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12 pages, 5581 KiB

Open AccessArticle

Multi-Modality, Multi-Dimensional Characterization of Pediatric Non-Alcoholic Fatty Liver Disease

by Neema Jamshidi, Alborz Feizi, Claude B. Sirlin, Joel E. Lavine and Michael D. Kuo

Metabolites 2023, 13(8), 929; https://doi.org/10.3390/metabo13080929 - 8 Aug 2023

Cited by 2 | Viewed by 1428

Abstract

Non-alcoholic fatty liver disease is a multifaceted disease that progresses through multiple phases; it involves metabolic as well as structural changes. These alterations can be measured directly or indirectly through blood, non-invasive imaging, and/or tissue analyses. While some studies have evaluated the correlations [...] Read more.

Non-alcoholic fatty liver disease is a multifaceted disease that progresses through multiple phases; it involves metabolic as well as structural changes. These alterations can be measured directly or indirectly through blood, non-invasive imaging, and/or tissue analyses. While some studies have evaluated the correlations between two sets of measurements (e.g., histopathology with cross-sectional imaging or blood biomarkers), the interrelationships, if any, among histopathology, clinical blood profiles, cross-sectional imaging, and metabolomics in a pediatric cohort remain unknown. We created a multiparametric clinical MRI–histopathologic NMR network map of pediatric NAFLD through multimodal correlation networks, in order to gain insight into how these different sets of measurements are related. We found that leptin and other blood markers were correlated with many other measurements; however, upon filtering out the blood biomarkers, the network was decomposed into three independent hubs centered around histopathological features, each with associated MRI and plasma metabolites. These multi-modality maps could serve as a framework for characterizing disease status and progression and could potentially guide medical interventions. Full article

(This article belongs to the Special Issue Metabolic Profiles and Fibrosis of Nonalcoholic Fatty Liver Disease)

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15 pages, 2843 KiB

Open AccessArticle

Exploring the Potential Performance of Fibroscan for Predicting and Evaluating Metabolic Syndrome using a Feature Selected Strategy of Machine Learning

by Kuan-Lin Chiu, Yu-Da Chen, Sen-Te Wang, Tzu-Hao Chang, Jenny L Wu, Chun-Ming Shih and Cheng-Sheng Yu

Metabolites 2023, 13(7), 822; https://doi.org/10.3390/metabo13070822 - 5 Jul 2023

Cited by 1 | Viewed by 2092

Abstract

Metabolic syndrome (MetS) includes several conditions that can increase an individual’s predisposition to high-risk cardiovascular events, morbidity, and mortality. Non-alcoholic fatty liver disease (NAFLD) is a predominant cause of cirrhosis, which is a global indicator of liver transplantation and is considered the hepatic [...] Read more.

Metabolic syndrome (MetS) includes several conditions that can increase an individual’s predisposition to high-risk cardiovascular events, morbidity, and mortality. Non-alcoholic fatty liver disease (NAFLD) is a predominant cause of cirrhosis, which is a global indicator of liver transplantation and is considered the hepatic manifestation of MetS. FibroScan^® provides an accurate and non-invasive method for assessing liver steatosis and fibrosis in patients with NAFLD, via a controlled attenuation parameter (CAP) and liver stiffness measurement (LSM or E) scores and has been widely used in current clinical practice. Several machine learning (ML) models with a recursive feature elimination (RFE) algorithm were applied to evaluate the importance of the CAP score. Analysis by ANOVA revealed that five symptoms at different CAP and E score levels were significant. All eight ML models had accuracy scores > 0.9, while treebags and random forest had the best kappa values (0.6439 and 0.6533, respectively). The CAP score was the most important variable in the seven ML models. Machine learning models with RFE demonstrated that using the CAP score to identify patients with MetS may be feasible. Thus, a combination of CAP scores and other significant biomarkers could be used for early detection in predicting MetS. Full article

(This article belongs to the Special Issue Metabolic Profiles and Fibrosis of Nonalcoholic Fatty Liver Disease)

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13 pages, 653 KiB

Open AccessArticle

Baseline Tyrosine Level Is Associated with Dynamic Changes in FAST Score in NAFLD Patients under Lifestyle Modification

by Hwi Young Kim, Da Jung Kim, Hye Ah Lee, Joo-Youn Cho and Won Kim

Metabolites 2023, 13(3), 444; https://doi.org/10.3390/metabo13030444 - 17 Mar 2023

Cited by 1 | Viewed by 2164

Abstract

Noninvasive risk stratification is a challenging issue in the management of patients with nonalcoholic fatty liver disease (NAFLD). This study aimed to identify multiomics-based predictors of NAFLD progression, as assessed by changes in serial FibroScan-aspartate aminotransferase (FAST) scores during lifestyle modification. A total [...] Read more.

Noninvasive risk stratification is a challenging issue in the management of patients with nonalcoholic fatty liver disease (NAFLD). This study aimed to identify multiomics-based predictors of NAFLD progression, as assessed by changes in serial FibroScan-aspartate aminotransferase (FAST) scores during lifestyle modification. A total of 266 patients with available metabolomics and genotyping data were included. The follow-up sub-cohort included patients with paired laboratory and transient elastography results (n = 160). The baseline median FAST score was 0.37. The PNPLA3 rs738409 genotype was significantly associated with a FAST score > 0.35. Circulating metabolomics significantly associated with a FAST score > 0.35 included SM C24:0 (odds ratio [OR] = 0.642; 95% confidence interval [CI], 0.463–0.891), PC ae C40:6 (OR = 0.477; 95% CI, 0.340–0.669), lysoPC a C18:2 (OR = 0.570; 95% CI, 0.417–0.779), and tyrosine (OR = 2.743; 95% CI, 1.875–4.014). A combination of these metabolites and PNPLA3 genotype yielded a c-index = 0.948 for predicting a FAST score > 0.35. In the follow-up sub-cohort (median follow-up = 23.7 months), 47/76 patients (61.8%) with a baseline FAST score > 0.35 had a follow-up FAST score ≤ 0.35. An improved FAST score at follow-up was significantly associated with age, serum alanine aminotransferase, and tyrosine. In conclusion, baseline risk stratification in NAFLD patients may be assisted using a multiomics-based model. Particularly, patients with increased tyrosine may benefit from an earlier switch to pharmacologic approaches. Full article

(This article belongs to the Special Issue Metabolic Profiles and Fibrosis of Nonalcoholic Fatty Liver Disease)

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14 pages, 1622 KiB

Open AccessArticle

Metabolome × Microbiome Changes Associated with a Diet-Induced Reduction in Hepatic Fat among Adolescent Boys

by Catherine C. Cohen, Helaina Huneault, Carolyn J. Accardi, Dean P. Jones, Ken Liu, Kristal M. Maner-Smith, Ming Song, Jean A. Welsh, Patricia A. Ugalde-Nicalo, Jeffrey B. Schwimmer and Miriam B. Vos

Metabolites 2023, 13(3), 401; https://doi.org/10.3390/metabo13030401 - 8 Mar 2023

Cited by 2 | Viewed by 2678

Abstract

Dietary sugar reduction is one therapeutic strategy for improving nonalcoholic fatty liver disease (NAFLD), and the underlying mechanisms for this effect warrant further investigation. Here, we employed metabolomics and metagenomics to examine systemic biological adaptations associated with dietary sugar restriction and (subsequent) hepatic [...] Read more.

Dietary sugar reduction is one therapeutic strategy for improving nonalcoholic fatty liver disease (NAFLD), and the underlying mechanisms for this effect warrant further investigation. Here, we employed metabolomics and metagenomics to examine systemic biological adaptations associated with dietary sugar restriction and (subsequent) hepatic fat reductions in youth with NAFLD. Data/samples were from a randomized controlled trial in adolescent boys (11–16 years, mean ± SD: 13.0 ± 1.9 years) with biopsy-proven NAFLD who were either provided a low free-sugar diet (LFSD) (n = 20) or consumed their usual diet (n = 20) for 8 weeks. Plasma metabolomics was performed on samples from all 40 participants by coupling hydrophilic interaction liquid chromatography (HILIC) and C₁₈ chromatography with mass spectrometry. In a sub-sample (n = 8 LFSD group and n = 10 usual diet group), 16S ribosomal RNA (rRNA) sequencing was performed on stool to examine changes in microbial composition/diversity. The diet treatment was associated with differential expression of 419 HILIC and 205 C₁₈ metabolite features (p < 0.05), which were enriched in amino acid pathways, including methionine/cysteine and serine/glycine/alanine metabolism (p < 0.05), and lipid pathways, including omega-3 and linoleate metabolism (p < 0.05). Quantified metabolites that were differentially changed in the LFSD group, compared to usual diet group, and representative of these enriched metabolic pathways included increased serine (p = 0.001), glycine (p = 0.004), 2-aminobutyric acid (p = 0.012), and 3-hydroxybutyric acid (p = 0.005), and decreased linolenic acid (p = 0.006). Microbiome changes included an increase in richness at the phylum level and changes in a few genera within Firmicutes. In conclusion, the LFSD treatment, compared to usual diet, was associated with metabolome and microbiome changes that may reflect biological mechanisms linking dietary sugar restriction to a therapeutic decrease in hepatic fat. Studies are needed to validate our findings and test the utility of these “omics” changes as response biomarkers. Full article

(This article belongs to the Special Issue Metabolic Profiles and Fibrosis of Nonalcoholic Fatty Liver Disease)

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15 pages, 1485 KiB

Open AccessArticle

Diet Quality and Liver Health in People Living with HIV in the MASH Cohort: A Multi-Omic Analysis of the Fecal Microbiome and Metabolome

by Haley R. Martin, Sabrina Sales Martinez, Vitalii Stebliankin, Javier A. Tamargo, Adriana Campa, Giri Narasimhan, Jacqueline Hernandez, Jose A. Bastida Rodriguez, Colby Teeman, Angelique Johnson, Kenneth E. Sherman and Marianna K. Baum

Metabolites 2023, 13(2), 271; https://doi.org/10.3390/metabo13020271 - 14 Feb 2023

Cited by 3 | Viewed by 2384

Abstract

The gut–liver axis has been recognized as a potential pathway in which dietary factors may contribute to liver disease in people living with HIV (PLWH). The objective of this study was to explore associations between dietary quality, the fecal microbiome, the metabolome, and [...] Read more.

The gut–liver axis has been recognized as a potential pathway in which dietary factors may contribute to liver disease in people living with HIV (PLWH). The objective of this study was to explore associations between dietary quality, the fecal microbiome, the metabolome, and liver health in PLWH from the Miami Adult Studies on HIV (MASH) cohort. We performed a cross-sectional analysis of 50 PLWH from the MASH cohort and utilized the USDA Healthy Eating Index (HEI)–2015 to measure diet quality. A Fibrosis-4 Index (FIB-4) score < 1.45 was used as a strong indication that advanced liver fibrosis was not present. Stool samples and fasting blood plasma samples were collected. Bacterial composition was characterized using 16S rRNA sequencing. Metabolomics in plasma were determined using gas and liquid chromatography/mass spectrometry. Statistical analyses included biomarker identification using linear discriminant analysis effect size. Compared to participants with FIB-4 ≥ 1.45, participants with FIB-4 < 1.45 had higher intake of dairy (p = 0.006). Fibrosis-4 Index score was inversely correlated with seafood and plant protein HEI component score (r = −0.320, p = 0.022). The relative abundances of butyrate-producing taxa Ruminococcaceae, Roseburia, and Lachnospiraceae were higher in participants with FIB-4 < 1.45. Participants with FIB-4 < 1.45 also had higher levels of caffeine (p = 0.045) and related metabolites such as trigonelline (p = 0.008) and 1-methylurate (p = 0.023). Dietary components appear to be associated with the fecal microbiome and metabolome, and liver health in PLWH. Future studies should investigate whether targeting specific dietary components may reduce liver-related morbidity and mortality in PLWH. Full article

(This article belongs to the Special Issue Metabolic Profiles and Fibrosis of Nonalcoholic Fatty Liver Disease)

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13 pages, 610 KiB

Open AccessArticle

Molecular Screening via Sanger Sequencing of the Genetic Variants in Non-Alcoholic Fatty Liver Disease Subjects in the Saudi Population: A Hospital-Based Study

by Faisal Alsaif, Waleed Al-hamoudi, Maram Alotaiby, Amani Alsadoon, Mohammed Almayouf, Hadeel Almadany, Jawahir Abuhaimed, Noman Ghufran, Ahmed Merajuddin and Imran Ali Khan

Metabolites 2022, 12(12), 1240; https://doi.org/10.3390/metabo12121240 - 9 Dec 2022

Cited by 4 | Viewed by 1848

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, along with steatosis and non-alcoholic steatohepatitis (NASH), and is associated with cirrhosis and hepatocellular carcinoma. Candidate gene and genome-wide association studies have validated the relationships between NAFLD, NASH, PNPLA3, [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, along with steatosis and non-alcoholic steatohepatitis (NASH), and is associated with cirrhosis and hepatocellular carcinoma. Candidate gene and genome-wide association studies have validated the relationships between NAFLD, NASH, PNPLA3, TM6SF2, and HFE. The present study utilized five polymorphisms in three genes: PNPLA3 (I148M and K434E) TM6SF2 (E167K), and HFE (H63D and C282Y), based on undocumented case–control studies in the Saudi Arabian population. A total of 95 patients with NAFLD and 78 non-NAFLD subjects were recruited. Genomic DNA was isolated, and polymerase chain reaction and Sanger sequencing were performed using specific primers for the I148M, K434E, E167K, H63D, and C282Y. NAFLD subjects were older when compared to controls and showed the significant association (p = 0.0001). Non-significant association was found between gender (p = 0.26). However, both weight and BMI were found to be associated. Hardy–Weinberg equilibrium analysis confirmed that H63D, I148M, and K434E polymorphisms were associated. Genotype analysis showed only K434E variant was associated with NAFLD and non-NAFLD (OR-2.16; 95% CI: 1.08–4.31; p = 0.02). However, other polymorphisms performed with NAFLD and NASH were not associated (p > 0.05), and similar analysis was found when ANOVA was performed (p > 0.05). In conclusion, we confirmed that K434E polymorphism showed a positive association in the Saudi population. Full article

(This article belongs to the Special Issue Metabolic Profiles and Fibrosis of Nonalcoholic Fatty Liver Disease)

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9 pages, 232 KiB

Open AccessArticle

Clinical and Metabolic Characteristics of Hyperuricemia with Risk of Liver Fibrosis: A Cross-Sectional Study

by Chun-Yi Wang, Hsiang-Han Kao, Kuan-Yu Lai, Ching-Chun Lin, Wen-Yuan Lin, Chiu-Shong Liu and Tsung-Po Chen

Metabolites 2022, 12(10), 893; https://doi.org/10.3390/metabo12100893 - 23 Sep 2022

Cited by 2 | Viewed by 1866

Abstract

The role of serum uric acid (SUA) in the role of advanced fibrosis is not fully explored. The study assesses the risk of advanced fibrosis according to SUA in an Asian population with a total of 3612 subjects enrolled in one health management [...] Read more.

The role of serum uric acid (SUA) in the role of advanced fibrosis is not fully explored. The study assesses the risk of advanced fibrosis according to SUA in an Asian population with a total of 3612 subjects enrolled in one health management center between 2006 and 2008. The fibrosis-4 score was used for the prediction of the high risk of advanced fibrosis. SUA scores higher than 7.6 mg/dL in men and 6.6 mg/dL in women were defined as hyperuricemia. A proportional odds model was used to assess cumulative risks of advanced fibrosis. The prevalence of high risk of advanced fibrosis was 2.5% in the hyperuricemia group and 0.6% in the normal SUA group (p < 0.001). After adjustment for confounding factors, the odds ratios (OR) for more severe advanced fibrosis were 1.37 (95% confidence interval [CI]: 1.07–1.78) in the hyperuricemia group. Hyperuricemia only increased the risk of advanced fibrosis in the non-T2DM group (OR, 1.29; 95% CI, 1.04 to 1.74) instead of T2DM group (OR, 1.85; 95% CI, 0.97 to 3.53). SUA is a risk factor for a higher risk of advanced fibrosis, with the disease likely progressing from a steatotic to a fibrotic picture. The focus should be more emphasized in non-T2DM groups. Full article

(This article belongs to the Special Issue Metabolic Profiles and Fibrosis of Nonalcoholic Fatty Liver Disease)

16 pages, 2237 KiB

Open AccessEditor’s ChoiceArticle

Association of Metabolic Signatures with Nonalcoholic Fatty Liver Disease in Pediatric Population

by Woori Chae, Kyung Jae Lee, Ki Young Huh, Jin Soo Moon, Jae Sung Ko and Joo-Youn Cho

Metabolites 2022, 12(9), 881; https://doi.org/10.3390/metabo12090881 - 19 Sep 2022

Cited by 4 | Viewed by 2773

Abstract

Several adult omics studies have been conducted to understand the pathophysiology of nonalcoholic fatty liver disease (NAFLD). However, the histological features of children are different from those of adults, and the onset and progression of pediatric NAFLD are not fully understood. In this [...] Read more.

Several adult omics studies have been conducted to understand the pathophysiology of nonalcoholic fatty liver disease (NAFLD). However, the histological features of children are different from those of adults, and the onset and progression of pediatric NAFLD are not fully understood. In this study, we aimed to evaluate the metabolome profile and metabolic pathway changes associated with pediatric NAFLD to elucidate its pathophysiology and to develop machine learning-based NAFLD diagnostic models. We analyzed the metabolic profiles of healthy control, lean NAFLD, overweight control, and overweight NAFLD groups of children and adolescent participants (N = 165) by assessing plasma samples. Additionally, we constructed diagnostic models by applying three machine learning methods (ElasticNet, random forest, and XGBoost) and multiple logistic regression by using NAFLD-specific metabolic features, genetic variants, and clinical data. We identified 18 NAFLD-specific metabolic features and metabolic changes in lipid, glutathione-related amino acid, and branched-chain amino acid metabolism by comparing the control and NAFLD groups in the overweight pediatric population. Additionally, we successfully developed and cross-validated diagnostic models that showed excellent diagnostic performance (ElasticNet and random forest model: area under the receiver operating characteristic curve, 0.95). Metabolome changes in the plasma of pediatric patients with NAFLD are associated with the pathophysiology of the disease and can be utilized as a less-invasive approach to diagnosing the disease. Full article

(This article belongs to the Special Issue Metabolic Profiles and Fibrosis of Nonalcoholic Fatty Liver Disease)

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12 pages, 665 KiB

Open AccessReview

What Do NAFLD, Liver Fibrosis, and Inflammatory Bowel Disease Have in Common? Review of the Current Literature

by Sara Jarmakiewicz-Czaja, Jolanta Gruszecka and Rafał Filip

Metabolites 2023, 13(3), 378; https://doi.org/10.3390/metabo13030378 - 3 Mar 2023

Cited by 3 | Viewed by 2408

Abstract

Liver disease is one of the most common extraintestinal manifestations of inflammatory bowel disease (IBD). Often the course of liver disease is associated with an exacerbation of the underlying disease (Crohn’s Disease/Ulcerative Colitis). Nonalcoholic steatohepatitis encompasses a wide spectrum of liver damage. The [...] Read more.

Liver disease is one of the most common extraintestinal manifestations of inflammatory bowel disease (IBD). Often the course of liver disease is associated with an exacerbation of the underlying disease (Crohn’s Disease/Ulcerative Colitis). Nonalcoholic steatohepatitis encompasses a wide spectrum of liver damage. The most common form is nonalcoholic fatty liver disease (NAFLD) (75–80%), and the less common but more dangerous form is nonalcoholic steatohepatitis (NASH). NAFLD is now the most common cause of chronic liver disease in developed countries and the leading indication for liver transplantation in the United States. Genetic, demographic, clinical, and environmental factors can play a role in the pathogenesis of NAFLD. The increasing prevalence of NAFLD is associated with a widespread obesity epidemic, metabolic complications, including hypertension, type 2 diabetes, and dyslipidaemia. Some of the most common manifestations of IBD are liver, biliary tract, and gallbladder diseases. The liver fibrosis process has a complex pathophysiology and is often dependent on exogenous factors such as the treatment used and endogenous factors such as the gut microbiome. However, the factors that link IBD and liver fibrosis are not yet clear. The main purpose of the review is to try to find links between IBD and selected liver diseases and to identify knowledge gaps that will inform further research. Full article

(This article belongs to the Special Issue Metabolic Profiles and Fibrosis of Nonalcoholic Fatty Liver Disease)

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12 pages, 794 KiB

Open AccessEditor’s ChoiceReview

Metabolic Role of Autophagy in the Pathogenesis and Development of NAFLD

by Lingxuan An, Ulrich Wirth, Dominik Koch, Malte Schirren, Moritz Drefs, Dionysios Koliogiannis, Hanno Niess, Joachim Andrassy, Markus Guba, Alexandr V. Bazhin, Jens Werner and Florian Kühn

Metabolites 2023, 13(1), 101; https://doi.org/10.3390/metabo13010101 - 7 Jan 2023

Cited by 12 | Viewed by 2765

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease, ranging from simple steatosis to hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Liver fibrosis, which portends a poor prognosis in NAFLD, is characterized by the excessive accumulation of extracellular matrix (ECM) proteins [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease, ranging from simple steatosis to hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Liver fibrosis, which portends a poor prognosis in NAFLD, is characterized by the excessive accumulation of extracellular matrix (ECM) proteins resulting from abnormal wound repair response and metabolic disorders. Various metabolic factors play crucial roles in the progression of NAFLD, including abnormal lipid, bile acid, and endotoxin metabolism, leading to chronic inflammation and hepatic stellate cell (HSC) activation. Autophagy is a conserved process within cells that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. Accumulating evidence has shown the importance of autophagy in NAFLD and its close relation to NAFLD progression. Thus, regulation of autophagy appears to be beneficial in treating NAFLD and could become an important therapeutic target. Full article

(This article belongs to the Special Issue Metabolic Profiles and Fibrosis of Nonalcoholic Fatty Liver Disease)

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10 pages, 2542 KiB

Open AccessSystematic Review

Trimethylamine N-Oxide Levels in Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis

by Panagiotis Theofilis, Aikaterini Vordoni and Rigas G. Kalaitzidis

Metabolites 2022, 12(12), 1243; https://doi.org/10.3390/metabo12121243 - 9 Dec 2022

Cited by 27 | Viewed by 2288

Abstract

Non-alcoholic fatty liver disease (NAFLD) represents an entity with an increasing prevalence which is characterized by significant hepatic and extrahepatic complications. Its pathophysiology is multifactorial, with gut dysbiosis being considered a major determinant. In this systematic review and meta-analysis, we tried to evaluate [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) represents an entity with an increasing prevalence which is characterized by significant hepatic and extrahepatic complications. Its pathophysiology is multifactorial, with gut dysbiosis being considered a major determinant. In this systematic review and meta-analysis, we tried to evaluate the association between the major gut microbial metabolite trimethylamine N-oxide (TMAO) and NAFLD. We performed a literature search for studies that determined circulating TMAO in patients with and without NAFLD. The database search identified 136 studies, and upon application of the exclusion criteria, 7 studies with 7583 individuals (NAFLD 2923, control 4660) were ultimately included in the meta-analysis. Compared to the control group, NAFLD patients had significantly higher circulating TMAO (SMD: 0.66, 95% CI −0.12 to 1.21, p = 0.02, I²: 94%). The results remained unaffected after the exclusion of one influential study. The subgroup analysis revealed significantly higher TMAO in individuals with histologically proven NAFLD and in studies measuring TMAO with high-performance liquid chromatography. No differences were observed according to the study design or study region. However, funnel plot asymmetry was observed, indicating publication bias. In conclusion, patients with NAFLD had increased levels of TMAO, a hazardous gut microbial metabolite, suggesting its important role in the gut–liver interaction. Full article

(This article belongs to the Special Issue Metabolic Profiles and Fibrosis of Nonalcoholic Fatty Liver Disease)

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