites, such as short-chain fatty acids, endogenous ethanol, bile acids and so forth, contribute to the pathogenesis of NAFLD.

Background Nonalcoholic fatty liver disease (NAFLD) is increasingly identified in patients with inflammatory bowel disease (IBD), but there are few systematic reviews and meta-analyses of the studies of NAFLD in IBD patients. Methods MEDLINE, Web of Science, Cochrane Library, and Scopus were searched (until August 2018) to identify observational studies that reported the prevalence and risk factors for NAFLD in IBD patients. Pooled prevalence, odds ratios (OR), mean difference (MD), and 95% confidence intervals (95% CI) were calculated. Study quality was assessed using the modified Newcastle-Ottawa scale. Results Of the 662 citations evaluated, 19 studies (including 5620 subjects) reported the prevalence of NAFLD in IBD population and were included for the analysis. The overall pooled prevalence was 27.5% (95% CI, 20.7%–34.2%). The prevalence was higher in older patients (MD = 8.22; 95% CI, 6.22–10.22), type 2 diabetes (OR = 3.85; 95% CI, 2.49–5.95), hypertension (OR = 3.18; 95% CI, 2.36–4.28), obesity (OR = 2.79; 95% CI, 1.73–4.50), insulin resistance (OR = 6.66; 95% CI, 1.28–34.77), metabolic syndrome (OR = 4.96; 95% CI, 3.05–8.05), chronic kidney disease (OR = 4.83; 95% CI, 1.79–13.04), methotrexate use (OR = 1.76; 95% CI, 1.02–3.06), surgery for IBD (OR = 1.28; 95% CI, 1.02–1.62), and longer duration of IBD (MD = 5.60; 95% CI, 2.24–8.97). Conclusions We found that NAFLD was not uncommon in the IBD population. Older age, metabolic risk factors, methotrexate use, prior surgery, and longer duration of IBD are predictors for the presence of NAFLD in IBD. Screening of NAFLD might be recommended among IBD patients with the aforementioned factors.

Insulin-induced gene (Insig) negatively regulates SREBP-mediated de novo fatty acid synthesis in the liver. However, the upstream regulation of Insig is incompletely understood. Here we report that AMPK interacts with and mediates phosphorylation of Insig. Thr222 phosphorylation following AMPK activation is required for protein stabilization of Insig-1, inhibition of cleavage and processing of SREBP-1, and lipogenic gene expression in response to metformin or A769662. AMPK-dependent phosphorylation ablates Insig’s interaction with E3 ubiquitin ligase gp78 and represses its ubiquitination and degradation, whereas AMPK deficiency shows opposite effects. Interestingly, activation of AMPK by metformin causes an augmentation of Insig stability and reduction of lipogenic gene expression, and leads to the attenuation of hepatic steatosis in HFHS diet-fed mice. Moreover, hepatic overexpression of Insig-1 rescues hepatic steatosis in liver-specific AMPKα2 knockout mice fed with HFHS diet. These findings uncover a novel effector of AMPK. Targeting Insig may have the therapeutic potential for treating fatty liver disease and related disorders., Insulin-related gene (Insig) negatively regulates hepatic fatty acid synthesis, a process involved in development of non-alcoholic fatty liver disease (NAFLD). Here, the authors show that AMPK activation by metformin promotes Insig phosphorylation, stabilizing it and inhibiting lipogenic gene expression. This is protective against steatosis in diabetic mice.

Recent studies have reported elevated expression of miR-181a in patients with non-alcoholic fatty liver disease (NAFLD), suggesting that it may play an important role in liver lipid metabolism and insulin resistance. We aimed to investigate the effect of miR-181a in lipid metabolism and find new treatments for NAFLD. The expression level of miR-181a in NAFLD patient serum and a palmitic acid (PA)-induced NAFLD cell model was examined by Q-PCR. Oil red O staining and triglyceride assays were used to assess lipid accumulation in hepatocytes. Western blotting was used to detect the protein expression levels of peroxisome proliferator-activated receptor-α (PPARα) and the fatty acid β-oxidation-related genes. Direct interactions were validated by dual-luciferase reporter gene assays. MiR-181a expression was significantly upregulated in the serum of NAFLD patients and PA-induced hepatocytes. Inhibition of miR-181a expression resulted in the increased expression of PPARα and its downstream genes, and PA-induced lipid accumulation in hepatocytes was also inhibited. Upregulation of miR-181a resulted in the downregulation of its direct target PPARα and downstream gene expression of PPARα as well as aggravated lipid accumulation in hepatocytes. At the same time, the increased expression of PPARα can offset lipid accumulation in hepatocytes induced by miR-181a mimics. This study demonstrates that reducing the expression of miR-181a may improve lipid metabolism in NAFLD. The downregulation of miR-181a expression can be a therapeutic strategy for NAFLD by modulating its target PPARα.

Glucagon-like peptide-1 (GLP-1) has a broad spectrum of biological activity by regulating metabolic processes via both the direct activation of the class B family of G protein-coupled receptors and indirect nonreceptor-mediated pathways. GLP-1 receptor (GLP-1R) agonists have significant therapeutic effects on non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) in animal models. However, clinical studies indicated that GLP-1 treatment had little effect on hepatic steatosis in some NAFLD patients, suggesting that GLP-1 resistance may occur in these patients. It is well-known that the gut metabolite sodium butyrate (NaB) could promote GLP-1 secretion from intestinal L cells. However, it is unclear whether NaB improves hepatic GLP-1 responsiveness in NAFLD. In the current study, we showed that the serum GLP-1 levels of NAFLD patients were similar to those of normal controls, but hepatic GLP-1R expression was significantly downregulated in NAFLD patients. Similarly, in the NAFLD mouse model, mice fed with a high-fat diet showed reduced hepatic GLP-1R expression, which was reversed by NaB treatment and accompanied by markedly alleviated liver steatosis. In addition, NaB treatment also upregulated the hepatic p-AMPK/p-ACC and insulin receptor/insulin receptor substrate-1 expression levels. Furthermore, NaB-enhanced GLP-1R expression in HepG2 cells by inhibiting histone deacetylase-2 independent of GPR43/GPR109a. These results indicate that NaB is able to prevent the progression of NAFL to NASH via promoting hepatic GLP-1R expression. NaB is a GLP-1 sensitizer and represents a potential therapeutic adjuvant to prevent NAFL progression to NASH., Fatty liver disease: A gutsy way to prevent disease progression A treatment for non-alcoholic fatty liver disease that incorporates a metabolite found in the gut could prevent progression to a more serious liver condition. Drugs that enhance the activity of glucagon-like peptide-1 (GLP-1), a protein involved in regulating metabolic processes, have shown promise in targeting non-alcoholic fatty liver disease and the more serious condition, steatohepatitis. However, some patients appear resistant to treatment. Jian-Gao Fan at Shanghai Jiao Tong University in China, Huiping Zhou at McGuire VA Medical Center in Richmond, USA, and co-workers demonstrated that a gut metabolite called sodium butyrate may help encourage responsiveness to GLP-1 treatment. The team found that liver GLP-1R expression was considerably reduced in patients with liver disease compared with healthy controls. Experiments on mouse models showed that treatment incorporating sodium butyrate improved GLP-1R levels and reduced fatty liver deposits.

Aims: To evaluate the prospective association of circulating PCSK9 levels with the cardiometabolic risk profiles (high LDL-cholesterol, high triglycerides, low HDL-cholesterol, hypertension, type 2 diabetes, and metabolic syndrome).Methods: A population-based prospective study was conducted among 7,104 Chinese individuals (age 56.2 ± 7.5 years; 32.0% men). Circulating PCSK9 levels were measured using ELISA.Results: Circulating PCSK9 levels were higher in women than men (286.7 ± 90.1 vs. 276.1 ± 86.4 ng/ml, p < 0.001). And circulating PCSK9 was positively correlated with LDL-cholesterol, total cholesterol, and triglycerides both in men and women (all p < 0.001). The positive correlation between PCSK9 and waist circumference, fasting glucose, insulin resistance, systolic blood pressure, diastolic blood pressure and C-reactive protein (all p < 0.01) was observed in women only. According to Cox regression analysis, circulating PCSK9 was positively associated with incidence of high LDL-cholesterol both in men (HR 1.33, 95% CI 1.09–1.65, p < 0.001) and women (HR 1.36, 95% CI 1.12–1.69, p < 0.001). Moreover, PCSK9 was significantly associated with incident high triglycerides (HR 1.31, 95% CI 1.13–1.72, p < 0.001), hypertension (HR 1.28, 95% CI 1.08–1.53, p = 0.011), type 2 diabetes (HR 1.34, 95% CI 1.09–1.76, p = 0.005), and metabolic syndrome (HR 1.30, 95% CI 1.11–1.65, p = 0.009) per SD change in women only. No statistically significant association was observed between circulating PCSK9 and incidence of low HDL-cholesterol (p > 0.1).Conclusions: Elevated circulating PCSK9 was significantly associated with cardiometabolic risk factors and independently contributed to the prediction of cardiometabolic risks in women.

Despite the rising health burden of metabolic (dysfunction) associated fatty liver disease (MAFLD), there are no approved pharmacotherapies for MAFLD currently. This situation led to a significant escalation in drug development and randomized controlled trials for MAFLD, particularly as novel information about its molecular pathogenesis unfolds. Currently, there are numerous investigational candidate drugs for MAFLD in various stages of clinical development that act on different pathophysiological processes, such as metabolism/steatosis, inflammation or fibrosis. Here, we provide an update on drug development for the treatment of MAFLD and discuss the prospects and challenges for improving and accelerating the nonalcoholic fatty liver disease drug discovery pipeline.

The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased rapidly and is associated with obesity in epidemiology and pathogenesis. A new study reports that hepatic and extrahepatic complications can develop in lean individuals with NAFLD, highlighting the importance of metabolic phenotypes in NAFLD assessment instead of BMI-based approaches.

Background Neck circumference, a proxy for upper-body subcutaneous fat, is a unique and pathogenic fat depot that confers additional metabolic risk. The purpose of present study was to determine whether neck circumference associates with nonalcoholic fatty liver disease (NAFLD) in postmenopausal women with normal body mass index. Methods A cross-sectional survey (n = 2492) and a 3.1-year follow-up investigation (n = 1354) were conducted among Chinese postmenopausal women with normal BMI (18.5 to 2). Neck circumference was measured horizontally at the lower margin of the laryngeal prominence. Results In the cross-sectional analysis, large neck circumference was associated with the presence of NAFLD (odds ratio 2.28; 95% CI 1.74–2.98; highest tertile versus lowest tertile) after adjustment for confounding factors. Among 1354 subjects without the NAFLD at baseline, 429 (31.7%) incident NAFLD cases occurred at 3.1 years. Neck circumference was positively associated with triglycerides, homeostasis model assessment of insulin resistance, C-reactive protein, and negatively associated with high-density lipoprotein cholesterol and adiponectin. Individuals with large baseline neck circumference had a significantly higher risk of NAFLD than those with small neck circumference. The multivariable adjusted hazard ratio was 1.42 (95% CI 1.15–1.97; p for trend = 0.004) for the highest versus the lowest tertile of neck circumference, and was 1.22 (95% CI 1.10–1.41; p = 0.006) per 1-standard deviation increment in neck circumference. Conclusions Among postmenopausal women with normal BMI, relatively large neck circumference levels are associated with an increased risk of NAFLD.

Fatty liver disease associated with metabolic dysfunction is of increasing concern in mainland China, the world's most populous country. The incidence of fatty liver disease is highest in China, surpassing the incidence in European countries and the USA. An international consensus panel recently published an influential report recommending a novel definition of fatty liver disease associated with metabolic dysfunction. This recommendation includes a switch in name from non-alcoholic fatty liver disease (NAFLD) to metabolic (dysfunction)-associated fatty liver disease (MAFLD) and adoption of a set of positive criteria for disease diagnosis that are independent of alcohol intake or other liver diseases. Given the unique importance of this proposal, the Chinese Society of Hepatology (CSH) invited leading hepatologists and gastroenterologists representing their respective provinces and cities to reach consensus on alternative definitions for fatty liver disease from a national perspective. The CSH endorses the proposed change from NAFLD to MAFLD (supported by 95.45% of participants). We expect that the new definition will result in substantial improvements in health care for patients and advance disease awareness, public health policy, and political, scientific and funding outcomes for MAFLD in China.

[Background & Aims] Globally, nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. We assessed the clinical presentation and patient-reported outcomes (PROs) among NAFLD patients from different countries., [Methods] Clinical, laboratory, and PRO data (Chronic Liver Disease Questionnaire–nonalcoholic steatohepatitis [NASH], Functional Assessment of Chronic Illness Therapy–Fatigue, and the Work Productivity and Activity Index) were collected from NAFLD patients seen in real-world practices and enrolled in the Global NAFLD/NASH Registry encompassing 18 countries in 6 global burden of disease super-regions., [Results] Across the global burden of disease super-regions, NAFLD patients (n = 5691) were oldest in Latin America and Eastern Europe and youngest in South Asia. Most men were enrolled at the Southeast and South Asia sites. Latin America and South Asia had the highest employment rates (>60%). Rates of cirrhosis varied (12%–21%), and were highest in North Africa/Middle East and Eastern Europe. Rates of metabolic syndrome components varied: 20% to 25% in South Asia and 60% to 80% in Eastern Europe. Chronic Liver Disease Questionnaire–NASH and Functional Assessment of Chronic Illness Therapy–Fatigue PRO scores were lower in NAFLD patients than general population norms (all P < .001). Across the super-regions, the lowest PRO scores were seen in Eastern Europe and North Africa/Middle East. In multivariate analysis adjusted for enrollment region, independent predictors of lower PRO scores included younger age, women, and nonhepatic comorbidities including fatigue (P < .01). Patients whose fatigue scores improved over time experienced a substantial PRO improvement. Nearly 8% of Global NAFLD/NASH Registry patients had a lean body mass index, with fewer metabolic syndrome components, fewer comorbidities, less cirrhosis, and significantly better PRO scores (P < .01)., [Conclusions] NAFLD patients seen in real-world practices in different countries experience a high comorbidity burden and impaired quality of life. Future research using global data will enable more precise management and treatment strategies for these patients.

[Background and Aim] There is debate among the hepatology community regarding the simple non-invasive scoring systems and histological scores (even it was developed for histological classification) in predicting clinical outcomes in patients with non-alcoholic fatty liver disease (NAFLD). This study aimed to determine whether the presence of simple non-invasive scoring systems and histological scores could predict all-cause mortality, liver-related mortality, and liver disease decompensation (liver failure, cirrhosis, hepatocellular carcinoma, or decompensated liver disease)., [Methods] The pooled hazard ratio of prognostic factors and incidence rate per 1000 person-years in patients with NAFLD was calculated and further adjusted by two different models of handling the duplicated data., [Results] A total of 19 longitudinal studies were included. Most simple non-invasive scoring systems (Fibrosis-4 Score, BARD, and aspartate aminotransferase-to-platelet ratio index ) and histological scores (NAFLD activity score, Brunt, and "steatosis, activity, and fibrosis" ) failed in predicting mortality, and only the NAFLD fibrosis score > 0.676 showed prognostic ability to all-cause mortality (four studies, 7564 patients, 118 352 person-years followed up, pooled hazard ratio 1.44, 95% confidence interval [CI] 1.05–1.96). The incidence rate per 1000 person-years of all-cause mortality, liver-related mortality, cardiovascular-related mortality, and liver disease decompensation resulted in a pooled incidence rate per 1000 person-years of 22.65 (14 studies, 95% CI 9.62–53.31), 3.19 (7 studies, 95% CI 1.14–8.93), 6.02 (6 studies, 95% CI 4.69–7.74), and 11.46 (4 studies, 95% CI 5.33–24.63), respectively., [Conclusion] Non-alcoholic fatty liver disease fibrosis score showed promising prognostic value to all-cause mortality. Most present simple non-invasive scoring systems and histological scores failed to predict clinical outcomes.

Aims Prolyl endopeptidase (PREP) is a serine endopeptidase widely distributed in the body, and accumulated evidence suggests that PREP participates in inflammation and oxidative stress. Here, we explored the effect of PREP gene disruption on hepatic inflammation and oxidative stress status in a methionine-choline-deficient (MCD)-induced nonalcoholic steatohepatitis (NASH) model. Main methods PREP gene disruption (PREPgt) mice and wild-type (WT) littermates were placed on a control or an MCD diet for 4 weeks, respectively. The liver histopathological analysis and the number of inflammatory cells were determined by hematoxylin-eosin (HE) and immunohistochemical staining. Inflammation-associated genes and cytokine levels in liver tissue were evaluated by quantitative PCR and ELISA. The levels of P53, Sesn2, Nrf2, HO-1, and oxidative stress indicators in mice and the palmitic acid (PA)-treated human hepatocellular carcinoma cells (HepG2) were examined by immunoblotting and commercially available kits, respectively. Key findings We found that PREP expression was upregulated in the MCD-induced NASH model. In addition, PREP disruption alleviated MCD-induced hepatic inflammation accompanied by diminished infiltration of inflammatory cells and secretion of inflammatory mediators. More importantly, the results of this study indicate that targeting PREP can improve oxidative stress status in the liver of MCD-diet mice and PA-exposed HepG2 cells. The effect is most likely mediated by the activation of P53 and its downstream signaling pathways (Sesn2/Nrf2/HO-1). Significance Our results showed that PREP disruption (or inhibition) could decrease oxidative stress and inflammation and improve liver function, indicating that targeting PREP might be a new potential therapeutic option for NAFLD/NASH.

Single-nucleotide polymorphisms (SNPs) of apolipoprotein C3 (APOC3) play important role in lipid metabolism, and dyslipidemia underlies nonalcoholic fatty liver disease (NAFLD). But the correlation of serum lipidomics, APOC3 SNPs, and NAFLD remains limited understood. Enrolling thirty-four biopsy-proven NAFLD patients from Tianjin, Shanghai, Fujian, we investigated their APOC3 genotype and serum lipid profile by DNA sequencing and ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), respectively. Scoring of hepatocyte steatosis, ballooning, lobular inflammation, and liver fibrosis was then performed to reveal the role of lipidomics-affecting APOC3 SNPs in NAFLD-specific pathological alterations. Here, we reported that APOC3 SNPs (rs4225, rs4520, rs5128, rs2070666, and rs2070667) intimately correlated to serum lipidomics in NAFLD patients. A allele instead of G allele at rs2070667, which dominated the SNPs underlying lipidomic alteration, exhibited downregulatory effect on triacylglycerols (TGs: TG 54 : 7, TG 54 : 8, and TG 56 : 9) containing polyunsaturated fatty acid (PUFA). Moreover, subjects with low-level PUFA-containing TGs were predisposed to high-grade lobular inflammation (TG 54 : 7,rho=−0.454andP=0.007; TG 54 : 8,rho=−0.411and P =0.016; TG 56 : 9,rho=−0.481andP=0.004). The significant correlation of APOC3 rs2070667 and inflammation grading [G/G vs. G/A+A/A: 0.00 (0.00 and 1.00) vs. 1.50 (0.75 and 2.00),P=0.022] further confirmed its pathological action on the basis of lipidomics-impacting activity. These findings suggest an inhibitory effect of A allele at APOC3 rs2070667 on serum levels of PUFA-containing TGs, which are associated with high-grade lobular inflammation in NAFLD patients.

Non-alcoholic fatty liver disease (NAFLD) is now the most common etiology of chronic liver disease threatening global public health. However, the name "NAFLD" is no longer appropriate with the change of time. Recently, a new term, "metabolic dysfunction-associated fatty liver disease" has been proposed by an international panel of experts, which implies profound conceptual changes in terms of its metabolism-related etiology and disease heterogeneity. In this article we discuss the specific conceptual changes that clinicians, researchers and patients must absorb.

Metabolic associated fatty liver disease (MAFLD) is the principal worldwide cause of liver disease and affects nearly a quarter of the global population. The objective of this work was to present the clinical practice guidelines of the Asian Pacific Association for the Study of the Liver (APASL) on MAFLD. The guidelines cover various aspects of MAFLD including its epidemiology, diagnosis, screening, assessment, and treatment. The document is intended for practical use and for setting the stage for advancing clinical practice, knowledge, and research of MAFLD in adults, with specific reference to special groups as necessary. The guidelines also seek to improve patient care and awareness of the disease and assist stakeholders in the decision-making process by providing evidence-based data. The guidelines take into consideration the burden of clinical management for the healthcare sector.

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease that causes worldwide morbidity and mortality, yet there is still a lack of pharmacological therapies. Liver inflammation is an important contributor for disease progression from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). We identified HDAC inhibitor givinostat as a potent inhibitor of macrophages inflammatory activation, and aimed to evaluate the therapeutic potential of givinostat for treatment of NASH. Daily administration of givoinostat (10mg/kg) alleviated inflammation and attenuated hepatic fibrosis in methionine- and choline-deficient diet (MCD)-induced NASH mice. RNA-seq analysis of liver tissues form MCD-fed mice revealed givinostat potently blocked expression of inflammation-related genes and regulated a broad set of lipid metabolism-related genes. In hepatocyte givinostat reduced palmitic acid induced intracellular lipid accumulation. The benefit of givinostat was further confirmed in fructose, palmitate, cholesterol diet (FPC) induced NASH mice. Givinostat attenuated hepatic steatosis, inflammation as well as liver injury in FPC-induced NASH. In conclusion, givinostat appears to be efficacious in reversing diet-induced NASH, and may serve as a therapeutic agent for treatment of human NASH.

BACKGROUND & AIMS Lifestyle modification is the cornerstone for the management of non-alcoholic fatty liver disease (NAFLD). We aim to understand lifestyle habits of NAFLD patients, compare across Asian regions and identify area of deficiency. METHODS In the multi-centre controlled attenuation parameter (CAP)-Asia study, we collected clinical data and lifestyle habit data of NAFLD patients from Singapore, mainland China, Hong Kong, Taiwan and Malaysia. Physical activity was assessed using the International Physical Activity Questionnaire. RESULTS A total of 555 patients were included in the final analysis (mean age 54.5 ± 11.2 years, 54.1% men and median liver stiffness 6.7 kPa). More patients from mainland China (27.4%) and Taipei (25.0%) were smokers. Modest drinking was more common in Taiwan (25.0%) and Hong Kong (18.2%); only 1.3% had binge drinking. Majority of patients drank coffee (64.0%) and tea (80.2%), with varying amounts and durations in different regions. Soft drinks consumption was most common in Singapore (62.2%) and Malaysia (57.7%). Only 29.7% of patients met the Physical Activity Guidelines Recommendations, with no major differences across regions. Patients with liver stiffness

Objective As a subgroup of nonalcoholic fatty liver disease (NAFLD), patients with non-obese NAFLD may also have an increased risk of adverse hepatic and metabolic outcomes. We aimed to estimate the prevalence and incidence of non-obese NAFLD and to describe its clinical characteristics in this systematic review and meta-analysis. Methods We performed a systematic search of 1235 citations published up to Mar 2020. Meta-analyses, stratified analyses and meta-regression were all performed. Results Of the 46 studies included, 28 cross-sectional and longitudinal studies of 155 846 non-obese participants reported a pooled NAFLD prevalence of 14.5% (95% confidence interval [CI] 12.3%-17.1%). A multivariate meta-regression analysis showed the trend that the prevalence varied by their geographical location. Further stratified analyses showed that NAFLD was relatively prevalent among people aged ≥45 years (16.2%; 95% CI 10.8-23.4) and those in South America (25.7%; 95% CI 24.4-27.0). The PNPLA3 rs738409 gene polymorphism was more frequently observed in non-obese NAFLD than in both obese NAFLD and non-obese controls, while the metabolic profiles of non-obese NAFLD were less severe than those of the obese NAFLD group. Patients with non-obese NAFLD had 4.81-fold and 5.43-fold higher risk of diabetes mellitus and metabolic syndrome, respectively, than the non-obese controls. Conclusions Non-obese NAFLD is common, particularly in South America and among people aged ≥45 years. Metabolic diseases and PNPLA3 rs738409 gene polymorphism are more frequent in the non-obese NAFLD group than in non-obese controls.

Background The Gut and Obesity in Asia (GOASIA) Workgroup was formed to study obesity and gastrointestinal diseases in the Asia Pacific region. We aimed to 1) compare the characteristics of elderly (i.e. age ≥ 60) vs. non-elderly patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD); 2) identify predictors of advanced fibrosis in elderly patients with NAFLD; and 3) assess the performance of non-invasive fibrosis scores in the prediction of advance fibrosis in the elderly population. Methods We abstracted the data of 1008 patients with NAFLD from nine centers across eight countries. Characteristics of elderly and non-elderly patients with NAFLD were compared using 1:3 sex-matched analysis. Results Of the 1008 patients, 175 were elderly [age 64 (62–67) years], who were matched with 525 non-elderly patients [46 (36–54) years]. Elderly patients were more likely to have advanced fibrosis (35.4% vs. 13.3%; p Conclusions Elderly patients with NAFLD had a higher prevalence of advanced fibrosis than non-elderly patients. Female and hypertension were predicting factors for advanced fibrosis in the elderly. Non-invasive fibrosis scores had a lower specificity in elderly.

The exclusion of other chronic liver diseases including “excess” alcohol intake has until now been necessary to establish a diagnosis of metabolic dysfunction-associated fatty liver disease (MAFLD). However, given our current understanding of the pathogenesis of MAFLD and its rising prevalence, “positive criteria” to diagnose the disease are required. In this work, a panel of international experts from 22 countries propose a new definition for the diagnosis of MAFLD that is both comprehensive and simple, and is independent of other liver diseases. The criteria are based on evidence of hepatic steatosis, in addition to one of the following three criteria, namely overweight/obesity, presence of type 2 diabetes mellitus, or evidence of metabolic dysregulation. We propose that disease assessment and stratification of severity should extend beyond a simple dichotomous classification to steatohepatitis vs. non-steatohepatitis. The group also suggests a set of criteria to define MAFLD-associated cirrhosis and proposes a conceptual framework to consider other causes of fatty liver disease. Finally, we bring clarity to the distinction between diagnostic criteria and inclusion criteria for research studies and clinical trials. Reaching consensus on the criteria for MAFLD will help unify the terminology (e.g. for ICD-coding), enhance the legitimacy of clinical practice and clinical trials, improve clinical care and move the clinical and scientific field of liver research forward., ME and JG are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant ( APP1053206 , APP1149976 ) and Project grants ( APP1107178 and APP1108422 ). PNN is supported by the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham .

A significant proportion of the non-alcoholic fatty liver disease (NAFLD) population is non-obese. Prior studies reporting the severity of NAFLD amongst non-obese patients were heterogenous. Our study, using data from the largest biopsy-proven NAFLD international registry within Asia, aims to characterize the demographic, metabolic and histological differences between non-obese and obese NAFLD patients.1812 biopsy-proven NAFLD patients across nine countries in Asia assessed between 2006 and 2019 were pooled into a curated clinical registry. Demographic, metabolic and histological differences between non-obese and obese NAFLD patients were evaluated. The performance of Fibrosis-4 index for liver fibrosis (FIB-4) and NAFLD fibrosis score (NFS) to identify advanced liver disease across the varying obesity subgroups was compared. A random forest analysis was performed to identify novel predictors of fibrosis and steatohepatitis in non-obese patients.One-fifth (21.6%) of NAFLD patients were non-obese. Non-obese NAFLD patients had lower proportions of NASH (50.5% vs 56.5%, p = 0.033) and advanced fibrosis (14.0% vs 18.7%, p = 0.033). Metabolic syndrome in non-obese individuals was associated with NASH (OR 1.59, 95% CI 1.01-2.54, p = 0.047) and advanced fibrosis (OR 1.88, 95% CI 0.99-3.54, p = 0.051). FIB-4 performed better than the NFS score (AUROC 81.5% vs 73.7%, p 0.001) when classifying patients with F2-4 fibrosis amongst non-obese NAFLD patients. Haemoglobin, GGT, waist circumference and cholesterol are additional variables found on random forest analysis useful for identifying non-obese NAFLD patients with advanced liver disease.A substantial proportion of non-obese NAFLD patients has NASH or advanced fibrosis. FIB-4, compared to NFS better identifies non-obese NAFLD patients with advanced liver disease. Serum GGT, cholesterol, haemoglobin and waist circumference, which are neither components of NFS nor FIB-4, are important biomarkers for advanced liver disease in non-obese patients.

Background Liver fibrosis is often accompanied by steatosis, particularly in patients with non-alcoholic fatty liver disease (NAFLD), and its non-invasive characterisation is of utmost importance. Vibration-controlled transient elastography is the non-invasive method of choice; however, recent research suggests that steatosis may influence its diagnostic performance. Controlled Attenuation Parameter (CAP) added to transient elastography enables simultaneous assessment of steatosis and fibrosis. Aim To determine how to use CAP in interpreting liver stiffness measurements. Methods This is a secondary analysis of data from an individual patient data meta-analysis on CAP. The main exclusion criteria for the current analysis were unknown aetiology, unreliable elastography measurement and data already used for the same research question. Aetiology-specific liver stiffness measurement cut-offs were determined and used to estimate positive and negative predictive values (PPV/NPV) with logistic regression as functions of CAP. Results Two thousand and fifty eight patients fulfilled the inclusion criteria (37% women, 18% NAFLD/NASH, 42% HBV, 40% HCV, 51% significant fibrosis ≥ F2). Youden optimised cut-offs were only sufficient for ruling out cirrhosis (NPV of 98%). With sensitivity and specificity-optimised cut-offs, NPV for ruling out significant fibrosis was moderate (70%) and could be improved slightly through consideration of CAP. PPV for significant fibrosis and cirrhosis were 68% and 55% respectively, despite specificity-optimised cut-offs for cirrhosis. Conclusions Liver stiffness measurement values below aetiology-specific cut-offs are very useful for ruling out cirrhosis, and to a lesser extent for ruling out significant fibrosis. In the case of the latter, Controlled Attenuation Parameter can improve interpretation slightly. Even if cut-offs are very high, liver stiffness measurements are not very reliable for ruling in fibrosis or cirrhosis.

BACKGROUND The Gut and Obesity Asia (GO ASIA) workgroup was formed to study the relationships between obesity and gastrointestinal diseases in the Asia Pacific region. AIM To study factors associated with nonalcoholic steatohepatitis (NASH) and advanced fibrosis, and medical treatment of biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients. METHODS Retrospective study of biopsy-proven NAFLD patients from centres in the GO ASIA Workgroup. Independent factors associated with NASH and with advanced fibrosis on binary logistic regression analyses in a training cohort were used for the development of their corresponding risk score, which were validated in a validation cohort. RESULTS We included 1008 patients from nine centres across eight countries (NASH 62.9%, advanced fibrosis 17.2%). Independent predictors of NASH were body mass index ≥30 kg/m2 , diabetes mellitus, dyslipidaemia, alanine aminotransferase ≥88 U/L and aspartate aminotransferase ≥38 U/L, constituting the Asia Pacific NASH risk score. A high score has a positive predictive value of 80%-83% for NASH. Independent predictors of advanced fibrosis were age ≥55 years, diabetes mellitus and platelet count

Aim To investigate micro (mi)R-34a-antagonizing circular (circ)RNA that underlies hepatocellular steatosis. Methods The effect of circRNA on miR-34a was recognized by the miRNA response element (MRE), and validated by the dual-luciferase reporter assay. Its association with hepatocellular steatosis was investigated in HepG2-based hepatocellular steatosis induced by free fatty acids (FFAs; 2:1 oleate:palmitate) stimulation. After normalization of the steatosis-related circRNA by expression vector, analysis of miR-34a activity, peroxisome proliferator-activated receptor (PPAR)α level, and expression of downstream genes were carried out so as to reveal its impact on the miR-34a/PPARα regulatory system. Both triglyceride (TG) assessment and cytopathological manifestations uncovered the role of circRNA in miR-34a-dependent hepatosteatogenesis. Results Bioinformatic and functional analysis verified circRNA_0046366 to antagonize the activity of miR-34a via MRE-based complementation. In contrast to its lowered level during FFA-induced hepatocellular steatosis, circRNA_0046366 up-regulation abolished the miR-34a-dependent inhibition of PPARα that played a critical role in metabolic signaling pathways. PPARα restoration exerted transcriptional improvement to multiple genes responsible for lipid metabolism. TG-specific lipolytic genes [carnitine palmitoyltransferase 1A (CPT1A) and solute-carrier family 27A (SLC27A)] among these showed significant increase in their expression levels. The circRNA_0046366-related rebalancing of lipid homeostasis led to dramatic reduction of TG content, and resulted in the ameliorated phenotype of hepatocellular steatosis. Conclusion Dysregulation of circRNA_0046366/miR-34a/PPARα signaling may be a novel epigenetic mechanism underlying hepatocellular steatosis. circRNA_0046366 serves as a potential target for the treatment of hepatic steatosis.

Yock Young Dan served as an advisory board member and has received research grants from AbbVie, Bristol-Myers Squibb, and Gilead Sciences. : This project was supported by a grant from the Journal of Gastroenterology and Hepatology Foundation.