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CC BY-NC-ND 4.0 · Semin Liver Dis 2021; 41(04): 421-434
DOI: 10.1055/s-0041-1730927
Review Article

Insights into Nonalcoholic Fatty-Liver Disease Heterogeneity

Marco Arrese
1   Department of Gastroenterology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
2   Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago, Chile
,
Juan P. Arab
1   Department of Gastroenterology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
2   Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago, Chile
,
Francisco Barrera
1   Department of Gastroenterology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
2   Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago, Chile
,
Benedikt Kaufmann
3   Department of Pediatric Gastroenterology, Rady Children's Hospital, University of California San Diego, California
,
Luca Valenti
4   Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Translational Medicine, Department of Transfusion, Medicine and Hematology, Fondazione IRCCS Ca' Granda, Pad Marangoni, Milan, Italy
,
Ariel E. Feldstein
3   Department of Pediatric Gastroenterology, Rady Children's Hospital, University of California San Diego, California
› Author Affiliations
Funding Sources This work was funded, in part, by grants from the Fondo Nacional De Ciencia y Tecnología de Chile (FONDECYT no.: 1191145 to M.A., no.:1200227 to J.P.A., and no.:1191183 to F.B.), the Comisión Nacional de Investigación, Ciencia y Tecnología (CONICYT, AFB170005, CARE, Chile, UC). M.A. is part of the European-Latin American ESCALON consortium funded by the European Union's Horizon 2020 Research and Innovation Program under grant agreement no. 825510. A.E.F. was supported was by NIH grants R01 DK113592 and R01 AA024206. L.V. was supported by project grants from MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016–02364358 (“Impact of whole exome sequencing on the clinical management of patients with advanced nonalcoholic fatty-liver and cryptogenic-liver disease”), Ricerca corrente Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, the European Union (EU) Program Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- “Liver Investigation: Testing Marker Utility in Steatohepatitis,” Program “Photonics” under grant agreement “101016726” for the project “REVEAL: Neuronal microscopy for cell behavioural examination and manipulation,” Gilead_IN-IT-989–5790 “Developing a model of care for risk stratification and management of diabetic patients with non-alcoholic fatty-liver disease (NAFLD),” Fondazione IRCCS Ca' Granda “Liver BIBLE” PR-0391, Fondazione IRCCS Ca' Granda core COVID-19 Biobank (RC100017A).
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Abstract

The acronym nonalcoholic fatty-liver disease (NAFLD) groups a heterogeneous patient population. Although in many patients the primary driver is metabolic dysfunction, a complex and dynamic interaction of different factors (i.e., sex, presence of one or more genetic variants, coexistence of different comorbidities, diverse microbiota composition, and various degrees of alcohol consumption among others) takes place to determine disease subphenotypes with distinct natural history and prognosis and, eventually, different response to therapy. This review aims to address this topic through the analysis of existing data on the differential contribution of known factors to the pathogenesis and clinical expression of NAFLD, thus determining the different clinical subphenotypes observed in practice. To improve our understanding of NAFLD heterogeneity and the dominant drivers of disease in patient subgroups would predictably impact on the development of more precision-targeted therapies for NAFLD.

Keywords

nonalcoholic fatty-liver disease - steatosis - cirrhosis - fibrosis - nonalcoholic - steatohepatitis - NAFLD - NASH - metabolic syndrome - heterogeneity

Abbreviations

ACC, acetyl-CoA carboxylase; APOB, apolipoprotein B; CaHSCs, central vein-associated HSCs; CRP, C-reactive protein; DAMPs, damage-associated molecular patterns; DNL, de novo lipogenesis; GCKR, glucokinase regulator; GWAS, genome-wide association studies; HCC, hepatocellular carcinoma; HSC, hepatic stellate cells; IL, interleukin; MBOAT7, membrane bound O-acyl transferase; MoMFs, monocyte-derived macrophages; NAFLD, nonalcoholic fatty-liver disease; NAFL, nonalcoholic fatty-liver; NASH, nonalcoholic steatohepatitis; NLRP3, NLR family pyrin domain containing 3; PaHSCs, portal vein-associated HSCs; PAMPs, pathogen-associated molecular patterns; PNPLA3, patatin-like phospholipase domain-containing 3; PRS, polygenic risk scores; scRNA-seq, single cell RNA sequencing; TDM2, type 2 diabetes mellitus; TM6SF2: transmembrane 6 superfamily member 2; TNF-a, tumor necrosis factor-a.




Publication History

Article published online:
07 July 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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