Multiomics biomarkers for the prediction of nonalcoholic fatty liver disease severity.
Ontology highlight
ABSTRACT:
SUBMITTER: Pirola CJ
PROVIDER: S-EPMC5910543 | biostudies-literature | 2018 Apr
REPOSITORIES: biostudies-literature
Publications
Multiomics biomarkers for the prediction of nonalcoholic fatty liver disease severity.
Pirola Carlos J CJ Sookoian Silvia S
World journal of gastroenterology 20180401 15
This review intends to uncover how information from large-scale genetic profiling (whole genome sequencing, and whole exome sequencing) of nonalcoholic fatty liver disease (NAFLD), as well as information from circulating transcriptomics (cell-free miRNAs) and metabolomics, contributes to the understanding of NAFLD pathogenesis. A further aim is to address the question of whether OMICs information is ready to be implemented in the clinics. The available evidence suggests that any new knowledge pe ...[more]
Similar Datasets
Project description:Despite the high prevalence of nonalcoholic fatty liver disease (NAFLD), therapeutic options and noninvasive markers of disease activity and severity remain limited. We investigated the association between plasma biomarkers and liver histology in order to identify markers of disease activity and severity in patients with biopsy-proven NAFLD. Thirty-two plasma biomarkers chosen a priori as possible discriminators of NAFLD were measured in participants enrolled in the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network. Dichotomized histologic outcomes were evaluated using centrally read biopsies. Biomarkers with statistically significant associations with NAFLD histology were evaluated in multivariable models adjusted for clinical factors. Of 648 participants (74.4% white, 61.7% female, mean age 47.7 years), 58.0% had definite NASH, 55.5% had mild/no fibrosis (stage 0-1), and 44.4% had significant fibrosis (stage 2-4). Increased activated plasminogen activator inhibitor 1 had a strong association with definite NASH compared to not NASH or borderline NASH in multivariable analysis (odds ratio = 1.20, 95% confidence interval 1.08-1.34, P < 0.001). Biomarkers associated with significant fibrosis (versus mild/no fibrosis) in multivariable analysis included higher levels of interleukin-8, monocyte chemoattractant protein-1, resistin, soluble interleukin-1 receptor I, soluble interleukin-2 receptor alpha, and tumor necrosis factor alpha and lower levels of insulin-like growth factor 2. CONCLUSIONS:Specific plasma biomarkers are significantly associated with disease activity and severity of fibrosis in NAFLD and are potentially valuable tools for noninvasive stratification of patients with NAFLD and identification of targets for therapeutic intervention. (Hepatology 2017;65:65-77).
| S-EPMC5191932 | biostudies-literature
Project description:BackgroundBiomarker for usefulness in diagnosing advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is expected. In order to discover novel biomarkers for NAFLD and its pathogenesis, we performed matabolomics screening.Methods(1) The initial cohort was 44 NAFLD patients. (2) This validation cohort was 105 NAFLD patients, 26 primary biliary cirrhosis (PBC) patients, and 48 healthy controls. Using capillary electrophoresis and liquid chromatography with mass spectrometry, we analyzed low molecular weight metabolites in these groups.Results1. In the initial cohort, we found 28 metabolites associated with advanced fibrosis. Among them, 4 sulfated steroids showed the greatest difference. A decrease of dehydroepiandrosterone sulfate (DHEA-S) and 5?-androstan-3? ol-17-one sulfate (etiocholanolone-S) was observed with the progression of fibrosis. Furthermore, 16 hydroxydehydroepiandrosterone sulfate (16-OH-DHEA-S) increased with the progression of fibrosis. 2. In the validation cohort, the decrease of DHEA-S and etiocholanolone-S, as well as the increase of 16-OH-DHEA-S, with the progression of fibrosis was confirmed. The 16-OH-DHEA-S/DHEA-S ratio and 16-OH-DHEA-S/etiocholanolone-S ratio were even more strongly associated with the grade of fibrosis. Among PBC patients, 16-OH-DHEA-S tended to be higher in stages 3 and 4 than in stages 1 and 2. However, levels of DHEA-S, etiocholanolone-S, and the two ratios were not associated with the stage of PBC.ConclusionSeveral metabolic products were found to be biomarkers of fibrosis in NAFLD and could also be useful for diagnosis of this condition. Our findings suggested disturbance of hormone metabolism in NAFLD and might lead to the development of new therapy.
| S-EPMC3889284 | biostudies-literature
Project description:Background and objectivesNonalcoholic fatty liver disease (NAFLD) is linked to obesity. Obesity is associated with lower socioeconomic status (SES). An independent link between pediatric NAFLD and SES has not been elucidated. The objective of this study was to evaluate the distribution of socioeconomic deprivation, measured using an area-level proxy, in pediatric patients with known NAFLD and to determine whether deprivation is associated with liver disease severity.MethodsRetrospective study of patients <21 years with NAFLD, followed from 2009 to 2018. The patients' addresses were mapped to census tracts, which were then linked to the community deprivation index (CDI; range 0--1, higher values indicating higher deprivation, calculated from six SES-related variables available publicly in US Census databases).ResultsTwo cohorts were evaluated; 1 with MRI (magnetic resonance imaging) and/or MRE (magnetic resonance elastography) findings indicative of NAFLD (n = 334), and another with biopsy-confirmed NAFLD (n = 245). In the MRI and histology cohorts, the majority were boys (66%), non-Hispanic (77%-78%), severely obese (79%-80%), and publicly insured (55%-56%, respectively). The median CDI for both groups was 0.36 (range 0.15-0.85). In both cohorts, patients living above the median CDI were more likely to be younger at initial presentation, time of MRI, and time of liver biopsy. MRI-measured fat fraction and liver stiffness, as well as histologic characteristics were not different between the high- and low-deprivation groups.ConclusionsChildren with NAFLD were found across the spectrum of deprivation. Although children from more deprived neighborhoods present at a younger age, they exhibit the same degree of NAFLD severity as their peers from less deprived areas.
| S-EPMC8054652 | biostudies-literature
Project description:Emerging data highlight the critical role for the innate immune system in the progression of nonalcoholic fatty liver disease (NAFLD). Connexin 32 (Cx32), the primary liver gap junction protein, is capable of modulating hepatic innate immune responses and has been studied in dietary animal models of steatohepatitis. In this work, we sought to determine the association of hepatic Cx32 with the stages of human NAFLD in a histologically characterized cohort of 362 patients with NAFLD. We also studied the hepatic expression of the genes and proteins known to interact with Cx32 (known as the connexome) in patients with NAFLD. Last, we used three independent dietary mouse models of nonalcoholic steatohepatitis to investigate the role of Cx32 in the development of steatohepatitis and fibrosis. In a univariate analysis, we found that Cx32 hepatic expression associates with each component of the NAFLD activity score and fibrosis severity. Multivariate analysis revealed that Cx32 expression most closely associated with the NAFLD activity score and fibrosis compared to known risk factors for the disease. Furthermore, by analyzing the connexome, we identified novel genes related to Cx32 that associate with NAFLD progression. Finally, we demonstrated that Cx32 deficiency protects against liver injury, inflammation, and fibrosis in three murine models of nonalcoholic steatohepatitis by limiting initial diet-induced hepatoxicity and subsequent increases in intestinal permeability. Conclusion: Hepatic expression of Cx32 strongly associates with steatohepatitis and fibrosis in patients with NAFLD. We also identify novel genes associated with NAFLD and suggest that Cx32 plays a role in promoting NAFLD development. (Hepatology Communications 2018;2:786-797).
| S-EPMC6123534 | biostudies-literature
Project description:BackgroundNonalcoholic fatty liver disease (NAFLD) is the most common liver disease. Metabolism-related genes significantly influence the onset and progression of the disease. Hence, it is necessary to screen metabolism-related biomarkers for the diagnosis and treatment of NAFLD patients.MethodsGSE48452, GSE63067, and GSE89632 datasets including nonalcoholic steatohepatitis (NASH) and healthy controls (HC) analyzed in this study were retrieved from the Gene Expression Omnibus (GEO) database. First, differentially expressed genes (DEGs) between NASH and HC samples were obtained. Next, metabolism-related DEGs (MR-DEGs) were identified by overlapping DEGs and metabolism-related genes (MRG). Further, a protein-protein interaction (PPI) network was developed to show the interaction among MR-DEGs. Subsequently, the "Least absolute shrinkage and selection operator regression" and "Random Forest" algorithms were used to screen metabolism-related genes (MRGs) in patients with NAFLD. Next, immune cell infiltration and gene set enrichment analyses (GSEA) were performed on these metabolism-related genes. Finally, the expression of metabolism-related gene was determined at the transcription level.ResultsFirst, 129 DEGs related to NAFLD development were identified among patients with nonalcoholic steatohepatitis (NASH) and healthy control. Next, 18 MR-DEGs were identified using the Venn diagram. Subsequently, four genes, including AMDHD1, FMO1, LPL, and P4HA1, were identified using machine learning algorithms. Moreover, a regulatory network consisting of four genes, 25 microRNAs (miRNAs), and 41 transcription factors (TFs) was constructed. Finally, a significant increase in FMO1 and LPL expression levels and a decrease in AMDHD1 and P4HA1 expression levels were observed in patients in the NASH group compared to the HC group.ConclusionMetabolism-related genes associated with NAFLD were identified, containing AMDHD1, FMO1, LPL, and P4HA1, which provide insights into diagnosing and treating patients with NAFLD.
| S-EPMC10494330 | biostudies-literature
Project description:Background & aimsAlterations in the gut microbiome have been associated with the severity of nonalcoholic fatty liver disease (NAFLD). Previous studies focused exclusively on the bacteria in the microbiome; we investigated changes in the viral microbiome (virome) in patients with NAFLD.MethodsIn a prospective, cross-sectional, observational study, we extracted RNA and DNA virus-like particles from fecal samples from 73 patients with NAFLD: 29 patients had an NAFLD Activity Score (NAS) of 0-4, 44 patients had an NAS of 5-8 or liver cirrhosis (LCI), 37 patients had F0-F1 fibrosis, and 36 patients had F2-F4 fibrosis. As controls, 9 individuals without liver disease and 13 patients with mild primary biliary cholangitis were included in the analysis. We performed shotgun metagenomic sequencing of virus-like particles.ResultsPatients with NAFLD and NAS 5-8/LCI had a significant decrease in intestinal viral diversity compared with patients with NAFLD and NAS 0-4 or control individuals. The presence of more advanced NAFLD was associated with a significant reduction in the proportion of bacteriophages compared with other intestinal viruses. Using multivariate logistic regression analysis with leave-1-out cross validation, we developed a model, including a viral diversity index and simple clinical variables, that identified patients with NAS 5-8/LCI with an area under the curve of 0.95 (95% confidence interval, 0.91-0.99) and F2-F4 fibrosis with an area under the curve of 0.88 (95% confidence interval, 0.80-0.95). Addition of data on viral diversity significantly improved multivariate models, including those based on only clinical parameters or bacterial diversity.ConclusionsIn a study of fecal viromes from patients with NAFLD and control individuals, we associated histologic markers of NAFLD severity with significant decreases in viral diversity and proportion of bacteriophages. We developed a model based on fecal viral diversity and clinical data that identifies patients with severe NAFLD and fibrosis more accurately than models based only on clinical or bacterial data.
| S-EPMC8404510 | biostudies-literature
Project description:ObjectivesTo determine the prevalence of renal impairment in a large cohort of youths with histologically confirmed nonalcoholic fatty liver disease (NAFLD), and to determine its association with liver disease severity.Study designClinical, laboratory, and histology data were collected retrospectively in a pediatric cohort with biopsy-confirmed NAFLD at a tertiary care center between 2010 and 2017. Histological NAFLD severity was scored using validated criteria. Glomerular filtration rate (GFR) was calculated and categorized as low (<90 mL/min/1.73 m2), normal (90-136 mL/min/1.73 m2), or high (>136 mL/min/1.73 m2). Univariate and multivariate modeling were used to determine differences between the GFR groups and to control for confounders.ResultsThe cohort comprised 179 patients (82% non-Hispanic; median age; 14 years; IQR, 12-16 years). One-third of the patients had abnormal renal function, including 36 (20%) with glomerular hyperfiltration and 26 (15%) with low GFR. In multivariable logistic regression, compared with normal GFR, hyperfiltration was independently associated with higher NAFLD activity score (aOR, 2.96; 95% CI, 1.49-5.87; P = .002), after adjusting for age, sex, ethnicity, obesity severity, presence of type 2 diabetes mellitus, and medications.ConclusionsIn this large cohort with histologically confirmed NAFLD, renal impairment was highly prevalent and associated with liver disease severity, independent of obesity severity. Screening patients with confirmed NAFLD for renal complication is recommended.
| S-EPMC8218655 | biostudies-literature
Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. NAFLD encompasses a spectrum of disease ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. However, despite the growing recognition of this important disease burden, there are significant challenges to accurately and noninvasively diagnose the various forms of NAFLD, especially to differentiate benign steatosis from the progressive NASH. This is of utmost importance because although liver biopsy is considered the current imperfect 'gold' standard for diagnosing NASH and staging fibrosis, it is an invasive procedure with significant limitations. Although, a number of noninvasive markers have been or are currently undergoing investigation, until date, no highly sensitive and specific tests are available to differentiate NASH from simple steatosis. At the moment, further investigations are needed before prediction models or blood-based biomarkers become available and acceptable for routine clinical care. There is a great need for developing inexpensive, easily accessible, highly sensitive and specific biomarkers that permit not only the identification of patients at high risk of adverse outcomes, but also the monitoring of disease progression and response after therapeutic interventions.
| S-EPMC6995889 | biostudies-literature
Project description:Nonalcoholic fatty liver disease (NAFLD) is considered a hepatic manifestation of metabolic syndrome, characterized from pathological changes in lipid and carbohydrate metabolism. Its main characteristics are excessive lipid accumulation and oxidative stress, which create a lipotoxic environment in hepatocytes leading to liver injury. Recently, many studies have focused on the identification of the genetic and epigenetic modifications that also contribute to NAFLD pathogenesis and their prognostic implications. The present review is aimed to discuss on cellular and metabolic alterations associated with NAFLD, which can be helpful to identify new noninvasive biomarkers. The identification of accumulated lipids in the cell membranes, as well as circulating cytokeratins and exosomes, provides new insights in understanding of NAFLD. This review also suggests that lifestyle modifications remain the main prevention and/or treatment for NAFLD.
| S-EPMC8069944 | biostudies-literature
Project description:Sex hormones have been linked with presence and severity of nonalcoholic fatty liver disease (NAFLD) in adults, but it is unknown if they affect severity of pediatric NAFLD. To examine associations of circulating SHBG, estrogens, and androgens with key histologic features of pediatric, biopsy-confirmed NAFLD. Baseline assessment of longitudinal cohorts and randomized clinical trials. Nonalcoholic Steatohepatitis Clinical Research Network. Children and adolescents ≤18 years with liver biopsy-confirmed NAFLD in the United States. We assayed SHBG, estrone, estradiol, dehydroepiandrosterone (DHEAS), androstenedione, and testosterone in relation to grade/stage of steatosis, portal inflammation, hepatic ballooning, fibrosis, and nonalcoholic steatohepatitis (NASH) severity using linear regression. Mean age of 573 children at the time of biopsy was 13.1 years (SD 2.8). Lower SHBG was inversely associated with steatosis severity in boys and girls (P = 0.001), and with portal inflammation in girls only (P for sex interaction <0.001). Higher testosterone was related to improved features of steatosis and fibrosis (P for sex interaction = 0.003 and 0.01, respectively) in boys, but detrimental in girls. In boys and girls, higher estrone, estradiol, and testosterone were associated with lower portal inflammation grade; higher estradiol was positively associated with hepatic ballooning severity; DHEAS was inversely associated with hepatic ballooning and NASH severity (all P < 0.05). Androstenedione was not associated with NAFLD features. Largely consistent with findings in adults, sex hormones are associated with distinct histologic features of NAFLD in children and adolescents. These hormone levels relate to differences with gender and pubertal change.
| S-EPMC7494240 | biostudies-literature