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Background The optimal strategy to support primary care practitioners (PCPs) to assess fibrosis severity in nonalcoholic fatty liver disease (NAFLD) and thereby make appropriate management decisions remains unclear. Aims We aimed to examine the feasibility of using a 2-step pathway that combined simple scores (NAFLD Fibrosis Score and Fibrosis-4 Index) with transient elastography (FibroScan®) to streamline NAFLD referrals from a 'routine' primary care population to specialist hepatology management clinics (HMC). Methods The 2-step "Towards Collaborative Management of NAFLD" (TCM-NAFLD) fibrosis risk assessment pathway was implemented at two outer metropolitan primary healthcare practices in Brisbane. Patients aged ≥18 years with a new or established PCP-diagnosis of NAFLD were eligible for assessment. The pathway triaged patients at "high risk" of clinically significant fibrosis to HMC for specialist review, and "low risk" patients to receive ongoing management and longitudinal follow-up in primary care. Results A total of 162 patient assessments between Jun-2019 and Dec-2020 were included. Mean age was 58.7 ± 11.7 years, 30.9% were male, 54.3% had type 2 diabetes or impaired fasting glucose, and mean body mass index was 34.2 ± 6.9 kg/m2 . 122 patients were considered "low risk" for clinically significant fibrosis, two patients had incomplete assessments, and 38 (23.5%) were triaged to HMC. Among 31 completed HMC assessments to date, 45.2% were considered to have clinically significant (or more advanced) fibrosis, representing 9.2% of 153 completed assessments. Conclusion Implementation of the 2-step TCM-NAFLD pathway streamlined hepatology referrals for NAFLD and may facilitate a more cost-effective and targeted use of specialist hepatology resources. This article is protected by copyright. All rights reserved.

BACKGROUND In recent years, sodium-glucose co-transporter 2 inhibitors (SGLT2is) have been increasingly used in the treatment of patients with non-alcoholic fatty liver disease (NAFLD). This updated meta-analysis aimed to evaluate the efficacy and safety of SGLT2is for patients with NAFLD. METHODS PubMed, Embase, Cochrane Library, Web of Science, Wan Fang, China National Knowledge Infrastructure and VIP databases were searched for relevant studies from inception to April 30, 2021. Values of weighted mean differences (WMDs) and risk ratios (RRs) were determined for continuous and dichotomous outcomes, respectively. RESULTS A total of 1,498 patients with NAFLD from 20 studies were included for further analysis. Pooled analyses indicated significant improvements in body mass index [WMD: -0.84 kg/m2, 95% CI (-1.09, -0.60)], alanine aminotransferase [WMD: -4.36 U/L, 95% CI (-7.17, -1.54)], aspartate aminotransferase [WMD: -2.94 U/L, 95% CI (-5.33, -0.55)], fasting plasma glucose [WMD: -4.08 mmol/L, 95% CI (-6.21, -1.95)] and fibrosis-4 index [WMD: -0.08, 95% CI (-0.11, -0.05)] following SGLT2i treatment (p

Objective Owing to limited research, the effect of non-alcoholic fatty liver disease (NAFLD) on type 2 diabetes outcomes remains unclear. This study aimed to investigate the association between NAFLD and microvascular complications in hospitalized patients with type 2 diabetes. Methods We included 1982 patients with type 2 diabetes. NAFLD was defined as hepatic steatosis detected by ultrasound without secondary causes of fat accumulation. The diagnosis of diabetic retinopathy (DR), diabetic kidney disease (DKD) and diabetic neuropathy was based on clinical medical records. Risk for advanced liver fibrosis was categorized as “low risk,” “indeterminate risk,” and “high risk,” based on the NAFLD Fibrosis Score (NAFLD-FS). Logistic regression was used to test the association between NAFLD, risk for advanced fibrosis and the presence of DR, DKD, and diabetic neuropathy. Results The prevalence of NAFLD was 61.3%. The presence of DR (odds ratio [OR]: 0.749, 95% confidence interval [CI]: 0.578–0.971), and DKD (OR: 0.667, 95% CI: 0.515–0.864) was inversely associated with NAFLD, after adjusting for covariates. The presence of DR and DKD was higher in the “indeterminate risk” (DR: OR: 1.237, 95% CI: 0.730–2.096; DKD: OR: 1.009, 95% CI: 0.640–1.591, respectively) and “high risk” group (DR: OR: 1.341, 95% CI: 0.730–2.463; DKD: OR: 1.732, 95% CI: 1.021–2.940, respectively) than in the “low risk” group, after adjusting for the same covariates. Only the presence of DKD significantly increased with high NAFLD-FS (P=0.01 for trend). Conclusion The presence of DR and DKD was inversely associated with NAFLD among hospitalized patients with type 2 diabetes. DKD was closely associated with high NAFLD-FS among patients with NAFLD.

The aim of this study was to investigate whether a nutritional intervention motivating increased vegetable consumption would be an effective treatment and diet therapy for patients with non-alcoholic fatty liver disease. We examined 15 patients with this disease (5 men and 10 women). During the 6-month intervention period, all participants received a small amount of vegetables twice a month as a nutritional education tool aimed at increasing vegetable consumption. They also received nutritional counseling and underwent ultrasound and blood biochemical examinations at baseline and 3 and 6 months after initiation of the intervention. Moreover, they were requested to submit dietary records for any 2 days. Green, white, and total vegetable intakes were significantly higher at 3 and 6 months than at baseline in 8 patients. These patients had significantly lower alanine amino­transferase and triglyceride concentrations than those whose vegetable intake did not increase. Additionally, green vegetable intake significantly negatively correlated with weight at 3 and 6 months (r = −0.617, p = 0.032 and r = −0.848, p = 0.008, respectively). These results suggest that our nutritional approach effectively increased vegetable consumption in at least some patients with non-alcoholic fatty liver disease, consequently improving their condition.

Graphical abstract, Introduction Non-alcoholic fatty liver disease (NAFLD) results from increased hepatic total cholesterol (TC) and total triglyceride (TG) accumulation. In our previous study, we found that rats treated with hyperoside became resistant to hepatic lipid accumulation. Objectives The present study aims to investigate the possible mechanisms responsible for the inhibitory effects of hyperoside on the lipid accumulation in the liver tissues of the NAFLD rats. Methods Label-free proteomics and metabolomics targeting at bile acid (BA) metabolism were applied to disclose the mechanisms for hyperoside reducing hepatic lipid accumulation among the NAFLD rats. Results In response to hyperoside treatment, several proteins related to the fatty acid degradation pathway, cholesterol metabolism pathway, and bile secretion pathway were altered, including ECI1, Acnat2, ApoE, and BSEP, etc. The expression of nuclear receptors (NRs), including farnesoid X receptor (FXR) and liver X receptor α (LXRα), were increased in hyperoside-treated rats’ liver tissue, accompanied by decreased protein expression of catalyzing enzymes in the hepatic de novo lipogenesis and increased protein level of enzymes in the classical and alternative BA synthetic pathway. Liver conjugated BAs were less toxic and more hydrophilic than unconjugated BAs. The BA-targeted metabolomics suggest that hyperoside could decrease the levels of liver unconjugated BAs and increase the levels of liver conjugated BAs. Conclusions Taken together, the results suggest that hyperoside could improve the condition of NAFLD by regulating the cholesterol metabolism as well as BAs metabolism and excretion. These findings contribute to understanding the mechanisms by which hyperoside lowers the cholesterol and triglyceride in NAFLD rats.

This study aims to systematically assess the effectiveness and safety of Huazhi Rougan granule in the treatment of non-alcoholic fatty liver.The PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), WanFang databases, VIP databases, Chinese Biomedical Literature Database (SinoMed) were searched to identify the relevant randomized controlled trials, from the establishment of the database to June 7, 2020. The Cochrane risk of bias tool for assessing risk of bias was employed to evaluate the quality of the literatures included. Meta-analyses were performed using RevMan 5.3 software.A total of 23 related literature were retrieved, 9 studies with 1,142 participants were included in the meta-analysis. The overall quality of evidence for this study is low. Meta-analysis results suggest that, Huazhi Rougan granule combined with conventional treatment was significantly superior to the silybin control group in the improvement of liver B-ultrasound, reduction of serological indexes, increase of high-density lipoprotein and total clinical effective rate, which was statistically significant. The improvement of serum lipid parameters included alanine aminotransferase (ALT): [mean deviation (MD) =-10.49, 95% confidence interval (CI): -17.09, -3.90, P0.05], aspartate transaminase (AST): (MD =-9.44, 95% CI: -14.62, -4.26, P0.05), total cholesterol (TC): (MD =-0.77, 95% CI: -0.94, -0.60, P0.05), triglyceride (TG): (MD =-0.40, 95% CI: -0.56, -0.24, P0.05). Reduce low-density lipoprotein cholesterol: (MD =-0.40, 95% CI: -0.56, -0.24, P0.05). Clinical effective rate: [risk ratio (RR) =1.25, 95% CI: 1.16, 1.36, P0.05]. Occurrence of adverse reactions: Of the 9 studies included, 5 reported adverse reactions, of which 3 reported no drug-related adverse reactions. Adverse reactions were reported in 2 cases, all of which were mild adverse reactions.The clinical efficacy of Huazhi Rougan granule combined with conventional basic therapy in the treatment of non-alcoholic fatty liver may be better than that of conventional basic therapy combined with silybin, which may improve the B-ultrasonic grading effect of the liver and reduce the serum lipid parameters of the patients. it may improve the clinical symptoms of non-alcoholic fatty liver, and the incidence of adverse reactions is low, but the number of existing clinical studies is small and the quality is low, in order to further verify the above conclusions. More high-quality clinical RCT trials need to be carried out, and internationally recognized outcome indicators should be selected and uniformly included in the scoring criteria.

Cassiae Semen (CS), the seeds of Cassia obtusifolia L. and C. tora L, have a long medicinal history in China, with suggestions for it to relieve constipation and exert hepatoprotective effects. However, the underlying mechanisms are still unclear. In this study, mice with high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) were used to study the hepatoprotective effects of CS. The relationship between gut microbiota and hepatoprotective effect mechanisms mediated by CS extracts, the total aglycone extracts of CS, rubrofusarin-6-β-gentiobioside, and aurantio-obtusin were examined. Our data indicate that CS extracts and components confer a protective effect by ameliorating lipid accumulation, intestinal barrier damage, liver damage, and inflammation on HFD-induced liver injury. Meanwhile, fecal microbe transplantation exerted the pharmacological effect of CS on HFD-fed mice; however, the efficacy of CS was inhibited or eliminated by antibiotic-induced dysbiosis. In conclusion, the therapeutic effects of CS on NAFLD were closely related to the gut microbiota, suggesting a role for TCM in treating disease., Luo, Wu, et al. assess the ability of Cassiae Semen and its extracted components to alleviate non-alcoholic fatty liver disease (NAFLD) in mice. In addition to reducing the symptoms of NAFLD, the authors find that Cassiae Semen modifies the gut microbiome of mice, and that its effects on the symptoms of NAFLD can also be conferred by fecal microbiome transfer.

Many studies have associated altered intestinal bacterial communities and non-alcoholic fatty liver disease, but the putative effects are inconclusive. The purpose of this network meta-analysis (NMA) was to evaluate the effects of probiotics, prebiotics, and synbiotics on non-alcoholic fatty liver disease through randomised intervention trials. Literature searches were performed until March 2020. For each outcome, a random NMA was performed, the surface under the cumulative ranking curve (SUCRA) was determined. A total of 22 randomised trials comparing prebiotic, probiotic, and synbiotic treatments included 1301 participants. Considering all seven results (aspartate aminotransferase, alanine aminotransferase, body mass index, weight, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol) together, the highest SUCRA values are probiotics (94%), synbiotics (61%) and prebiotics (56%), respectively. NMA results provide evidence that probiotics, prebiotics, and synbiotics can alleviate non-alcoholic fatty liver disease. However, due to the lack of high-quality randomised trials, this research also has some limitations.

This study aims to evaluate the effect of non‐alcoholic fatty liver disease (NAFLD) on the susceptibility and consequences of coronavirus disease 2019 (COVID‐19). We retrospectively collected data from 218 adult COVID‐19 patients who showed no evidence of excessive alcohol consumption and underwent abdominal ultrasound examinations. Of these patients, 39.4% patients had been diagnosed with NAFLD, which indicates a much higher prevalence of NAFLD than that reported in the general population. Significantly elevated white blood cell count (p = 0.008), alanine aminotransferase (p = 0.000), aspartate aminotransferase (p = 0.006) and C reactive protein (p = 0.012) were found in the patients with NAFLD. These patients also had significantly higher proportions of hypertension (p = 0.006) and diabetes (p = 0.049) than the non‐NAFLD cases. No significant differences existed in the severity, mortality, viral shedding time and length of hospital stay between patients with or without NAFLD in the sample population. However, subgroup analyses found that in patients with normal body mass index (BMI), NAFLD sufferers were more likely to experience a severe event (30.0% vs 11.5%, p = 0.021). Kaplan‐Meier curve (log‐rank p = 0.017) and Cox regression (HR = 3.26, 95% CI: 1.17–9.04, p = 0.023) analyses confirmed that before and after adjusting for gender, age and comorbidities, NAFLD patients with normal BMI had a higher incidence of suffering severe events. People with NAFLD may have a higher proportion of COVID‐19. NAFLD may be correlated with the severity of COVID‐19 patients in the normal BMI group.

Aim The aim of the study was to explore the experiences of self‐management in patients with non‐alcoholic fatty liver disease (NAFLD). Design The study employed an exploratory descriptive qualitative study using focus group interviews. Methods Twelve participants with NAFLD were recruited from a university hospital in South Korea. The date of data collection was from November–December 2018, and the data were analysed using Braun and Clarke's thematic analysis. Results Three themes and seven subthemes were identified. The themes were (1) facing unexpected obstacles, (2) finding my own path and (3) unmet support needs from healthcare providers. Subthemes included (1) ambiguity in changing lifestyle, (2) confusion caused by inconsistent information overload, (3) not knowing much about the liver nor NAFLD, (4) putting small plans into action every day, (5) getting help from family and friends as care partners, (6) needs for tailored medical help and (7) needs for caring and attentive attitudes.

Non-alcoholic fatty liver disease is a chronic metabolic disorder representing the most common cause of chronic liver disease in western civilization and one of the main causes of cirrhosis with a significant impact on all-cause mortality in the most advanced phases. It is characterized by hepatic fat accumulation in the absence of significant ethanol consumption, virus infection or other specific causes of liver disease. Accumulation of fat in liver tissue occurs as a consequence of the imbalance between overconsumption of high-fat diet and increased de novo lipogenesis and decreased lipid disposal. Novel dietary and pharmacological therapies for the prevention of fatty liver disease and the progression to cirrhosis are an actual field of study but still poorly understood. In this perspective, the current review aims to summarise and clarify the transcription factor NFκB effects, which may exert among non-alcoholic fatty liver diseases and their progression. Through extensive previous research, it has become clear that several signaling pathways are involved: metabolic dysregulation (such as free fatty acids increase, adipokine alteration, insulin resistance), oxidative stress and inflammation contribute together in a “vicious circle” to the pathogenesis of non-alcoholic fatty liver diseases. Within this, NFκB signaling is a primary factor in inflammatory reactions and diseases, with important molecular connections between metabolic, oxidative, immune and inflammation systems.

The review contains updated information on the epidemiology, etiology, pathogenesis, diagnosis, treatment and prevention of non-alcoholic fatty liver disease (NAFLD). We searched for terms including NAFLD, non-alcoholic steatohepatitis (NASH), metabolic syndrome and type 2 diabetes mellitus in literature published over the past 5 years using the Scopus, Web of Science, CyberLeninka, PubMed databases. The concept of NAFLD includes two morphological forms of the disease with different prognosis: non-alcoholic fatty hepatosis and NASH. The severity of NASH is quite variable, including fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD, a spectrum of fatty liver disorders of viral, autoimmune, drug-induced, and genetic origin, which are not caused by alcohol abuse, has recently been renamed as metabolic (dysfunction) associated fatty liver disease (MAFLD). The average prevalence of NAFLD is approximately 25 % among the adult population worldwide, and in some regions exceeds 30 %. An increase in the prevalence of this pathology is in parallel with the global epidemic of obesity and type 2 diabetes mellitus in the world. It is time to reach a general consensus in the scientific community on changing the nomenclature and moving from a negative to a positive definition of NAFLD/NASH. The new nomenclature points to the “positive” determinants of the disease, namely the close relationship with metabolic disorders, instead of defining it as what it is not (ie. non-alcoholic). The MAFLD abbreviation more accurately discloses existing knowledge about fatty liver diseases associated with metabolic dysfunction and should replace NAFLD/NASH, as this will stimulate the research community’s efforts to update the disease nomenclature and subphenotype and accelerate the transition to new treatments. It is important that primary care physicians, endocrinologists, and other specialists are aware of the extent and long-term consequences of NAFLD. Early identification of patients with NASH can help improve treatment outcomes, avoid liver transplantation in patients with decompensated cirrhosis. There are currently no effective treatments for NAFLD, so it is important to follow a multidisciplinary approach, which means using measures to improve prognosis, reduce the risk of death associated with NAFLD, the development of cirrhosis or hepatocellular carcinoma. Epidemiological data suggest a close relationship between unhealthy lifestyles and NAFLD, so lifestyle adjustments are needed to all patients. Insulin sensitizers, statins, ezetimibe, a cholesterol absorption inhibitor, hepatoprotectors, antioxidants, incretin analogues, dipeptidyl peptidase 4 inhibitors, pentoxifylline, probiotics, angiotensin-converting enzyme inhibitors, and endocannabinoid antagonists are used in the treatment of NAFLD.

Summary Background & Aims Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in children and one of the leading indications for liver transplantation in adults. However, current screening methods are inadequate and are accompanied by several disadvantages. This meta-analysis aims to identify the anthropometrical and biochemical characteristics most commonly appearing in pediatric NAFLD that could contribute to the diagnosis of the disease in the every-day clinical setting. Methods A systematic search was conducted in major electronic databases (MEDLINE, Scopus and Embase) up to 15th of August 2021. Primary outcome was the comparison of the anthropometric characteristics, whereas secondary outcomes were the comparisons of biochemical profile, lipid profile, and metabolic parameters in children with NAFLD compared with age-matched healthy controls. Quality assessment was performed with Newcastle-Ottawa Scale (NOS) and results were expressed as mean differences with 95% confidence intervals. Results Sixty-four studies were included. Two different comparisons were designed regarding the body mass status. Statistically significant differences were demonstrated by comparing children with NAFLD vs lean/normal weighted controls in body weight (23.0 kg, 95% CI: 14.0-31.8, P Conclusions Anthropometrical and biochemical characteristics of children and adolescents with NAFLD are statistically significantly different compared to age-matched controls; these characteristics could be used to identify individuals at risk of developing NAFLD and related comorbidities.

Background: The prevalence of non-alcoholic fatty liver disease (NAFLD) has rapidly increased worldwide. The aim of this study was to investigate whether there is an independent relationship between regional fat distribution, especially leg fat mass, and the presence of NAFLD using nationally representative data in Korea.Methods: This cross-sectional study analyzed data from 14,502 participants in the Korea National Health and Nutrition Examination Survey 2008 to 2011. Total fat mass, leg fat mass, and appendicular skeletal muscle mass were measured by dual-energy X-ray absorptiometry. Validated NAFLD prediction models and scoring systems for hepatic fibrosis were used.Results: The leg fat to total fat (LF/TF) ratio showed a negative relationship with many factors, including body mass index, waist circumference, blood pressure, fasting blood glucose, and liver enzyme levels. When the LF/TF ratio and indices of hepatic steatosis were stratified by quartiles, the LF/TF ratio showed a negative correlation with the scoring systems that were used. The LF/TF ratio showed better accuracy in predicting NAFLD than total fat mass or leg fat mass alone. After adjusting for various traditional and lifestyle factors, a low LF/TF ratio remained a risk factor for NAFLD. Among NAFLD subjects, the LF/TF ratio showed a negative relationship with hepatic fibrosis.Conclusion: A lower LF/TF ratio was markedly associated with a higher risk of hepatic steatosis and advanced hepatic fibrosis using various predictive models in a Korean population. Therefore, the LF/TF ratio could be a useful anthropometric parameter to predict NAFLD or advanced hepatic fibrosis.

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease globally and is estimated to affect approximately 25% of the world's population. Data about the prevalence and incidence of NAFLD in Africa are scarce, but the prevalence is estimated to be 13·5% for the general population. This is likely to be an underestimate considering the increasing burden of non-communicable diseases, particularly the rising prevalence of obesity and type 2 diabetes, driven by the overlapping challenges of food insecurity, nutritional transition, and associated increased consumption of calorie-dense foods. Establishing the true prevalence of NAFLD, raising public awareness around the risk factors behind the increase in NAFLD, and proactively addressing all components of metabolic syndrome will be important to combat this silent epidemic, which will have long-term health-care costs and economic consequences for the region.

Background Non-alcoholic fatty liver disease (NAFLD) is a frequently occurring clinical disease, which could be treated by traditional Chinese medicine. However, the effects and mechanisms of xiao-zhi-fang (XZF) alone or in combination with fructooligosaccharides (FOS) on NAFLD remains unclear. Methods This study established the NAFLD mouse model by feeding with a high-fat diet and by administering with XZF and/or FOS. Moreover, the fat content in the liver tissues was evaluated by oil red O and hematoxylin and eosin staining, and the liver function indices were examined using a biochemical analyzer. Changes in the intestinal flora were monitored using 16S rRNA gene sequencing. The results of the current study showed that the alanine aminotransferase, aspartate aminotransferase, total triglyceride, total cholesterol levels, and the amount of lipid accumulation were markedly elevated in NAFLD mice. Results XZF alone or in combination with FOS significantly reduced lipid accumulation in the liver and blood lipid levels in NAFLD mice. Moreover, XZF alone or in combination with FOS notably altered the intestinal flora structure in NAFLD mice. Consequently, 17 operational taxonomic units were decreased and nine were increased in the XZF and/or FOS groups. Conclusions FOS may accelerate the intestinal microecological balance in NAFLD mice after treatment with XZF by promoting intestinal flora growth, thereby enhancing the therapeutic effect of XZF on NAFLD.

The prevalence of non-obese nonalcoholic fatty liver disease (NAFLD) is increasing worldwide with unclear etiology and pathogenesis. Here, we show GP73, a Golgi protein upregulated in livers from patients with a variety of liver diseases, exhibits Rab GTPase-activating protein (GAP) activity regulating ApoB export. Upon regular-diet feeding, liver-GP73-high mice display non-obese NAFLD phenotype, characterized by reduced body weight, intrahepatic lipid accumulation, and gradual insulin resistance development, none of which can be recapitulated in liver-GAP inactive GP73-high mice. Common and specific gene expression signatures associated with GP73-induced non-obese NAFLD and high-fat diet (HFD)-induced obese NAFLD are revealed. Notably, metformin inactivates the GAP activity of GP73 and alleviates GP73-induced non-obese NAFLD. GP73 is pathologically elevated in NAFLD individuals without obesity, and GP73 blockade improves whole-body metabolism in non-obese NAFLD mouse model. These findings reveal a pathophysiological role of GP73 in triggering non-obese NAFLD and may offer an opportunity for clinical intervention., Dysregulation of lipid metabolism and transport contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here the authors identify GP73 as a TBC-domain Rab GTPase-activating protein that regulates very low-density lipoprotein export and promotes NAFLD development in mice.

Sub-Saharan Africa, which has a population of more than 1 billion people, carries 24% of the global burden of disease and spends the least on health care of any region, relying heavily on international development assistance to deliver health care for HIV, tuberculosis, and malaria. The demographic and epidemiological transitions occurring in sub-Saharan Africa, with rising prevalences of obesity and diabetes, enhance the risk of non-alcoholic fatty liver disease (NAFLD), yet this remains an unrecognised complication of metabolic syndrome. There are no guidance documents on NAFLD from sub-Saharan Africa, and non-communicable disease (NCD) guidance documents do not include the associated burden of fatty liver disease. Combating the health and socioeconomic burden of NAFLD requires an integrated liver health approach, with task-shifting to primary health care. Using clear guidance documents to link education and management of HIV, viral hepatitis, NAFLD, and associated NCDs is also crucial to an integrated approach to infectious diseases and NCDs, which requires targeted funding from both governments and international development agencies.

With the rising incidence of both obesity and diabetes, non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. However, lifestyle intervention remains to be an effective approach for NAFLD due to lack of therapeutic medication. Recently, salt, an essential micronutrient free of calories, has raised a global concern owing to its wide-range healthy relevance. Accumulated evidence has suggested that a long-term high-salt diet (HSD) independently increases the risk of NAFLD. In the past decades, a number of studies have been reported regarding the mechanism of much investigation concerning HSD-induced NAFLD. Here, we review the updates in epidemiology and molecular mechanism of HSD-induced NAFLD and provide a novel insight into the role of HSD in the regulation of lipid metabolism.

Non-alcoholic fatty liver disease (NAFLD) is currently considered the most common cause of liver disease. Its prevalence is increasing in parallel with the obesity and type 2 diabetes mellitus (DM2) epidemics in developed countries. Several recent studies have suggested that NAFLD may be the hepatic manifestation of a systemic inflammatory metabolic disease that also affects other organs, such as intestine, lungs, skin and vascular endothelium. It appears that local and systemic proinflammatory/anti-inflammatory cytokine imbalance, together with insulin resistance and changes in the intestinal microbiota, are pathogenic mechanisms shared by NAFLD and other comorbidities. NAFLD is more common in patients with extrahepatic diseases such as inflammatory bowel disease (IBD), obstructive syndrome apnea (OSA) and psoriasis than in the general population. Furthermore, there is evidence that this association has a negative impact on the severity of liver lesions. Specific risk characteristics for NAFLD have been identified in populations with IBD (i.e. age, obesity, DM2, previous bowel surgery, IBD evolution time, methotrexate treatment), OSA (i.e. obesity, DM2, OSA severity, increased transaminases) and psoriasis (i.e. age, metabolic factors, severe psoriasis, arthropathy, elevated transaminases, methotrexate treatment). These specific phenotypes might be used by gastroenterologists, pneumologists and dermatologists to create screening algorithms for NAFLD. Such algorithms should include non-invasive markers of fibrosis used in NAFLD to select subjects for referral to the hepatologist. Prospective, controlled studies in NAFLD patients with extrahepatic comorbidities are required to demonstrate a causal relationship and also that appropriate multidisciplinary management improves these patients’ prognosis and survival.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Therapeutic activity of icariin, a major bioactive component of Epimedii Herba, in NAFLD is still unknown. Herein, the C57BL/6J mice were fed with a high-fat diet for 16 weeks to establish a NAFLD model. Mice were assigned to five groups: control group, NAFLD group, and icariin treatment groups. Effects of icariin on blood indices, glucose tolerance, insulin sensitivity, histopathological morphology, cell apoptosis, lipid accumulation, and AMPK signaling were analyzed. In addition, another cohort of mice were assigned to five groups: control group, NAFLD group, dorsomorphin treatment group, icariin treatment group, and dorsomorphin + icariin treatment group. Expression of proteins in liver tissues associated with AMPK signaling, and levels of ALT and AST were evaluated. Icariin attenuated the NAFLD-induced increase of the TG, TC, LDL-C, ALT, AST levels. HDL-C levels were affected neither by NAFLD nor by icariin. Furthermore, icariin treatment (100-200 mg/kg) counteracted the NAFLD-reduced glucose tolerance and insulin sensitivity and modulated histopathological changes, cell apoptosis, and lipid accumulation in liver tissues. Additionally, icariin mitigated the NAFLD-induced up-regulation of the cleaved caspase 3/9, SREBP-1c, and DGAT-2 levels, and enhanced the expression level of CPT-1, p-ACC/ACC, AMPKα1, PGC-1α, and GLUT4. Effects of icariin on the AMPK signaling and levels of AST and ALT could be reversed by AMPK inhibitor, dorsomorphin. This paper investigates the glucose-reducing and lipid-lowering effects of icariin in NAFLD. Moreover, icariin might function through activating the AMPKα1/PGC-1α/GLTU4 pathway.

Summary Background AMP kinase (AMPK) is an energy sensor implicated in regulation of lipid metabolism, inflammation, and insulin sensitivity. We aimed to assess efficacy and safety of PXL770, a novel direct AMPK activator, in patients with non-alcoholic fatty liver disease (NAFLD). Methods STAMP-NAFLD, a randomised, double-blind, placebo-controlled phase 2a study, was done across 15 US clinical sites. Patients aged 18–75 years with liver fat content of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned (1:1:1:1), via an interactive web response system, to receive oral PXL770 250 mg once daily, 250 mg twice daily, or 500 mg once daily, or matched placebo. Patients were stratified according to type 2 diabetes status and study site. The primary endpoint was relative change in liver fat content from baseline compared with placebo at week 12, assessed by MRI-PDFF. The primary endpoint was analysed in an ANCOVA model with treatment and stratification criteria as factors and baseline liver fat content as a covariate in the modified intention-to-treat population, defined as all as-randomised patients who received at least one dose of study treatment. Safety was analysed in the safety population, defined as all as-treated patients receiving at least one dose of the study treatment. The trial has been completed and the final results are reported. The trial is registered with ClinicalTrials.gov , NCT03763877 . Findings Between March 29, 2019, and March 13, 2020, 387 patients were screened, of whom 120 were included in the modified intention-to-treat and safety analyses (30 in the 250 mg once daily group, 30 in the 250 mg twice daily group, 29 in the 500 mg once daily group, and 31 in the placebo group). The mean relative change from baseline in liver fat content at week 12 was −1·1% in the placebo group, −1·0% in the 250 mg once daily group (mean difference versus placebo 0·1% [95% CI −15·4 to 15·7], p=0·99), −14·3% in the 250 mg twice daily group (−13·1% [–28·1 to 1·8], p=0·084), and −14·7% in the 500 mg once daily group (−13·5% [–28·5 to 1·4], p=0·076). At least one treatment-emergent adverse event occurred in 23 (77%) of 30 patients in the 250 mg once daily group, 20 (67%) of 30 patients in the 250 mg twice daily group, 21 (72%) of 29 patients in the 500 mg once daily group, and 21 (68%) of 31 patients in the placebo group. The most common treatment-emergent adverse event was diarrhoea (five [17%] of patients in the 250 mg once daily group, seven [23%] in the 250 mg twice daily group, six [21%] in the 500 mg once daily group, and none in the placebo group). No life-threatening events or treatment-related deaths occurred. Interpretation PXL770 treatment did not meet the primary outcome of liver fat improvement compared with placebo. Treatment was well tolerated. Given indications that metabolic features improved with PXL770 treatment, AMPK activation might be a promising pharmacological target for patients with type 2 diabetes and NAFLD, and could also be considered for further assessment in patients with non-alcoholic steatohepatitis. Funding Poxel.

Summary Background Studies have reported a significant association between non-alcoholic fatty liver disease (NAFLD) and increased incidence of cardiovascular disease (CVD). However, the magnitude of the risk and whether this risk changes with the severity of NAFLD remains uncertain. We performed a meta-analysis of observational studies to quantify the magnitude of the association between NAFLD and risk of incident CVD events. Methods We systematically searched PubMed, Scopus, and Web of Science from database inception to July 1, 2021, to identify eligible observational studies examining the risk of incident CVD events amongst adult (age ≥18 years) individuals with and without NAFLD and in which NAFLD was diagnosed by imaging, International Classification of Diseases codes, or liver biopsy. The primary outcomes were CVD death, non-fatal CVD events, or both. Data from selected studies were extracted, and meta-analysis was performed using random-effects models to obtain summary hazard ratios (HRs) with 95% CIs. The quality of the evidence was assessed with the Cochrane risk of bias tool. This study is registered on Open Science Framework, number osf.io/5z7gf. Findings We identified 36 longitudinal studies with aggregate data on 5 802 226 middle-aged individuals (mean age 53 years [SD 7]) and 99 668 incident cases of fatal and non-fatal CVD events over a median follow-up of 6·5 years (IQR 5·0–10·2). NAFLD was associated with a moderately increased risk of fatal or non-fatal CVD events (pooled random-effects HR 1·45, 95% CI 1·31–1·61; I2=86·18%). This risk markedly increased across the severity of NAFLD, especially the stage of fibrosis (pooled random-effects HR 2·50, 95% CI 1·68–3·72; I2=73·84%). All risks were independent of age, sex, adiposity measures, diabetes, and other common cardiometabolic risk factors. Sensitivity analyses did not modify these results. Interpretation NAFLD is associated with an increased long-term risk of fatal or non-fatal CVD events. CVD risk is further increased with more advanced liver disease, especially with higher fibrosis stage. These results provide evidence that NAFLD might be an independent risk factor for CVD morbidity and mortality. Funding None.

Background Previous studies have revealed obesity, nutrition, lifestyle, genetic and epigenetic factors may be risk factors for the occurrence and development of non-alcoholic fatty liver disease (NAFLD). However, the effect of total polyunsaturated fatty acid (PUFA) consumption on the risk of NAFLD is uncertain. Therefore, this study aimed to determine whether the total PUFA intake is independently associated with the risk of NAFLD and explore the threshold of PUFA intake better illustrate the correlation between them in Chinese Han adults. Methods The present study was a retrospective case–control study. A total of 534 NAFLD patients and 534 controls matched by gender and age in the same center were included in this study. Using a semi-quantitative food frequency questionnaire in a health examination center in China to collect information about dietary intake and calculate nutrient consumption. A multivariate logistic regression model was used to estimate the association between total PUFA daily intake and its quartile and the incidence of NAFLD. Results Multivariate analyses suggested a significant association between total PUFA intake and the occurrence of NAFLD. A non-linear relationship between total PUFA consumption and NAFLD risk was detected after adjusting for potential confounding factors. There was a significant connection between PUFA and the risk of NAFLD (OR: 1.32, 95% CI: 1.23–1.41, P Conclusions The relationship between total PUFA intake and NAFLD is non-linear. Total PUFA was positively related to the risk of NAFLD when PUFA intake is between 18.8 and 29.3 g/day among Chinese Han adults.

Non‐alcoholic fatty liver disease (NAFLD) is an increasingly prevalent and potentially severe liver disease, emphasizing the need for implementation of widely supported care paths for patients at risk for advanced stages of NAFLD. In particular, the distinction of patients with a progressive and/or advanced, fibrotic NAFLD from those with simple steatosis requires improvement, as well as the awareness for NAFLD among health care professionals. Broad acceptance and implementation of interdisciplinary care paths in the near future will bring enhanced identification of those patients that benefit from surveillance, intensive lifestyle management, and empirical or investigational pharmacotherapy and enhance our epidemiological grasp of NAFLD in relation to lifestyle, genetic background, and cardiometabolic comorbidities related to NAFLD.

OBJECTIVE Abdominal obesity is strongly associated with the development of non-alcoholic fatty liver disease (NAFLD). Early identification and intervention may reduce the risk. We aim to improve pediatric NAFLD screening by comparing discriminative performance of six abdominal obesity indicators. METHODS We measured anthropometric indicators (waist circumference [WC], waist-to-hip ratio [WHR], waist-to-height ratio [WHtR]), body composition indicators (trunk fat index [TFI], visceral fat area [VFA]), and endocrine indicator (visceral adiposity index [VAI]) among 1350 Chinese children aged 6-8 years. Using Spearman correlation, receiver operating characteristic (ROC) curves, and Logistic regression, we validated their ability to predict NAFLD. RESULTS All six indicators can predict NAFLD robustly, with area under the curve (AUC) values ranged from 0.69 to 0.96. TFI, WC, and VFA rank in the top three for the discriminative performance. TFI was the best predictor with AUC values of 0.94 (0.92-0.97) and 0.96 (0.92-0.99), corresponding to cut-off values of 1.83 and 2.31 kg/m2 for boys and girls, respectively. Boys with higher TFI (aOR = 13.8), VFA (aOR = 11.1), WHtR (aOR = 3.1), or VAI (aOR = 2.8), and girls with higher TFI (aOR = 21.0) or VFA (aOR = 17.5), were more likely to have NAFLD. CONCLUSION User-friendly body composition indicators like TFI can identify NAFLD and help prevent the progress of liver disease. TRIAL REGISTRATION Chinese Clinical Trial Registry (ChiCTR) ( www.chictr.org.cn/enIndex.aspx , No. ChiCTR2100044027); retrospectively registered on 6 March 2021. IMPACT Abdominal obesity increases the risk of pediatric non-alcoholic fatty liver disease (NAFLD). This study compared the discriminative performance of multiple abdominal obesity indicators measured by different methods in terms of accuracy and fastidious cut-off values through a population-based child cohort. Our results provided solid evidence of abdominal obesity indicators as an optimal screening tool for pediatric NAFLD, with area under the curve (AUC) values ranged from 0.69 to 0.96. User-friendly body composition indicators like TFI show a greater application potential in helping physicians perform easy, reliable, and interpretable weight management to prevent the progress of liver damage.

Aim This study assessed the diagnostic performance of liver stiffness measurement (LSM) in detecting liver fibrosis in paediatric patients with non-alcoholic fatty liver disease (NAFLD) through meta-analysis. Methods Online database searches of PubMed, EMBASE, the Cochrane Library and the Web of Science were conducted for studies that evaluated the performance of LSM for diagnosing liver fibrosis in paediatric patients with NAFLD until 1 January 2021. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to assess the quality of the included studies. Three measures were used to assess the performance of LSM for detecting liver fibrosis in paediatric patients with NAFLD, including the summary sensitivities and specificities, the summary area under the receiver operating characteristic curves and the summary diagnostic odds ratios. Results Our final data included seven studies with a total of 436 paediatric patients with NAFLD for meta-analysis. The overall prevalence of mild fibrosis, significant fibrosis, advanced fibrosis and cirrhosis was 66.3, 31.5, 14.9 and 1.2%, respectively. The summary sensitivity, specificity and area under the receiver operating characteristic values of LSM were 80, 92 and 0.94 for the prediction of mild fibrosis; 91, 97 and 0.98 for the prediction of significant fibrosis; and 89, 93 and 0.96 for the prediction of advanced fibrosis, respectively. Conclusion Liver stiffness measurement exhibited good diagnostic performance in predicting liver fibrosis and can be used as a non-invasive tool in the management of paediatric patients with non-alcoholic fatty liver disease.

Background & Aims Non-alcoholic fatty liver disease (NAFLD), the hepatic correlate of the metabolic syndrome, is a major risk factor for hepatobiliary cancer (HBC). Although chronic inflammation is thought to be the root cause of all these diseases, the mechanism whereby it promotes HBC in NAFLD remains poorly understood. Herein, we aim to evaluate the hypothesis that inflammation-related dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes HB carcinogenesis. Methods We use murine NAFLD models, liver biopsies from patients with NAFLD, human liver cancer registry data, and studies in liver cancer cell lines. Results Our results confirm the hypothesis that inflammation-related dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes HB carcinogenesis, supporting a model whereby chronic inflammation suppresses hepatocyte expression of ESRP2, an RNA splicing factor that directly targets and activates NF2, a tumor suppressor that is necessary to constrain YAP/TAZ activation. The resultant loss of NF2 function permits sustained YAP/TAZ activity that drives hepatocyte proliferation and de-differentiation. Conclusion Herein, we report on a novel mechanism by which chronic inflammation leads to sustained activation of YAP/TAZ activity; this imposes a selection pressure that favors liver cells with mutations enabling survival during chronic oncogenic stress. Lay summary Non-alcoholic fatty liver disease (NAFLD) increases the risk of hepatobiliary carcinogenesis. However, the underlying mechanism remains unknown. Our study demonstrates that chronic inflammation suppresses hepatocyte expression of ESRP2, an adult RNA splicing factor that activates NF2. Thus, inactive (fetal) NF2 loses the ability to activate Hippo kinases, leading to the increased activity of downstream YAP/TAZ and promoting hepatobiliary carcinogenesis in chronically injured livers.

Telomere length has been linked to the prevalence and progression of metabolic disease. However, clinical implications of telomere length in biopsy-proven non-alcoholic fatty liver disease (NAFLD) patients remain unclear. Therefore, this study aimed to investigate the association of telomere length with the histological severity of NAFLD. The cross-sectional data derived from the prospectively enrolled Boramae NAFLD registry (n = 91) were analyzed. The liver tissues and clinical information were obtained from both NAFLD patients and non-NAFLD subjects. Binary logistic regression was performed to identify the independent association between telomere length and the histological severity of NAFLD. A total of 83 subjects with or without biopsy-proven NAFLD were included for analysis: non-NAFLD in 23 (27.7%), non-alcoholic fatty liver in 15 (18.1%), and non-alcoholic steatohepatitis (NASH) in 45 (54.2%). Telomere length measured from liver tissues showed a strong negative correlation (p p p = 0.019) and high-density lipoprotein cholesterol (OR 0.94; 95% CI 0.80–0.99; p = 0.039) were independently associated with significant fibrosis. The age-adjusted telomere length tends to decrease along with the fibrosis stage of NAFLD. In particular, among the histological components of NAFLD, fibrosis severity seems to be related to telomere length in the liver.

Background and Aim High levels of physical activity and cardiorespiratory fitness may protect against non-alcoholic fatty liver disease. We investigated whether different physical activity intensities and cardiorespiratory fitness were independent predictors of non-alcoholic fatty liver disease. Methods We included healthy adults with no prior diagnosis of liver dysfunction. Non-alcoholic fatty liver disease prevalence was estimated based on fatty liver index scores. We created tertiles of self-reported low, moderate, and vigorous physical activity. Participants completed an incremental treadmill test to estimate cardiorespiratory fitness, and data were subsequently separated into quintile groups (Q1 [least fit] through Q5 [most fit]). Results Non-alcoholic fatty liver disease prevalence in our sample of 7111 adults was 28.3% in male adults and 6.5% in female adults. Logistic regression showed the relative odds of non-alcoholic fatty liver disease were 42% lower if > 60 min/week of vigorous physical activity was maintained (odds ratio [OR] = 0.58, confidence interval [CI]: 0.49–0.68). There was a negative dose–response association between cardiorespiratory fitness and non-alcoholic fatty liver disease between Q1 and Q4. Compared with Q1, odds were 39% (OR = 0.61, CI: 0.51–0.73) lower in Q2, through to 51% lower in Q5 (OR = 0.49, CI: 0.41–0.60). Moderate physical activity did not reduce the odds of non-alcoholic liver disease. Conclusions We found the lowest prevalence of non-alcoholic fatty liver disease in adults achieving > 60 min/week of vigorous physical activity. However, a stronger dose–response relationship existed between cardiorespiratory fitness and non-alcoholic fatty liver disease. Improving cardiorespiratory fitness as a potential therapeutic target for treatment and prevention of non-alcoholic fatty liver disease warrants further investigation.

Background Sarcopenia is an independent risk factor not only for advanced‐stage non‐alcoholic fatty liver disease (NAFLD) but also for mortality. We investigated the association of sarcopenia and/or NAFLD with mortality among the Korean general population. Methods Individuals aged 35–75 years without any history of cancer, ischaemic heart disease, ischaemic stroke, or secondary causes of chronic liver disease were selected from the Korean National Health and Nutrition Examination Surveys from 2008 to 2015. Their mortality data until December 2018 were retrieved from the National Death Registry. NAFLD and sarcopenia were defined by hepatic steatosis index and appendicular skeletal muscle mass divided by body mass index (BMI), respectively. Results A total of 28 060 subjects were analysed [mean age, 50.6 (standard error, 0.1) years, 48.2 (0.3) % men]; the median follow‐up duration was of 6.8 (interquartile range, 4.8, 8.4) years. NAFLD predicted mortality after adjustment for age, sex, BMI, hypertension, dyslipidaemia, and smoking (HR 1.32, 95% CI 1.03–1.70), but this prediction lost its statistical significance after additional adjustment for diabetes mellitus. In contrast, NAFLD with advanced fibrosis independently increased the risk of mortality after adjustment for all covariates (HR 1.68, 95% CI 1.02–2.79). Stratified analysis revealed that NAFLD and sarcopenia additively increased the risk of mortality as an ordinal scale (HR 1.46, 95% CI 1.18–1.81, P for trend = 0.001). The coexistence of NAFLD and sarcopenia increased the risk of mortality by almost twice as much, even after adjustment for advanced fibrosis (HR 2.18, 95% CI 1.38–3.44). Conclusions Concurrent NAFLD and sarcopenia conferred a two‐fold higher risk of mortality. The observation that NAFLD and sarcopenia additively increase mortality suggests that risk stratification would be helpful in predicting mortality among those with metabolic derangement.

Background Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition associated with aging, insulin resistance, metabolic syndrome, genetic factors and more. Although genetic traits are among the most important risks factors for NAFLD, the understanding of their influence is still quite limited. The present study aimed at identifying novel single nucleotide polymorphisms (SNPs) that may confer a risk for NAFLD in the Han Chinese population. Methods Based on the “two-hit hypothesis”, candidate SNPs, including Sirtuin3 rs28365927, were genotyped by MassARRAY in B-type ultrasonography-proven NAFLD patients (n = 292) and healthy controls (n = 387). Results In a model analysis of individuals matched based on gender and age that compared 223 NAFLD and 223 non-NAFLD patients, the rs28365927 GA + AA genotype was a significant risk factor for the development of NAFLD in a dominant model. Rs28365927 was significantly associated with a higher NAFLD risk in both an additive model (A vs G) and genotypic model (GA vs GG). Among the NAFLD patients, serum levels of total bilirubin (TBIL), DBIL direct bilirubin (DBIL) and glutamic-pyruvic transaminase (ALT) in rs28365927 A allele carriers (GA + AA) were 11.1, 14.7 and 41.5% higher, respectively, than in non-carriers (GG). Furthermore, among the NAFLD patients, the carriers of Rs28365927 allele A were positively correlated with higher ALT levels. Conclusion Sirtuin3 rs28365927 functional variant confers to the high risk of non-alcoholic fatty liver disease in Chinese Han population. The rs28365927 A allele significantly increased the ALT levels of NAFLD patients.

Summary Background & aims The prevention and treatment of non-alcoholic fatty liver disease (NAFLD) has become one of the most urgent problems to be solved. To date, only a lifestyle modification related to diet and physical activity is considered for these patients. Polyphenols are a group of plant natural products that when regularly consumed has been related to a reduction in the risk of several metabolic disorders associated with NAFLD. In this study, we aimed to present an overview of the relationship between polyphenols and NAFLD with current approaches. Methods We performed a comprehensive literature search for articles on polyphenols and NAFLD published in English between January 2018 to August 2020. Keywords included in this review: “Phenolic” OR “Polyphenol” AND “Non-Alcoholic Fatty Liver Disease”. The editorials, communications and conference abstracts were excluded. Results Different polyphenols decreased the pro-inflammatory cytokines in both serum and liver that contribute to a decrease in fatty liver dysfunction. Additionally, polyphenols may improve the regulation of adipokines and prevent hepatic steatosis. According to human clinical studies, polyphenols are promising for NAFLD patients and associated diseases that lead to NAFLD. Conclusion Preclinical and clinical studies suggest that various polyphenols could prevent steatosis and its progression to non-alcoholic steatohepatitis, as well as ameliorate NAFLD. However, more clinical studies are needed to confirm this hypothesis.

Background and Aim This retrospective study investigated the effect of 48‐week pemafibrate therapy in non‐alcoholic fatty liver disease (NAFLD) with hypertriglyceridemia, as evaluated by the FibroScan‐aspartate aminotransferase (FAST) score. Methods A total of 31 NAFLD patients who were treated with pemafibrate in Gunma Saiseikai Maebashi Hospital and Kusunoki Hospital from September 2018 to April 2020 were included in the current study. We used the FAST score, which is a novel index of steatohepatitis that can be calculated based on the AST value, controlled attenuation parameter (CAP), and liver stiffness measurement (LSM), to evaluate the effect of pemafibrate treatment. Results The median age was 64.0 (interquartile range [IQR] 55.0–75.0) years and 14 patients (45.2%) were male. Median body mass index was 26.8 (IQR 23.8–28.8). Hypertension and diabetes mellitus were detected in 14 (45.2%) and five (16.1%) patients, respectively. Fasting triglyceride and high‐density lipoprotein cholesterol were significantly improved (P, The FibroScan‐aspartate aminotransferase (FAST) score, which stratifies patients with risk of progressive non‐alcoholic steatohepatitis effectively, was significantly improved during pemafibrate treatment. The delta FAST score was correlated with the variations of alanine aminotransferase, which represents the effect of pemafibrate. Pemafibrate may prevent disease progression in non‐alcoholic fatty liver disease patients with hypertriglyceridemia.

Aims/Introduction We aimed to determine whether mean and visit‐to‐visit glycated hemoglobin (HbA1c) variability independently increase the incidence of non‐alcoholic fatty liver disease (NAFLD) across the diabetic continuum from normal glucose tolerance (NGT) to established diabetes. Materials and Methods In a longitudinal cohort study, 21,123 participants underwent five or more annual health screening checkups. Participants were categorized into diabetes (n = 1,635), prediabetes (n = 6,650) and NGT (n = 12,838) groups. Mean, standard deviation (SD) and coefficient of variation data on HbA1c were obtained from three consecutive measurements. The associations between those data and incident NAFLD were analyzed using Cox regressions. Results Over a median follow‐up period of 57 months, 3,860 (18.3%) participants developed NAFLD. The risk of NAFLD increased continuously, with the mean HbA1c beginning at 4.9%, even in the NGT group. We found a significant association between increasing HbA1c variability and incident NAFLD (coefficient of variation, adjusted hazard ratio 1.14, 95% confidence interval 1.01–1.29; standard deviation, adjusted hazard ratio 1.19, 95% confidence interval 1.05–1.36) in the diabetes group, but not in the NGT or prediabetes group. Consistent findings were observed when NAFLD patients with a low possibility of fibrosis were excluded. The association between the coefficient of variation of HbA1c and incident NAFLD in the diabetes group was significant only in those with an increasing trend of post‐baseline HbA1c (adjusted hazard ratio 1.24, 95% confidence interval 1.01–1.52). Conclusions Increased mean HbA1c levels elevated the risk of incident NAFLD, even with NGT. Increases in visit‐to‐visit variability of HbA1c independently elevated the risk of incident NAFLD, but only in the diabetes group., In a cohort comprising individuals with various glucose statuses at baseline (n = 21,123), the risk of non‐alcoholic fatty liver disease continuously increased according to increasing mean HbA1c from 4.9%, even in the normal glucose tolerance group. We found a significant association between increasing HbA1c variability and incident non‐alcoholic fatty liver disease in diabetes, but not in the normal glucose tolerance and prediabetes groups.

Aims/Introduction Non‐alcoholic fatty liver disease, especially with liver fibrosis, is associated with cardiovascular diseases. The Non‐Alcoholic Fatty Liver Disease Fibrosis Score (NFS), a non‐invasive marker of advanced fibrosis, was found to be associated with cardiovascular diseases in different populations. The aim of the present study was to determine whether the NFS is associated with subclinical myocardial remodeling in type 2 diabetes patients. Materials and Methods A cross‐sectional study was carried out in type 2 diabetes patients. The NFS derived from available parameters was calculated, and the participants were divided according to the quartiles of the NFS and grades of the NFS (low, intermediate and high). Fibrosis‐4 and Aspartate Aminotransferase to Platelet Ratio Index, another two liver fibrosis scores, were also calculated. Subclinical myocardial remodeling was examined by echocardiography, and its associations with NFS, Fibrosis‐4 and Aspartate Aminotransferase to Platelet Ratio Index were analyzed. Results A total of 1,878 type 2 diabetes patients were enrolled in the present study. The NFS was independently associated with sex, age, body mass index, low‐density lipoprotein cholesterol and glycated hemoglobin in type 2 diabetes patients. Parameters of subclinical myocardial remodeling including left atrial dimension, interventricular septum thickness, left ventricular end‐diastolic diameter, left ventricular end‐systolic diameter, left ventricular posterior wall thickness (LVPWT) and left ventricular mass index were all gradually increased with the increment of the NFS. Linear regression analysis further showed that the NFS was positively associated with left atrial dimension, interventricular septum thickness, left ventricular end‐diastolic diameter, left ventricular end‐systolic diameter, LVPWT and left ventricular mass index after adjustment for the confounding factors. Similarly, Fibrosis‐4 was associated with left atrial dimension, interventricular septum thickness, LVPWT and left ventricular mass index. In contrast, the Aspartate Aminotransferase to Platelet Ratio Index was only associated with LVPWT. Conclusions Non‐invasive liver fibrosis scores, especially the NFS, are independently associated with subclinical myocardial remodeling in type 2 diabetes patients., The Non‐Alcoholic Fatty Liver Disease Fibrosis Score is independently associated with subclinical myocardial remodeling in type 2 diabetes patients.

Aims/Introduction This study aims to evaluate the prevalence of and factors associated with non‐alcoholic fatty liver disease (NAFLD) in Indian women with prior gestational diabetes mellitus (GDM) diagnosed using International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Materials and Methods This cross‐sectional study (2018–2019) enrolled women with and without prior GDM. Study participants underwent detailed assessments, including relevant medical, obstetric and demographic details; 75‐g oral glucose tolerance test with glucose and insulin estimation at 0, 30 and 120 min; and other relevant biochemical and anthropometric measurements. NAFLD status was defined by ultrasonography. Results We evaluated a total of 309 women (201 and 108 with and without prior GDM, respectively) at a mean age of 31.9 ± 5.0 years and median of 16 months (interquartile range 9–38 months) following the index delivery. The prevalence of NAFLD was significantly higher in women with prior GDM (62.7% vs 50.0%, P = 0.038; grade 2 and 3 disease, 13.9% vs 6.5%). On logistic regression analysis (fully adjusted model), the odds of NAFLD were 2.11‐fold higher in women with prior GDM (95% confidence interval 1.16–3.85, P = 0.014). Overweight/obesity, metabolic syndrome, prediabetes and homeostasis model of assessment of insulin resistance (a measure of insulin resistance) were positively associated with NAFLD, whereas the Matsuda index (a measure of insulin sensitivity) showed a negative association with NAFLD. Conclusions The prevalence of NAFLD is high in women with prior GDM. Such women also have a high burden of cardiometabolic risk factors. Future studies should evaluate the intermediate and long‐term hepatic and cardiovascular risk, and the impact of lifestyle interventions in reducing morbidity in such women., This study evaluated the prevalence and risk factors of non‐alcoholic fatty liver disease in Indian women with prior gestational diabetes mellitus diagnosed using International Association of Diabetes and Pregnancy Study Groups criteria. Ultrasonography of abdomen was used to define non‐alcoholic fatty liver disease status. Prevalence of non‐alcoholic fatty liver disease was significantly higher in women with prior gestational diabetes mellitus (62.7% vs 50.0%, P = 0.038; grade 2 and 3 disease, 13.9% vs 6.5%).

Soybean has become an important world commodity because of its low price, good nutritional value and recognized functional health benefits in recent years. β-conglycinin is one of the major storage proteins in soybean. It has captured a growing interest recently because of its allergenicity and potential health benefits, which continues to drive the research and commercial development of β-conglycinin-based food products and ingredients. In this review, the structure, the amino acid composition, extraction methods and electrophoretic pattern of β-conglycinin are briefly summarized. Studies on β-conglycinin by allergenicity, plasma lipid-controlling, obesity and nonalcoholic fatty liver disease are highlighted, critically discussing their main shortcomings and challenges and identifying the research gaps. Studies to date have demonstrated the cultivation of β-conglycinin with health benefits as functional ingredients and foodstuffs. The current research focuses on proteins, mainly challenging the mechanisms of subunit/peptide effects interaction and identifying and characterizing the hidden biological activities in the polypeptide chains. There is much scope for further exploration into various aspects of β-conglycinin, such as the selection of mutant strains and genetic engineering and prospects on targeted β-conglycinin exploitation in the nutraceutical area. In addition, the safety evaluation of β-conglycinin and its stabilized emulsions deserve more attention to food-related applications.

PURPOSE To evaluate the association between severity of hepatic steatosis/fibrosis with clinical, laboratory, and echocardiographic characteristics, including visceral obesity and type 2 diabetes mellitus (T2DM)-related micro- and macrovascular complications in diabetic patients with non-alcoholic fatty liver disease (NAFLD). METHODS We studied 60 consecutive NAFLD outpatients with T2DM, recording several demographic and clinical characteristics, trunk and visceral fat, cardiac ultrasound, and micro- and macrovascular complications of diabetes mellitus including microalbuminuria, diabetic peripheral neuropathy, peripheral vascular disease, and cardiac autonomic function. Severity of steatosis and fibrosis was evaluated with abdominal ultrasound and liver stiffness measurements, respectively. RESULTS Twenty-three (41%) of the patients had grade 1 steatosis and mean liver stiffness was 7.5 ± 3 kPa. After applying Bonferroni correction for multiple comparisons, ferritin concentration was the only factor significantly different between patients with mild (grade 1) compared to those with moderate/severe (grade 2/3) steatosis and showed good discriminative ability for the presence of moderate/severe steatosis (AUC: 0.74, sensitivity 88%, specificity 48%, PPV 74%, and NPV 72%). In addition, waist circumference was the only factor associated with the presence of significant fibrosis (≥ F2) with very good discriminative ability (AUC: 0.77, sensitivity 89%, specificity 45%, PPV 75%, and NPV 70%). CONCLUSION Specific clinical and laboratory characteristics, which may be determined via widely accessible and noninvasive techniques, were associated with severity of diabetics NAFLD, taking into account echocardiographic characteristics, visceral obesity, and T2DM-related systemic complications.

BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, affecting over 30% of the United States population. Early patient identification using a simple method is highly desirable. AIM To create machine learning models for predicting NAFLD in the general United States population. METHODS Using the NHANES 1988-1994. Thirty NAFLD-related factors were included. The dataset was divided into the training (70%) and testing (30%) datasets. Twenty-four machine learning algorithms were applied to the training dataset. The best-performing models and another interpretable model (i.e., coarse trees) were tested using the testing dataset. RESULTS There were 3235 participants (n = 3235) that met the inclusion criteria. In the training phase, the ensemble of random undersampling (RUS) boosted trees had the highest F1 (0.53). In the testing phase, we compared selective machine learning models and NAFLD indices. Based on F1, the ensemble of RUS boosted trees remained the top performer (accuracy 71.1% and F1 0.56) followed by the fatty liver index (accuracy 68.8% and F1 0.52). A simple model (coarse trees) had an accuracy of 74.9% and an F1 of 0.33. CONCLUSION Not every machine learning model is complex. Using a simpler model such as coarse trees, we can create an interpretable model for predicting NAFLD with only two predictors: fasting C-peptide and waist circumference. Although the simpler model does not have the best performance, its simplicity is useful in clinical practice.

The widespread prevalence of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM), as well as their combination, determines the need for a targeted analysis of this pathology in order to optimize approaches to the diagnosis and treatment of patients with NAFLD and T2DM. As components of the metabolic syndrome, these two diseases have largely similar mechanisms of development and progression, simultaneously increasing the risk of adverse outcomes in comorbid patients. Despite the common pathophysiological mechanisms, the question of the development of NAFLD and T2DM remains significant. Upon conducting literature analysis, two main theories have been identified: alimentary and metabolic. According to the alimentary theory, the primary link in the pathogenesis is obesity and the associated excessive accumulation of free fatty acids and triglycerides in the liver, which subsequently leads to insulin resistance and the development of T2DM. In contrast, the metabolic theory considers diabetes-related insulin resistance as the first hit, which, regardless of obesity, creates preconditions for liver damage. In addition, the review focuses on the consideration of the new concept of Metabolic associated fatty liver disease (MAFLD) as a hepatic manifestation of the metabolic syndrome and considers the clinical phenotypes identified within this pathology. In conclusion, pathogenically based treatment goals in patients with NAFLD and T2DM are overcoming insulin resistance, correcting atherogenic dyslipidemia, and restoring the structures and functions of liver cells.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a growing problem in the United States and Hispanics experience the highest burden of this disease. Weight loss, physical activity (PA) and a healthy diet are the mainstay for NAFLD treatment, but patients experience barriers to behavior change. The purpose of this study was to identify barriers hindering Hispanic patients with NAFLD from making changes to PA and dietary habits. Methods: Participants referred to a multidisciplinary clinic completed self-administered questionnaires that measured barriers to greater PA engagement and eating healthier, with both close-ended and open-ended responses. One bilingual coder reviewed and categorized all open-ended responses. Results: The study population included 414 patients. The top five barriers for eating healthier were cost, perceptions that healthier food does not taste good, lack of time to cook, difficulty of cooking, and difficulty in going to the grocery store. Lack of time, feeling lazy, pain, a lack of place to exercise, and the perception that exercise is difficult were the top five barriers to PA engagement. Conclusions: Since Hispanic adults with NAFLD experience similar barriers to Hispanic adults more generally, existing behavioral lifestyle interventions may work well in this clinical population with some adaption for NAFLD-specific education.

Background Non-alcoholic fatty liver disease (NAFLD) has high morbidity and mortality related to cardiovascular disease (CVD), but statins have been historically underutilised in these patients due to concern for hepatotoxicity. Aims To characterise trends in statin use among individuals with NAFLD and to determine predictors of statin utilisation in this population. Methods Individuals with NAFLD were identified from 2005 to 2018 continuous National Health and Nutrition Examination Survey. Trends in statin use over time were assessed, and predictors of statin under-utilisation for primary prevention were identified. The roles of a known diagnosis of liver disease and disease severity were examined. Results We included 14 113 individuals; 34.6% had NAFLD, of whom 5.4% reported a liver disease diagnosis. There was a significant increase in statin use for primary prevention between 2005 and 2018 (18.1%-25.0%; P = 0.03), but guideline-indicated use for this purpose was low (54.5% between 2005 and 2012; 48.6% between 2013 and 2018). A known NAFLD diagnosis was a negative predictor of statin use during the earlier time period but not more recently. Utilisation did not decrease with increasing liver disease severity. Conclusions In a nationally representative population with NAFLD, statin use for primary prevention has increased over time, but guideline-concordant use remains low. A known liver disease diagnosis was associated with lack of statin use in the earlier time period but not more recently, suggesting a changing perspective of underlying liver disease impacting statin utilisation. Further work to improve guideline-indicated statin use in this high-risk population is needed.

The relationship between metabolic non-alcoholic fatty liver disease (NAFLD) and gallstone disease (GSD) is complex and seemingly interrelated. There is no doubt that there is an increased risk of cholelithiasis in patients with NAFLD, which is primarily associated with general pathogenetic mechanisms. These include central and peripheral insulin resistance, changes in the expression of transcription factors (hepatic X-receptor, farnesoid X-receptor (FXR) and membrane bile acid receptors (TGR5)). At the same time, the effect of gallstone disease on the course of NAFLD is assumed, although the pathogenetic factors of this association are still insufficient. There are accumulating data on an increased risk of other pathologies of the biliary tract in patients with NAFLD, in particular, of gallbladder polyps and tumors of the biliary tract. Recently there have been convincing data on the role of cholecystectomy in the progression of NAFLD, which may be due to disruption of endocrine balance and signaling function of bile acids, as well as the development of bacterial overgrowth in the small intestine. General therapeutic approaches to the treatment of interrelated hepatobiliary pathology may include new generation insulinsensitizers, FXR agonists, and ursodeoxycholic acid. The link between NAFLD and the pathology of the biliary tract is complex and multifaceted, and its further study opens up prospects for the development of new methods of treatment.

Abstract. Some epidemiological evidence suggests an inverse correlation between non-alcoholic fatty liver disease (NAFLD) frequency and vitamin D levels. Likewise, a beneficial effect of vitamin D on diabetes mellitus (DM) and insulin resistance has been observed, but this is an unsolved issue. Thus, we aimed to investigate the prevalence of hypovitaminosis D in a NAFLD Brazilian population and its association with disease severity and presence of comorbidities. In a cross-sectional study, the clinical, biochemical and histological parameters of 139 NAFLD patients were evaluated according to two different cut-off points of serum 25-hydroxyvitamin D levels (20 ng/mL and 30 ng/mL). The mean age of the population was 56 ± 16 years, most patients were female (83%), 72% had hypertension, 88% dyslipidemia, 46% DM, 98% central obesity, and 82% metabolic syndrome. Serum vitamin D levels were

Background Non-alcoholic fatty liver disease (NAFLD) is increasing in recognition as a hepatic condition that is unrelated to significant alcoholic consumption, but has rather, been suggested to constitute cardiovascular risk (irrespective of traditional risk factors and high-risk plaque features). Both coronary artery disease and NAFLD share the same pathophysiology and metabolic profile. NAFLD can theoretically be a source/initiator for coronary artery disease (CAD). We aimed to study the association between NAFLD, CAD, the presence of high-risk plaque features, and the severity of stenosis. Results We recruited 800 patients with suspected obstructive CAD and planned for coronary computed tomography angiography (CCTA), Exclusion criteria: heavy alcohol consumption; contraindications to contrast media; unevaluated coronary-artery segments; other known liver disease; and use of oral corticosteroids and/or amiodarone. Non-enhanced Computed Tomography abdomen was performed before the CCTA to detect NAFLD. To study the association between NAFLD and the presence of CAD, patients were classified as to either have, or not have CAD. The CAD group were then further studied for the presence of high-risk plaque features: napkin ring sign, Positive remodelling, Low Hounsfield unit (HU), and Spotty calcium; and their association with NAFLD. Thirty-two per cent of patients had NAFLD and 45% had CAD. A significant association between NAFLD and CAD was found (OR 4.21, 95% CI (confidence interval) (2.83–6.25), p = 0.000). In CAD patients, significant associations were present between NAFLD and high-risk plaque features: Napkin ring sign, Positive remodelling, Low HU, and Spotty calcium (OR 7.88, 95% CI (4.39–14.12), p p p p 50% stenosis or 3V disease, and Total occlusion, respectively, p Conclusions NAFLD is strongly associated with CAD, high-risk plaque features and higher grade of stenosis.

Background Non-alcoholic fatty liver disease (NAFLD) patients are at a substantial risk for developing cardiovascular disease (CVD). High-density lipoprotein (HDL) is well known to have protective effects against the development of atherosclerotic CVD. One of the major antiatherogenic effects of HDL is its anti-oxidative function. Objectives This study investigated the association of anti-oxidative capacity of HDL with subclinical atherosclerosis in NAFLD and non-NAFLD subjects. Methods A total of 143 subjects including 51 NAFLD and 92 control subjects were included in this case–control study. HDL oxidative index (HOI) was determined spectrophotometrically using a cell-free method in the presence of a fluorescent substrate dichlorofluorescein diacetate (DCFDA). Paraoxonase 1 (PON1) activity, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) plasma levels were assessed in both groups. Results The NAFLD patients with impaired HDL anti-oxidative function (HOI ≥ 1) had higher MDA levels, aspartate amino transferase (AST), liver stiffness (LS), and carotid intima-media thickness (cIMT) values compared to the controls. HDL oxidative index (HOI) was positively correlated with MDA levels and cIMT and negatively correlated with SOD activity. Conclusions Higher circulating levels of MDA were associated with the impaired anti-oxidative function of HDL in NAFLD. The impaired anti-oxidative capacity of HDL might be related to NAFLD severity and subclinical atherosclerosis in NAFLD patients.

Non-alcoholic fatty liver disease (NAFLD) has become a major cause of chronic liver disease (CLD) worldwide. Our aim was to assess the burden of liver complications (LC, cirrhosis and liver cancer) related to NAFLD (LC-NAFLD) between 2009-2019 in Asia and the Middle East and North Africa (MENA) region.We used Global Burden of Disease data to assess incidence, mortality, and disability-adjusted life years (DALYs) for LC-NAFLD from Asia and the MENA region. Annual % change (APC) in rates were computed using a joinpoint regression model. Associations of LC-NAFLD with low physical activity, diet and metabolic risks were determined by partial Spearman correlation coefficients (ρ).Globally in 2019, there were 170,000 incident cases of LC-NAFLD, accounting for 6.6% of LC incident cases from all CLDs. There were 168,969 deaths related to LC-NAFLD, accounting for 8.6% of LC deaths from all CLDs. Asia accounted for 48.3% of the global incidence of LC-NAFLD and for 46.2% of deaths attributable to LC-NAFLD, while MENA accounted for 8.9% and 8.6%, respectively. There were 2.08 million DALYs in Asia and 340,000 DALYs in MENA. From 2009 to 2019, regions in Asia and MENA experienced a rise in DALYs attributable to LC-NAFLD (compared to LC from other CLDs), ranging from South Asia (APC = +2.12% vs. -0.94%) to high-income Asia Pacific (APC = -0.07%, p = 0.646 vs. -0.97%). In Asia, NAFLD-related DALYs were significantly correlated with dietary risks (95% CI 0.280-0.763, p = 0.004), metabolic risks (0.341-0.790, p0.001) and tobacco use (0.134-0.691, p = 0.007). In MENA, low physical activity (0.557-0.918, p0.001), metabolic risks (0.432-0.888, p = 0.001), and dietary risks (0.315-0.855, p = 0.001) correlated with DALYs.NAFLD is posing a substantial burden in Asia and MENA. About half of the global burden of LC-NAFLD is accounted for by these regions.Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the most common causes of chronic liver disease worldwide. We used Global Burden of Disease data to assess the incidence, mortality, and disability-adjusted life years attributable to NAFLD-related liver complications in Asia, the Middle East and North Africa. NAFLD is poised to contribute to a substantial liver disease burden in these regions. Regional and global policies are needed to address the increasing burden of complications of NAFLD.

Summary Background and aims Prospective cohort studies linking dietary patterns and non-alcoholic fatty liver disease (NAFLD) are limited, especially in Asian populations. This study aimed to prospectively investigate the association between dietary patterns and risk of NAFLD in a general Chinese adult population. Methods This study included a total of 17,360 participants free from NAFLD at baseline. Dietary patterns at baseline were identified with factor analysis based on responses to a validated 100-item food frequency questionnaire. NAFLD was diagnosed by abdominal ultrasound after excluding other causes related to chronic liver disease. Cox proportional regression models were used to assess the association between dietary patterns and risk of NAFLD. Results During a median follow-up of 4.2 years, 4034 NAFLD cases were documented. Three main dietary patterns were extracted: sugar rich dietary pattern, vegetable rich dietary pattern, and animal food dietary pattern. After adjusting for age, sex, body mass index, smoking, alcohol, education, occupation, income, physical activity, total energy intake, personal and family history of disease, depressive symptoms, dietary supplement use, inflammation markers, and each other dietary pattern score, comparing the highest with the lowest quartiles of dietary pattern scores, the multivariable hazard ratios (95% confidence interval) of NAFLD were 1.11 (1.01, 1.23) for sugar rich dietary pattern, 0.96 (0.86, 1.07) for vegetable rich dietary pattern, and 1.22 (1.10, 1.36) for animal food dietary pattern. Further adjustment for waist circumference instead of body mass index provided similar results. Conclusion Dietary patterns rich in animal foods or sugar were associated with a higher risk of NAFLD among Chinese adults, whereas a vegetable rich dietary pattern was not associated.