•A total of 5 metabolites were identified and composed diagnostic model for screening NAFLD.•There were some significant metabolic differences between Lean-/Obese-NAFLD.•The metabolism of amino acids ...and fatty acids played important roles in Obese-NAFLD and Lean-NAFLD, respectively.
The aim of this study was to identify novel serum metabolites associated with non-alcoholic fatty liver disease (NAFLD), and to explore the metabolic discrepancies between Lean-NAFLD and Obese-NAFLD.
Serum samples from patients with NAFLD (n = 161) and healthy participants (n = 149) were collected, and metabolites were analyzed with UPLC-Q-TOF MS/MS. Subgroup analyses were performed to explore the metabolic differences among Lean-NAFLD, Obese-NAFLD and healthy controls
A total of 24 differentially present metabolites were found between patients with NAFLD and healthy controls. Marked metabolic pathway differences were observed among the NAFLD subtypes, including in fatty acid and amino acid metabolism. Ultimately, five metabolites (prasterone, indoxylsulfuric acid, sebacic acid, arachidonic acid and pregnenolone sulfate) were used to establish a diagnostic model to distinguish patients with NAFLD regardless of Lean- or Obese-NAFLD type.
This study suggested that significant metabolic differences existed among subtypes of NAFLD, and our model might be useful to distinguish patients with NAFLD. These findings may lay a foundation for the detection and treatment of NAFLD subtypes.
Purpose
To examine the association of serum Ism1, a new adipokine that can regulate glucose uptake, with type 2 diabetes (T2D) in a Chinese population. Considering high prevalence of Nonalcoholic ...Fatty Liver Disease in patients with type 2 diabetes and the regulating role of Ism1 on glucose uptake of peripheral tissues, we further explored the association between Ism1 and diabetes-associated nonalcoholic fatty liver disease.
Methods
A total of 120 newly diagnosed T2D patients and 60 control subjects with normal glucose were recruited in the case-control study. Serum Ism1 concentrations were determined by ELISA. Multivariate logistic regression analysis was used to evaluate the independent association of serum Ism1 concentration with the risk of T2D. The 120 newly diagnosed T2D patients were divided into uncomplicated T2D group and diabetes-associated NAFLD group according to the FLI score.
Results
The Ism1 level of normoglycemic controls was higher than that of T2D patients (3.91 ± 0.24 ng/ml vs 3.01 ± 0.16 ng/ml,
P
=0.001). Based on quartile analysis of Ism1 level, the proportion of high circulating Ism1 levels in the control group increased while T2D group decreased, and the distribution difference was statistically significant (P=0.015). Logistic regression analysis indicated that the serum Ism1 level was an independent protective factor of type 2 diabetes (OR=0.69, 95%CI: 0.54-0.89). The decrease of Ism1 level did not increase the risk of non-alcoholic fatty liver disease in diabetic patients by Binary logistic regression analysis (OR=1.08, 95% CI: 0.69-1.69).
Conclusions
The increase of serum Ism1 was associated with a decreased risk of diabetes, and it did not reduce the risk of non-alcoholic fatty liver disease in diabetic patients.
Liver fibrosis is the main determinant of long-term outcome in chronic liver diseases. Little is known about the prevalence of liver fibrosis in the general population. The aim of the study was to ...investigate the prevalence of liver fibrosis in the general adult population with unknown liver disease.
This was a population-based, cross-sectional study performed in the Barcelona metropolitan area. Subjects aged 18 to 75 years old were identified randomly from citizens included in the primary health care registry. Of 4866 subjects invited, 3076 participated (63.2%). Liver fibrosis was estimated by measuring liver stiffness (LS) with transient elastography (TE). Liver histology was assessed in 92 subjects with increased LS.
Prevalence estimates of increased LS (≥6.8, ≥8.0, and ≥9.0 kPa) were 9.0%, 5.8%, and 3.6%, respectively. The etiology of liver disease was mainly nonalcoholic fatty liver disease (NAFLD), followed by alcohol risk consumption (consumption of ≥21 standard drinking units/wk in men and ≥14 standard drinking units/wk in women). Factors independently associated with increased LS were male sex, abdominal obesity, type 2 diabetes, serum glucose, high-density lipoprotein, and triglyceride levels. Subjects without risk factors for NAFLD or without alcohol risk consumption had a very low prevalence of increased LS. The best cut-off value of LS for significant liver fibrosis (F2–F4) was 9.2 kPa, with high sensitivity and specificity. TE was more accurate than alanine aminotransferase, NAFLD fibrosis score, or Fibrosis 4. An algorithm for screening for liver fibrosis using TE in the community setting is proposed.
These findings show a high prevalence of silent liver disease with advanced fibrosis mainly related to NAFLD in adult European subjects without known liver disease. An LS value less than 9.2 kPa predicts the absence of significant liver fibrosis with high accuracy and could be used for screening purposes.
Aldafermin, an engineered analog of fibroblast growth factor 19, inhibits bile acid synthesis and regulates metabolic homeostasis. We report results from a 24-week, phase 2 study, with serial liver ...biopsies, of patients with nonalcoholic steatohepatitis (NASH).
We performed a double-blind study of 78 patients with NASH at 9 centers in the United States. Key inclusion criteria were biopsy-proven NASH with Nonalcoholic Fatty Liver Disease Activity Score ≥4, stage 2 or 3 fibrosis by NASH Clinical Research Network classification, and absolute liver fat content ≥8%, measured by magnetic resonance imaging-proton density fat fraction. Patients were randomly assigned (1:2) to groups given subcutaneous placebo (n = 25) or aldafermin 1 mg (n = 53) daily for 24 weeks. The primary outcome was change in absolute liver fat content from baseline at week 24. Secondary outcomes included serum markers and histologic measures of fibrosis improvement and NASH resolution.
At week 24, the aldafermin group had a significant reduction in absolute liver fat content (reduction of 7.7%) compared with placebo (reduction of 2.7%; difference, reduction of 5.0%; 95% confidence interval, reduction of 8.0%−1.9%; P = .002). Aldafermin produced significantly greater decreases in levels of 7α-hydroxy-4-cholesten-3-one, bile acids, alanine and aspartate aminotransferases, and neoepitope-specific N-terminal pro-peptide of type III collagen (Pro-C3) than placebo. Fibrosis improvement (≥1 stage) with no worsening of NASH was achieved in 38% of patients receiving aldafermin vs 18% of patients receiving placebo (P = .10). NASH resolution with no worsening of fibrosis was observed in 24% of patients given aldafermin vs 9% of patients given placebo (P = .20). Discontinuations due to adverse events occurred in no patients in the aldafermin group and 4% of patients in the placebo group.
In a phase 2 trial of patients with NASH, aldafermin reduced liver fat and produced a trend toward fibrosis improvement. ClinicalTrials.gov, Number: NCT02443116.
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Background and Aims
The clinical efficacy of fecal microbiota transplantation (FMT) in patients with non-alcoholic fatty liver disease (NAFLD) and the variant effects of FMT on lean and obese NAFLD ...patients remain elusive. Our study aimed to determine the clinical efficacy and safety of FMT for patients with NAFLD, elucidating its different influences on lean and obese patients with NAFLD.
Methods
We performed a randomized and controlled clinical trial. Patients in the non-FMT group were administered oral probiotics. In the FMT group, patients were randomized to receive FMT with donor stool (heterologous)
via
colonoscopy, followed by three enemas over 3 days. Both groups were also required to maintain a healthy diet and keep regular exercise for more than 40 min every day. They returned to the hospital for reexamination 1 month after treatment.
Results
FMT can decrease the fat accumulation in the liver by improving the gut microbiota dysbiosis, thus attenuating fatty liver disease. Significant differences in the clinical features and gut microbiota between lean and obese NAFLD patients were unveiled. Moreover, FMT had better effects on gut microbiota reconstruction in lean NAFLD than in obese NAFLD patients.
Conclusions
FMT could successfully improve the therapeutic effects on patients with NAFLD, and its clinical efficacy was higher in lean NAFLD than in obese NAFLD patients.
Nonalcoholic fatty liver disease (NAFLD) is traditionally associated with obesity. However, there is a subtype of NAFLD, namely NAFLD in lean, that occurs without obesity. However, a recent call to ...redefine NAFLD to metabolic-associated fatty liver disease focuses on obesity and metabolic dysfunction. Criticism has arisen from the perceived over emphasis on systemic comorbidities, which may disadvantage the lean. The current analysis seeks to quantify the degree of metabolic dysfunction in NAFLD in lean and compare with NAFLD in overweight and obese and non-NAFLD.
Medline and Embase databases were searched from inception to March 3, 2022. The inclusion criteria were articles with NAFLD in lean patients presenting with baseline metabolic parameters. Comparisons were conducted with subgroup analysis.
Eighty-five articles were included in the meta-analysis. NAFLD in lean accounted for 13.11% (95% confidence interval CI, 10.26%-16.62%) of the global population and 14.55% (95% CI, 11.32%-18.51%) in Asia. The degree of metabolic dysfunction was weight dependent with significantly less metabolic dysfunction in NAFLD in lean subjects as compared with NAFLD in overweight counterparts. For NAFLD in lean, only 19.56% (95% CI, 15.28%-24.69%) of the subjects were diabetic, whereas 45.70% (95% CI, 35.01%-56.80%) of obese subjects with NAFLD had diabetes (P < .01). Fasting blood glucose and systolic and diastolic blood pressure values were significantly lower in subjects with NAFLD in lean than in overweight and obese.
The current analysis highlights the weight-dependent nature of metabolic dysfunction in NAFLD. Lean subjects with NAFLD were significantly less metabolically unhealthy than were obese and overweight persons with NAFLD. An overreliance on metabolic dysfunction in defining fatty liver will be a flaw in potentially excluding previously characterized NAFLD.
Background
Nonalcoholic fatty liver disease (NAFLD) is the fastest-growing chronic liver disease. However, little is known about NAFLD inpatient resource utilization and clinical outcomes.
Aims
The ...aim of this study was to quantify inpatient NAFLD encounters using patient-level data over time.
Methods
This was a retrospective analysis of de-identified data for NAFLD patients from the California Patient Discharge Database from 2006 to 2013. NAFLD patients were identified by ICD9 codes 571.40, 571.41, 571.49, 571.8, and 571.9.
Results
NAFLD patients (
n
= 91,558) were predominantly female (60%), 45–65 years old (44%), and white (53%). Inpatient encounters increased from 8153 in 2006 to 16,457 in 2013 and were associated with a 207% increase in charges ($686 million in 2006 to $1.42 billion in 2013) and average increase in charges of 9.8% per year adjusting for inflation. Comorbidities (obesity, diabetes, hyperlipidemia, cardiovascular disease, other cancer, and renal disease) increased significantly over time (all
P
< 0.05). From 2006 to 2011, there were 11,463 deaths (1849 for liver-related hospitalizations) (mean follow-up 4.00 ± 2.13 years). The most significant predictors of death were age > 75 (aHR 3.9,
P
< 0.0001), male gender (aHR 1.10,
P
< 0.0001), white race (aHR 1.2,
P
< 0.0001), decompensated cirrhosis (aHR 2.1,
P
< 0.0001), and cancer other than HCC (aHR 3.2,
P
< 0.0001). Within the liver-related hospitalization cohort, mortality predictors were similar, except for Hispanic race (aHR 0.92,
P
< 0.0096) and renal disease (aHR 1.50,
P
< 0.0001).
Conclusions
The number of NAFLD inpatient encounters increased significantly from 2006 to 2013, as did the inflation-adjusted inpatient charges. The most significant predictors of death were non-liver cancers (HR 3.11,
P
< 0.0001, CI 3.06–3.16) and age > 75 years (HR 3.94,
P
< 0.0001, HR 3.86–4.03).
Background & Aims: The nuclear receptor coactivator 5 (NCOA5) is a putative type 2 diabetes susceptibility gene. NCOA5 haploinsufficiency results in the spontaneous development of nonalcoholic fatty ...liver disease (NAFLD), insulin resistance, and hepatocellular carcinoma (HCC) in male mice; however, the cell-specific effect of NCOA5 haploinsufficiency in various types of cells, including macrophages, on the development of NAFLD and HCC remains unknown. Methods: Control and myeloid-lineage–specific Ncoa5 deletion (Ncoa5ΔM/+) mice fed a normal diet were examined for the development of NAFLD, nonalcoholic steatohepatitis (NASH), and HCC. Altered genes and signaling pathways in the intrahepatic macrophages of Ncoa5ΔM/+ male mice were analyzed and compared with those of obese human individuals. The role of platelet factor 4 (PF4) in macrophages and the underlying mechanism by which PF4 affects NAFLD/NASH were explored in vitro and in vivo. PF4 expression in HCC patient specimens and prognosis was examined. Results: Myeloid-lineage–specific Ncoa5 deletion sufficiently causes spontaneous NASH and HCC development in male mice fed a normal diet. PF4 overexpression in Ncoa5ΔM/+ intrahepatic macrophages is identified as a potent mediator to trigger lipid accumulation in hepatocytes by inducing lipogenesis-promoting gene expression. The transcriptome of intrahepatic macrophages from Ncoa5ΔM/+ male mice resembles that of obese human individuals. High PF4 expression correlated with poor prognosis of HCC patients and increased infiltrations of M2 macrophages, regulatory T cells, and myeloid-derived suppressor cells in HCCs. Conclusions: Our findings reveal a novel mechanism for the onset of NAFLD/NASH and HCC initiated by NCOA5-deficient macrophages, suggesting the NCOA5-PF4 axis in macrophages as a potential target for developing preventive and therapeutic interventions against NAFLD/NASH and HCC.
Background: Hepatic steatosis (HS) identified on CT may provide an integrated cardiometabolic and COVID-19 risk assessment. This study presents a deep-learning-based hepatic fat assessment (DeHFt) ...pipeline for (a) more standardised measurements and (b) investigating the association between HS (liver-to-spleen attenuation ratio <1 in CT) and COVID-19 infections severity, wherein severity is defined as requiring invasive mechanical ventilation, extracorporeal membrane oxygenation, death. Methods: DeHFt comprises two steps. First, a deep-learning-based segmentation model (3D residual-UNet) is trained (N.ß=.ß80) to segment the liver and spleen. Second, CT attenuation is estimated using slice-based and volumetric-based methods. DeHFt-based mean liver and liver-to-spleen attenuation are compared with an expert's ROI-based measurements. We further obtained the liver-to-spleen attenuation ratio in a large multi-site cohort of patients with COVID-19 infections (D1, N.ß=.ß805; D2, N.ß=.ß1917; D3, N.ß=.ß169) using the DeHFt pipeline and investigated the association between HS and COVID-19 infections severity. Findings: The DeHFt pipeline achieved a dice coefficient of 0.95, 95% CI 0.93...0.96 on the independent validation cohort (N.ß=.ß49). The automated slice-based and volumetric-based liver and liver-to-spleen attenuation estimations strongly correlated with expert's measurement. In the COVID-19 cohorts, severe infections had a higher proportion of patients with HS than non-severe infections (pooled OR.ß=.ß1.50, 95% CI 1.20...1.88, P.ß<.ß.001). Interpretation: The DeHFt pipeline enabled accurate segmentation of liver and spleen on non-contrast CTs and automated estimation of liver and liver-to-spleen attenuation ratio. In three cohorts of patients with COVID-19 infections (N.ß=.ß2891), HS was associated with disease severity. Pending validation, DeHFt provides an automated CT-based metabolic risk assessment. Funding: For a full list of funding bodies, please see the Acknowledgements.
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