Resolution Of Nonalcoholic Fatty Liver Disease Research Articles

New Nonalcoholic Fatty Liver Disease and Fibrosis Progression Associate With the Risk of Incident Chronic Kidney Disease.

Little is known about the link between nonalcoholic fatty liver disease (NAFLD) evolution and incident chronic kidney disease (CKD). We aim to assess the associations of NALFD status changes and NAFLD fibrosis progression with the risk of incident CKD. We conducted a community-based prospective study that included participants aged 40 years or older and free of CKD at baseline in 2010, with follow-up evaluations after a mean of 4.4 years. NAFLD was diagnosed by ultrasonography and NAFLD fibrosis score (NFS) was used to evaluate fibrosis stage and progression. CKD was defined by estimated glomerular filtration rate or urine albumin-to-creatinine ratio. All the measurements were performed at baseline and follow-up examination. Among 4042 participants with 4 NAFLD status change groups, incident NAFLD was associated with an increased risk of incident CKD (odds ratio [OR] = 1.44; 95% CI, 1.003-2.06; P = 0.048) compared with non-NAFLD after adjustments for the confounders, including evolution of diabetes, hypertension, and obesity, in addition to the baseline levels. However, the risk of incident CKD was not significantly different between NAFLD resolution and persistent NAFLD. Among 534 participants in the persistent NAFLD group, fibrosis progression from low NFS to intermediate or high NFS was associated with a significantly increased risk of incident CKD compared with stable fibrosis in low NFS (OR = 2.82; 95% CI, 1.22-6.56; P = 0.016). NAFLD development and fibrosis progression are associated with increased risk of incident CKD.

The complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments.

Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions worldwide. NAFLD and type 2 diabetes mellitus (T2DM) are known to frequently coexist and act synergistically to increase the risk of adverse (hepatic and extra-hepatic) clinical outcomes. T2DM is also one of the strongest risk factors for the faster progression of NAFLD to nonalcoholic steatohepatitis, advanced fibrosis or cirrhosis. However, the link between NAFLD and T2DM is more complex than previously believed. Strong evidence indicates that NAFLD is associated with an approximate twofold higher risk of developing T2DM, irrespective of obesity and other common metabolic risk factors. This risk parallels the severity of NAFLD, such that patients with more advanced stages of liver fibrosis are at increased risk of incident T2DM. In addition, the improvement or resolution of NAFLD (on ultrasonography) is associated with a reduction of T2DM risk, adding weight to causality and suggesting that liver-focused treatments might reduce the risk of developing T2DM. This Review describes the evidence of an association and causal link between NAFLD and T2DM, discusses the putative pathophysiological mechanisms linking NAFLD to T2DM and summarizes the current pharmacological treatments for NAFLD or T2DM that might benefit or adversely affectthe risk of T2DM or NAFLD progression.

Electronic Health Record-Based Genome-Wide Meta-Analysis Identifies New Susceptibility Loci for Non-Alcoholic Fatty Liver Disease

Background: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of liver disease. Observational studies documented associations of NAFLD with several chronic and infectious diseases but whether these associations underlie causal effects is unknown. The molecular mechanisms and genetic architecture of NAFLD are poorly understood. Our objectives were to identify genetic loci associated with NAFLD and determine whether the presence of NAFLD was causally associated with human diseases. Methods: We created a NAFLD genetic instrument through the identification of independent single-nucleotide polymorphisms (SNPs) associated with NAFLD in a meta-analysis of genome-wide association study (GWAS) (6715 cases and 682,748 controls). Using inverse-variance weighted Mendelian Randomization (MR), we investigated the impact of NAFLD on human disease-related phenotypes in the UK Biobank and FinnGen cohorts as well as in the COVID-19 host genetics initiative. Results: We first performed a GWAS meta-analysis of four cohorts and found variants significantly associated with NAFLD (p<5.0E-8) at six genetic loci (MTARC1, GCKR, TRIB1, LMO3, SUGP1 [TM6SF2] and PNPLA3). Using a risk factor informed Bayesian approach (bGWAS), we identify variants at three additional loci (LPL, FTO, and APOE). To determine if the association between NAFLD and human diseases shows evidence of causality, we performed MR across the human disease-related phenome (>800 diseases) using a genetic instrument for NAFLD. Results of these analyses suggest that NAFLD was not causally associated with diseases outside the spectrum of liver diseases. We also found no causal association between genetically predicted NAFLD and COVID-19-related outcomes. Conclusions: This study identified several new genetic loci associated with NAFLD. NAFLD was not causally associated with diseases outside those of the spectrum of liver diseases. This finding suggests that the resolution of NAFLD might not prevent other diseases previously associated with NAFLD.

Improving insulin sensitivity, liver steatosis and fibrosis in type 2 diabetes by\xa0a food-based digital education-assisted lifestyle intervention program: a feasibility study

PurposeRecent trials demonstrated remission of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) following formula diet-induced weight loss. To improve the outreach for populations in need, many mobile health apps targeting weight loss have been developed with limited scientific evaluation of these apps. The present feasibility study investigated the effects of a novel approach incorporating a regular ‘whole food-based’ low-calorie diet combined with app-based digital education and behavioral change program on glucose metabolism and disease management.MethodsTwenty-four individuals with type 2 diabetes followed this approach supported by weekly coaching calls for 12 weeks. Phenotyping included bioimpedance analysis, mixed-meal tolerance test, magnetic resonance spectroscopy and transient elastography for assessing liver fat content and liver stiffness.ResultsOver 12 weeks, participants reduced their body weight by 9% (97 ± 13 to 88 ± 12 kg), body mass index (BMI; 33 ± 5 to 29 ± 4 kg/m2), total fat mass (31 ± 10 to 27 ± 10%) (all p < 0.01) and liver fat by 50% alongside with decreased liver stiffness. Target HbA1c (< 6.5%) was achieved by 38% and resolution of NAFLD (liver fat content < 5.6%) was observed in 30% of the participants.ConclusionThis novel approach combining digital education with a low-calorie diet results in effective improvements of body weight, glycemic control and NAFLD and could complement existing care for patients with type 2 diabetes.Trial registrationNCT04509245

Caspase-Cleaved Keratin 18 Measurements Identified Ongoing Liver Injury after Bariatric Surgery.

Bariatric surgery has emerged as an effective treatment option in morbidly obese patients with non-alcoholic fatty liver disease (NAFLD). However, worsening or new onset of non-alcoholic steatohepatitis (NASH) and fibrosis have been observed. Caspase-cleaved keratin 18 (ccK18) has been established as a marker of hepatocyte apoptosis, a key event in NASH development. Thus, ccK18 measurements might be feasible to monitor bariatric surgery patients. Clinical data and laboratory parameters were collected from 39 patients undergoing laparoscopic Roux-en-Y gastric bypass at six timepoints, prior to surgery until one year after the procedure. ccK18 levels were measured and a high-throughput analysis of serum adipokines and cytokines was carried out. Half of the cohort’s patients (20/39) presented with ccK18 levels indicative of progressed liver disease. 21% had a NAFLD-fibrosis score greater than 0.676, suggesting significant fibrosis. One year after surgery, a mean weight loss of 36.87% was achieved. Six and twelve months after surgery, ccK18 fragments were significantly reduced compared to preoperative levels (p < 0.001). Yet nine patients did not show a decline in ccK18 levels ≥ 10% within one year postoperatively, which was considered a response to treatment. While no significant differences in laboratory parameters or ccK18 could be observed, they presented with a greater expression of leptin and fibrinogen before surgery. Consecutive ccK18 measurements monitored the resolution of NAFLD and identified non-responders to bariatric surgery with ongoing liver injury. Further studies are needed to elicit the pathological mechanisms in non-responders and study the potential of adipokines as prognostic markers.

Exercise improves lipid droplet metabolism disorder through activation of AMPK-mediated lipophagy in NAFLD

AimTo emphasize the mechanism of the effect of exercise on lipid droplet (LD) metabolism disorder in nonalcoholic fatty liver disease (NAFLD). Main methodsC57BL/6J mice were randomly divided into three groups: The first group was fed with a normal diet (CON), the second group was fed a high-fat diet (HF), and finally group with a high-fat diet intervention and swim training (HF-EX). The total intervention period was 16 weeks. RT-PCR and Western blot were performed to evaluate the effect of exercise on LDs metabolism and the AMPK pathway. Histopathological examinations and immunofluorescence were performed to evaluate the lipid deposition and lipophagy in the liver. Key findingsExercise reduced liver steatosis and insulin resistance along with the stimulation of AMPK/SIRT1 signaling and downstream regulation of lipid metabolism. In addition, exercise increased the expression of autophagy marker and colocalization of LC3 and LAMP1 with LDs. SignificanceExercise stimulated AMPK/SIRT1 and activated lipophagy in NAFLD.Enhancing lipophagy may be one of the key mechanisms of regulation and resolution of NAFLD by exercise.

Gastric Bypass Increases Circulating Bile Acids and Activates Hepatic Farnesoid X Receptor (FXR) but Requires Intact Peroxisome Proliferator Activator Receptor Alpha (PPARα) Signaling to Significantly Reduce Liver Fat Content

BackgroundWe interrogate effects of gastric bypass (RYGB), compared with a low-calorie diet, on bile acid (BA), liver fat, and FXR, PPARα, and targets in rats with obesity and non-alcoholic fatty liver disease (NAFLD). MethodsMale Wistar rats received a high-fat diet (obese/NAFLD, n=24) or standard chow (lean, n=8) for 12 weeks. Obese/NAFLD rats had RYGB (n=11), sham operation pair-fed to RYGB (pair-fed sham, n=8), or sham operation (sham, n=5). Lean rats had sham operation (lean sham, n=8). Post-operatively, five RYGB rats received PPARα antagonist GW6417. Sacrifice occurred at 7 weeks. We measured weight changes, fasting total plasma BA, and liver % steatosis, triglycerides, and mRNA expression of the nuclear receptors FXR, PPARα, and their targets SHP and CPT-I. ResultsAt sacrifice, obese sham was heavier (p<0.01) than all other groups that had lost similar weight loss. Obese sham had lower BA levels and lower hepatic FXR, SHP, and CPT-I mRNA expression than lean sham (P<0.05, for all comparisons). RYGB had increased BA levels compared with obese and pair-fed sham (P<0.05, for both), while pair-fed sham had BA levels, similar to obese sham. Compared with pair-fed sham, RYGB animals had increased liver FXR and PPARα expression and signaling (P<0.05). Percentage of steatosis was lower in RYGB and lean sham, relative to obese and pair-fed sham (P<0.05, for all comparisons). PPARα inhibition after RYGB resulted in similar weight loss but higher liver triglyceride content (P=0.01) compared with RYGB alone. ConclusionsRYGB led to greater liver fat loss than low-calorie diet, an effect associated to increased fasting BA levels and increased expression of modulators of liver fat oxidation, FXR, and PPARα. However, intact PPARα signaling was necessary for resolution of NAFLD after RYGB.

Metabolic and Hepatic Effects of Energy-Reduced Anti-Inflammatory Diet in Younger Adults with Obesity.

Background Associated with epidemics of obesity, nonalcoholic fatty liver disease (NAFLD) is becoming the most prevalent liver disease worldwide. The cornerstone of therapy for NAFLD is lifestyle intervention, mainly focused on weight loss. Significant weight loss results from energy-restricted diets, regardless of macronutrient distribution. An anti-inflammatory diet was related to lower odds of NAFLD among daily alcohol drinkers and individuals with metabolic syndrome. This study aims to evaluate the effect of an energy-reduced anti-inflammatory diet on liver status in younger adults with obesity after a 6-month follow-up. Methods A two-arm randomized controlled trial surveyed 81 participants' (mean age, 43 years) anthropometric and body composition changes. Metabolic status was determined with glycaemic and lipid status, inflammatory status with hs-CRP, IL-6, and TNF-α, and liver status with liver enzymes, NAFLD-FLS, FLI, and FIB-4 indices. The inflammatory potential of the diet was assessed by the Dietary Inflammatory Index, DII®. Results Energy-restricted anti-inflammatory diet resulted in significant weight loss (−7.1%, p < 0.001), in reducing the visceral adiposity (−22.3%, p < 0.001), metabolic (HOMA-IR, −15.5%; total cholesterol, −5.3%; LDL-C, −4.6%; triglycerides, −12.2%), and inflammatory biomarkers (hs-CRP, −29.5%; IL-6, −18.2%; TNF-α, −34.2%), with significant improvement of liver parameters (NAFLD-FLS, −143.4%; FLI, −14.3%; FIB-4, −2.5%). Conclusion The study showed the effectiveness of the anti-inflammatory diet with significant improvement of liver parameters in younger adults with obesity, which may reinforce the effectiveness of nutrition-based lifestyle programs, with an anti-inflammatory dietary approach for the treatment and resolution of NAFLD.

Dynamics of hepatic steatosis resolution and changes in gut microbiome with weight loss in nonalcoholic fatty liver disease.

BackgroundWeight loss is recommended as the primary treatment for nonalcoholic fatty liver disease (NAFLD). However, the magnitude and velocity of hepatic steatosis resolution with weight loss is unclear, making it difficult to counsel patients seeking weight loss for treatment of NAFLD. The aim of this study was to determine the rate of hepatic steatosis improvement and stool microbiome changes associated with rapid diet‐induced weight loss in NAFLD.MethodsFourteen NAFLD patients (mean ± standard deviation, body mass index [BMI] 36.4 ± 4 kg/m2) enrolled in a 12‐week meal replacement program underwent frequent measurement of Fibroscan‐controlled attenuation parameter (CAP). Magnetic resonance imaging (MRI‐Dixon method) for hepatic fat quantitation and stool microbiome analysis (16S rRNA gene sequencing) were completed in 11 subjects at baseline and Week 12.ResultsAt Week 12, mean (95% confidence interval) weight loss was −13.4 (−15.2, −11.5)% and CAP score −26.6 (−35.6, −17.6)% (both Ps < 0.001). CAP scores changed at a rate of −4.9 dB/m/kg (−30.1 dB/m per unit BMI) in Weeks 1–4 and −0.6 dB/m/kg (−2.4 dB/m per unit BMI) in Weeks 8–12. MRI‐determined hepatic fat fraction decreased by −74.1% (p < 0.001) at a rate of −0.51%/kg (−3.19% per unit BMI), with complete steatosis resolution in 90% patients. BMI change was associated with decreased stool microbial diversity (coefficient = 0.17; Shannon Index), increased abundance of Prevotella_9 (Bacteroidetes; coefficient = 0.96) and decreased abundance of Phascolarctobacterium (Firmicutes; coefficient = −0.42) (both Ps < 0.05).ConclusionsDiet‐induced intensive weight loss is associated with rapid improvement and complete resolution of hepatic steatosis and decreased stool microbial diversity. These findings highlight the dynamic nature of hepatic fat and may help clinicians to develop evidence‐based treatment goals for patients with NAFLD and obesity who undertake weight loss interventions. Further research is warranted to understand the effects of intensive weight loss and gut microbiome changes on long‐term NAFLD resolution.

The effect of the magnitude of weight loss on non-alcoholic fatty liver disease: A systematic review and meta-analysis

BackgroundTrials show that weight loss interventions improve biomarkers of non-alcoholic fatty liver disease (NAFLD), but it is unclear if a dose-response relationship exists. ObjectiveWe aimed to quantify the dose-response relationship between the magnitude of weight loss and improvements in NAFLD. MethodsNine databases and trial registries were searched until October 2020. Single-arm, non-randomized comparative, or randomized trials of weight loss interventions (behavioral weight loss programs [BWLPs], pharmacotherapy, or bariatric surgery) in people with NAFLD were eligible for inclusion if they reported an association between changes in weight and changes in blood, radiological, or histological biomarkers of liver disease. The review followed Cochrane methods and the risk of bias was assessed using the Newcastle-Ottawa scale. Pooled unstandardized b coefficients were calculated using random-effect meta-analyses. ResultsForty-three studies (BWMPs: 26, pharmacotherapy: 9, surgery: 8) with 2809 participants were included. The median follow-up was 6 (interquartile range: 6) months. The direction of effect was generally consistent but the estimates imprecise. Every 1 kg of weight lost was associated with a 0.83-unit (95% CI: 0.53 to 1.14, p < 0.0001, I2 = 92%, n = 18) reduction in alanine aminotransferase (U/L), a 0.56-unit (95% CI: 0.32 to 0.79, p < 0.0001, I2 = 68%, n = 11) reduction in aspartate transaminase (U/L), and a 0.77 percentage point (95% CI: 0.51 to 1.03, p < 0.0001, I2 = 72%, n = 11) reduction in steatosis assessed by radiology or histology. There was evidence of a dose-response relationship with liver inflammation, ballooning, and resolution of NAFLD or NASH, but limited evidence of a dose-response relationship with fibrosis or NAFLD activity score. On average, the risk of bias for selection and outcome was medium and low, respectively. ConclusionClinically significant improvements in NAFLD are achieved even with modest weight loss, but greater weight loss is associated with greater improvements. Embedding support for formal weight loss programs as part of the care pathway for the treatment of NAFLD could reduce the burden of disease.PROSPERO: CRD42018093676.

Effects of Dietary and Lifestyle Interventions on Liver, Clinical and Metabolic Parameters in Children and Adolescents with Non-Alcoholic Fatty Liver Disease: A Systematic Review.

Non-alcoholic fatty liver disease (NAFLD) affects 5.5–10.3% of children worldwide, while in obese individuals, it increases to almost 34%. Pediatric NAFLD is consistently associated with metabolic syndrome and insulin resistance. As no pharmacological agents exist for the treatment of NAFLD, lifestyle modifications remain the only therapy. However, as not all overweight/obese children have NAFLD, high-quality data, focused exclusively on NAFLD population are needed. Therefore, the present systematic review assessed the efficacy of lifestyle (diet or exercise) based on randomized controlled clinical trials (RCTs) on liver, anthropometric, glucose, and lipid parameters in children, with imaging or biopsy-proven NAFLD. In general, the results were inconclusive and therefore no specific recommendations could be drawn. In most studies, differences were derived from within group comparisons, which are known to be highly misleading. However, both low-carbohydrate and low-fat diets could benefit liver outcomes, as long as weight loss is achieved, but not necessary glucose and lipid parameters. No RCTs were found on exercise alone, as compared to no intervention on pediatric NAFLD. Concerning diet plus exercise interventions, all studies led to improvements in liver outcomes accompanied with weight loss. Resolution of NAFLD was found in considerably high percentages, while improvements were also seen in glucose but were modest in lipid parameters.

Glycemic Measures and Development and Resolution of Nonalcoholic Fatty Liver Disease in Nondiabetic Individuals.

Type 2 diabetes (T2D) is closely associated with nonalcoholic fatty liver disease (NAFLD); however, evidence regarding the link between blood glucose, especially below the threshold for T2D, and NAFLD is scarce. The objective of this work is to examine the associations of fasting glucose, oral glucose tolerance test (OGTT) 2-hour glucose, and hemoglobin A1c (HbA1c), and changes in these measures with development and resolution of NAFLD in nondiabetic individuals. This longitudinal cohort study comprised 4273 Chinese adults age 40 years or older and free of baseline T2D from 2010 to 2015. Blood sampling was performed during the OGTT test. NAFLD was ascertained by hepatic ultrasonography. Risk ratios (RRs) were calculated using modified Poisson regression models. During a mean 4.4 years of follow-up, NAFLD occurred in 573 (17.9%) of the 3209 participants without baseline NAFLD and resolved in 304 (28.6%) of the 1064 participants with baseline NAFLD. OGTT 2-h glucose was positively associated with NAFLD incidence (RR per 1-SD increase: 1.16, 95% CI: 1.08-1.25), whereas fasting (RR: 0.86, 95% CI: 0.78-0.94) and 2-hour glucose (RR: 0.85, 95% CI: 0.77-0.93) were inversely associated with resolution of NAFLD. Glycemic deterioration conferred increased risk of developing NAFLD and decreased likelihood of resolution of NAFLD than maintaining normal glycemic regulation (NGR). The strongest associations were observed for individuals who developed T2D. Meanwhile, baseline or incident NAFLD significantly increased the risk of deterioration in glucose metabolism. Increased glycemic levels within the nondiabetic range, as well as progression from NGR to T2D or prediabetes, were adversely associated with development and improvement of NAFLD.

Non-resolution of non-alcoholic fatty liver disease (NAFLD) among urban, adult Sri Lankans in the general population: Aprospective, cohort follow-up study.

BackgroundThere are few studies investigating the natural course of non-alcoholic fatty liver disease (NAFLD) in the community. We assessed resolution of NAFLD in a general population cohort of urban Sri Lankans adults.MethodsParticipants were selected by age-stratified random sampling from electoral lists. They were initially screened in 2007 and re-evaluated in 2014. On both occasions structured interview, anthropometric-measurements, liver ultrasonography, and biochemical/serological tests were performed. NAFLD was diagnosed on ultrasound criteria for fatty liver, safe-alcohol consumption (<14-units/week for men, <7-units/week for women) and absence of hepatitis B/C markers. Non-NAFLD was diagnosed on absence of any ultrasound criteria for fatty liver and safe-alcohol consumption. Resolution of NAFLD was defined as absence of ultrasound criteria for fatty liver. Changes in anthropometric indices [Weight, Body-Mass-Index (BMI), waist-circumference (WC), waist-hip ratio (WHR)], clinical [systolic blood pressure (SBP), diastolic blood pressure (DBP)] and biochemical measurements [Triglycerides (TG), High Density Lipoprotein (HDL), Total Cholesterol (TC), HbA1c%] at baseline and follow-up were compared.ResultsOf the 2985 original study participants, 2148 (71.9%) attended follow-up after 7 years. This included 705 who had NAFLD in 2007 and 834 who did not have NAFLD in 2007. Out of 705 who had NAFLD in 2007, 11(1.6%) changed their NAFLD status due to excess alcohol consumption. After controlling for baseline values, NAFLD patients showed significant reduction in BMI, weight, WHR, HDL and TC levels and increase in HbA1c levels compared to non-NAFLD people. Despite this, none of them had complete resolution of NAFLD.ConclusionWe did not find resolution of NAFLD in this general population cohort. The observed improvements in anthropometric, clinical and biochemical measurements were inadequate for resolution of NAFLD.

Liraglutide ameliorates non-alcoholic steatohepatitis by inhibiting NLRP3 inflammasome and pyroptosis activation via mitophagy

Non-alcoholic steatohepatitis (NASH) is a key step in the progression of non-alcoholic fatty liver disease (NAFLD), which causes serious health problems worldwide. The nucleotide-binding oligomerization domain, leucine-rich repeat-containing receptor-containing pyrin domain 3 (NLRP3) inflammasome and pyroptosis play crucial roles in the progression of NASH. Our team has provided clinical evidence of the effects of glucagon-like peptide-1 (GLP-1) on the improvement in liver function and histological resolution of NAFLD. Preliminary work has demonstrated that GLP-1 inhibited NLRP3 inflammasome activation in a mouse model of NAFLD. We further explored the potential molecular mechanisms underlying the anti-inflammatory effect of liraglutide, a long-acting GLP-1 analog, in the treatment of NASH. We established a HepG2 cell model of NASH using double stimulation with palmitic acid and lipopolysaccharide to assess NLRP3 inflammasome and pyroptotic cell activity and to evaluate mitochondrial function and mitophagy. Liraglutide reduced lipid accumulation, inhibited NLRP3 inflammasome and pyroptosis activation, attenuated mitochondrial dysfunction and reactive oxygen species generation, augmented mitophagy in hepatocytes. Mitophagy inhibition with 3-methyladenine/PINK1-directed siRNA weakened the liraglutide-mediated suppression of inflammatory injury. We propose that liraglutide suppresses NLRP3 inflammasome-induced hepatocyte pyroptosis via mitophagy to slow the progression of NASH.

Laparoscopic Sleeve Gastrectomy on the Horizon as a Promising Treatment Modality for NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is viewed as the hepatic manifestation of the metabolic syndrome with hepatic fatty infiltration is the common liver pathology. NAFLD can lead to nonalcoholic steatohepatitis (NASH), liver cirrhosis, liver cell failure, and liver malignancy.The present work aims to prospectively study the histological changes that occur in NAFLD obese patients 1-year post-laparoscopic sleeve gastrectomy (LSG) based on standardized NAS (NAFLD activity score). This prospective study included 94 obese patients who underwent laparoscopic sleeve gastrectomy. Intraoperative wedge liver biopsy was taken from all patients with a follow-up liver biopsy at 12months after the operation. LSG produced a marked reduction in body weight with a mean reduction in BMI from 44.54 + 5.45 to 34.23 + 2.66kg/m2 at 12months. There were statistically highly significant improvements regarding metabolic comorbidities, blood pressure, lipid profile, and HbA1C at 12-month post-LSG (P < 0.001). The current study showed a highly statistically significant improvement at 1-year post LSG regarding steatosis grade, hepatocyte ballooning, lobular inflammation as well as fibrosis stage (P < 0.001). Moreover, the present study showed that NAS score significantly decreased from 5.20 + 1.96 at baseline to 2.63 + 1.55 at 1-year follow-up (P < 0.001). Our relatively large patient cohort shows a significant improvement of steatosis, steatohepatitis, and fibrosis at a 1-year follow-up. LSG can lead to resolution of NAFLD, and it may be in the near future another routine indication for bariatric surgery.

Improvement of Nonalcoholic Fatty Liver Disease Reduces the Risk of Type 2 Diabetes Mellitus.

Background/AimsLittle evidence is available about the effect of change in nonalcoholic fatty liver disease (NAFLD) status on risk of diabetes mellitus (DM) development. In this study, we tried to analyze the DM risk according to change in NAFLD status over time.MethodsAmong a total of 10,141 individuals for whom routine healthcare assessment was performed, 2,726 subjects were selected according to the inclusion/exclusion criteria. NAFLD status change was determined by using serial abdominal ultrasonography and fatty liver index (FLI) during the follow-up period.ResultsSubjects were categorized according to change in NAFLD status as follows: 670 subjects in the persistent NAFLD group, 155 subjects in the resolved NAFLD group, 498 subjects in the incident NAFLD group, and 1,403 subjects in the no NAFLD group. Multivariate Cox regression analysis revealed that incident NAFLD (hazard ratio [HR], 1.94; 95% confidence interval [CI], 1.08 to 3.50; p=0.026) and persistent NAFLD (HR, 3.59; 95% CI, 2.05 to 6.27; p<0.001) were independent risk factors for predicting DM development, whereas the risk with resolved NAFLD was not significantly different from that with no NAFLD. FLI could reproduce the results acquired by ultrasonography.ConclusionsThis study demonstrated that future DM risk could be influenced by changes in NAFLD status over time. Resolution of NAFLD could reduce the risk of future DM development, while the development of new NAFLD could increase the risk of DM development.

SAT-110 Long-Term Impact of Gastric Bypass versus Sleeve Gastrectomy on Nonalcoholic Fatty Liver Disease: Retrospective Observations from Michigan Bariatric Surgery Cohort

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in obese patients. Bariatric surgery is highly effective for treatment of NAFLD. We have previously reported 4 and 5-year weight loss outcomes in patients who underwent bariatric surgery at Michigan Medicine from 2008 to 2013. The aim of this study was to assess the impact of weight loss surgery on persistence of NAFLD up to 5 years post-surgery. Retrospective data on weight, blood pressure, lipid panel, A1c, liver enzymes, NAFLD Fibrosis scores (NFS) and imaging were analyzed with respect to the type of surgery [sleeve gastrectomy (SG) or Roux-en Y gastric bypass (GB)] at baseline and yearly for 5 years. Patients were assessed for presence of underlying NAFLD based on liver biopsy, imaging, or clinical diagnosis (ICD-9 or 10 codes) prior to surgery. Persistent NAFLD was assessed based on presence of hepatic steatosis on abdominal imaging (ultrasound, CT or MRI) over follow-up. Follow up data were available on 221 patients with NAFLD at baseline (GB =128, SG=93); median age 47 years (IQR 40-54) with 73% females and a median BMI of 46.2 kg/m2 (IQR 41.2-52.4). Median BMI was higher in the SG group versus GB owing to the criteria for approval in 2008-2012 (48.1 kg/m2 vs. 45.3 kg/m2, p=0.01). Median NFS was higher in SG vs GB (0.04 vs -0.50, p =0.01). Only 38 patients (17.2%) had a liver biopsy, among which 25 (65.8%) showed non-alcoholic steatohepaitis (NASH) and 3 (7.9%) demonstrated cirrhosis. Both groups had a reduction in NFS over follow up with median NFS significantly lower at all-time points in the GB group, p<0.01); improvement in NFS was more pronounced in the GB group at year 1, p=0.03. Overall, 83 patients (37.5%) had follow-up abdominal imaging with 28 (33.7%) having evidence of persistent NAFLD; 28.7% at 1-2 years, 16.3% at 2-4 years, and 55% at >4 years post-surgery. The nadir of BMI occurred at 1 year (median 31.3 and 37.2, in BG versus SG, respectively), with a peak at year 4 for GB (median 35.6) and year 5 for SG (median 40.4). At all-time points, the median weight loss was highest in the GB group. All metabolic parameters remained improved compared to baseline. The following differences were noted in the GB group versus SG group: LDL was significantly lower at year 1, 2 and 5; cholesterol significantly lower at year 1 and 2; significantly larger reduction in hemoglobin A1c at year 2, 4 and 5; and reduction in TG significantly higher at year 1. In a multivariable model integrating type of surgery, baseline diabetes and baseline hyperlipidemia, baseline hyperlipidemia was independently associated with persistent NAFLD (OR: 3.2, 95% CI 1.04-10.10, p=0.04). Change in weight was not predictive of persistent NAFLD. In conclusion, these observations suggest that bariatric surgery may have a weight-independent effect on NAFLD. Further studies are needed to examine the effect of disease severity and co-morbidities on NAFLD resolution after bariatric surgery.

SAT-LB004 Therapeutic Potential of LPCN 1144 in NAFLD and NASH

Background & Aims Male hypogonadism is an underappreciated comorbidity in non-alcoholic fatty liver disease (NAFLD)/ steatohepatitis (NASH). A significant overlap of comorbidities such as obesity, hypertension, hypertriglyceridemia, type 2 diabetes, and metabolic syndrome, exists between hypogonadism and NAFLD/NASH. Herein we report the prevalence of NAFLD in hypogonadal patients and the potential utility of orally bioavailable prodrug of bioidentical testosterone (LPCN1144), delivered lymphatically, in NAFLD/NASH. Method The Liver Fat Study (LFS) is a 16-week open-label, multi-center, single arm study with LPCN 1144 treatment in subjects (N=36) assessing potential NAFLD/NASH prevalence and liver fat (LF) changes. The Study of Androgen Replacement (SOAR) trial was an active controlled (topical testosterone gel) randomized multicenter 52-week study with LPCN 1144. Results In the LFS, about 58 % of hypogonadal patients were identified as having NAFLD. Among the patients with NAFLD, obesity was the most prevalent comorbidity. NAFLD was about 2-fold overrepresented in hypogonadal patients compared to US general population. At interim visit (8 weeks) mean absolute and relative liver fat reduction in patients with LF ≥ 10 % at baseline were 7.6% and 38%, respectively. 28% of NAFLD (LF ≥ 5 %) confirmed subjects experienced NAFLD resolution with LPCN 1144. In the SOAR trial, subjects with elevated baseline serum liver enzymes (ALT, GGT) and cardiovascular risk markers (TG, Lp-PLA2, LDL-C) experienced significant reductions. Significant rates of patients with above-normal levels of liver enzymes and lipids at BL ended with normal levels post LPCN 1144 therapy: ALT = 52%, GGT = 31%, TG = 34%, and LDL-C = 56%. Changes of TG for patients with above-normal levels at BL were reduced with oral LPCN 1144 compared with topical T gel: -64 mg/dL vs. +13 mg/dL, respectively. SHBG change for all patients with oral LPCN 1144 and Topical T gel: -19.5% vs. +8.3%, respectively. Greater reductions of TG and ALP were observed with oral LPCN 1144 as in patients key comorbidities compared with topical T gel. LPCN 1144, with up to 52 weeks exposure, exhibited no adverse drug reaction in the Hepatobilliary System Organ Class (e.g., peliosis hepatitis, hepatic neoplasms, cholestatic hepatitis and jaundice), no major adverse cardiac events (MACE), no signs of increased skeletal fragility or nephrotoxicity, and good gastrointestinal tolerability. Conclusion Evaluation of NAFLD/NASH should be considered in hypogonadal males. LPCN 1144 therapy meaningfully reduces liver fat in hypogonadal males, suggesting utility as a NAFLD/NASH therapy. Biomarker data support unique benefits of oral over topical testosterone options. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Dietary Niacin Intake Predicts the Decrease of Liver Fat Content During a Lifestyle Intervention

Niacin inhibits fatty acid flux from adipose tissue to liver, reduces hepatic triglyceride synthesis and increases hepatic lipid oxidation. Thus, niacin may have a role in the regulation of liver fat content in humans. We tested if dietary intake of niacin predicts change of liver fat content during a lifestyle intervention. To this end, we estimated the composition of diet from diaries of 202 healthy subjects at risk of type 2 diabetes undergoing lifestyle intervention comprising physical activity and diet counselling. Total-, subcutaneous- and visceral adipose tissue mass were measured by magnetic resonance (MR) tomography and liver fat content by 1H-MR spectroscopy at baseline and after 9 months of follow-up. Among fat compartments, liver fat content showed the largest decrease (−32%, p < 0.0001). High baseline niacin intake predicted a larger decrease of liver fat (p = 0.004). Subjects in the highest quartile of niacin intake at baseline also had the largest decrease of liver fat (1st:−10%; 2nd:−27%; 3rd:−35%; 4th:−37%). Among 58 subjects with nonalcoholic fatty liver disease (NAFLD) at baseline, NAFLD resolved in 23 subjects during the lifestyle intervention. For one standard deviation increase in niacin intake, the odds ratio for resolution of NAFLD was 1.77 (95% CI, 1.00–3.43). High dietary niacin intake may have a favorable effect on the reduction of liver fat during lifestyle intervention.

Complete Resolution of Nonalcoholic Fatty Liver Disease After Bariatric Surgery: A Systematic Review and Meta-analysis

Bariatric surgery has been reported to lead to complete resolution of nonalcoholic fatty liver disease (NAFLD) following the sustained weight loss induced in obese patients. We performed a systematic review and meta-analysis to evaluate the effects of bariatric surgery on NAFLD in obese patients. We searched MEDLINE, EMBASE, CENTRAL, and Web of Science databases through May 2018 for studies that compared liver biopsy results before and after bariatric surgery in obese patients. Primary outcomes were biopsy-confirmed resolution of NAFLD and NAFLD activity score. Secondary outcomes were worsening of NAFLD after surgery and liver volume. The Grading of Recommendations, Assessment, Development, and Evidence approach was conducted to assess overall quality of evidence. We analyzed data from 32 cohort studies comprising 3093 biopsy specimens. Bariatric surgery resulted in a biopsy-confirmed resolution of steatosis in 66% of patients (95% CI, 56%-75%), inflammation in 50% (95% CI, 35%-64%), ballooning degeneration in 76% (95% CI, 64%-86%), and fibrosis in 40% (95% CI, 29%-51%). Patients' mean NAFLD activity score was reduced significantly after bariatric surgery (mean difference, 2.39; 95% CI, 1.58-3.20; P < .001). However, bariatric surgery resulted in new or worsening features of NAFLD, such as fibrosis, in 12% of patients (95% CI, 5%-20%). The overall Grading of Recommendations, Assessment, Development, and Evidence quality of evidence was very low. Through this systematic review and meta-analysis, we found that bariatric surgery leads to complete resolution of NAFLD in obese patients. However, some patients develop new or worsened features of NAFLD. Randomized controlled trials are needed to further examine the therapeutic benefits of bariatric surgery for patients with NAFLD.