Impact of non-invasive biomarkers on hepatology practice: Past, present and future

Journal of Hepatology, Год журнала: 2022, Номер 76(6), С. 1362 - 1378

Опубликована: Май 16, 2022

Язык: Английский

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Multiomics study of nonalcoholic fatty liver disease

Nature Genetics, Год журнала: 2022, Номер 54(11), С. 1652 - 1663

Опубликована: Окт. 24, 2022

Nonalcoholic fatty liver (NAFL) and its sequelae are growing health problems. We performed a genome-wide association study of NAFL, cirrhosis hepatocellular carcinoma, integrated the findings with expression proteomic data. For we utilized 9,491 clinical cases proton density fat fraction extracted from 36,116 magnetic resonance images. identified 18 sequence variants associated NAFL 4 cirrhosis, found rare, protective, predicted loss-of-function in MTARC1 GPAM, underscoring them as potential drug targets. leveraged messenger RNA expression, splicing coding effects to identify 16 putative causal genes, which many implicated lipid metabolism. analyzed levels 4,907 plasma proteins 35,559 Icelanders 1,459 47,151 UK Biobank participants, identifying multiple involved disease pathogenesis. show that proteomics can discriminate between cirrhosis. The present provides insights into development noninvasive evaluation new therapeutic options.

Язык: Английский

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Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma

Hepatology, Год журнала: 2022, Номер 77(1), С. 77 - 91

Опубликована: Май 14, 2022

Background and Aims: Immunotherapy has become the standard‐of‐care treatment for hepatocellular carcinoma (HCC), but its efficacy remains limited. To identify immunotherapy‐susceptible HCC, we profiled molecular abnormalities tumor immune microenvironment (TIME) of rapidly increasing nonviral HCC. Approaches Results: We performed RNA‐seq tissues in 113 patients with HCC cancer genome sequencing 69 genes recurrent genetic alterations reported Unsupervised hierarchical clustering classified HCCs into three classes (Class I, II, III), which stratified patient prognosis. Class poorest prognosis, was associated TP53 mutations, whereas class III, best cadherin‐associated protein beta 1 (CTNNB1) mutations. Thirty‐eight percent defined as an characterized by a high frequency intratumoral steatosis low CTNNB1 Steatotic accounts 23% cases, presented immune‐enriched immune‐exhausted TIME T cell exhaustion, M2 macrophage cancer‐associated fibroblast (CAF) infiltration, PD‐L1 expression, TGF‐β signaling activation. Spatial transcriptome analysis suggested that macrophages CAFs may be close proximity to exhausted CD8+ cells steatotic An vitro study showed palmitic acid‐induced lipid accumulation upregulated expression promoted immunosuppressive phenotypes cocultured fibroblasts. Patients confirmed chemical‐shift MR imaging, had significantly longer PFS combined immunotherapy using anti–PD‐L1 anti‐VEGF antibodies. Conclusions: Multiomics according prognosis or TIME. identified link between

Язык: Английский

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A proteo-transcriptomic map of non-alcoholic fatty liver disease signatures

Nature Metabolism, Год журнала: 2023, Номер 5(4), С. 572 - 578

Опубликована: Апрель 10, 2023

Abstract Non-alcoholic fatty liver disease (NAFLD) is a common, progressive strongly associated with the metabolic syndrome. It unclear how progression of NAFLD towards cirrhosis translates into systematic changes in circulating proteins. Here, we provide detailed proteo-transcriptomic map steatohepatitis and fibrosis during NAFLD. In this multicentre proteomic study, characterize 4,730 proteins 306 patients histologically characterized integrate transcriptomic analysis paired tissue. We identify signatures for active advanced fibrosis, correlate these hepatic transcriptomics to develop signature 31 markers. Deconvolution by single-cell RNA sequencing reveals cell types likely contribute progression. As an exemplar use as non-invasive diagnostic, logistic regression establishes composite model comprising four (ADAMTSL2, AKR1B10, CFHR4 TREM2), body mass index type 2 diabetes mellitus status, at-risk steatohepatitis.

Язык: Английский

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Advances in the Diagnosis and Treatment of Non-Alcoholic Fatty Liver Disease

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(3), С. 2844 - 2844

Опубликована: Фев. 2, 2023

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic that affects approximately one-quarter of global adult population, posing a significant threat to human health with wide-ranging social and economic implications. The main characteristic NAFLD considered excessive fat accumulated deposited in hepatocytes without excess alcohol intake or some other pathological causes. progressive disease, ranging from steatosis non-alcoholic steatohepatitis (NASH), cirrhosis, hepatocellular carcinoma, transplantation, death. Therefore, will probably emerge as leading cause end-stage coming decades. Unlike highly diseases, has received little attention public community. Liver biopsy currently gold standard for diagnosis staging because absence noninvasive specific biomarkers. Due complex pathophysiological mechanisms heterogeneity phenotype, no pharmacological therapies have been approved at present, although several drugs are advanced stages development. This review summarizes current evidence on pathogenesis, treatment NAFLD.

Язык: Английский

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Non-invasive Scores and Serum Biomarkers for Fatty Liver in the Era of Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD): A Comprehensive Review From NAFLD to MAFLD and MASLD

Current Obesity Reports, Год журнала: 2024, Номер 13(3), С. 510 - 531

Опубликована: Май 29, 2024

The prevalence of non-alcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide, making it the leading cause related morbidity and mortality. Currently, biopsy gold standard for assessing individuals with steatohepatitis fibrosis. However, its invasiveness, sampling variability, impracticality large-scale screening has driven search non-invasive methods early diagnosis staging. In this review, we comprehensively summarise evidence on diagnostic performance limitations existing serum biomarkers scores in evaluation steatosis, steatohepatitis,

Язык: Английский

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Current Options and Future Directions for NAFLD and NASH Treatment

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(14), С. 7571 - 7571

Опубликована: Июль 15, 2021

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic worldwide, with a broad spectrum ranging from simple steatosis to advanced stage of nonalcoholic steatohepatitis (NASH). Although there are many undergoing clinical trials for NAFLD treatment, no currently approved treatment. accounts as major causing factor development hepatocellular carcinoma (HCC), and its incidence rises accompanying prevalence obesity diabetes. Reprogramming antidiabetic anti-obesity medicine treatment option NASH. Liver inflammation cellular death, or without fibrosis account progression Therefore, molecules signaling pathways involved in hepatic inflammation, fibrosis, cell death critically important targets therapy In addition, avoidance aberrant infiltration inflammatory cytokines by treating CCR antagonists also provides therapeutic option. Currently, an increasing number pre-clinical evaluate effects drugs, antibiotics, pan-caspase inhibitors, CCR2/5 antagonists, others on NAFLD, NASH, fibrosis. Non-invasive serum diagnostic markers developed fulfilling need testing large amount cases. Overall, better understanding underlying mechanism pathogenesis helpful choose optimized

Язык: Английский

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Diagnostic Modalities of Non-Alcoholic Fatty Liver Disease: From Biochemical Biomarkers to Multi-Omics Non-Invasive Approaches

Diagnostics, Год журнала: 2022, Номер 12(2), С. 407 - 407

Опубликована: Фев. 4, 2022

Non-Alcoholic Fatty Liver Disease (NAFLD) is currently the most common cause of chronic liver disease worldwide, and its prevalence increasing globally. NAFLD a multifaceted disorder, spectrum includes steatosis to steatohepatitis, which may evolve advanced fibrosis cirrhosis. In addition, presence independently associated with higher cardiometabolic risk increased mortality rates. Considering that vast majority individuals are mainly asymptomatic, early diagnosis non-alcoholic steatohepatitis (NASH) accurate staging crucial for better stratification, monitoring targeted management patients at risk. To date, biopsy remains gold standard procedure NASH NAFLD. However, due invasive nature, research on non-invasive tests rapidly significant advances having been achieved during last decades in diagnostic field. New promising biomarkers techniques have developed, evaluated assessed, including biochemical markers, imaging modalities recent multi-omics approaches. Our article provides comprehensive review available emerging tools used assessing NAFLD, also highlighting importance validated tools.

Язык: Английский

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Clinically important alterations in pharmacogene expression in histologically severe nonalcoholic fatty liver disease

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Март 17, 2023

Abstract Polypharmacy is common in patients with nonalcoholic fatty liver disease (NAFLD) and previous reports suggest that NAFLD associated altered drug disposition. This study aims to determine if are at risk for response by characterizing changes hepatic mRNA expression of genes mediating disposition (pharmacogenes) across the histological severity spectrum. We utilize RNA-seq 93 biopsies histologically staged Activity Score (NAS), fibrosis stage, steatohepatitis (NASH). identify 37 significant pharmacogene-NAFLD associations including CYP2C19 downregulation. chose validate due its actionability prescribing. Meta-analysis 16 independent studies demonstrate significantly downregulated 46% NASH, 58% high NAS, 43% severe fibrosis. Our data downregulation which supports developing personalized medicine approaches drugs sensitive metabolism enzyme.

Язык: Английский

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Aging promotes metabolic dysfunction-associated steatotic liver disease by inducing ferroptotic stress

Nature Aging, Год журнала: 2024, Номер 4(7), С. 949 - 968

Опубликована: Июнь 25, 2024

Язык: Английский

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