Adult Non-alcoholic Fatty Liver Disease Research Articles

Gender-Specific Bile Acid Profiles in Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. A main cause is the obesogenic, so-called Western lifestyle. NAFLD follows a long, unperceived course, and ends potentially fatally. Early diagnosis of aggressive subtypes saves lives. So far, non-invasive means of detection are limited. A better understanding of the pathogenic interplay among insulin resistance, immune inflammation, microbiome, and genetic background is important. Metabolomics may give insight into these interlaced processes. In this study, we measured bile acids (BA) in the plasma of adult NAFLD and alcohol-associated liver disease (ALD) patients and healthy controls with targeted mass spectrometry. We focused on gender-related bile acid production pathology in NAFLD and ALD. Compared to healthy controls, women with NAFLD had significantly higher concentrations of total BA, total primary BA, total cholic (CA), total chenodeoxycholic (CDCA), total glycine-conjugated, and total non-12-a-OH BA. Concerning subtypes, glycocholic (GCA) and glycochenodeoxycholic (GCDCA), BA were elevated in women with NAFLD. In contrast, men with NAFLD had no significantly altered total BA fractions. However, the subtypes GCA, glycodeoxycholic (GDCA), glycolithocholic (GLCA), lithocholic (LCA), taurolithocholic (TLCA), and tauroursodeoxycholic acid (TUDCA) were elevated, while CA was significantly decreased. In NAFLD, except ursodeoxycholic acid (UDC), all total BA correlated significantly positively in both sexes with the ELF score, while in ALD, only males showed significant correlations exceptive for total UDC BA. In NAFLD, total BA, total primary BA, total secondary BA, total free secondary BA, total CA, total CDCA, total taurine conjugated, total glycine conjugated, total 12-a-OH, and total non-12-a-OH were significantly higher in cases of a high enhanced liver fibrosis (ELF) score above 9.8. In ALD, total UDC was additionally elevated. Between NAFLD with and without NASH, we found no significant differences. Our data show gender-specific bile acid profiles in NAFLD and markedly different BA patterns in ALD. Women with NAFLD had more severe cholestasis. Men may better compensate fat storage-driven bile acid dynamics, indicated by higher levels of taurine-conjugated BA, which associate with beneficial metabolic functions.

Vagal Stimulation Ameliorates Non-Alcoholic Fatty Liver Disease in Rats.

The harmful consequences of non-alcoholic fatty liver disease (NAFLD) are posing an increasing threat to public health as the incidence of diabetes and obesity increases globally. A non-invasive treatment with a range of autonomic and metabolic benefits is transcutaneous vagus nerve stimulation (tVNS). To investigate the possible preventive impacts of VNS against adult rats' NAFLD caused by a high-fat diet (HFD) and to clarify the underlying mechanisms. A total of thirty-two adult male rats were split into two groups: the HFD-induced NAFLD group (n = 24) and the control normal group (n = 8). The obesogenic diet was maintained for 12 weeks to induce hepatic steatosis. The HFD-induced NAFLD group (n = 24) was separated into three groups: the group without treatment (n = 8), the group with sham stimulation (n = 8), and the group with VNS treatment (n = 8). VNS was delivered for 30 min per day for 6 weeks after the establishment of NAFLD using a digital TENS device. The subsequent assessments included hepatic triglyceride, cholesterol content, serum lipid profile, and liver function testing. In this context, inflammatory biomarkers (TNF-α, IL-6) and hepatic oxidative stress (MDA, SOD, and GPx) were also assessed. To clarify the possible mechanisms behind the protective benefits of VNS, additional histological inspection and immunohistochemistry analysis of TNF-α and Caspase-3 were performed. In the NAFLD-affected obese rats, VNS markedly decreased the rats' body mass index (BMI) and abdominal circumference (AC). Liver function markers (albumin, ALT, and AST) and the serum lipid profile-which included a notable decrease in the amounts of hepatic triglycerides and cholesterol-were both markedly improved. Additionally, oxidative stress and inflammatory indicators showed a considerable decline with VNS. Notably, the liver tissues examined by histopathologists revealed that there is evidence of the protective impact of VNS on the oxidative and inflammatory states linked to HFD-induced NAFLD while maintaining the architectural and functional condition of the liver. Our findings suggest that VNS may represent a promising therapeutic candidate for managing NAFLD induced by obesity. It can be considered to be an effective adjuvant physiological intervention for the obese population with NAFLD to spare the liver against obesity-induced deleterious injury.

Leukocyte cell-derived chemotaxin 2 correlates with pediatric non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD), newly renamed metabolic dysfunction-associated liver disease (MASLD), is a leading cause of liver disease in children and adults. There is a paucity of data surrounding potential biomarkers and therapeutic targets, especially in pediatric NAFLD. Leukocyte cell-derived chemotaxin 2 (LECT2) is a chemokine associated with both liver disease and skeletal muscle insulin resistance. Our aim was to determine associations between LECT2 and common clinical findings of NAFLD in pediatric patients. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum LECT2 concentrations in children (aged 2-17 years) with and without NAFLD. LECT2 concentrations were then correlated to clinical parameters in NAFLD. Mean LECT2 was significantly elevated in children with NAFLD versus healthy controls (n = 63 vs. 42, 5.83 ± 1.98 vs. 4.02 ± 2.02 ng/mL, p < 0.005). Additionally, LECT2 had strong correlations with body mass index (BMI) (Pearson r = 0.301, p = 0.002). A LECT2 concentration of 3.76 mg/mL predicts NAFLD with a sensitivity of 90.5% and specificity of 54.8%. Principal component analysis and logistic regression models further confirmed associations between LECT2 and NAFLD status. This study demonstrates increased serum LECT2 concentrations in pediatric NAFLD, which correlates with BMI and shows strong predictive value within these patients. Our data indicate that LECT2 is a potential diagnostic biomarker of disease and should be further investigated in pediatric as well as adult NAFLD.

Cathepsin D mediates prenatal caffeine exposure-caused NAFLD susceptibility in male rat offspring by regulating autophagy

Epidemiological evidence has revealed that non-alcoholic fatty liver disease (NAFLD) harbors an intrauterine origin. Autophagy is known to be involved in the protective mechanism in the development of adult NAFLD, but whether it engages in the occurrence of fetal-originated NAFLD remains unclear. In this study, a rat model of fetal-originated NAFLD was established by giving a high-fat diet or chronic stress after birth on prenatal caffeine exposure (PCE) male offspring. The alterations of liver morphologic analysis, lipid metabolism, and autophagy before and after birth were determined to confirm autophagy mechanism, NAFLD susceptibility, and intrauterine origin in PCE male adult offspring. Our results revealed that PCE-induced intrauterine high concentration of corticosterone exposure blocked autophagic flux by inhibiting cathepsin D expression in hepatocytes, leading to β-oxidation inhibition and lipid accumulation in the liver. Moreover, high concentration of corticosterone upregulated miR-665 by activating the glucocorticoid receptor to suppress cathepsin D, thus causing lysosomal degradation dysfunction and autophagy flux blockade. Notably, hepatic overexpression of cathepsin D could reverse PCE-induced postnatal NAFLD susceptibility in male rat offspring. This study elucidates the epigenetic programming mechanism of intrauterine autophagy-related fetal-originated NAFLD susceptibility, and identifies cathepsin D as its early intervention target, providing an experimental basis for exploring early prevention and treatment strategies for fetal-originated NAFLD.

Effect of exercise-based interventions in nonalcoholic fatty liver disease: A systematic review with meta-analysis.

The global burden of nonalcoholic fatty liver disease (NAFLD) is rapidly increasing. This study aimed to evaluate the effect of exercise on intrahepatic lipid (IHL), serum alanine aminotransferase (ALT), body mass index (BMI), and insulin resistance in NAFLD patients. We searched MEDLINE, Embase, Cochrane CENTRAL, KMbase, and the Korean Studies Information Service System through April 2022. The included studies were randomised control trials (RCTs) of exercise, in which IHL was measured using magnetic resonance imaging in adult NAFLD patients. Eleven RCTs with 577 participants were included in this meta-analysis. Exercise was significantly associated with a reduction in IHL (mean difference (MD), -2.03; 95% CI, -3.26 to -0.79; P=0.001) and a decrease in ALT (MD, -4.17; 95% CI, -6.60 to -1.73; P=0.0008). Regarding the duration of exercise, maintaining exercise for more than 3 months significantly improved IHL (MD, -3.62; 95% CI, -5.76 to -1.48; P=0.0009), while exercise for less than 3 months did not (MD, -1.23; 95% CI, -2.74 to 0.29; P=0.11). BMI and insulin resistance did not improve significantly with exercise. We found that exercise improved IHL and ALT levels in NAFLD patients. The effect of exercise is particularly increased when one engages in exercises that last longer than 3 months.

Early-life stress perturbs the epigenetics of Cd36 concurrent with adult onset of NAFLD in mice

BackgroundNon-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the U.S. and worldwide. The roles of early postnatal life stress (EPLS) and the fatty acid translocase (CD36) on the pathogenesis of adult-onset NAFLD remain unknown. We hypothesized that EPLS, in the form of neonatal maternal separation (NMS), would predispose mice towards developing adult NAFLD, increase hepatic CD36 expression, and differentially methylate Cd36 promoter concurrently.MethodsNMS was performed on mice from postnatal day 1 to 21 and a high-fat/high-sucrose (HFS) diet was started at 4 weeks of age to generate four experimental groups: Naive-control diet (CD), Naive-HFS, NMS-CD, and NMS-HFS.ResultsNMS alone caused NAFLD in adult male mice at 25 weeks of age. The effects of NMS and HFS were generally additive in terms of NAFLD, hepatic Cd36 mRNA levels, and hepatic Cd36 promoter DNA hypomethylation. Cd36 promoter methylation negatively correlated with Cd36 mRNA levels. Two differentially methylated regions (DMRs) within Cd36 promoter regions appeared to be vulnerable to NMS in the mouse.ConclusionsOur findings suggest that NMS increases the risk of an individual, particularly male, towards NAFLD when faced with a HFS diet later in life.ImpactThe key message of this article is that neonatal maternal separation and a postweaning high-fat/high-sucrose diet increased the risk of an individual, particularly male, towards NAFLD in adult life.What this study adds to the existing literature includes the identification of two vulnerable differentially methylated regions in hepatic Cd36 promoters whose methylation levels very strongly negatively correlated with Cd36 mRNA.The impact of this article is that it provides an early-life environment-responsive gene/promoter methylation model and an animal model for furthering the mechanistic study on how the insults in early-life environment are “transmitted” into adulthood and caused NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is associated with an increased incidence of chronic kidney disease (CKD)

BackgroundNon-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in the western world. The excess mortality in NAFLD patients is strongly related to extrahepatic comorbidities. Recently, an association between NAFLD and chronic kidney disease (CKD) has been reported in various populations.MethodsBased on the IQVIA Disease Analyzer database, this retrospective study examined two cohorts from Germany matched for sex, age, index year, annual visit frequency, hypertension, and diabetes, including 92,225 patients with and without NAFLD. The incidence of CKD was assessed as a function of NAFLD using Cox regression models.ResultsA total of 92,225 NAFLD patients as well as 92,225 patients without NAFLD were included into analyses. CKD was diagnosed in 19.1% vs. 11.1% of patients with and without NAFLD within the 10 years observation period (p < 0.001). Cox regression confirmed a significant association between NAFLD and CKD with a hazard ratio (HR) of 1.80 (95%CI: 1.73–1.86, p < 0.001). Subgroup analyses revealed that this association was most pronounced in the age group of 18 to 50 years (HR: 2.13, 95%CI: 1.91–2.37, p < 0.001) and among female NAFLD patients (HR 1.85, 95%CI: 1.76–1.95, p < 0.001).ConclusionsThe results of this study confirm a significantly increased risk of developing CKD in a large, real-world cohort of adult NAFLD patients in Germany. Interdisciplinary care of NAFLD patients, which is currently gaining importance worldwide, should be considered to include systematic measures for prevention and/or early detection of CKD with the aim of minimizing long-term renal complications.

Effects of aerobic exercise on metabolic indicators and physical performance in adult NAFLD patients: A systematic review and network meta-analysis.

nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of fat in the liver without alcoholism. We conducted a systematic review and meta-analysis to elucidate the efficacy of aerobic exercise on metabolic indicators and physical performance of adult patients with NAFLD. To conduct the systematic review and network meta-analysis, 2 researchers searched PubMed, EBSCO, and Web of science databases to identify randomized clinical trials of aerobic exercise interventions for adults with NAFLD published between inception and July 2022. We assessed the methodological quality of the included literature using the Cochrane Risk Assessment Scale and the PEDro Scale. Relevant data were extracted, variables were converted to the same units, and meta-analysis was performed using RevMan 5.4 software. We compared mean differences (MD) between experimental and control groups. For each outcome analyzed, we expressed data as MD with 95% CI to compare metabolic markers and exercise capacity between the experimental and control NAFLD patients. Eleven randomized clinical trials with a total of 491 individuals with NAFLD were included in accordance with the criteria of this study. Types of aerobic exercise include moderate or high-intensity interval running, cycling, Nordic walking, equipment training, etc; Training duration 4 to 16 weeks, 30 to 60 minutes 3 or more times a week. Compared with the control group, aerobic exercise group had reduced weight of patients, (MD) 1.20 kg (95% CI: -1.38 to -1.01 kg, P < .00001). Seven studies confirmed that aerobic exercise significantly reduced triglycerides, (MD) 3.00 mg/dL (95% CI: -5.80 to -0.21 mg/dL, P = .04); increased high density lipoproteins (MD) 5.96 mg/dL (95% CI: 2.95 to 8.96 mg/dL, P = .0001) and reduced low-density lipoproteins (MD) 6.45 mg/dL (95% CI: -8.53 to -4.37 mg/dL, P < .00001); the study also showed that aerobic exercise reduced the liver enzymes aspartate aminotransferase and alanine aminotransferase to varying degrees. Aerobic exercise can improve physical performance and increase peak oxygen consumption of (MD) 6.29 mL/Kg*minutes, (95% CI: 3.05-9.53mL/Kg*minutes, P = .0001). Aerobic exercise significantly reduced weight and improved metabolic index and physical performance. Impacted by the limitations of various regimens, doses, duration, center settings, populations enrolled, the study had certain limitations. The randomized controlled trials with larger sample sizes, multiple centers, and high quality should be conducted to validate the above conclusion. Further studies will be required to focus on the total duration of the intervention, duration and frequency of sessions, and intensity that are optimal for the promotion of physical performance and metabolic capacity in this population.

Differential DNA methylation of steatosis and non-alcoholic fatty liver disease in adolescence

Background and aimsEpigenetic modifications are associated with hepatic fat accumulation and non-alcoholic fatty liver disease (NAFLD). However, few epigenetic modifications directly implicated in such processes have been identified during adolescence, a critical developmental window where physiological changes could influence future disease trajectory. To investigate the association between DNA methylation and NAFLD in adolescence, we undertook discovery and validation of novel methylation marks, alongside replication of previously reported marks.Approach and resultsWe performed a DNA methylation epigenome-wide association study (EWAS) on DNA from whole blood from 707 Raine Study adolescents phenotyped for steatosis score and NAFLD by ultrasound at age 17. Next, we performed pyrosequencing validation of loci within the most 100 strongly associated differentially methylated CpG sites (dmCpGs) for which ≥ 2 probes per gene remained significant across four statistical models with a nominal p value < 0.007. EWAS identified dmCpGs related to three genes (ANK1, MIR10a, PTPRN2) that met our criteria for pyrosequencing. Of the dmCpGs and surrounding loci that were pyrosequenced (ANK1 n = 6, MIR10a n = 7, PTPRN2 n = 3), three dmCpGs in ANK1 and two in MIR10a were significantly associated with NAFLD in adolescence. After adjustment for waist circumference only dmCpGs in ANK1 remained significant. These ANK1 CpGs were also associated with γ-glutamyl transferase and alanine aminotransferase concentrations. Three of twenty-two differentially methylated dmCpGs previously associated with adult NAFLD were associated with NAFLD in adolescence (all adjusted p < 2.3 × 10–3).ConclusionsWe identified novel DNA methylation loci associated with NAFLD and serum liver biochemistry markers during adolescence, implicating putative dmCpG/gene regulatory pathways and providing insights for future mechanistic studies.Graphical abstract

Cardiovascular disease risk in paediatric and young adult non-alcoholic fatty liver disease

ObjectiveLongitudinal evidence is lacking regarding the long-term risk of major adverse cardiovascular events (MACE) in children and young adults with non-alcoholic fatty liver disease (NAFLD).DesignThis nationwide cohort study included all...

Nutritional, pharmacological, and environmental programming of NAFLD in early life.

Nonalcoholic fatty liver disease (NAFLD) is the main liver disease worldwide, and its prevalence in children and adolescents has been increasing in the past years. It has been demonstrated that parental exposure to different conditions, both preconceptionally and during pregnancy, can lead to fetal programming of several metabolic diseases, including NAFLD. In this article, we review some of the maternal and paternal conditions that may be involved in early-life programing of adult NAFLD. First, we describe the maternal nutritional factors that have been suggested to increase the risk of NAFLD in the offspring, such as an obesogenic diet, overweight/obesity, and altered lipogenesis. Second, we review the association of certain vitamin supplementation and the use of some drugs during pregnancy, for instance, glucocorticoids, with a higher risk of NAFLD. Furthermore, we discuss the evidence showing that maternal-fetal pathologies, including gestational diabetes mellitus (GDM), insulin resistance (IR), and intrauterine growth restriction (IUGR), as well as the exposure to environmental contaminants, and the impact of microbiome changes, are important factors in early-life programming of NAFLD. Finally, we review how paternal preconceptional conditions, such as exercise and diet (particularly obesogenic diets), may impact fetal growth and liver function. Altogether, the presented evidence supports the hypothesis that both in utero exposure and parental conditions may influence fetal outcomes, including the development of NAFLD in early life and adulthood. The study of these conditions is crucial to better understand the diverse mechanisms involved in NAFLD, as well as for defining new preventive strategies for this disease.

S1345 Weight Loss Outcomes With and Without Diabetes in Patients With NAFLD in a Specialty Fatty Liver Disease Program

Introduction: Nonalcoholic fatty liver disease (NAFLD) is strongly linked to insulin resistance. As a result, type 2 diabetes mellitus (T2DM) is commonly comorbid in NAFLD and can increase morbidity and reduce weight loss treatment efficacy. We studied weight loss in adult NAFLD patients without and with T2DM (NAFLD-DM) receiving care in the Yale Fatty Liver Disease Program (YFLDP), which focuses on the integration of medical weight management treatments and hepatology care. Methods: We analyzed retrospective data for adult patients with diagnostic codes for NAFLD and T2DM with complete data on body weight and at least one clinic visit between 5/23/2018 and 5/02/2022. Patients were categorized as NAFLD or NAFLD-DM. Total body weight loss (WL) was quantified using 0%, 5%, and 10% thresholds. Between NAFLD and NAFLD-DM groups, we compared total body weight loss (WL) and across WL threshold groups, we also compared initial weights, follow-up time, medical interventions received, and results of non-invasive liver fibrosis tests. Results: There were 933 patients with NAFLD, of whom 463 (49.6%) had NAFLD-DM. After a median follow-up of 7.7 months, 632 (67.7%) of all patients achieved any weight loss. Significantly more patients with NAFLD-DM lost weight compared to NAFLD alone (73.9 vs 61.7%, p< 0.0001). Weight loss between NAFLD and NAFLD-DM groups varied, respectively: 0-5% WL: 34.7% vs. 34.8% (p=0.98); 5-10% WL: 13.2% vs. 19.2% (p=0.01), >10% WL: 13.8% vs. 19.9% (p=0.01). Compared to those not losing weight, NAFLD and NAFLD-DM patients with >10% WL had significantly greater proportion of participation in a complete meal replacement program (Optifast®) or treatment with GLP-1 agonist semaglutide. For NAFLD and NAFLD-DM groups, there was no significant difference between initial Fibroscan stiffness or FIB-4 index and subsequent WL percentages (Table). Conclusion: The majority of NAFLD and NAFLD-DM patients receiving care in a specialty clinic incorporating medical weight management with liver care successfully achieved weight loss in a relatively short period. Patients with NAFLD-DM did not have significantly worse outcomes with weight loss, and NAFLD-T2DM patients lost more weight than NAFLD patients. These findings suggest that an integrative care liver clinic with concurrent weight management care can help patients improve metabolic diseases associated with NAFLD, particularly T2DM, and in turn improve liver-related outcomes.Figure 1.: Comparison of Clinic Interventions between No Weight Loss (WL) versus >10% WL patients with NAFLD (top panel, a) and NAFLD-DM (bottom panel, b). *Statistically significant p-values using chi-square analysis, which can be found in Table Table 1. - Characteristics of and Clinical Interventions for NAFLD and NAFLD-DM Patients in the Yale Fatty Liver Disease Program (YFLDP). There was a significantly lower proportion of patients with NAFLD compared to NAFLD-DM who were able to achieve > 10% Weight Loss (13.8 vs. 19.9, p=0.014), and significantly more NAFLD patients compared to NAFLD-DM who did not achieve any weight loss (38.3 vs. 26.1, p<0.001) NAFLD (n=470 patients) NAFLD-DM (n=463 patients) Patient Categories n (%) No WL180 (38.3) >10% WL65 (13.8) p No WL121 (26.1) >10% WL92 (19.9) p Clinic Interventions n (%) Nutrition Consultation 80 (44.4) 31 (47.7) 0.652 58 (47.9) 40 (43.5) 0.518 OPTIFAST® Program 4 (2.2) 5 (7.7) 0.045 2 (1.7) 8 (8.7) 0.016 Naltrexone/Buproprion 6 (3.3) 5 (7.7) 0.146 16 (13.2) 6 (6.5) 0.111 Semaglutide 15 (8.3) 17 (26.2) < 0.001 30 (24.8) 37 (40.2) 0.016 Liraglutide 11 (6.1) 7 (10.8) 0.217 21 (17.4) 7 (7.6) 0.037 Phentermine 9 (5.0) 10 (15.4) 0.007 15 (12.4) 17 (18.5) 0.219 Bariatric Surgery Referral 13 (7.2) 5 (7.7) 0.901 21 (17.4) 31 (33.7) 0.006 Health Outcomes mean (SD) Follow-Up Time, days 256 (276.5) 422 (296.8) < 0.001 271 (280.2) 403 (297.3) 0.001 Initial FibroScan® Stiffness, kPa 8.63 (6.72) 13.18 (14.01) 0.663 13.18 (14.01) 12.48 (12.49) 0.701 Initial FIB-4 Score 1.32 (1.13) 1.70 (1.98) 0.068 1.70 (1.98) 1.83 (2.11) 0.648 Initial Weight, kg 93.82 (25.45) 102.20 (24.90) 0.015 102.20 (24.90) 109.61 (25.07) 0.056 *Denotes statistical significance p<0.05. WL = Weight Loss.

The discriminatory ability of FibroScan liver stiffness measurement, controlled attenuation parameter, and FibroScan-aspartate aminotransferase to predict severity of liver disease in children.

Vibration controlled transient elastography (FibroScan) is used to predict the severity of liver fibrosis and steatosis. In pediatrics, few studies have been performed directly comparing liver histologic features with FibroScan liver stiffness measurements (LSMs) and controlled attenuation parameters (CAPs). The FibroScan–aspartate aminotransferase (FAST) score, which predicts liver disease severity in adult nonalcoholic fatty liver disease (NAFLD), has not been analyzed in children. The aims of this study were to determine if LSM and CAP correlated with liver histologic fibrosis stage and steatosis grade, respectively, and to determine the predictive capacity of FAST in pediatric NAFLD. Research participants (n = 216) included those with FibroScan within 90 days of a liver biopsy. The ability of LSM, CAP, and FAST to predict severity of liver disease was analyzed by Spearman correlation, linear regression, and receiver operating characteristic and C statistic. Significant correlations were identified between LSM and Ishak fibrosis stages, with the strongest correlation occurring in the non‐NAFLD group (Spearman r = 0.47, p < 0.0001). LSM adequately predicted Ishak stages F0–2 versus F3–F6 (area under the receiver operating characteristic curve [AUROC], 0.73 for all; 0.77 for non‐NAFLD). CAP strongly predicted histologic steatosis grade (r = 0.84; p < 0.0001; AUROC, 0.98). FAST had acceptable discriminatory ability for significant liver disease (AUROC, 0.75). A FAST cutoff ≥0.67 had a sensitivity of 89% but a specificity of only 62% at determining significant liver disease. This study encompasses one of the largest pediatric cohorts describing the accuracy of FibroScan LSM and CAP to predict liver histologic fibrosis stage and steatosis grade, respectively. In order to determine specific LSM, CAP, and FAST cut‐off values for fibrosis stages, steatosis grades, and significant liver disease, respectively, a much larger cohort is necessary and will likely entail the need for multicentered studies.

GLP-1 RAs and SGLT-2 Inhibitors for Insulin Resistance in Nonalcoholic Fatty Liver Disease: Systematic Review and Network Meta-Analysis.

ObjectiveGlucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduce glycaemia and weight and improve insulin resistance (IR) via different mechanisms. We aim to evaluate and compare the ability of GLP-1 RAs and SGLT-2 inhibitors to ameliorate the IR of nonalcoholic fatty liver disease (NAFLD) patients.Data SynthesisThree electronic databases (Medline, Embase, PubMed) were searched from inception until March 2021. We selected randomized controlled trials comparing GLP-1 RAs and SGLT-2 inhibitors with control in adult NAFLD patients with or without T2DM. Network meta-analyses were performed using fixed and random effect models, and the mean difference (MD) with corresponding 95% confidence intervals (CI) were determined. The within-study risk of bias was assessed with the Cochrane collaborative risk assessment tool RoB.Results25 studies with 1595 patients were included in this network meta-analysis. Among them, there were 448 patients, in 6 studies, who were not comorbid with T2DM. Following a mean treatment duration of 28.86 weeks, compared with the control group, GLP-1 RAs decreased the HOMA-IR (MD [95%CI]; -1.573[-2.523 to -0.495]), visceral fat (-0.637[-0.992 to -0.284]), weight (-2.394[-4.625 to -0.164]), fasting blood sugar (-0.662[-1.377 to -0.021]) and triglyceride (- 0.610[-1.056 to -0.188]). On the basis of existing studies, SGLT-2 inhibitors showed no statistically significant improvement in the above indicators. Compared with SGLT-2 inhibitors, GLP-1 RAs decreased visceral fat (-0.560[-0.961 to -0.131]) and triglyceride (-0.607[-1.095 to -0.117]) significantly.ConclusionsGLP-1 RAs effectively improve IR in NAFLD, whereas SGLT-2 inhibitors show no apparent effect.Systematic Review RegistrationPROSPERO https://www.crd.york.ac.uk/PROSPERO/, CRD42021251704

Plasminogen Activator Inhibitor-1 Levels in Non-alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Several studies have investigated the role of multiple proteins in nonalcoholic fatty liver disease (NAFLD); one that has recently gained attention is plasminogen activator inhibitor-1 (PAI-1). However, studies evaluating PAI-1 levels in NAFLD demonstrated conflicting results. Our objective was to understand the role of PAI-1 in NAFLD more clearly by carrying out a systematic review and meta-analysis. We gathered evidence by performing a systematic search on PubMed, EMBASE, and Cochrane Library, through using a predefined search string. The included studies diagnosed NAFLD through either liver biopsy, ultrasonography, computed tomography (CT), magnetic resonance spectroscopy, or using one of the latter methods with blood parameters. Studies had to fulfill predefined inclusion and exclusion criteria. To assess the quality of the studies included, we used the NHLBI quality assessment tools. The main summary outcome was the mean difference (MD) in serum PAI-1 levels reported as ng/mL Results: 33 articles involving 10,840 subjects fulfilled our inclusion criteria and were systematically reviewed. 11 studies were included in our meta-analyses. We found a significant MD in PAI-1 levels in NAFLD patients vs. controls [17.147 (95%CI: 7.720-26.574)]. Moreover, subgroup analysis evaluating PAI-1 levels in biopsy- proven NAFLD vs. controls remained significant [24.086 (95%CI: 3.812-44.361)], as well as in CT-diagnosed NAFLD [15.523 (95%CI: 7.163-23.883)]. However, no significant MD in PAI-1 levels was found in ultrasound- diagnosed NAFLD patients vs. controls [10.394 (95%CI: -13.335-34.123)]. No significant MD in PAI-1 levels in NASH patients vs. controls was observed [26.835 (95%CI: -0.879-54.549)]. In summary, elevated serum PAI-1 levels are associated with adult NAFLD (biopsy-proven and CT-diagnosed). However, no significant difference was found in ultrasound-diagnosed NAFLD and NASH patients. Nonetheless, the included studies have methodological variance, dictating that the obtained results should be carefully interpreted.

The Role of Macronutrients in the Pathogenesis, Prevention and Treatment of Non-Alcoholic Fatty Liver Disease (NAFLD) in the Paediatric Population-A Review.

Paediatric non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in childhood. Obesity is the main risk factor. Nutrition and lifestyle are the key elements in preventing and treating NAFLD in the absence of approved drug therapy. Whilst recommendations and studies on macronutrients (carbohydrates, fat and protein) in adult NAFLD exist, the discussion of this topic in paediatric NAFLD remains contradictory. The purpose of this review is to provide state-of-the-art knowledge on the role of macronutrients in paediatric NAFLD regarding quality and quantity. PubMed was searched and original studies and review articles were included in this review. Fructose, sucrose, saturated fatty acids, trans-fatty acids and ω-6-fatty-acids are strongly associated with paediatric NAFLD. High consumption of fibre, diets with a low glycaemic index, mono-unsaturated-fatty-acids and ω-3-fatty-acids reduce the risk of childhood-onset NAFLD. Data regarding the role of dietary protein in NAFLD are contradictory. No single diet is superior in treating paediatric NAFLD, although the composition of macronutrients in the Mediterranean Diet appears beneficial. Moreover, the optimal proportions of total macronutrients in the diet of paediatric NAFLD patients are unknown. Maintaining a eucaloric diet and avoiding saturated fatty acids, simple sugars (mainly fructose) and a high-caloric Western Diet are supported by literature.

Maternal Pyrroloquinoline Quinone Supplementation Improves Offspring Liver Bioactive Lipid Profiles throughout the Lifespan and Protects against the Development of Adult NAFLD.

Maternal obesity and consumption of a high-fat diet significantly elevate risk for pediatric nonalcoholic fatty liver disease (NAFLD), affecting 10% of children in the US. Almost half of these children are diagnosed with nonalcoholic steatohepatitis (NASH), a leading etiology for liver transplant. Animal models show that signs of liver injury and perturbed lipid metabolism associated with NAFLD begin in utero; however, safe dietary therapeutics to blunt developmental programming of NAFLD are unavailable. Using a mouse model of maternal Western-style diet (WD), we previously showed that pyrroloquinoline quinone (PQQ), a potent dietary antioxidant, protected offspring of WD-fed dams from development of NAFLD and NASH. Here, we used untargeted mass spectrometry-based lipidomics to delineate lipotoxic effects of WD on offspring liver and identify lipid targets of PQQ. PQQ exposure during pregnancy altered hepatic lipid profiles of WD-exposed offspring, upregulating peroxisome proliferator-activated receptor (PPAR) α signaling and mitochondrial fatty acid oxidation to markedly attenuate triglyceride accumulation beginning in utero. Surprisingly, the abundance of very long-chain ceramides, important in promoting gut barrier and hepatic function, was significantly elevated in PQQ-treated offspring. PQQ exposure reduced the hepatic phosphatidylcholine/phosphatidylethanolamine (PC/PE) ratio in WD-fed offspring and improved glucose tolerance. Notably, levels of protective n − 3 polyunsaturated fatty acids (PUFAs) were elevated in offspring exposed to PQQ, beginning in utero, and the increase in n − 3 PUFAs persisted into adulthood. Our findings suggest that PQQ supplementation during gestation and lactation augments pathways involved in the biosynthesis of long-chain fatty acids and plays a unique role in modifying specific bioactive lipid species critical for protection against NAFLD risk in later life.

Variants in mitochondrial amidoxime reducing component 1 and hydroxysteroid 17-beta dehydrogenase 13 reduce severity of nonalcoholic fatty liver disease in children and suppress fibrotic pathways through distinct mechanisms.

Genome‐wide association studies in adults have identified variants in hydroxysteroid 17‐beta dehydrogenase 13 (HSD17B13) and mitochondrial amidoxime reducing component 1 (MTARC1) as protective against nonalcoholic fatty liver disease (NAFLD). We aimed to test their association with pediatric NAFLD liver histology and investigate their function using metabolomics. A total of 1450 children (729 with NAFLD, 399 with liver histology) were genotyped for rs72613567T>TA in HSD17B13, rs2642438G>A in MTARC1, and rs738409C>G in patatin‐like phospholipase domain‐containing protein 3 (PNPLA3). Genotype–histology associations were tested using ordinal regression. Untargeted hepatic proteomics and plasma lipidomics were performed in a subset of children. We found rs72613567T>TA in HSD17B13 to be associated with lower odds of NAFLD diagnosis (odds ratio, 0.7; 95% confidence interval, 0.6–0.9) and a lower grade of portal inflammation (p < 0.001). rs2642438G>A in MTARC1 was associated with a lower grade of hepatic steatosis (p = 0.02). Proteomics found reduced expression of HSD17B13 in carriers of the protective ‐TA allele. MTARC1 levels were unaffected by genotype. Both variants were associated with down‐regulation of fibrogenic pathways. HSD17B13 perturbs plasma phosphatidylcholines and triglycerides. In silico modeling suggested p.Ala165Thr disrupts the stability and metal binding of MTARC1. Conclusion: Both HSD17B13 and MTARC1 variants are associated with less severe pediatric NAFLD. These results provide further evidence for shared genetic mechanisms between pediatric and adult NAFLD.

The Visceral Adiposity Index in Non-Alcoholic Fatty Liver Disease and Liver Fibrosis-Systematic Review and Meta-Analysis.

(1) Background: In order to avoid a liver biopsy in non-alcoholic fatty liver disease (NAFLD), several noninvasive biomarkers have been studied lately. Therefore, we aimed to evaluate the visceral adiposity index (VAI) in NAFLD and liver fibrosis, in addition to its accuracy in predicting NAFLD and NASH. (2) Methods: We searched PubMed, Embase, Scopus, and Cochrane Library, identifying observational studies assessing the VAI in NAFLD and liver fibrosis. QUADAS-2 was used to evaluate the quality of included studies. The principal summary outcomes were mean difference (MD) and area under the curve (AUC). (3) Results: A total of 24 studies were included in our review. VAI levels were significantly increased in NAFLD (biopsy-proven and ultrasound-diagnosed), simple steatosis vs. controls, and severe steatosis vs. simple steatosis. However, no significant MD was found according to sex, liver fibrosis severity, simple vs. moderate and moderate vs. severe steatosis, pediatric NAFLD, and NASH patients. The VAI predicted NAFLD (AUC 0.767) and NASH (AUC 0.732). (4) Conclusions: The VAI has a predictive value in diagnosing NAFLD and NASH, with significantly increased values in adult NAFLD patients, simple steatosis compared to controls, and severe steatosis compared to simple steatosis.

Evaluation of MACK-3 parameters, metabolic and fibrotic characteristics of non-alcoholic fatty liver disease patients with hypertension.

Non-alcoholic steatohepatitis (NASH) is an inflammatory subtype of non-alcoholic fatty liver disease (NAFLD) and recent non-invasive test, MACK-3, demonstrated good diagnostic characteristics for fibrosis in several studies. The aim of our study was to assess the liver state using the non-invasive MACK-3 Test, and its link with liver fibrosis stage, inflammatory activity, steatosis, and metabolic markers in NAFLD patients with hypertension (HT). Thirty adult NAFLD patients with HT, aged 30 to 60 years (mean age 46.36±5.1 years) were included in our study. The control group consisted of 20 healthy volunteers. In addition to basic laboratory tests and ultrasonographic examination, validated non-invasive fibrosis test were performed. MACK-3 was calculated using the online calculator with the following variables: fasting glucose, fasting insulin, aspartate aminotransferase (AST) and cytokeratin 18 (CK18). All NAFLD patients with HT were characterized with increased liver enzymatic activity, lipid profile, increased levels of insulin and HOMA-IR˂0.001. MACK-3 parameters were positively correlated with thymol test = 0.45 (P<0.013), with aspartataminotransferase (AST) = 0.38 (P<0.03) and alanineaminotransferase (ALT) - =0.38 (P<0.03), with the stage of Fibrotest activity = 0.25 (P<0.018) and steatosis = 0.76 (P<0.001). MACK-3 parameters associations with hepatic enzymatic activity, steatosis and activity stage suggest this test as a promising for screening use in such patients and requires further studies.