Borderline Nonalcoholic Steatohepatitis Research Articles

Prospective Study to Analyze the Concordance Between a Standardized Visual Method With Pathology to stratify Nonalcoholic Fatty Liver Disease in Cadaveric Liver Grafts Evaluated for Transplantation.

The main challenge of liver transplantation is the discrepancy in demand and availability. Marginal grafts or full organs from donors with expansion criteria have been considered to reduce the shortage and assist a greater number of patients. Nonalcoholic fatty liver disease (NAFLD) is one of the most important defining criteria for expanded criteria organs. The present study proposes that an organized visual analysis method could correctly identify and classify NAFLD and organ viability without the need for liver biopsy and its logistical concerns. Pictures from the grafts were taken at a standardized method (same distance, light conditions, and register device) before and after the perfusion. The visual liver score (VLS) was applied by transplant surgeons; biopsies of the grafts were analyzed by a pathologist in a double-blind design. Score performance and interobserver agreement for NAFLD detection and grading, as graft viability evaluation, were calculated. Fifty-seven grafts were analyzed. At least 1 previous expansion criterion was presented by 59.64% of donors. The prevalence of NAFLD was 94.73%, with 31.57% borderline nonalcoholic steatohepatitis and 5.26% nonalcoholic steatohepatitis. Steatosis was identified with 48.68% (preperfusion) and 64.03% (postperfusion) accuracy. NAFLD stratification was performed with 49.53% (preperfusion) and 46.29% (postperfusion) accuracy. Viability related to NAFLD was identified with 51.96% (preperfusion) and 48.52% (postperfusion) accuracy. Interobserver agreement was moderate for total VLS and poor for individual components of VLS. Although a standardized method was not reliable enough for visual evaluation of NALFD compared with pathology, efforts should be made to expand access to biopsy. Further studies are needed to understand whether the VLS needs to be adapted or even excluded in the liver transplant scenario, to assess the importance of ectoscopy related to posttransplant clinical outcomes, and to determine its role in graft selection.

The Effect of Non-Alcoholic Fatty Liver Disease on Weight Loss and Resolution of Obesity-Related Disorders After Bariatric Surgery

BackgroundPatients undergoing bariatric surgery have a high incidence of non-alcoholic fatty liver disease (NAFLD). However, the effect of NAFLD or non-alcoholic steatohepatitis (NASH) on the weight loss and resolution of obesity-related disorders is a matter of debate.MethodsIn this study, we compare the long-term outcomes after bariatric with the presence of NAFLD in the liver biopsy at the time of surgery.ResultsThe follow-up was available for 226 out of 288 patients. The mean follow-up time was 24.9 (± 13.6) months. The baseline histology showed that 112 patients (38.9%) had no NASH, 70 (24.3%) were borderline, and 106 (36.8%) had NASH. At follow-up, the mean BMI dropped from (52 ± 10.2) to (36.6 ± 8) kg/m 2. Excess weight loss (EWL) was similar in all NAFLD groups. Type 2 diabetes mellitus dropped from 35.7 to 11.4%, hypertension from 65.6 to 36.7%, hyperlipidemia from 62.3 to 33%, and obstructive sleep apnea from 37.5 to 14.9%. Only hyperlipidemia was significantly associated with NASH compared to the groups with no NASH or borderline NASH (p value = 0.002 and p value = 0.04, respectively) during the first two years of follow-up.ConclusionThe beneficial effects of bariatric surgery are evident across all patients with NAFLD. Patients with NASH have comparable outcomes regarding weight loss and resolution of obesity-related comorbidities.

Phosphatidylethanolamines Are Associated with Nonalcoholic Fatty Liver Disease (NAFLD) in Obese Adults and Induce Liver Cell Metabolic Perturbations and Hepatic Stellate Cell Activation.

Pathogenesis roles of phospholipids (PLs) in nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This study investigated the role of PLs in the progression of NAFLD among obese individuals via studying the alterations in serum PL composition throughout the spectrum of disease progression and evaluating the effects of specific phosphatidylethanolamines (PEs) on FLD development in vitro. A total of 203 obese subjects, who were undergoing bariatric surgery, were included in this study. They were histologically classified into 80 controls (C) with normal liver histology, 93 patients with simple hepatic steatosis (SS), 16 with borderline nonalcoholic steatohepatitis (B-NASH) and 14 with progressive NASH (NASH). Serum PLs were profiled by automated electrospray ionization tandem mass spectrometry (ESI-MS/MS). HepG2 (hepatoma cells) and LX2 (immortalized hepatic stellate cells or HSCs) were used to explore the roles of PL in NAFLD/NASH development. Several PLs and their relative ratios were significantly associated with NAFLD progression, especially those involving PE. Incubation of HepG2 cells with two phosphatidylethanolamines (PEs), PE (34:1) and PE (36:2), resulted in significant inhibition of cell proliferation, reduction of mitochondrial mass and membrane potential, induction of lipid accumulation and mitochondrial ROS production. Meanwhile, treatment of LX2 cells with both PEs markedly increased cell activation and migration. These effects were associated with a significant change in the expression levels of genes involved in lipogenesis, lipid oxidation, autophagy, apoptosis, inflammation, and fibrosis. Thus, our study demonstrated that elevated level of PEs increases susceptibility to the disease progression of obesity associated NAFLD, likely through a causal cascade of impacts on the function of different liver cells.

Comparative Analysis of Global Hepatic Gene Expression in Adolescents and Adults with Non-alcoholic Fatty Liver Disease.

To gain insights into the mechanisms underlying distinct nonalcoholic fatty liver disease (NAFLD) histological phenotypes between children and adults, we compared hepatic gene expression profiles associated with NAFLD phenotypes between the two age groups. Histological characteristics of intra-operative liver biopsies from adolescents and adults undergoing bariatric surgery were assessed by the same pathologist using the non-alcoholic steatohepatitis (NASH) Clinical Research Network scoring system. Hepatic gene expression was measured by microarray analysis. Transcriptomic signatures of histological phenotypes between the two groups were compared, with significance defined as p-value <0.05 and a fold change >1.5. In 67 adolescents and 76 adults, distribution of histological phenotypes was: not-NAFLD (controls) 51% vs 39%, NAFL 39% vs 37%, and NASH 10% vs 24%, respectively. There were 279 differentially expressed genes in adolescents and 213 in adults with NAFLD vs controls. In adolescents, transcriptomes for NAFL vs controls, and borderline vs definite NASH were undifferentiable, whereas in adults, NAFL and borderline NASH demonstrated a transcriptomic gradient between controls and definite NASH. When applied to adolescents, significant adult genes discriminated borderline and definite NASH from control and NAFL, but the majority of significant pediatric genes were not portable to adults. Genes associated with NASH in adolescents and adults showed some ontological consistency but notable differences. There is some similarity but major differences in the transcriptomic profiles associated with NAFLD between adolescents and adults with severe obesity. These data suggest different mechanisms contribute to the pathogenesis of NAFLD severity at different stages in life.

TH8.9 Impact of laparoscopic sleeve gastrectomy on fibrosis stage in patientswith child–A NASH–related cirrhosis

Abstract Introduction Bariatric surgery can improve non-alcoholic fatty liver disease (NAFLD). This work endeavored to evaluate laparoscopic sleeve gastrectomy (LSG) in cases with compensated non-alcoholic steatohepatitis (NASH)-related cirrhosis and its impact on fibrosis stage. Methods A prospective work involved 132 cases with Child-A NASH-related cirrhosis suffering from morbid obesity scheduled for LSG. They had preoperative assessment, wedge biopsy, and ultrasound-guided true-cut liver biopsy after 30 months. Patients with F4 fibrosis were included. Liver condition was assessed based on NALFD Activity Score (NAS).primary outcome measure was the impact of LSG on fibrosis stage and its relation to weight loss. Results Analysis included only 71 patients who completed the 30-month follow-up period. By the end of follow-up interval, there was a substantial weight loss with a reasonable resolution of comorbidities. median NAS decreased from 6 (1–8) to 3 (0–6) after surgery. Fibrosis score regressed to F2 in 19 patients (26.8%) and F3 in 29 (40.8%). Patients with improved scores had a significantly higher amount of weight loss (p &amp;lt; 0.001). Improvement was more frequent in males (p = 0.007). By 30 months after treatment, 53.8% of cases with borderline NASH and 36.8% of those with probable NASH showed complete resolution, and 44.7% of patients with NASH showed improvement. Steatosis improved in 74.6% of patients. Conclusion Patients with NASH-related liver cirrhosis of Child class A, LSG may be a secure approach for the management of morbid obesity. It has a long-term benefit for both obesity and liver condition with significant improvement of steatosis, steatohepatitis, and fibrosis.

Periodontal and Hepatic Parameters in Obese Patients Undergoing Bariatric Surgery.

Current discoveries imply a connection between periodontitis and metabolic associated fatty liver disease (MAFLD). This study aimed to determine the prevalence of periodontitis and MAFLD in obese patients with BMI >40, employing the most reliable diagnostic methods, namely liver biopsy, and detailed periodontal examination. Liver biopsy and periodontal examination were performed in 30 obese patients with BMI BMI >40 undergoing bariatric surgery. Kleiner's classification was used to determine non-alcoholic steatohepatitis (NAS) activity score, non-alcoholic steatohepatitis (NASH) and liver fibrosis. The periodontal condition was classified following the recent AAP/EFP classification. Patients were divided into periodontitis (PG) and non-periodontitis groups (NPG). Data on systemic health parameters were collected from patients' medical records. Descriptive statistics and simple statistical tests were used to determine the differences between the two groups. The prevalence of NASH in the sample was 43% (13/30), borderline NASH 37% (11/30), while fibrosis stage 1 was most common (72%, [22/30]). Periodontitis prevalence was 67% (20/30), while all non-periodontitis patients (33%; 10/30) exhibited gingivitis. PG and NPG did not differ in NAS or NASH prevalence (p > 0.05). However, the periodontitis group showed higher C-reactive protein levels, while NPG showed higher gamma-glutamyl transpeptidase levels (p < 0.05). The study results suggest the considerable prevalence of MAFLD, periodontitis and gingivitis in obese patients with BMI >40 undergoing bariatric surgery. Patients with periodontitis had higher CRP levels, while those with gingivitis presented higher gamma-glutamyl transpeptidase levels.

Longitudinal 16S rRNA Sequencing Reveals Relationships among Alterations of Gut Microbiota and Nonalcoholic Fatty Liver Disease Progression in Mice.

ABSTRACTNonalcoholic fatty liver disease (NAFLD) is a prevalent and progressive disease spectrum ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), yet there is no effective treatment and efficient noninvasive diagnostic method for NASH. The present study investigated the longitudinal alternations of gut microbiota in the Western diet (WD) induced murine NAFLD model using 16S rRNA sequencing. Evident steatosis and inflammation were detected in the liver at the 8th and 12th week, while prompted hepatic oxidative injury and fibrosis were found at the 16th week. In this progressive process, impaired bile acid (BA) metabolism plays a vital part. Long-term WD intervention alters microbial richness and composition in the intestine, shaping characteristic microbial feature correspondence to each NAFLD stage. Descending abundances of Clostridia and Ruminococcaceae were found in NAFLD progression, while inflammation-related microbes [Eubacterium]_fissicatena_group, Romboutsia, and Erysipelatoclostridium were verified to identify borderline NASH at 8th and 12th week, and BA-associated taxa Dubosiella, Bosea, Helicobacter, and Alistipes were recognized as special symbols reflecting the state of oxidative damage and fibrosis in NASH at 16th week. Further, feces and colon abundances of Akkermansia were verified to be depleted in the process of borderline NASH progressed to NASH, and exhibited substantial correlations with NAFLD indexes ALT, AST, TC, and TBA. These characteristic taxa were effective to identify NAFLD and NASH, and microbiota-derived predictive models for NAFLD and NASH exhibited great potential (AUC 0.983 and 0.784). These findings demonstrate that a core set of gut microbiome especially BA-related taxa may be adopted as a noninvasive diagnostic tool for NAFLD and NASH.IMPORTANCE This study concentrates on longitudinal alternations of gut microbiota in NAFLD progression and discovers the interrelationships between them. These findings may uncover the role of gut microbiota in NAFLD progression and identify novel noninvasive diagnostic tools for NAFLD based on microbial biomarkers.

Nonalcoholic Fatty Liver Disease in Living Donor Liver Transplant Recipients: A Histology-Based Study

Recurrent or de novo nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are common after liver transplantation (LT) and may be associated with rapid progression to fibrosis; however, there is limited data in this regard after living donor liver transplantation (LDLT). This is a retrospective study at a high volume LDLT center of all liver biopsies performed in patients with post-transplant NAFLD diagnosed on ultrasound of the abdomen. Liver biopsy was indicated for raised transaminases and/or high liver stiffness on TE. The association between these prebiopsy parameters and inflammation and fibrosis on histology was analyzed. Data are shown as mean±standard deviation or median (25-75 interquartile range). The study cohort consisted of 31 males and 3 females, aged 43±10 years. The LT to liver biopsy interval was 44 (28-68) months. The prebiopsy AST and ALT were 71 (38-119) and 66 (50-156), respectively. The histology suggested no nonalcoholic steatohepatitis (NASH) in 7 (20%), borderline NASH in 15 (44%), and NASH in 12 (35%) patients. A total of 15 patients (44%) had stage 1 or stage 2 fibrosis. The proportion of patients having fibrosis was significantly higher in patients with NASH (83%) compared to patients with borderline NASH (33%) or no NASH (none had fibrosis, P= 0.001). Among 18 patients who underwent TE (on FibroScan), liver stiffness was significantly higher in patients with fibrosis [18.1 (9.7-22.5)] than in those without fibrosis [9.7 (4.0-12.7); P= 0.043]. Over a third of the LDLT recipients with post-transplant NAFLD developed NASH, and nearly half, borderline NASH 3-5 years after transplant. Most with established NASH also had fibrosis on histology. Prevention of risk factors and early diagnosis is warranted in these patients.

Hyperacetylation of Toll‐like receptor 4 (TLR4): a potential factor contributing to non‐alcoholic liver disease (NAFLD), a silent killer in obesity

BackgroundObesity frequently leads to non‐alcoholic fatty liver disease (NAFLD), the most common liver problem affecting the American population. In fact, the prevalence of NAFLD in adult Americans ranges from 25‐46%. To date, there is no specific treatment for NAFLD. In severe cases, NAFLD can lead to fibrosis and cirrhosis which evolves into nonalcoholic steatohepatitis (NASH). Most patients with NAFLD experience no symptoms, making it a silent killer. Evidence has suggested that Toll‐like receptor 4 (TLR4) signaling, a key component of innate immunity, is implicated in the pathogenesis of NAFLD; however, the mechanisms of TLR4 activation remain unclear. We hypothesized that hyperacetylation of TLR4 leads to its overactivation in obesity, contributing to NAFLD development.MethodsEight‐week‐old male C57BL/6 mice were randomized into two experimental groups: the control group (n=4) received a regular chow diet (5% fat, 48.7% carbohydrates [3.2% sucrose], 24.1% protein) and the Western diet (WD) group (n=4) received a WD (21% fat, 50% carbohydrates [34% sucrose], and 20% protein) for 36 weeks. Body weight was obtained and intraperitoneal glucose tolerance test (IPGTT) was performed over the course of the dietary protocol at weekly and monthly intervals, respectively. During terminal experiments, liver tissue was isolated and processed for cross‐section histology. Staining with H&amp;E and Oil‐Red‐O were used for grading of liver injury with the NAFLD Score, which involves summation of steatosis (0–3), lobular inflammation (0–3), and hepatocellular ballooning (0–2) scores. A final score of 0–2 indicates no NASH, 3–4 indicates borderline NASH, and 5–8 indicates NASH. TLR4 and its downstream protein expression was detected by western blot and immunoprecipitation was utilized to determine the acetylation levels of TLR4.ResultsThe WD group exhibited increased body weight (41.22 ± 7.71 g vs 29.94 ± 1.16 g controls, p&lt;0.05) and liver weight (1.27 ± 0.0.07 g vs 1.27 ± 0.07 g controls, p&lt;0.05). Results from IPGTT demonstrated that male mice develop early intolerance to glucose, within 8 weeks on WD. Hepatic histology showed ballooned hepatocytes, lobular inflammation, and steatosis, confirming presence of NAFLD with borderline NASH. Livers from the WD group exhibited increased TLR4 expression (1.4‐fold increase, p&lt;0.05). Of note, this was accompanied by an increase in TLR4 signaling in WD livers as confirmed by elevated expression of the downstream signaling protein TNF receptor associated factor 6 (TRAF6) (0.8‐fold increase, p&lt;0.05). Strikingly, immunoprecipitation assay revealed that TLR4 is hyperacetylated in the livers from the WD group.ConclusionsOur results demonstrate for the first time that hepatic TLR4 is hyperacetylated in obesity‐related NAFLD. This hyperacetylation may serve as a trigger for the TLR4/TRAF6 signaling activation and may prove to be crucial to the development of NAFLD and NASH in obesity.

Study the level of selenoprotein P in Egyptian patients with nonalcoholic fatty liver

ObjectivesThe study aims to evaluate circulating selenoprotein P levels in patients with the nonalcoholic fatty liver disease compared with healthy controls.BackgroundNonalcoholic fatty liver disease represents a spectrum of liver diseases with key stages consisting of nonalcoholic fatty liver, nonalcoholic steatohepatitis, fibrosis, and eventual cirrhosis. Nonalcoholic fatty liver disease affects more than 20% of the population worldwide.MethodsThis is a case–control, retrospective study that was conducted on 72 patients with nonalcoholic fatty liver disease (cases), and 36 healthy volunteers without nonalcoholic fatty liver disease or any chronic liver disease as controls. Ultrasonography of the liver of all patients will be done and performed by the same operator using a Toshiba Apilo XV scanner equipped with a broadband 3.5-MHz curved array probe to assess the presence of liver steatosis (bright liver), evaluation of the liver size, and focal region.ResultsThere was a statistically significant difference between groups regarding serum selenoprotein P with a higher level among healthy controls (P value < 0.001).ConclusionThe present study demonstrated that hepatokine selenoprotein P concentrations were decreased in patients with definite nonalcoholic steatohepatitis compared with controls but not different between controls, simple steatosis, and borderline nonalcoholic steatohepatitis.

Association of Body Composition and Sarcopenia with NASH in Obese Patients.

Obese patients often suffer from sarcopenia or sarcopenic obesity (SO) that can trigger inflammatory diseases including non-alcoholic steatohepatitis (NASH). Sarcopenia and SO can be diagnosed through measuring parameters of body composition such as skeletal muscle mass (SMM), skeletal muscle index (SMI) and fat mass (FM) obtained by bioelectrical impedance analysis (BIA). The aim of this study was to assess the relationship of body composition and NASH in patients with obesity. A total of 138 patients with obesity that underwent bariatric surgery were included in this study. BIA was used to estimate body composition. A liver biopsy was taken intraoperatively and histological assessment of NASH was performed. A total of 23 patients (17%) were classified as NASH and 65 patients (47%) met the criteria for borderline NASH. Body mass index (BMI) was significantly higher in patients with NASH compared to borderline NASH and no NASH (56.3 kg/m2 vs. 51.6 kg/m2 vs. 48.6 kg/m2, p = 0.004). Concerning body composition, FM, but also SMM and SMI were significantly higher in patients with NASH (p-values 0.011, 0.005 and 0.006, resp.). Fat mass index (FMI) and weight-adjusted skeletal muscle index (SMI_weight) failed to reach statistical significance (p-values 0.067 and 0.661). In patients with obesity, higher FM were associated with NASH. Contrary to expectations, SMM and SMI were also higher in patients with NASH. Therefore, higher body fat, rather than sarcopenia and SO, might be decisive for development of NASH in patients with obesity.

Evaluation of NAFLD and fibrosis in obese patients \u2013 a comparison of histological and clinical scoring systems

BackgroundNon-alcoholic fatty liver disease (NAFLD) is a frequent condition in obese patients and regularly progresses to non-alcoholic steatohepatitis (NASH) and subsequent cirrhosis. Histologic evaluation is the gold standard for grading and staging, but invasive biopsies are associated with obvious risks. The aim of this study was to evaluate different non-invasive tools for screening of NAFLD and fibrosis in obese patients.MethodsIn a prospective cohort study liver specimens of 141 patients were taken during bariatric surgery. Serological parameters and clinical data were collected and the following scores calculated: NASH clinical scoring system (NCS), aspartate aminotransferase to platelet ratio index (APRI), FIB-4 as well as NAFLD fibrosis score (NFS). Liver function capacity was measured preoperatively by LiMAx test (enzymatic capacity of cytochrome P450 1A2). Intraoperative liver biopsies were classified using NAFLD activity score (NAS) and steatosis, activity and fibrosis (SAF) score.ResultsAPRI was able to differentiate between not NASH and definite NASH with a sensitivity of 74% and specificity of 67% (AUROC 0.76). LiMAx and NCS also showed significant differences between not NASH and definite NASH. No significant differences were found for NFS and Fib-4. APRI had a high sensitivity (83%) and specificity (76%) in distinguishing fibrosis from no fibrosis (AUROC = 0.81). NCS and Fib-4 also revealed high AUROCs (0.85 and 0.67), whereas LiMAx and NFS did not show statistically significant differences between fibrosis stages. Out of the patients with borderline NASH in the histologic NAS score, 48% were classified as NASH by SAF score.ConclusionsAPRI allows screening of NAFLD as well as fibrosis in obese patients. This score is easy to calculate and affordable, while conveniently only using routine clinical parameters. Using the NAS histologic scoring system bears the risk of underdiagnosing NASH in comparison to SAF score.

Progression of Fatty Liver Disease in Children Receiving Standard of Care Lifestyle Advice

Nonalcoholic fatty liver disease (NAFLD) is the most common pediatric chronic liver disease. Little is known about outcomes in recognized youth. We compared paired liver biopsies from 122 of 139 children with NAFLD (74% male; 64% white; 71% Hispanic; mean age, 13 ± 3 years; age range, 8-17 years) who received placebo and standard of care lifestyle advice in 2 double-blind, randomized clinical trials within the nonalcoholic steatohepatitis (NASH) clinical research network from 2005 through 2015. We analyzed histologic changes with respect to baseline and longitudinal change in clinical variables using regression analysis. At enrollment, 31% of the children had definite NASH, 34% had borderline zone 1 NASH, 13% had borderline zone 3 NASH, and 21% had fatty liver but not NASH. Over a mean period of 1.6 ± 0.4 years, borderline or definite NASH resolved in 29% of the children, whereas 18% of the children with fatty liver or borderline NASH developed definite NASH. Fibrosis improved in 34% of the children but worsened in 23%. Any progression to definite NASH and/or in fibrosis was associated with adolescent age, and higher waist circumference, levels of alanine or aspartate aminotransferase, total and low-density lipoprotein cholesterol at baseline (<0.05), and over follow-up time, with increasing level of alanine aminotransferase, hemoglobin A1C (P<.05), gamma-glutamyl transferase and development of type 2 diabetes (P<.01). Increasing level of gamma-glutamyl transferase was also associated with reduced odds of any improvement (P= .003). One-third of children with NAFLD enrolled in placebo groups of clinical trials had histologic features of progression within 2 years, in association with increasing obesity and serum levels of aminotransferases and loss of glucose homeostasis.

Impact of laparoscopic sleeve gastrectomy on fibrosis stage in patients with child-A NASH-related cirrhosis.

Bariatric surgery can improve non-alcoholic fatty liver disease (NAFLD). Yet data on the effect on fibrosis are insufficient and controversial. This work endeavored to evaluate the safety of laparoscopic sleeve gastrectomy (LSG) in cases that have compensated non-alcoholic steatohepatitis (NASH)-related cirrhosis and its impact on fibrosis stage. The current prospective work involved 132 cases with Child-A NASH-related cirrhosis suffering from morbid obesity scheduled for LSG. They were subjected to preoperative assessment, wedge biopsy, and ultrasound-guided true-cut liver biopsy after 30months. Patients were included if proved to have F4 fibrosis initially. The liver condition was assessed based on the NALFD Activity Score (NAS). The primary outcome measure was the impact of LSG on fibrosis stage and its relation to weight loss. The analysis included only 71 patients who completed the 30-month follow-up period. By the end of the follow-up interval, there was a substantial weight loss with a reasonable resolution of comorbidities. The median NAS decreased significantly from 6 (1-8) to 3 (0-6) after surgery. Fibrosis score regressed to F2 in 19 patients (26.8%) and F3 in 29 (40.8%). Patients with improved scores had a significantly higher amount of weight loss (p < 0.001). Improvement was more frequent in males (p = 0.007). By 30months after treatment, 53.8% of cases with borderline NASH and 36.8% of those with probable NASH showed complete resolution, and 44.7% of patients with NASH showed improvement. Steatosis improved in 74.6% of patients (p < 0.001). In patients with NASH-related liver cirrhosis of Child class A, LSG may be a secure approach for the management of morbid obesity. It has a long-term benefit for both obesity and liver condition with significant improvement of steatosis, steatohepatitis, and fibrosis.

Imbalanced insulin substrate-1 and insulin substrate-2 signaling trigger hepatic steatosis in vitamin D deficient rats: 8-methoxypsoralen, a vitamin D receptor ligand with a promising anti-steatotic action

The exact role of VD deficiency in the development of non-alcoholic fatty liver disease (NAFLD) remains unknown. In this study, we induced VD deficiency by feeding Female Sprague-Dawley rats a VD deficient (VDD) Diet and studied the hepatic changes associated with VD deficiency. Simultaneously, we provided the VDD rats with VD or 8-methoxy psoralen (8-MOP), a suggested vitamin D receptor agonist, to test the reversibility of the hepatic changes. VDD Rats developed borderline non-alcoholic steatohepatitis (NASH) with considerable elevation in hepatic triglycerides, total cholesterol, and malondialdehyde.Furthermore, VD deficiency induced the expression of crucial enzymes and transcription factors involved in denovo lipogenesis, which justified the hepatic lipid accumulation. Insulin receptor signaling was affected by VD deficiency, demonstrated by the elevation in insulin substrate-1 (IRS1) and reduction in insulin substrate-2 (IRS2) signaling. Treatment with VD or 8-MOP attenuated IRS1 signaling and its downstream targets, leading to a decline in de novo lipogenesis, while the elevation in IRS2 expression resulted in the nuclear exclusion of forkhead box O1 (FoxO1) and diminished gluconeogenesis, a vital source of acetyl-CoA for de novo lipogenesis. Moreover, 8-MOP and Calcipotriol modulated insulin signaling in human hepatocyte cell line L02, which highlighted the crucial role of VD in the regulation of hepatic lipid contents in rats and humans. Silencing of the vitamin D receptor expression in L02 diminished the inhibitory effect of Calcipotriol and 8-MOP on fatty acid synthase and acetyl- CoA carboxylase 1 and provided the evidence that 8-MOP actions mediated via vitamin D receptor.

Novel Application of the Traditional Lipid Ratios as Strong Risk Predictors of NASH.

PurposeLimited data are available regarding the role of triglycerides, cholesterol and lipoproteins ratios as risk factors for nonalcoholic fatty liver disease (NAFLD) progression. In the present study, the investigators aimed to investigate the value of cardiovascular risk ratios of triglycerides, cholesterol, and lipoproteins as predictors of nonalcoholic steatohepatitis (NASH) and the correlation of such ratios with disease severity.Patients and MethodsThis study included 131 overweight and obese patients with NAFLD who were divided into NASH, borderline NASH, and non-NASH fatty liver (NNFL) subgroups according to NAFLD activity score (NAS) in liver biopsy, and 60 healthy participants as a control group. Lipid profile and lipid ratios including triglycerides/HDL (TGs/HDL), low-density lipoprotein/high-density lipoprotein (LDL/HDL) and total cholesterol/HDL (TC/HDL) ratios were measured.ResultsSignificantly higher triglycerides/HDL ratio was found in NASH and borderline NASH, while higher cholesterol/HDL ratio was found in borderline NASH in comparison to controls. There were positive correlations between TGs/HDL and steatosis, ballooning, inflammation, BMI, and NAS; between LDL/HDL and inflammation; and between cholesterol/HDL and BMI, steatosis, and NAS. The highest AUC was that of TG/HDL (0.744), at a cut-off point of 3, with 71.8% sensitivity and 76.8% specificity.ConclusionTriglycerides, cholesterol and lipoprotein ratios showed higher levels in NASH and correlated with NAFLD severity, and above these cut-off ratios, we can rule in the NASH cases which confer also the cardiovascular morbidities. Structured lipid ratios could serve as markers to screen NASH progression from simple steatosis cases and clarify the link of NASH with the cardiovascular risk prediction in overweight and obese patients.

Diagnostic performance on multiple parameters of real-time ultrasound shear wave elastography for evaluating nonalcoholic fatty liver disease: A rabbit model.

To study the diagnostic value of real-time ultrasound shear wave elastography (US-SWE) in evaluating the histological stages of nonalcoholic fatty liver disease (NAFLD) in a rabbit model. Twenty-one 8-week-old rabbits were fed a high-fat, high-cholesterol diet (experimental groups), and seven rabbits were fed a standard diet (control group). All rabbits underwent real-time US-SWE at various time points to document the histological stages of NAFLD. We categorized the histological stages as normal, NAFL, borderline nonalcoholic steatohepatitis (NASH), and NASH. We measured the elastic modulus of the liver parenchyma and analyzed the diagnostic efficacy of real-time US-SWE using the area under receiver operating characteristic curve (AUC) for the four histological stages. The mean, minimum, and maximum elastic modulus increase for NAFL, borderline NASH, and NASH. For the mean, minimum, and maximum elastic modulus, AUCs are 0.891 (95% confidence interval [CI]: 0.716-0.977), 0.867 (95% CI: 0.686-0.965), and 0.789 (95% CI:0.594-0.919) for differentiating normal liver from liver with NAFLD, respectively; AUCs are 0.846 (95% CI: 0.660-0.954), 0.818 (95% CI: 0.627-0.937), and 0.797 (95% CI:0.627-0.913) for differentiating normal liver or liver with NAFL from liver with borderline NASH or NASH, respectively; AUCs are 0.889 (95% CI: 0.713-0.976), 0.787 (95% CI: 0.591-0.918), and 0.895 (95% CI:0.720-0.978) for differentiating liver with NASH from liver with lower severity NAFLD or normal liver, respectively. Real-time US-SWE is an accurate, noninvasive technique for evaluating the histological stages of NAFLD by measuring liver stiffness. We recommend using the mean elastic modulus to differentiate the histological stages, with the minimum and maximum elastic modulus as valuable complements.

Association of Hepatic Global DNA Methylation and Serum One-Carbon Metabolites with Histological Severity in Patients with NAFLD.

Clinical relevance of global DNA methylation and one-carbon metabolite levels with histological severity remains uncertain in patients with nonalcoholic fatty liver disease (NAFLD). This study aimed to evaluate hepatic global DNA methylation and serum one-carbon metabolite concentrations in patients with NAFLD and the possible associations of these parameters with liver histology. Liver biopsies from 18 control participants and 47 patients with NAFLD were evaluated. The hepatic global DNA methylation level was significantly lower in the NAFLD group than in the control group among participants with overweight. Participants with moderate inflammation and mild fibrosis had significantly lower levels of global DNA methylation than those without these characteristics. Participants with borderline nonalcoholic steatohepatitis had significantly lower global DNA methylation levels than controls. The hepatic global DNA methylation level tended to decrease with the increasing hepatic inflammation grade and disease progression. The NAFLD group had a significantly higher serum homocysteine concentration than the control group among participants with overweight. This level tended to increase with increasinghepatic steatosis grade and disease progression. Patients with NAFLD exhibited lower hepatic levels of global DNA methylation and elevated serum homocysteine concentrations, which are associated with the histological severity of NAFLD.

Evaluation of diffusion kurtosis imaging in stratification of nonalcoholic fatty liver disease and early diagnosis of nonalcoholic steatohepatitis in a rabbit model

PurposeTo examine the feasibility of MR diffusion kurtosis imaging (DKI) for characterizing nonalcoholic fatty liver disease (NAFLD) and diagnosing nonalcoholic steatohepatitis (NASH). MethodsThirty-two rabbits on high fat diet with different severities of NAFLD were imaged at 3 T MR including diffusion weighted imaging (DWI) and DKI using b values of 0, 400, 800 s/mm2 with 15 diffusion directions at each b value. Apparent diffusion coefficient (ADC) was derived from the linear exponential DWI model. Mean diffusion (MD) and mean kurtosis (MK) were derived from the quadratic exponential model of DKI. Correlations between MR parameters and hepatic pathology determined by the NAFLD activity scoring system were analyzed by Spearman rank correlation analysis. Receiver operating characteristic analyses were applied to determine the cutoff values of MD, MK as well as ADC in distinguishing NASH from non-NASH. The diagnostic efficacies of MD and MK in detecting NASH were compared with that of ADC. ResultsValues for ADC and MD significantly decreased as the severity of NAFLD increased (ρ = −0.529, −0.904, respectively; P < 0.05). MK values significantly increased as the severity of NAFLD increased (ρ = 0.761; P < 0.05). In addition, both MD and MK values were significantly different between borderline NASH and NASH groups (MD: 1.729 ± 0.144 vs. 1.458 ± 0.240[×10−3 mm2/s]; MK: 1.096 ± 0.079 vs. 1.237 ± 0.180; P < 0.05). Moreover, there was a significantly higher area under the curve (AUC) for both MD (0.955) and MK (0.905), as compared to ADC (0.736). ConclusionDiffusion kurtosis imaging was feasible for stratifying NAFLD, and more accurately discriminated NASH from non-NASH when compared with DWI.

Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease

The intestinal microbiome might affect the development and severity of nonalcoholic fatty liver disease (NAFLD). We analyzed microbiomes of children with and without NAFLD. We performed a prospective, observational, cross-sectional study of 87 children (age range, 8-17 years) with biopsy-proven NAFLD and 37 children with obesity without NAFLD (controls). Fecal samples were collected and microbiome composition and functions were assessed using 16S ribosomal RNA amplicon sequencing and metagenomic shotgun sequencing. Microbial taxa were identified using zero-inflated negative binomial modeling. Genes contributing to bacterial pathways were identified using gene set enrichment analysis. Fecal microbiomes of children with NAFLD had lower α-diversity than those of control children (3.32 vs 3.52, P= .016). Fecal microbiomes from children with nonalcoholic steatohepatitis (NASH) had the lowest α-diversity (control, 3.52; NAFLD, 3.36; borderline NASH, 3.37; NASH, 2.97; P= .001). High abundance of Prevotella copri was associated with more severe fibrosis (P= .036). Genes for lipopolysaccharide biosynthesis were enriched in microbiomes from children with NASH (P < .001). Classification and regression tree model with level of alanine aminotransferase and relative abundance of the lipopolysaccharide pathway gene encoding 3-deoxy-d-manno-octulosonate 8-phosphate-phosphatase identified patients with NASH with an area under the receiver operating characteristic curve value of 0.92. Genes involved in flagellar assembly were enriched in the fecal microbiomes of patients with moderate to severe fibrosis (P < .001). Classification and regression tree models based on level of alanine aminotransferase and abundance of genes encoding flagellar biosynthesis protein had good accuracy for identifying case children with moderate to severe fibrosis (area under the receiver operating characteristic curve, 0.87). In an analysis of fecal microbiomes of children with NAFLD, we associated NAFLD and NASH with intestinal dysbiosis. NAFLD and its severity were associated with greater abundance of genes encoding inflammatory bacterial products. Alterations to the intestinal microbiome might contribute to the pathogenesis of NAFLD and be used as markers of disease or severity.