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Chen VL, Kuppa A, Oliveri A, Chen Y, Ponnandy P, Patel PB, Palmer ND, Speliotes EK. Human genetics of metabolic dysfunction-associated steatotic liver disease: from variants to cause to precision treatment. J Clin Invest 2025; 135:e186424. [PMID: 40166930 PMCID: PMC11957700 DOI: 10.1172/jci186424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by increased hepatic steatosis with cardiometabolic disease and is a leading cause of advanced liver disease. We review here the genetic basis of MASLD. The genetic variants most consistently associated with hepatic steatosis implicate genes involved in lipoprotein input or output, glucose metabolism, adiposity/fat distribution, insulin resistance, or mitochondrial/ER biology. The distinct mechanisms by which these variants promote hepatic steatosis result in distinct effects on cardiometabolic disease that may be best suited to precision medicine. Recent work on gene-environment interactions has shown that genetic risk is not fixed and may be exacerbated or attenuated by modifiable (diet, exercise, alcohol intake) and nonmodifiable environmental risk factors. Some steatosis-associated variants, notably those in patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), are associated with risk of developing adverse liver-related outcomes and provide information beyond clinical risk stratification tools, especially in individuals at intermediate to high risk for disease. Future work to better characterize disease heterogeneity by combining genetics with clinical risk factors to holistically predict risk and develop therapies based on genetic risk is required.
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Affiliation(s)
- Vincent L. Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Annapurna Kuppa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Antonino Oliveri
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Yanhua Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Prabhu Ponnandy
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Puja B. Patel
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Nicholette D. Palmer
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Elizabeth K. Speliotes
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
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Tavaglione F, Pennisi G, Pelusi S. PNPLA3 I148M and Hepatocellular Carcinoma. Liver Int 2025; 45:e70051. [PMID: 40029157 DOI: 10.1111/liv.70051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 02/20/2025] [Accepted: 02/21/2025] [Indexed: 03/05/2025]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. With the widespread implementation of HBV vaccination and the availability of highly effective antiviral therapies, the incidence of metabolic dysfunction-associated steatotic liver disease (MASLD)-related HCC has proportionally increased. Notably, up to 20%-30% of MASLD-related HCC cases develop in the absence of overt cirrhosis. Several genetic variants, primarily in genes related to lipid metabolism, play a key role in HCC development in individuals with MASLD and alcohol-related liver disease. Among these, the rs738409 C>G polymorphism (I148M) in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene is the strongest genetic factor predisposing to the entire spectrum of MASLD conditions, including cirrhosis and HCC. Importantly, combining PNPLA3 I148M with multiple genetic variants robustly associated with progressive liver disease (i.e., polygenic risk scores) improves risk stratification and prediction of HCC in at-risk individuals compared to the single variant alone. In this review, we will discuss the latest evidence on the epidemiology of HCC and the contribution of PNPLA3 and PNPLA3-based polygenic risk scores to the development of HCC in at-risk individuals.
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Affiliation(s)
- Federica Tavaglione
- Division of Gastroenterology and Hepatology, MASLD Research Center, University of California at San Diego, La Jolla, California, USA
| | - Grazia Pennisi
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Serena Pelusi
- Transfusion Medicine Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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Chen VL, Vespasiani‐Gentilucci U. Integrating PNPLA3 into clinical risk prediction. Liver Int 2025; 45:e16103. [PMID: 39282715 PMCID: PMC11815612 DOI: 10.1111/liv.16103] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/02/2024] [Accepted: 09/04/2024] [Indexed: 02/05/2025]
Abstract
The PNPLA3-rs738409-G variant was the first common variant associated with hepatic fat accumulation and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Nevertheless, to date, the clinical translation of this discovery has been minimal because it has not yet been clearly demonstrated where the genetic information may play an independent and additional role in clinical risk prediction. In this mini-review, we will discuss the most relevant evidence regarding the potential integration of the PNPLA3 variant into scores and algorithms for liver disease diagnostics and risk stratification, specifically focusing on MASLD but also extending to liver diseases of other etiologies. The PNPLA3 variant adds little in diagnosing the current state of the disease, whether in terms of presence/absence of metabolic dysfunction-associated steatohepatitis or the stage of fibrosis. While it can play an important role in prediction, allowing for the early definition of risk profiles that enable tailored monitoring and interventions over time, this is most valuable when applied to populations with relatively high pre-test probability of having significant fibrosis based on either non-invasive tests (e.g. Fibrosis-4) or demographics (e.g. diabetes). Indeed, in this context, integrating FIB4 with the PNPLA3 genotype can refine risk stratification, though there is still no evidence that genetic information adds to liver stiffness determined by elastography. Similarly, in patients with known liver cirrhosis, knowing the PNPLA3 genotype can play a role in predicting the risk of hepatocellular carcinoma, while more doubts remain about the risk of decompensation.
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Affiliation(s)
- Vincent L. Chen
- Division of Gastroenterology and Hepatology, Department of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborMichiganUSA
| | - Umberto Vespasiani‐Gentilucci
- Research Unit of HepatologyUniversità Campus Bio‐Medico di RomeRomeItaly
- Hepatology and Clinical Medicine UnitFondazione Policlinico Universitario Campus‐Biomedico di RomaRomeItaly
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Kozlitina J, Sookoian S. Global Epidemiological Impact of PNPLA3 I148M on Liver Disease. Liver Int 2025; 45:e16123. [PMID: 39373119 PMCID: PMC11815610 DOI: 10.1111/liv.16123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 09/19/2024] [Accepted: 09/23/2024] [Indexed: 10/08/2024]
Abstract
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has increased exponentially over the past three decades, in parallel with the global rise in obesity and type 2 diabetes. It is currently the most common cause of liver-related morbidity and mortality. Although obesity has been identified as a key factor in the increased prevalence of MASLD, individual differences in susceptibility are significantly influenced by genetic factors. PNPLA3 I148M (rs738409 C>G) is the variant with the greatest impact on the risk of developing progressive MASLD and likely other forms of steatotic liver disease. This variant is prevalent across the globe, with the risk allele (G) frequency exhibiting considerable variation. Here, we review the contribution of PNPLA3 I148M to global burden and regional differences in MASLD prevalence, focusing on recent evidence emerging from population-based sequencing studies and prevalence assessments. We calculated the population attributable fraction (PAF) as a means of quantifying the impact of the variant on MASLD. Furthermore, we employ quantitative trait locus (QTL) analysis to ascertain the associations between rs738409 and a range of phenotypic traits. This analysis suggests that these QTLs may underpin pleiotropic effects on extrahepatic traits. Finally, we outline potential avenues for further research and identify key areas for investigation in future studies.
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Affiliation(s)
- Julia Kozlitina
- Eugene McDermott Center for Human Growth and DevelopmentUniversity of Texas Southwestern Medical CenterDallasTexasUSA
| | - Silvia Sookoian
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)Buenos AiresArgentina
- Clinical and Molecular Hepatology, Translational Health Research Center (CENITRES)Maimónides UniversityBuenos AiresArgentina
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Armisen J, Rauschecker M, Sarv J, Liljeblad M, Wernevik L, Niazi M, Knöchel J, Eklund O, Sandell T, Sherwood J, Bergenholm L, Hallén S, Wang S, Kamble P, Bhat M, Maxvall I, Wang Y, Lee RG, Bhanot S, Guo S, Romeo S, Lawitz E, Fjellström O, Lindén D, Blau JE, Loomba R. AZD2693, a PNPLA3 antisense oligonucleotide, for the treatment of MASH in 148M homozygous participants: Two randomized phase I trials. J Hepatol 2025:S0168-8278(25)00003-0. [PMID: 39798707 DOI: 10.1016/j.jhep.2024.12.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 12/20/2024] [Accepted: 12/26/2024] [Indexed: 01/15/2025]
Abstract
BACKGROUND & AIMS A common genetic variant (rs738409) encoding an isoleucine to methionine substitution at position 148 in the PNPLA3 protein is a determinant of hepatic steatosis, inflammation, fibrosis, cirrhosis, and liver-related mortality. AZD2693 is a liver-targeted antisense oligonucleotide against PNPLA3 mRNA. We evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics in single and multiple ascending dose studies. METHODS AZD2693 was assessed in 3D cultures of homozygous PNPLA3 148M primary human hepatocytes and mice expressing human PNPLA3. The single ascending dose study investigated 2-110 mg doses in overweight/mildly obese but otherwise healthy volunteers. The multiple ascending dose study investigated three monthly doses (25 mg, 50 mg and 80 mg) in participants with MRI-proton density fat fraction (MRI-PDFF) ≥7%. Changes in liver fat content were assessed at baseline, weeks 8 and 12 by MRI-PDFF. PNPLA3 mRNA and protein knockdown levels were evaluated for the 80 mg dose. RESULTS AZD2693 potently reduced PNPLA3 expression in human hepatocytes and livers of mice. Clinically, AZD2693 was generally well tolerated (no adverse events leading to discontinuation or treatment-related serious adverse events). Half-life was 14-33 days across investigated doses. A least-square mean liver PNPLA3 mRNA knockdown of 89% and reduction of protein levels demonstrated target engagement. Changes in hepatic steatosis at week 12 were -7.6% and -12.2% (placebo-corrected least-square means) for the 25 mg and 50 mg doses, respectively. There was a dose-dependent increase of polyunsaturated fatty acids in serum triglycerides and decreases vs. placebo in high-sensitivity C-reactive protein and interleukin 6. CONCLUSIONS AZD2693 reduced liver PNPLA3 with an acceptable safety and tolerability profile. These findings support the continued development of AZD2693. IMPACT AND IMPLICATIONS Clinical treatment options for metabolic dysfunction-associated steatohepatitis (MASH) are limited. The genetic risk factor with the largest effect size for progressing to poor liver-related outcomes in MASH is a single-nucleotide polymorphism in the gene PNPLA3 (p.I148M). In phase I single and multiple ascending dose studies, AZD2693, a liver-targeted antisense oligonucleotide, was well tolerated, reduced liver PNPLA3 mRNA and protein levels, and dose-dependently reduced liver fat content in homozygous PNPLA3 148M risk allele carriers. These data support continued development of AZD2693 as a potential precision medicine treatment for MASH. The phase IIb FORTUNA study is now ongoing. CLINICAL TRIAL NUMBER NCT04142424, NCT04483947.
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Affiliation(s)
- Javier Armisen
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals, R&D, AstraZeneca, Cambridge, UK
| | - Mitra Rauschecker
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals, R&D, AstraZeneca, Gaithersburg, MD, USA
| | - Janeli Sarv
- Late Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals, R&D, AstraZeneca, Gothenburg, Sweden
| | - Mathias Liljeblad
- Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals, R&D, AstraZeneca, Gothenburg, Sweden
| | - Linda Wernevik
- Clinical Operations, Cardiovascular, Renal and Metabolism, BioPharmaceuticals, R&D, AstraZeneca, Gothenburg, Sweden
| | - Mohammad Niazi
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Jane Knöchel
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Olof Eklund
- Global Patient Safety, Cardiovascular, Renal and Metabolism, BioPharmaceuticals, R&D, AstraZeneca, Gothenburg, Sweden
| | - Therése Sandell
- Global Patient Safety, Cardiovascular, Renal and Metabolism, BioPharmaceuticals, R&D, AstraZeneca, Gothenburg, Sweden
| | - James Sherwood
- Precision Medicine and Biosamples, Diagnostic and HBS Science, Biopharma Diagnostics, Oncology, R&D, AstraZeneca, Cambridge, UK
| | - Linnéa Bergenholm
- Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Stefan Hallén
- Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Shan Wang
- Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Prasad Kamble
- Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Maria Bhat
- Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals, R&D, AstraZeneca, Gothenburg, Sweden
| | - Ingela Maxvall
- Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals, R&D, AstraZeneca, Gothenburg, Sweden
| | - Yixin Wang
- Image Analysis & Platform, Pathology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | | | | | - Shuling Guo
- Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden; Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy
| | - Eric Lawitz
- Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Ola Fjellström
- Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Daniel Lindén
- Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Jenny E Blau
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals, R&D, AstraZeneca, Gaithersburg, MD, USA.
| | - Rohit Loomba
- MASLD Research Center, Division of Gastroenterology and Hepatology, University of California at San Diego, La Jolla, CA, USA
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Galvanin C, Buch S, Nahon P, Trépo E. PNPLA3 in Alcohol-Related Liver Disease. Liver Int 2025; 45:e16211. [PMID: 39679853 DOI: 10.1111/liv.16211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 11/28/2024] [Accepted: 11/29/2024] [Indexed: 12/17/2024]
Abstract
The discovery of PNPLA3 as a genetic risk factor for liver disease has transformed our understanding of the pathogenesis of alcohol-related liver disease (ALD). The recent reclassification of fatty liver disease as steatotic liver disease (SLD), introducing metabolic dysfunction and alcohol-related liver disease (MetALD), has highlighted how genetic and environmental factors synergistically drive liver damage. The PNPLA3 rs738409 variant stands as a paradigmatic example of gene-environment interaction, where its effect on liver disease is dramatically amplified by alcohol consumption, obesity and type 2 diabetes. Understanding these interactions has revealed novel pathogenic mechanisms. The robust genetic evidence and a growing understanding of molecular mechanisms have made PNPLA3 an attractive therapeutic target. Several compounds targeting PNPLA3 are now in clinical development. While initial trials have focused on metabolic dysfunction-associated SLD, the recognition that almost all individuals with excessive alcohol consumption have metabolic comorbidities provides an unprecedented opportunity to evaluate these genetically informed therapies in MetALD. In this review, we examine the role of PNPLA3 in ALD, focusing on gene-environment interactions and therapeutic implications in the context of the new disease classification framework.
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Affiliation(s)
- Clélia Galvanin
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
| | - Stephan Buch
- Department of Medicine I, Dresden University Hospital, Dresden, Germany
- Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Pierre Nahon
- Service d'Hépatologie, AP-HP Avicenne, Bobigny, France
- Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Team «Functional Genomics of Solid Tumors», Paris, France
| | - Eric Trépo
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
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Chen VL, Brady GF. Recent advances in MASLD genetics: Insights into disease mechanisms and the next frontiers in clinical application. Hepatol Commun 2025; 9:e0618. [PMID: 39774697 PMCID: PMC11717516 DOI: 10.1097/hc9.0000000000000618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 11/14/2024] [Indexed: 01/11/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease in the world and a growing cause of liver-related morbidity and mortality. Yet, at the same time, our understanding of the pathophysiology and genetic underpinnings of this increasingly common yet heterogeneous disease has increased dramatically over the last 2 decades, with the potential to lead to meaningful clinical interventions for patients. We have now seen the first pharmacologic therapy approved for the treatment of MASLD, and multiple other potential treatments are currently under investigation-including gene-targeted RNA therapies that directly extend from advances in MASLD genetics. Here we review recent advances in MASLD genetics, some of the key pathophysiologic insights that human genetics has provided, and the ways in which human genetics may inform our clinical practice in the field of MASLD in the near future.
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Armandi A, Rosso C, Caviglia GP, Bugianesi E. An updated overview on hepatocellular carcinoma in patients with Metabolic dysfunction-Associated Steatotic Liver Disease: Trends, pathophysiology and risk-based surveillance. Metabolism 2025; 162:156080. [PMID: 39571891 DOI: 10.1016/j.metabol.2024.156080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 11/13/2024] [Accepted: 11/14/2024] [Indexed: 11/25/2024]
Abstract
Hepatocellular carcinoma (HCC) is a relevant complication occurring in individuals with advanced Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD). Recent epidemiological data suggest an alarming increase in the HCC burden worldwide, with a relevant proportion attributable to MASLD (up to 38 %), either in cirrhotic or non-cirrhotic livers. In view of the changing landscape of metabolic syndrome as "silent pandemic", this narrative review aims to provide an updated picture of the burden of HCC in individuals with MASLD. In the complex pathophysiological pathways linking insulin resistance to MASLD and cardiometabolic syndrome, metabolic inflammation appears a relevant driver of systemic as well as organ-specific complications. Novel insights from the field of immunology, gut-derived liver damage, and association with extra-hepatic cancers will be discussed. Finally, strategies for risk-based HCC surveillance (circulating biomarkers, prognostic models and polygenic risk scores) will be provided and the potential impact of novel drug targeting fibrosing Metabolic dysfunction-Associated Steatohepatitis (MASH) on incident HCC will be discussed.
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Affiliation(s)
- Angelo Armandi
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126 Torino, Italy.
| | - Chiara Rosso
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126 Torino, Italy.
| | - Gian Paolo Caviglia
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126 Torino, Italy.
| | - Elisabetta Bugianesi
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126 Torino, Italy.
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Azariadis K, Gatselis NK, Lyberopoulou A, Arvaniti P, Zachou K, Gabeta S, Dalekos GN. PNPLA3 I148 M genetic variant in autoimmune hepatitis characterises advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related mortality. J Transl Autoimmun 2024; 9:100243. [PMID: 38974691 PMCID: PMC11225017 DOI: 10.1016/j.jtauto.2024.100243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 05/22/2024] [Accepted: 06/02/2024] [Indexed: 07/09/2024] Open
Abstract
Background Autoimmune hepatitis (AIH) is a relatively rare autoimmune disease with a strong genetic background. The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148 M (rs738409 C/G) variant has been associated with hepatic inflammation and fibrosis in chronic hepatic diseases beyond metabolic dysfunction-associated steatotic liver disease (MASLD). Aim Our aim was to investigate the significance of PNPLA3 I148 M variant in AIH. Method Two hundred AIH patients, followed in our centre, were evaluated while 100 healthy subjects served as controls. Genotyping was performed with allelic discrimination end-point polymerase chain reaction (PCR). Results The I148 M variant was present in 95/200 (47.5 %) AIH patients compared to 47/100 (47 %) healthy controls (p = 1.000). Patients with GG/CG genotypes were more likely to present with decompensated cirrhosis at diagnosis (GG/CG 6.3 % vs. CC 1 %, p = 0.039). Comorbidity with cardiometabolic risk factors and concurrence of MASLD was similar across genotypes. Simple steatosis was present in 37/186 (19.9 %) and steatohepatitis in 14/186 (7.5 %) patients with available liver biopsy without correlation with PNPLA3 genotype. Fibrosis stage and grade of inflammation were not correlated with any genotype. Response to treatment was also independent of the presence of the I148 M variant, even though a longer time was needed to achieve complete biochemical response in those carrying the GG/CG genotypes (p = 0.07). On Kaplan Meier analysis homozygosity for the G allele corelated with reduced survival free of decompensation (p = 0.006), cirrhotic events (decompensation, liver transplantation, hepatocellular carcinoma; p = 0.001) and liver-related death or liver transplantation (p = 0.011) in treated patients. Conclusions The PNPLA3 I148 M variant in AIH patients is associated with increased risk of advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related death or liver transplantation, regardless of the presence of MASLD. This signifies a potential role for the PNPLA3 I148 M variant as a new AIH biomarker allowing to identify patients at increased risk of disease progression.
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Affiliation(s)
- Kalliopi Azariadis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece
| | - Nikolaos K. Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece
| | - Aggeliki Lyberopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece
| | - Pinelopi Arvaniti
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece
| | - Stella Gabeta
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece
| | - George N. Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece
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Rahdan F, Saberi A, Saraygord-Afshari N, Hadizadeh M, Fayeghi T, Ghanbari E, Dianat-Moghadam H, Alizadeh E. Deciphering the multifaceted role of microRNAs in hepatocellular carcinoma: Integrating literature review and bioinformatics analysis for therapeutic insights. Heliyon 2024; 10:e39489. [PMID: 39498055 PMCID: PMC11532857 DOI: 10.1016/j.heliyon.2024.e39489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 08/06/2024] [Accepted: 10/15/2024] [Indexed: 11/07/2024] Open
Abstract
Hepatocellular carcinoma (HCC) poses a significant global health challenge, necessitating innovative therapeutic strategies. MicroRNAs (miRNAs) have emerged as pivotal regulators of HCC pathogenesis, influencing key processes such as self-renewal, angiogenesis, glycolysis, autophagy, and metastasis. This article integrates findings from a comprehensive literature review and bioinformatics analysis to elucidate the role of miRNAs in HCC. We discuss how dysregulation of miRNAs can drive HCC initiation, progression, and metastasis by modulating various signaling pathways and target genes. Moreover, leveraging high-throughput technology and bioinformatics tools, we identify key miRNAs involved in multiple cancer hallmarks, offering insights into potential combinatorial therapeutic strategies. Through our analysis considering p-values and signaling pathways associated with key features, we unveil miRNAs with simultaneous roles across critical cancer characteristics, providing a basis for the development of high-performance biomarkers. The microRNAs, miR-34a-5p, miR-373-3p, miR-21-5p, miR-214-5p, miR-195-5p, miR-139-5p were identified to be shared microRNAs in stemness, angiogenesis, glycolysis, autophagy, EMT, and metastasis of HCC. However, challenges such as miRNA stability and delivery hinder the translation of miRNA-based therapeutics into clinical practice. This review underscores the importance of further research to overcome existing barriers and realize the full potential of miRNA-based interventions for HCC management.
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Affiliation(s)
- Fereshteh Rahdan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alihossein Saberi
- Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Neda Saraygord-Afshari
- Department of Medical Biotechnology, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, 1449614535, Iran
| | - Morteza Hadizadeh
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Tahura Fayeghi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Ghanbari
- Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Dianat-Moghadam
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran
| | - Effat Alizadeh
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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11
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Demirtas CO, Yilmaz Y. Decoding 17-Beta-hydroxysteroid Dehydrogenase 13: A Multifaceted Perspective on Its Role in Hepatic Steatosis and Associated Disorders. J Clin Transl Hepatol 2024; 12:857-864. [PMID: 39440221 PMCID: PMC11491501 DOI: 10.14218/jcth.2024.00257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 09/07/2024] [Accepted: 09/10/2024] [Indexed: 10/25/2024] Open
Abstract
Chronic liver disease (CLD) represents a significant global health burden, with hepatic steatosis-associated disorders-such as metabolic dysfunction-associated steatohepatitis (MASH), alcoholic liver disease, and hepatitis C virus infection-being major contributors. Recent genome-wide association studies have identified the rs72613567:TA variant in the 17-beta-hydroxysteroid dehydrogenase 13 (HSD17B13) gene as a protective factor against the development and progression of these conditions. In this review, we summarized the current evidence surrounding the HSD17B13 rs72613567 variant, aiming to elucidate its impact on CLD risk and outcomes, and to explore the potential mechanisms behind its hepatoprotective effects. The rs72613567:TA variant induces a splice donor site mutation, resulting in a truncated, non-functional HSD17B13 protein. Numerous studies have demonstrated that this loss-of-function mutation confers protection against the development of cirrhosis and hepatocellular carcinoma (HCC) in patients with MASH, alcoholic liver disease, and hepatitis C virus infection. Moreover, the rs72613567:TA variant has been associated with reduced liver enzyme levels and improved survival in HCC patients. Integrating this variant into genetic risk scores has shown promise in predicting the progression of fatty liver disease to cirrhosis and HCC. Furthermore, inhibiting HSD17B13 expression through RNA interference and small molecule inhibitors has emerged as a potential therapeutic strategy for MASH. However, the precise molecular mechanisms underlying the hepatoprotective effects of the HSD17B13 rs72613567 variant remain to be fully elucidated. Future research should focus on clarifying the structure-function relationship of HSD17B13 and its role in liver pathophysiology to facilitate the development of targeted therapies for CLD associated with hepatic steatosis.
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Affiliation(s)
- Coskun Ozer Demirtas
- Department of Gastroenterology, School of Medicine, Marmara University, İstanbul, Türkiye
- Institute of Gastroenterology, Marmara University, İstanbul, Türkiye
| | - Yusuf Yilmaz
- Department of Gastroenterology, School of Medicine, Marmara University, İstanbul, Türkiye
- Institute of Gastroenterology, Marmara University, İstanbul, Türkiye
- Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Türkiye
- The Global NASH Council, Washington, DC, USA
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12
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Chen VL, Du X, Oliveri A, Chen Y, Kuppa A, Halligan BD, Province MA, Speliotes EK. Genetic risk accentuates dietary effects on hepatic steatosis, inflammation and fibrosis in a population-based cohort. J Hepatol 2024; 81:379-388. [PMID: 38582304 PMCID: PMC11347099 DOI: 10.1016/j.jhep.2024.03.045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 03/16/2024] [Accepted: 03/23/2024] [Indexed: 04/08/2024]
Abstract
BACKGROUND & AIMS Steatotic liver disease (SLD), characterized by elevated liver fat content (LFC), is influenced by genetics and diet. However, whether diet has a differential effect based on genetic risk is not well-characterized. We aimed to determine how genetic factors interact with diet to affect SLD in a large national biobank. METHODS We included UK Biobank participants with dietary intake measured by 24-hour recall and genotyping. The primary predictors were dietary pattern, PNPLA3-rs738409-G, TM6SF2-rs58542926-T, a 16-variant hepatic steatosis polygenic risk score (PRS), and gene-environment interactions. The primary outcome was LFC, and secondary outcomes were iron-controlled T1 time (cT1, a measure of liver inflammation and fibrosis) and liver-related events/mortality. RESULTS A total of 21,619 participants met inclusion criteria. In non-interaction models, Mediterranean diet and intake of fruit/vegetables/legumes and fish associated with lower LFC, while higher red/processed meat intake and all genetic predictors associated with higher LFC. In interaction models, all genetic predictors interacted with Mediterranean diet and fruit/vegetable/legume intake, while the steatosis PRS interacted with fish intake and the TM6SF2 genotype interacted with red/processed meat intake, to affect LFC. Dietary effects on LFC were up to 3.8-fold higher in PNPLA3-rs738409-GG vs. -CC individuals, and 1.4-3.0-fold higher in the top vs. bottom quartile of the steatosis PRS. Gene-diet interactions were stronger in participants with vs. without overweight. The steatosis PRS interacted with Mediterranean diet and fruit/vegetable/legume intake to affect cT1 and most dietary and genetic predictors associated with risk of liver-related events or mortality by age 70. CONCLUSIONS Effects of diet on LFC and cT1 were markedly accentuated in patients at increased genetic risk for SLD, implying dietary interventions may be more impactful in these populations. IMPACT AND IMPLICATIONS Genetic variants and diet both influence risk of hepatic steatosis, inflammation/fibrosis, and hepatic decompensation; however, how gene-diet interactions influence these outcomes has previously not been comprehensively characterized. We investigated this topic in the community-based UK Biobank and found that genetic risk and dietary quality interacted to influence hepatic steatosis and inflammation/fibrosis on liver MRI, so that the effects of diet were greater in people at elevated genetic risk. These results are relevant for patients and medical providers because they show that genetic risk is not fixed (i.e. modifiable factors can mitigate or exacerbate this risk) and realistic dietary changes may result in meaningful improvement in liver steatosis and inflammation/fibrosis. As genotyping becomes more routinely used in clinical practice, patients identified to be at high baseline genetic risk may benefit even more from intensive dietary counseling than those at lower risk, though future prospective studies are required.
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Affiliation(s)
- Vincent L Chen
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA
| | - Xiaomeng Du
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA
| | - Antonino Oliveri
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA
| | - Yanhua Chen
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA
| | - Annapurna Kuppa
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA
| | - Brian D Halligan
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA
| | - Michael A Province
- Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
| | - Elizabeth K Speliotes
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
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13
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Rieman-Klingler MC, Jung J, Tesfai K, Loomba R, Non AL. Integrating genetic and socioeconomic data to predict the progression of nonalcoholic fatty liver disease. AMERICAN JOURNAL OF BIOLOGICAL ANTHROPOLOGY 2024; 184:e24979. [PMID: 38778456 DOI: 10.1002/ajpa.24979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 04/25/2024] [Accepted: 05/08/2024] [Indexed: 05/25/2024]
Abstract
OBJECTIVES Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease globally, with an estimated prevalence exceeding 25%. Variants in the PNPLA3 and HSD17B13 genes have been a focus of investigations surrounding the etiology and progression of NAFLD and are believed to contribute to a greater burden of disease experienced by Hispanic Americans. However, little is known about socioeconomic factors influencing NAFLD progression or its increased prevalence among Hispanics. MATERIALS AND METHODS We cross-sectionally analyzed 264 patients to assess the role of genetic and socioeconomic variables in the development of advanced liver fibrosis in individuals at risk for NAFLD. RESULTS Adjusting for age, sex, body mass index, and PNPLA3 genotype, lacking a college degree was associated with 3.3 times higher odds of advanced fibrosis (95% confidence interval [CI]: 1.21-8.76, p = 0.019), an effect comparable to that of possessing the major PNPLA3 risk variant. Notably, the effect of PNPLA3 genotype on advanced fibrosis was attenuated to nonsignificance following adjustment for education and other socioeconomic markers. The effect of the protective HSD17B13 variant, moreover, diminished after adjustment for education (odds ratio [OR]: 0.39 [95% CI: 0.13-1.16, p = 0.092]), while lower education continued to predict advanced fibrosis following multivariable adjustment with an OR of 8.0 (95% CI: 1.91-33.86, p = 0.005). DISCUSSION Adjusting for education attenuated the effects of genotype and Hispanic ethnicity on liver fibrosis, suggesting that social factors-rather than genes or ethnicity-may be driving disease severity within some populations. Findings reveal the importance of including socioenvironmental controls when considering the role of genetics or ethnicity in complex disease.
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Affiliation(s)
- Maria C Rieman-Klingler
- Department of Anthropology, University of California, San Diego, La Jolla, California, USA
- School of Medicine, University of California, San Diego, La Jolla, California, USA
- Medical Scientist Training (MD/PhD) Program, University of California, San Diego, La Jolla, California, USA
| | - Jinho Jung
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Kaleb Tesfai
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla, California, USA
- Division of Epidemiology, Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, California, USA
| | - Amy L Non
- Department of Anthropology, University of California, San Diego, La Jolla, California, USA
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14
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Murakawa M, Nakagawa M, Nishimura H, Kaneko S, Miyoshi M, Kawai-Kitahata F, Nitta S, Tsuchiya J, Shimizu T, Watakabe K, Mochida T, Inada K, Iizuka Y, Sakai H, Sakurai Y, Sato A, Azuma S, Kawamura T, Maeyashiki C, Kurosaki M, Kusano F, Watanabe H, Kurata H, Karakama Y, Fujiwara T, Nagata Y, Tanaka T, Kakinuma S, Okamoto R, Asahina Y. High serum gamma-glutamyltransferase level after hepatitis C virus elimination is a risk factor for the development of hepatocellular carcinoma. Hepatol Res 2024. [PMID: 39073391 DOI: 10.1111/hepr.14094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 07/30/2024]
Abstract
AIM Gamma-glutamyltransferase (GGT) is known as an oxidative stress marker, induced by alcohol consumption and metabolic disorders, and is reported as a predictor of hepatocellular carcinoma (HCC) development after hepatitis C virus (HCV) elimination. However, it is not clear whether GGT serves simply as a surrogate marker for overlapping metabolic diseases or reflects HCV-specific carcinogenicity. We investigated the association between GGT and hepatocarcinogenesis after achieving a sustained viral response (SVR), accounting for drinking habits or diabetes, and examined predisposing factors associated with GGT levels after SVR. METHODS This is a prospective, multicenter, and observational study using the database of 1001 patients after HCV eradication with direct-acting antiviral agents. The association of GGT at SVR with cumulative HCC development was examined in a multivariate analysis using Cox proportional hazard models after adjustment for covariates including alcohol and diabetes. The association between oxidative stress markers or genetic factors and GGT levels was analyzed. RESULTS High GGT levels at SVR were associated with HCC development (HR] 2.38, 95% CI 1.10-5.17). This association was also significant when restricted to patients without alcohol consumption or diabetes (HR 8.38, 95% CI 2.87-24.47). GGT levels were correlated with serum growth differentiation factor 15 levels, a marker of mitochondrial dysfunction. Single-nucleotide polymorphisms of ZNF827 and GDF15 were associated with high GGT levels. CONCLUSIONS High GGT levels at SVR were associated with HCC development after accounting for alcohol consumption and diabetes. GGT levels are influenced by genetic predisposition and may reflect mitochondrial dysfunction after HCV eradication.
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Affiliation(s)
- Miyako Murakawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mina Nakagawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
- Institute of Education, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hisaaki Nishimura
- Department of Public Health, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shun Kaneko
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masato Miyoshi
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Fukiko Kawai-Kitahata
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Sayuri Nitta
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Jun Tsuchiya
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Taro Shimizu
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Keiya Watakabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomohiro Mochida
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kento Inada
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yasuhiro Iizuka
- Department of Gastroenterology and Hepatology, Kashiwa Municipal Hospital, Chiba, Japan
| | - Hideki Sakai
- Department of Gastroenterology and Hepatology, Kashiwa Municipal Hospital, Chiba, Japan
| | - Yuki Sakurai
- Department of Gastroenterology and Hepatology, Showa General Hospital, Tokyo, Japan
| | - Ayako Sato
- Department of Gastroenterology and Hepatology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan
| | - Seishin Azuma
- Department of Gastroenterology and Hepatology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan
| | - Takahiro Kawamura
- Department of Gastroenterology and Hepatology, JA Toride Medical Center, Ibaraki, Japan
| | - Chiaki Maeyashiki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Fumihiko Kusano
- Department of Gastroenterology and Hepatology, Tsuchiura Kyodo General Hospital, Ibaraki, Japan
| | - Hideki Watanabe
- Department of Gastroenterology and Hepatology, Yokosuka Kyosai Hospital, Kanagawa, Japan
| | - Hitoshi Kurata
- Department of Gastroenterology and Hepatology, Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan
| | - Yuko Karakama
- Department of Gastroenterology and Hepatology, Tokyo Kyosai Hospital, Tokyo, Japan
| | - Takeo Fujiwara
- Department of Public Health, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yuki Nagata
- Department of Human Genetics and Disease Diversity, Tokyo Medical Dental University, Tokyo, Japan
| | - Toshihiro Tanaka
- Department of Human Genetics and Disease Diversity, Tokyo Medical Dental University, Tokyo, Japan
| | - Sei Kakinuma
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Clinical and Diagnostic Laboratory Science, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
- Department for Liver Disease Control, Tokyo Medical and Dental University, Tokyo, Japan
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15
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Shang Y, Grip ET, Modica A, Skröder H, Ström O, Ntanios F, Gudbjörnsdottir S, Hagström H. Metabolic Syndrome Traits Increase the Risk of Major Adverse Liver Outcomes in Type 2 Diabetes. Diabetes Care 2024; 47:978-985. [PMID: 38498331 PMCID: PMC11116921 DOI: 10.2337/dc23-1937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 02/20/2024] [Indexed: 03/20/2024]
Abstract
OBJECTIVE Type 2 diabetes (T2D) increases the risk for major adverse liver outcomes (MALOs), including cirrhosis and its complications. Patients with T2D frequently have other traits of the metabolic syndrome (MetS). It remains uncertain whether there is a synergistic effect of accumulating MetS traits on future MALO risk. RESEARCH DESIGN AND METHODS Patients with T2D without a history of liver disease were identified from national registers in Sweden from 1998 to 2021. MetS traits included hypertension, low HDL level, hypertriglyceridemia, obesity, and albuminuria, in addition to T2D. MALO events were identified based on administrative coding from national registers until 31 October 2022. Data were analyzed using Cox regression models. RESULTS In total, 230,992 patients were identified (median age 64 years; 58% male), of whom 3,215 (1.39%) developed MALOs over a median follow-up of 9.9 years. Compared with patients with one MetS trait (only T2D) at baseline, those with more than one MetS trait had a higher rate of MALOs (adjusted hazard ratio [aHR] 2.33, 95% CI 1.53-3.54). The rate of MALOs increased progressively with increasing numbers of MetS traits at baseline (aHR 1.28 per added trait, 95% CI 1.23-1.33). During follow-up, patients who acquired additional MetS traits had a progressively higher rate of MALOs. The MetS trait with the largest association with incident MALOs was hypertension (aHR 2.06, 95% CI 1.57-2.71). CONCLUSIONS Having or acquiring additional traits of MetS increase the rate of progression to MALOs in patients with T2D. These results could be used to inform screening initiatives for liver disease.
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Affiliation(s)
- Ying Shang
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Emilie Toresson Grip
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
- Quantify Research, Stockholm, Sweden
| | | | | | - Oskar Ström
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
- Quantify Research, Stockholm, Sweden
| | | | - Soffia Gudbjörnsdottir
- Swedish National Diabetes Register
- Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Hannes Hagström
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
- Division of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden
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16
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Yeyeodu S, Hanafi D, Webb K, Laurie NA, Kimbro KS. Population-enriched innate immune variants may identify candidate gene targets at the intersection of cancer and cardio-metabolic disease. Front Endocrinol (Lausanne) 2024; 14:1286979. [PMID: 38577257 PMCID: PMC10991756 DOI: 10.3389/fendo.2023.1286979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 12/07/2023] [Indexed: 04/06/2024] Open
Abstract
Both cancer and cardio-metabolic disease disparities exist among specific populations in the US. For example, African Americans experience the highest rates of breast and prostate cancer mortality and the highest incidence of obesity. Native and Hispanic Americans experience the highest rates of liver cancer mortality. At the same time, Pacific Islanders have the highest death rate attributed to type 2 diabetes (T2D), and Asian Americans experience the highest incidence of non-alcoholic fatty liver disease (NAFLD) and cancers induced by infectious agents. Notably, the pathologic progression of both cancer and cardio-metabolic diseases involves innate immunity and mechanisms of inflammation. Innate immunity in individuals is established through genetic inheritance and external stimuli to respond to environmental threats and stresses such as pathogen exposure. Further, individual genomes contain characteristic genetic markers associated with one or more geographic ancestries (ethnic groups), including protective innate immune genetic programming optimized for survival in their corresponding ancestral environment(s). This perspective explores evidence related to our working hypothesis that genetic variations in innate immune genes, particularly those that are commonly found but unevenly distributed between populations, are associated with disparities between populations in both cancer and cardio-metabolic diseases. Identifying conventional and unconventional innate immune genes that fit this profile may provide critical insights into the underlying mechanisms that connect these two families of complex diseases and offer novel targets for precision-based treatment of cancer and/or cardio-metabolic disease.
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Affiliation(s)
- Susan Yeyeodu
- Julius L Chambers Biomedical/Biotechnology Institute (JLC-BBRI), North Carolina Central University, Durham, NC, United States
- Charles River Discovery Services, Morrisville, NC, United States
| | - Donia Hanafi
- Julius L Chambers Biomedical/Biotechnology Institute (JLC-BBRI), North Carolina Central University, Durham, NC, United States
| | - Kenisha Webb
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Nikia A. Laurie
- Julius L Chambers Biomedical/Biotechnology Institute (JLC-BBRI), North Carolina Central University, Durham, NC, United States
| | - K. Sean Kimbro
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA, United States
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Miteva D, Peshevska-Sekulovska M, Snegarova V, Peruhova M, Vasilev GH, Vasilev GV, Sekulovski M, Lazova S, Gulinac M, Tomov L, Mihova A, Velikova T. Microbiome and Genetic Factors in the Pathogenesis of Liver Diseases. GASTROENTEROLOGY INSIGHTS 2023; 14:575-597. [DOI: 10.3390/gastroent14040041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2024] Open
Abstract
Our genetic background has not changed over the past century, but chronic diseases are on the rise globally. In addition to the genetic component, among the critical factors for many diseases are inhabitants of our intestines (gut microbiota) as a crucial environmental factor. Dysbiosis has been described in liver diseases with different etiologies like non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease (ALD), viral hepatitis, autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), cirrhosis, hepatocellular carcinoma (HCC). On the other hand, new technologies have increased our understanding of liver disease genetics and treatment options. Genome-wide association studies (GWAS) identify unknown genetic risk factors, positional cloning of unknown genes associated with different diseases, gene tests for single nucleotide variations (SNVs), and next-generation sequencing (NGS) of selected genes or the complete genome. NGS also allowed studying the microbiome and its role in various liver diseases has begun. These genes have proven their effect on microbiome composition in host genome–microbiome association studies. We focus on altering the intestinal microbiota, and supplementing some bacterial metabolites could be considered a potential therapeutic strategy. The literature data promote probiotics/synbiotics role in reducing proinflammatory cytokines such as TNF-α and the interleukins (IL-1, IL-6, IL-8), therefore improving transaminase levels, hepatic steatosis, and NAFLD activity score. However, even though microbial therapy appears to be risk-free, evaluating side effects related to probiotics or synbiotics is imperative. In addition, safety profiles for long-term usage should be researched. Thus, this review focuses on the human microbiome and liver diseases, recent GWASs on liver disease, the gut-liver axis, and the associations with the microbiome and microbiome during/after liver disease therapy.
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Affiliation(s)
- Dimitrina Miteva
- Department of Genetics, Faculty of Biology, Sofia University St. Kliment Ohridski, 8 Dragan Tzankov Str., 1164 Sofia, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
| | - Monika Peshevska-Sekulovska
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Department of Gastroenterology, University Hospital Lozenetz, Kozyak 1 Str., 1407 Sofia, Bulgaria
| | - Violeta Snegarova
- Clinic of Internal Diseases, Naval Hospital—Varna, Military Medical Academy, Medical Faculty, Medical University, Blvd. Hristo Smirnenski 3, 9000 Varna, Bulgaria
| | - Milena Peruhova
- Department of Gastroenterology, Heart and Brain Hospital, Zdrave 1 Str., 8000 Burgas, Bulgaria
| | - Georgi H. Vasilev
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Laboratory of Hematopathology and Immunology, National Specialized Hospital for Active Treatment of Hematological Diseases, “Plovdivsko Pole” Str. 6, 1756 Sofia, Bulgaria
| | - Georgi V. Vasilev
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Department of Emergency Medicine and Clinic of Neurology, University Hospital “Sv. Georgi”, Blvd. Peshtersko Shose 66, 4000 Plovdiv, Bulgaria
| | - Metodija Sekulovski
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Department of Anesthesiology and Intensive Care, University Hospital Lozenetz, 1 Kozyak Str., 1407 Sofia, Bulgaria
| | - Snezhina Lazova
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Pediatric Department, University Hospital “N. I. Pirogov”, 21 “General Eduard I. Totleben” Blvd, 1606 Sofia, Bulgaria
- Department of Healthcare, Faculty of Public Health, “Prof. Tsekomir Vodenicharov, MD, DSc”, Medical University of Sofia, Bialo More 8 Str., 1527 Sofia, Bulgaria
| | - Milena Gulinac
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Department of General and Clinical Pathology, Medical University of Plovdiv, Bul. Vasil Aprilov 15A, 4000 Plovdiv, Bulgaria
| | - Latchezar Tomov
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Department of Informatics, New Bulgarian University, Montevideo 21 Str., 1618 Sofia, Bulgaria
| | - Antoaneta Mihova
- SMDL Ramus, Department of Immunology, Blvd. Kap. Spisarevski 26, 1527 Sofia, Bulgaria
| | - Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
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18
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Kocas-Kilicarslan ZN, Cetin Z, Faccioli LAP, Motomura T, Amirneni S, Diaz-Aragon R, Florentino RM, Sun Y, Pla-Palacin I, Xia M, Miedel MT, Kurihara T, Hu Z, Ostrowska A, Wang Z, Constantine R, Li A, Taylor DL, Behari J, Soto-Gutierrez A, Tafaleng EN. Polymorphisms Associated With Metabolic Dysfunction-Associated Steatotic Liver Disease Influence the Progression of End-Stage Liver Disease. GASTRO HEP ADVANCES 2023; 3:67-77. [PMID: 38292457 PMCID: PMC10827334 DOI: 10.1016/j.gastha.2023.09.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/01/2024]
Abstract
BACKGROUND AND AIMS Chronic liver injury that results in cirrhosis and end-stage liver disease (ESLD) causes more than 1 million deaths annually worldwide. Although the impact of genetic factors on the severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease (ALD) has been previously studied, their contribution to the development of ESLD remains largely unexplored. METHODS We genotyped 6 MASLD-associated polymorphisms in healthy (n = 123), metabolic dysfunction-associated steatohepatitis (MASH) (n = 145), MASLD-associated ESLD (n = 72), and ALD-associated ESLD (n = 57) cohorts and performed multinomial logistic regression to determine the combined contribution of genetic, demographic, and clinical factors to the progression of ESLD. RESULTS Distinct sets of factors are associated with the progression to ESLD. The PNPLA3 rs738409:G and TM6SF2 rs58542926:T alleles, body mass index (BMI), age, and female sex were positively associated with progression from a healthy state to MASH. The PNPLA3 rs738409:G allele, age, male sex, and having type 2 diabetes mellitus were positively associated, while BMI was negatively associated with progression from MASH to MASLD-associated ESLD. The PNPLA3 rs738409:G and GCKR rs780094:T alleles, age, and male sex were positively associated, while BMI was negatively associated with progression from a healthy state to ALD-associated ESLD. The findings indicate that the PNPLA3 rs738409:G allele increases susceptibility to ESLD regardless of etiology, the TM6SF2 rs58542926:T allele increases susceptibility to MASH, and the GCKR rs780094:T allele increases susceptibility to ALD-associated ESLD. CONCLUSION The PNPLA3, TM6SF2, and GCKR minor alleles influence the progression of MASLD-associated or ALD-associated ESLD. Genotyping for these variants in MASLD and ALD patients can enhance risk assessment, prompting early interventions to prevent ESLD.
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Affiliation(s)
- Zehra N. Kocas-Kilicarslan
- Department of Pathology, Center for Transcriptional Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Zeliha Cetin
- Department of Pathology, Center for Transcriptional Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Lanuza A. P. Faccioli
- Department of Pathology, Center for Transcriptional Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Takashi Motomura
- Department of Pathology, Center for Transcriptional Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Sriram Amirneni
- Department of Pathology, Center for Transcriptional Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Ricardo Diaz-Aragon
- Department of Pathology, Center for Transcriptional Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Rodrigo M. Florentino
- Department of Pathology, Center for Transcriptional Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Yiyue Sun
- Department of Pathology, Center for Transcriptional Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- School of Medicine, Tsinghua University, Beijing, China
| | - Iris Pla-Palacin
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Mengying Xia
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Mark T. Miedel
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Takeshi Kurihara
- Department of Pathology, Center for Transcriptional Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Zhiping Hu
- Department of Pathology, Center for Transcriptional Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Alina Ostrowska
- Department of Pathology, Center for Transcriptional Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Zi Wang
- Department of Statistics, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Albert Li
- Discovery Life Sciences, Huntsville, Alabama
| | - D. Lansing Taylor
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jaideep Behari
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Alejandro Soto-Gutierrez
- Department of Pathology, Center for Transcriptional Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
- McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania
| | - Edgar N. Tafaleng
- Department of Pathology, Center for Transcriptional Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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19
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Salaheldin M, Aly H, Lau L, Afify S, El-Kassas M. Nonalcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma: The Next Threat after Viral Hepatitis. Diagnostics (Basel) 2023; 13:2631. [PMID: 37627890 PMCID: PMC10453181 DOI: 10.3390/diagnostics13162631] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 07/26/2023] [Accepted: 07/28/2023] [Indexed: 08/27/2023] Open
Abstract
For many years, we have faced the complications of viral hepatitis and alcohol-related liver diseases such as cirrhosis, decompensation, portal hypertension, and hepatocellular carcinoma (HCC). Recently, we have seen a dynamic change in the field of hepatology. With the significant achievements in eradicating the hepatitis C virus by direct-acting antiviral agents and the rising epidemic of obesity, diabetes mellitus, and metabolic syndrome, there is a paradigm shift in the leading cause of liver cirrhosis and cancer to nonalcoholic fatty liver disease (NAFLD). Current data highlight the rapidly rising incidence of NAFLD-related HCC worldwide and expose the unseen part of the iceberg. In this review, we aim to update knowledge about the pathogenesis of NAFLD-induced HCC, surveillance difficulties, and promising disease markers. Molecular biomarkers, for example, may become a promising cornerstone for risk-stratified surveillance, early detection, and treatment selection for NAFLD-related HCC. Physicians can offer personalized and tailor-made clinical decisions for this unique patient subgroup.
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Affiliation(s)
- Mohamed Salaheldin
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt; (M.S.); (H.A.)
| | - Heba Aly
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt; (M.S.); (H.A.)
| | - Louis Lau
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 518172, China;
| | - Shimaa Afify
- National Hepatology and Tropical Medicine Research Institute, Cairo 11796, Egypt
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo 11795, Egypt
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20
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Antwi SO, Heckman M, White L, Yan I, Sarangi V, Lauer KP, Reddy J, Ahmed F, Veliginti S, Mejías Febres ED, Hatia RI, Chang P, Izquierdo-Sanchez L, Boix L, Rojas A, Banales JM, Reig M, Stål P, Gómez MR, Singal AG, Li D, Hassan MM, Roberts LR, Patel T. Metabolic liver cancer: associations of rare and common germline variants in one-carbon metabolism and DNA methylation genes. Hum Mol Genet 2023; 32:2646-2655. [PMID: 37369012 PMCID: PMC10407694 DOI: 10.1093/hmg/ddad099] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/29/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Animal studies implicate one-carbon metabolism and DNA methylation genes in hepatocellular carcinoma (HCC) development in the setting of metabolic perturbations. Using human samples, we investigated the associations between common and rare variants in these closely related biochemical pathways and risk for metabolic HCC development in a multicenter international study. We performed targeted exome sequencing of 64 genes among 556 metabolic HCC cases and 643 cancer-free controls with metabolic conditions. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for multiple comparisons. Gene-burden tests were used for rare variant associations. Analyses were performed in the overall sample and among non-Hispanic whites. The results show that among non-Hispanic whites, presence of rare functional variants in ABCC2 was associated with 7-fold higher risk of metabolic HCC (OR = 6.92, 95% CI: 2.38-20.15, P = 0.0004), and this association remained significant when analyses were restricted to functional rare variants observed in ≥2 participants (cases 3.2% versus controls 0.0%, P = 1.02 × 10-5). In the overall multiethnic sample, presence of rare functional variants in ABCC2 was nominally associated with metabolic HCC (OR = 3.60, 95% CI: 1.52-8.58, P = 0.004), with similar nominal association when analyses were restricted to functional rare variants observed in ≥2 participants (cases 2.9% versus controls 0.2%, P = 0.006). A common variant in PNPLA3 (rs738409[G]) was associated with higher HCC risk in the overall sample (P = 6.36 × 10-6) and in non-Hispanic whites (P = 0.0002). Our findings indicate that rare functional variants in ABCC2 are associated with susceptibility to metabolic HCC in non-Hispanic whites. PNPLA3-rs738409 is also associated with metabolic HCC risk.
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Affiliation(s)
- Samuel O Antwi
- Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Michael Heckman
- Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA
| | - Launia White
- Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA
| | - Irene Yan
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
| | - Vivekananda Sarangi
- Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Kimberly P Lauer
- Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Joseph Reddy
- Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, Florida, USA
| | - Fowsiyo Ahmed
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Swathi Veliginti
- Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA
| | | | - Rikita I Hatia
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ping Chang
- Department of Gastrointestinal Medical Oncology, The MD Anderson Cancer Center, Houston, TX, USA
| | - Laura Izquierdo-Sanchez
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute—Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, San Sebastian, Spain
| | - Loreto Boix
- BCLC Group, Liver Unit, ICMDM, IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
| | - Angela Rojas
- SeLiver Group, UCM Digestive Diseases, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital/CSIC/University of Seville, Seville, Spain
- Hepatic and Digestive Diseases Networking Biomedical Research Centre (CIBERehd), Madrid, Spain
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute—Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, San Sebastian, Spain
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Maria Reig
- BCLC Group, Liver Unit, ICMDM, IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
| | - Per Stål
- Department of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Manuel Romero Gómez
- SeLiver Group, UCM Digestive Diseases, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital/CSIC/University of Seville, Seville, Spain
- Hepatic and Digestive Diseases Networking Biomedical Research Centre (CIBERehd), Madrid, Spain
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Donghui Li
- Department of Gastrointestinal Medical Oncology, The MD Anderson Cancer Center, Houston, TX, USA
| | - Manal M Hassan
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Tushar Patel
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
- Department of Transplantation, Mayo Clinic, Jacksonville, FL, USA
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21
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Miller MJ, Harding-Theobald E, DiBattista JV, Zhao Z, Wijarnpreecha K, Lok AS, Chen VL. Progression to cirrhosis is similar among all ages in nonalcoholic fatty liver disease, but liver-related events increase with age. Hepatol Commun 2023; 7:e0148. [PMID: 37267221 PMCID: PMC10241497 DOI: 10.1097/hc9.0000000000000148] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 03/01/2023] [Indexed: 06/04/2023] Open
Abstract
BACKGROUND NAFLD is increasingly common among young people. Whether NAFLD carries a more benign course in younger adults is not known. We aimed to characterize genetic and metabolic risk factors for NAFLD and their effects on disease progression across age groups. METHODS We conducted a retrospective study of adults with NAFLD seen within Michigan Medicine, a tertiary care center, between 2010 and 2021. NAFLD was defined by hepatic steatosis on imaging, biopsy, or transient elastography in the absence of other chronic liver diseases. Cirrhosis was determined by validated International Classification of Diseases-9/10 codes or imaging. Fine-Gray competing risk models were generated, with incident cirrhosis and liver-related events (LREs) as the primary outcomes and death without cirrhosis or LREs as a competing risk. The primary predictor was the age category. RESULTS We included 31,505 patients with NAFLD, with 8,252 aged 18 to younger than 40, 15,035 aged 40 to younger than 60, and 8,218 aged 60 years or older years at diagnosis. Compared with older patients, young adults more often had obesity, higher ALT, and high-risk PNPLA3 alleles, and fewer had prevalent cirrhosis, hypertension, hyperlipidemia, and diabetes. The 10-year risk of incident cirrhosis was similar between ages (3.4% in age 18 to <40 vs 3.7% in age 40 to <60 vs 4.7% in age ≥60; p = 0.058). Predictors of LREs were advancing age and diabetes, with a significantly higher 10-year risk of LREs in the oldest age group (0.2% in age 18 to <40 vs 0.7% in age 40 to <60 vs 1.1% in age ≥60; p = 0.008). CONCLUSIONS While the baseline prevalence of cirrhosis was higher among older adults, the rate of NAFLD progression to cirrhosis was similar in young and older adults. Older patients were more likely to have LREs.
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Affiliation(s)
- Matthew J. Miller
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Emily Harding-Theobald
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Ann Arbor, Michigan, USA
| | - Jacob V. DiBattista
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Zhe Zhao
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Ann Arbor, Michigan, USA
| | - Karn Wijarnpreecha
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Ann Arbor, Michigan, USA
| | - Anna S. Lok
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Ann Arbor, Michigan, USA
| | - Vincent L. Chen
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Ann Arbor, Michigan, USA
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22
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Thrift AP, Kanwal F, Liu Y, Khaderi S, Singal AG, Marrero JA, Loo N, Asrani SK, Luster M, Al-Sarraj A, Ning J, Tsavachidis S, Gu X, Amos CI, El-Serag HB. Risk stratification for hepatocellular cancer among patients with cirrhosis using a hepatic fat polygenic risk score. PLoS One 2023; 18:e0282309. [PMID: 36854015 PMCID: PMC9974109 DOI: 10.1371/journal.pone.0282309] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 02/12/2023] [Indexed: 03/02/2023] Open
Abstract
BACKGROUND Polygenic risk scores (PRS) hold the promise to refine prognostication in hepatocellular cancer (HCC). The few available HCC PRS include germline risk variants identified among individuals of mostly European ancestry, but data are lacking on the transportability of these PRS in multiethnic U.S patients with cirrhosis from multiple etiologies. METHODS We used data from 1644 patients with cirrhosis enrolled in two prospective cohort studies in the U.S. Patients were followed until HCC diagnosis, death, liver transplantation, or last study visit through June 30, 2021. The high-risk variants in PNPLA3-MBOAT7-TM6SF2-GCKR were combined in a PRS and we evaluated its association with HCC. Discriminatory accuracy was assessed using the C-statistic. RESULTS During 4,759 person-years of follow-up, 93 patients developed HCC. Mean age was 59.8 years, 68.6% were male, 27.2% Hispanic, 25.1% non-Hispanic Black, 25.7% had NAFLD, 42.1% had heavy alcohol use, and 19.5% had active HCV. HCC risk increased by 134% per unit increase in PRS (HR = 2.30; 95% CI, 1.35-3.92). Compared to cirrhosis patients in the lowest tertile of the PRS, those in the highest tertile had 2-fold higher risk of HCC (HR = 2.05; 95% CI, 1.22-3.44). The PRS alone had modest discriminatory ability (C-statistic = 0.58; 95% CI, 0.52-0.63); however, adding PRS to a predictive model with traditional HCC risk factors had a C-statistic of 0.70 (95% CI, 0.64-0.76), increasing from 0.68 without the PRS (p = 0.0012). CONCLUSIONS Our findings suggest that PRS may enhance risk prediction for HCC in contemporary U.S. cirrhosis patients.
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Affiliation(s)
- Aaron P. Thrift
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States of America
| | - Fasiha Kanwal
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
- Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E DeBakey Veterans Affairs Medical Center, Houston, TX, United States of America
| | - Yanhong Liu
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States of America
| | - Saira Khaderi
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
| | - Amit G. Singal
- Division of Digestive and Liver Diseases, Department of Medicine, UT Southwestern Medical Center, Dallas, Texas, United States of America
| | - Jorge A. Marrero
- Division of Digestive and Liver Diseases, Department of Medicine, UT Southwestern Medical Center, Dallas, Texas, United States of America
| | - Nicole Loo
- Texas Liver Institute, San Antonio, Texas, United States of America
| | - Sumeet K. Asrani
- Baylor University Medical Center, Dallas, Texas, United States of America
| | - Michelle Luster
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
| | - Abeer Al-Sarraj
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
- Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E DeBakey Veterans Affairs Medical Center, Houston, TX, United States of America
| | - Jing Ning
- Department of Biostatistics, UT MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Spiridon Tsavachidis
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
| | - Xiangjun Gu
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
| | - Christopher I. Amos
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States of America
| | - Hashem B. El-Serag
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
- Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E DeBakey Veterans Affairs Medical Center, Houston, TX, United States of America
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23
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Mohamed Fteah A, Abdel Rahim A, Ahmed AbdelHady A, Shawky H, A Elrefaiy M, Mamdouh Aly D. Association of PNPLA3 (rs738409) & TM6SF2 (rs58542926) and ATG16L1 (rs2241880) genetic variants with susceptibility to hepatocellular carcinoma in a group of Egyptian patients with HCV-induced liver cirrhosis. Tumour Virus Res 2023; 15:200256. [PMID: 36804832 PMCID: PMC9975679 DOI: 10.1016/j.tvr.2023.200256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 01/16/2023] [Accepted: 02/10/2023] [Indexed: 02/17/2023] Open
Affiliation(s)
| | - Ali Abdel Rahim
- Hepato-gastroentrology Department - Theodor Bilharz Research Institute, Egypt
| | | | - Hanan Shawky
- Clinical Chemistry Department - Theodor Bilharz Research Institute, Egypt
| | - Mohamed A Elrefaiy
- Hepato-gastroentrology Department - Theodor Bilharz Research Institute, Egypt
| | - Doaa Mamdouh Aly
- Clinical Chemistry Department - Theodor Bilharz Research Institute, Egypt
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Campani C, Zucman-Rossi J, Nault JC. Genetics of Hepatocellular Carcinoma: From Tumor to Circulating DNA. Cancers (Basel) 2023; 15:cancers15030817. [PMID: 36765775 PMCID: PMC9913369 DOI: 10.3390/cancers15030817] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/21/2023] [Accepted: 01/23/2023] [Indexed: 02/01/2023] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for 90% of primary hepatic malignancies and is one of the major causes of cancer-related death. Over the last 15 years, the molecular landscape of HCC has been deciphered, with the identification of the main driver genes of liver carcinogenesis that belong to six major biological pathways, such as telomere maintenance, Wnt/b-catenin, P53/cell cycle regulation, oxidative stress, epigenetic modifiers, AKT/mTOR and MAP kinase. The combination of genetic and transcriptomic data composed various HCC subclasses strongly related to risk factors, pathological features and prognosis. However, translation into clinical practice is not achieved, mainly because the most frequently mutated genes are undruggable. Moreover, the results derived from the analysis of a single tissue sample may not adequately catch the intra- and intertumor heterogeneity. The analysis of circulating tumor DNA (ctDNA) is broadly developed in other types of cancer for early diagnosis, prognosis and monitoring under systemic treatment in order to identify primary and secondary mechanisms of resistance. The aim of this review is to describe recent data about the HCC molecular landscape and to discuss how ctDNA could be used in the future for HCC detection and management.
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Affiliation(s)
- Claudia Campani
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris Cité, Team «Functional Genomics of Solid Tumors», 75006 Paris, France
- Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, 75006 Paris, France
- Internal Medicine and Hepatology Unit, Department of Experimental and Clinical Medicine, University of Firenze, 50134 Firenze, Italy
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris Cité, Team «Functional Genomics of Solid Tumors», 75006 Paris, France
- Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, 75006 Paris, France
- Hôpital Européen Georges Pompidou, APHP, 75015 Paris, France
| | - Jean-Charles Nault
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris Cité, Team «Functional Genomics of Solid Tumors», 75006 Paris, France
- Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, 75006 Paris, France
- Liver Unit, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, 93000 Bobigny, France
- Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris Nord, 93000 Bobigny, France
- Correspondence: ; Tel.: +33-6-1067-9461
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Horackova K, Frankova S, Zemankova P, Nehasil P, Cerna M, Neroldova M, Otahalova B, Kral J, Hovhannisyan M, Stranecky V, Zima T, Safarikova M, Kalousova M, Consortium CZECANCA, Novotny J, Sperl J, Borecka M, Jelinkova S, Vocka M, Janatova M, Kleiblova P, Kleibl Z, Jirsa M, Soukupova J. Low Frequency of Cancer-Predisposition Gene Mutations in Liver Transplant Candidates with Hepatocellular Carcinoma. Cancers (Basel) 2022; 15:cancers15010201. [PMID: 36612198 PMCID: PMC9818325 DOI: 10.3390/cancers15010201] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/22/2022] [Accepted: 12/23/2022] [Indexed: 12/31/2022] Open
Abstract
Hepatocellular carcinoma (HCC) mainly stems from liver cirrhosis and its genetic predisposition is believed to be rare. However, two recent studies describe pathogenic/likely pathogenic germline variants (PV) in cancer-predisposition genes (CPG). As the risk of de novo tumors might be increased in PV carriers, especially in immunosuppressed patients after a liver transplantation, we analyzed the prevalence of germline CPG variants in HCC patients considered for liver transplantation. Using the panel NGS targeting 226 CPGs, we analyzed germline DNA from 334 Czech HCC patients and 1662 population-matched controls. We identified 48 PVs in 35 genes in 47/334 patients (14.1%). However, only 7/334 (2.1%) patients carried a PV in an established CPG (PMS2, 4×NBN, FH or RET). Only the PV carriers in two MRN complex genes (NBN and RAD50) were significantly more frequent among patients over controls. We found no differences in clinicopathological characteristics between carriers and non-carriers. Our study indicated that the genetic component of HCC is rare. The HCC diagnosis itself does not meet criteria for routine germline CPG genetic testing. However, a low proportion of PV carriers may benefit from a tailored follow-up or targeted therapy and germline testing could be considered in liver transplant recipients.
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Affiliation(s)
- Klara Horackova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
| | - Sona Frankova
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
| | - Petra Zemankova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12853 Prague, Czech Republic
| | - Petr Nehasil
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12853 Prague, Czech Republic
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
| | - Marta Cerna
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
| | - Magdalena Neroldova
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
| | - Barbora Otahalova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
- Department of Biochemistry, Faculty of Natural Science, Charles University, 12800 Prague, Czech Republic
| | - Jan Kral
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
| | - Milena Hovhannisyan
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
| | - Viktor Stranecky
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
| | - Tomas Zima
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
| | - Marketa Safarikova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
| | - Marta Kalousova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
| | - CZECANCA Consortium
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
| | - Jan Novotny
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12800 Prague, Czech Republic
| | - Jan Sperl
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
- Department of Internal Medicine, First Faculty of Medicine, Charles University and Military University Hospital, 16902 Prague, Czech Republic
| | - Marianna Borecka
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
| | - Sandra Jelinkova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
| | - Michal Vocka
- Department of Oncology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
| | - Marketa Janatova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
| | - Petra Kleiblova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12800 Prague, Czech Republic
| | - Zdenek Kleibl
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12853 Prague, Czech Republic
| | - Milan Jirsa
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
| | - Jana Soukupova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12808 Prague, Czech Republic
- Correspondence: ; Tel.: +420-22496-4501
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Färkkilä M, Kautiainen H, Tenca A, Jokelainen K, Arola J. PNPLA3 allele frequency has no impact on biliary bile acid composition or disease course in patients with primary sclerosing cholangitis. PLoS One 2022; 17:e0277084. [PMID: 36454904 PMCID: PMC9714899 DOI: 10.1371/journal.pone.0277084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 10/19/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND AND AIMS Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease that leads to bile duct strictures, cholestasis, and biliary cirrhosis. PNPLA3 (patatin-like phospholipase domain containing 3), regulates cellular lipid synthesis by converting lysophosphatidic acid into phosphatidic acid. Isoleucine mutation to methionine at position 148 (I148M) causes a loss of this function. Only two studies, with contradictory results, have evaluated the role of PNPLA3 in PSC. The rs738409(G) variant of PNPLA3 has been associated with an increased risk for transplantation in male patients with dominant strictures (DS). The study aimed to evaluate the PNPLA3 allele frequency effect on the clinical outcomes, progression, and prognosis of PSC. Furthermore, we analyzed the impact of PNPLA3 on phospholipid and bile acid composition to evaluate the effect of the PNPLA3 status on UDCA response. PATIENTS AND METHODS We recruited 560 patients prospectively and collected clinical and laboratory data as well as liver histology and imaging findings. PNPLA3 (CC, CG, GG) alleles were analyzed with TaqManTM. We also analyzed bile acids (BA), cholesterol and phospholipids and individual BA from a sample aspirated during endoscopic retrograde cholangiography (ERC). RESULTS Among the recruited patients, 58.4%, 35.7% and 5.9% had the wild (CC), heterozygous (CG) and homozygous (GG) alleles, respectively. The PNPLA3 haplotype did not impact bile composition or individual BA. In addition, we found no differences in age at diagnosis, disease progression, liver fibrosis or survival between the cohorts. CONCLUSIONS The PNPLA3 I148M variant had no significant impact on on bile composition, including UDCA content, clinical outcomes, progression of liver fibrosis, hepatobiliary cancer risk, liver transplantation, or overall survival.
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Affiliation(s)
- Martti Färkkilä
- Department of Gastroenterology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- * E-mail:
| | - Hannu Kautiainen
- Folkhälsan Research Center, Helsinki, Finland
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Andrea Tenca
- Department of Gastroenterology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Kalle Jokelainen
- Department of Gastroenterology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Johanna Arola
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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Youssef SS, Youness RA, Abbas EAER, Osman NM, ELFiky A, El-Kassas M. miR-516a-3P, a potential circulating biomarker in hepatocellular carcinoma, correlated with rs738409 polymorphism in PNPLA3. Per Med 2022; 19:483-493. [PMID: 36239555 DOI: 10.2217/pme-2022-0005] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 07/10/2022] [Indexed: 12/02/2022]
Abstract
Aim: The aim was to investigate the expression profile of miR-516a-3P and its correlation with the PNPLA3 rs738409 polymorphism in Egyptian hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) patients. Materials & methods: miR-516a-3P was quantified and rs738409 was genotyped by quantitative reverse transcription PCR. Results: miR-516a-3P was significantly upregulated in HCC patients compared with HCV patients (p = 0.001). Receiver operating characteristic curve analysis confirmed that miR-516a-3P discriminates HCC from HCV (p = 0.001). A significant (p = 0.015) correlation between miR-516a-3p level and PNPLA3 rs738409 genotypes was recorded in HCV patients, yet it was not recorded in either healthy individuals or HCC patients. miR-516a-3p level was significantly (p = 0.001) higher in HCV patients carrying the rs738409 GG genotype than in those carrying the CC genotype. Conclusion: miR-516a-3P is a potential biomarker in HCC. PNPLA3 rs738409 GG carriers affect miR-516a-3P expression in HCV, and this may highlight a new mechanism in liver disease.
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Affiliation(s)
- Samar Samir Youssef
- Microbial Biotechnology Department, National Research Centre, 33 El Buhouth St., Dokki, Cairo, 12622, Egypt
| | - Rana Ahmed Youness
- School of Life & Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital, Cairo, 11578, Egypt
- Pharmaceutical Biology Department, Faculty of Pharmacy & Biotechnology, German University in Cairo, Cairo, Egypt
| | - Eman Abd El-Razek Abbas
- Microbial Biotechnology Department, National Research Centre, 33 El Buhouth St., Dokki, Cairo, 12622, Egypt
| | - Noha Mohamed Osman
- Cell Biology Department, National Research Centre, 33 El Buhouth St., Dokki, Cairo, 12622, Egypt
| | - Asmaa ELFiky
- Environmental & Occupational Medicine Department, Environmental Research Division, National Research Centre, 33 El Buhouth St., Dokki, Cairo, 12622, Egypt
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, 11795, Egypt
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Youssef SS, Abbas EAER, Elfiky AM, Seif S, Nabeel MM, Shousha HI, Abdelaziz AO. The impact of polymorphism in PNPLA3 and TM6SF2 genes on the susceptibility and survival of hepatitis C-related hepatocellular carcinoma. EGYPTIAN LIVER JOURNAL 2022; 12:56. [DOI: 10.1186/s43066-022-00212-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 08/28/2022] [Indexed: 12/02/2022] Open
Abstract
Abstract
Background
Genetic variants of Patatin-like phospholipase domain-containing protein 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) genes have been reported with the development of hepatocellular carcinoma (HCC). This study aims to explore the role of The PNPLA3 rs738409 and TM6SF2 rs58542926 single-nucleotide polymorphisms (SNPs) on the incidence and survival of HCV-induced HCC in Egyptians.
Methods and results
This case-control study included (120) HCC and (144) hepatitis C virus (HCV) patients. Baseline clinical, laboratory, tumor characteristics data, HCC recurrence, and overall survival were collected. PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphism were detected by TaqMan allelic discrimination assay. We found that HCC patients were significantly older with male predominance. A significant difference between the TT genotypes of TM6SF2 frequency was observed in HCC compared with HCV patients. Moreover, the T allele of TM6SF2 distributions revealed a significant contribution to the different stages of HCC (p=0.03). Both PNPLA3 rs738409 and TM6SF2 rs58542926 variants showed a significant relation with treatment response according to the modified RECIST criteria. Age and diabetes mellitus were the independent factors associated with the development of HCC by multivariate regression analysis.
Conclusions
TM6SF2 rs58542926 polymorphism, not PNPLA3 rs738409, could be implicated in the development of HCV-induced HCC and its progression.
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29
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Mitsala A, Tsalikidis C, Romanidis K, Pitiakoudis M. Non-Alcoholic Fatty Liver Disease and Extrahepatic Cancers: A Wolf in Sheep’s Clothing? Curr Oncol 2022; 29:4478-4510. [PMID: 35877216 PMCID: PMC9325209 DOI: 10.3390/curroncol29070356] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/23/2022] [Accepted: 06/23/2022] [Indexed: 12/02/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is now considered the main driver and leading cause of chronic liver disease globally. The umbrella term NAFLD describes a range of liver conditions closely related to insulin resistance, metabolic syndrome, diabetes mellitus, obesity, and dyslipidemia. At the same time, several malignancies, including hepatocellular carcinoma and colorectal cancer, are considered to be common causes of death among patients with NAFLD. At first, our review herein aims to investigate the role of NAFLD in developing colorectal neoplasms and adenomatous polyps based on the current literature. We will also explore the connection and the missing links between NAFLD and extrahepatic cancers. Interestingly, any relationship between NAFLD and extrahepatic malignancies could be attributable to several shared metabolic risk factors. Overall, obesity, insulin resistance, metabolic syndrome, and related disorders may increase the risk of developing cancer. Therefore, early diagnosis of NAFLD is essential for preventing the progression of the disease and avoiding its severe complications. In addition, cancer screening and early detection in these patients may improve survival and reduce any delays in treatment.
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30
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Zanotti S, Boot GF, Coto-Llerena M, Gallon J, Hess GF, Soysal SD, Kollmar O, Ng CKY, Piscuoglio S. The Role of Chronic Liver Diseases in the Emergence and Recurrence of Hepatocellular Carcinoma: An Omics Perspective. Front Med (Lausanne) 2022; 9:888850. [PMID: 35814741 PMCID: PMC9263082 DOI: 10.3389/fmed.2022.888850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 05/23/2022] [Indexed: 12/02/2022] Open
Abstract
Hepatocellular carcinoma (HCC) typically develops from a background of cirrhosis resulting from chronic inflammation. This inflammation is frequently associated with chronic liver diseases (CLD). The advent of next generation sequencing has enabled extensive analyses of molecular aberrations in HCC. However, less attention has been directed to the chronically inflamed background of the liver, prior to HCC emergence and during recurrence following surgery. Hepatocytes within chronically inflamed liver tissues present highly activated inflammatory signaling pathways and accumulation of a complex mutational landscape. In this altered environment, cells may transform in a stepwise manner toward tumorigenesis. Similarly, the chronically inflamed environment which persists after resection may impact the timing of HCC recurrence. Advances in research are allowing an extensive epigenomic, transcriptomic and proteomic characterization of CLD which define the emergence of HCC or its recurrence. The amount of data generated will enable the understanding of oncogenic mechanisms in HCC from the CLD perspective and provide the possibility to identify robust biomarkers or novel therapeutic targets for the treatment of primary and recurrent HCC. Importantly, biomarkers defined by the analysis of CLD tissue may permit the early detection or prevention of HCC emergence and recurrence. In this review, we compile the current omics based evidence of the contribution of CLD tissues to the emergence and recurrence of HCC.
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Affiliation(s)
- Sofia Zanotti
- Anatomic Pathology Unit, IRCCS Humanitas University Research Hospital, Milan, Italy
| | - Gina F. Boot
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Mairene Coto-Llerena
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - John Gallon
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Gabriel F. Hess
- Clarunis, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Savas D. Soysal
- Clarunis, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Otto Kollmar
- Clarunis, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Charlotte K. Y. Ng
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- Bern Center for Precision Medicine, Bern, Switzerland
| | - Salvatore Piscuoglio
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
- *Correspondence: Salvatore Piscuoglio
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Chuaypen N, Siripongsakun S, Hiranrat P, Tanpowpong N, Avihingsanon A, Tangkijvanich P. Improvement of liver fibrosis, but not steatosis, after HCV eradication as assessment by MR-based imaging: Role of metabolic derangement and host genetic variants. PLoS One 2022; 17:e0269641. [PMID: 35696400 PMCID: PMC9191717 DOI: 10.1371/journal.pone.0269641] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 05/22/2022] [Indexed: 12/05/2022] Open
Abstract
Significant liver fibrosis regression occurs after hepatitis C virus (HCV) therapy. However, the impact of direct-acting antivirals (DAAs) on steatosis is less clear. This study was aimed at evaluating serial fibrosis and steatosis alterations in patients with HCV genotype 1, who achieved sustained virological response (SVR). We enrolled 55 HCV mono-infected and 28 HCV/HIV co-infected patients receiving elbasvir/grazoprevir from a clinical trial. Fibrosis and steatosis were assessed at baseline, follow-up week-24 (FUw24) and week-72 (FUw72) by magnetic resonance elastography (MRE) and proton density fat fraction (PDFF), respectively. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409, transmembrane six superfamily member 2 (TM6SF2) rs58542926 and membrane bound O-acyltransferase domain-containing 7 (MBOAT7) rs641738 polymorphisms were determined by allelic discrimination. Overall, mean MRE decreased significantly from baseline to FUw24 and FUw72. At FUw72, patients with baseline F2-F4 had higher rate of ≥30% MRE decline compared with individuals with baseline F0-F1 (30.2%vs.3.3%, P = 0.004). In multivariate analysis, significant fibrosis was associated with MRE reduction. The prevalence of steatosis (PDFF≥5.2%) at baseline was 21.7%. Compared to baseline, there were 17 (20.5%) patients with decreased PDFF values at FUw72 (<30%), while 23 (27.7%) patients had increased PDFF values (≥30%). Regarding the overall cohort, mean PDFF significantly increased from baseline to FUw72, and displayed positive correlation with body mass index (BMI) alteration. In multivariate analysis, the presence of diabetes, PNPLA3 CG+GG genotypes and increased BMI at FUw72 were significantly associated with progressive steatosis after SVR. Other genetic variants were not related to fibrosis and steatosis alteration. This study concluded that HCV eradication was associated with fibrosis improvement. However, progressive steatosis was observed in a proportion of patients, particularly among individuals with metabolic derangement and PNPLA3 variants. The combined clinical parameters and host genetic factors might allow a better individualized strategy in this sub-group of patients to alleviate progressive steatosis after HCV cure.
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Affiliation(s)
- Natthaya Chuaypen
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Surachate Siripongsakun
- Sonographer School, Faculty of Health Science Technology, Chulabhorn Royal Academy, Bangkok, Thailand
| | - Pantajaree Hiranrat
- Sonographer School, Faculty of Health Science Technology, Chulabhorn Royal Academy, Bangkok, Thailand
| | - Natthaporn Tanpowpong
- Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Anchalee Avihingsanon
- The HIV Netherlands Australia Thailand Research Collaboration (HIV NAT), Bangkok, Thailand
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- * E-mail:
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Patsenker E, Thangapandi VR, Knittelfelder O, Palladini A, Hefti M, Beil-Wagner J, Rogler G, Buch T, Shevchenko A, Hampe J, Stickel F. The Pnpla3 Variant I148M Reveals Protective Effects Towards Hepatocellular Carcinoma in Mice via Restoration of Omega-3 Polyunsaturated Fats. J Nutr Biochem 2022; 108:109081. [PMID: 35691594 DOI: 10.1016/j.jnutbio.2022.109081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 02/02/2022] [Accepted: 05/03/2022] [Indexed: 12/02/2022]
Abstract
Alcohol consumption and high caloric diet are leading causes of progressive fatty liver disease. Genetic variant rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3 rs738409 C>G) has been repeatedly described as one of the major risk loci for alcoholic liver cirrhosis (ALC) and hepatocellular carcinoma (HCC) in humans, however, the mechanism behind this association is incompletely understood. We generated mice carrying the rs738409 variant (PNPLA3 I148M) in order to detect genotype-phenotype relationships in mice upon chow and alcohol-high fat/high sugar diet (EtOH/WD). We could clearly demonstrate that the presence of rs738409 per se is sufficient to induce spontaneous development of steatosis after one year in mice on a chow diet, whereas in the setting of unhealthy diet feeding, PNPLA3 I148M did not affect hepatic inflammation or fibrosis, but induced a striking lipid remodelling, microvesicular steatosis and protected from HCC formation. Using shot gun lipidomics, we detected a striking restoration of reduced long chain-polyunsaturated fatty acids (LC-PUFA)-containing TGs, docosapentaenoic acid (C22:5 n3) and omega-3-derived eicosanoids (5-HEPE, 20-HEPE, 19,20-EDP, 21-HDHA) in PNPLA3 I148M mice upon EtOH/WD. At the molecular level, PNPLA3 I148M modulated enzymes for fatty acid and TG transport and metabolism. These findings suggest (dietary) lipids as an important and independent driver of hepatic tumorigenesis. Genetic variant in PNPLA3 exerted protective effects in mice, conflicting with findings in humans. Species-related differences in physiology and metabolism should be taken into account when modelling unhealthy human lifestyle, as genetic mouse models may not always allow for translation of insight gained in humans.
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Affiliation(s)
- Eleonora Patsenker
- Department of Gastroenterology and Hepatology, University of Zurich, 8091 Zurich, Switzerland.
| | - Veera Raghavan Thangapandi
- Department of Gastroenterology and Hepatology, Universitätsklinikum Dresden, 01304 Dresden, Germany; Center for Regenerative Therapies, TU Dresden, 01307 Dresden, Germany
| | - Oskar Knittelfelder
- Max Plank Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
| | - Alessandra Palladini
- Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; German Center for Diabetes Research, 85764 Neuherberg, Germany
| | - Michaela Hefti
- Department of Gastroenterology and Hepatology, University of Zurich, 8091 Zurich, Switzerland
| | - Jane Beil-Wagner
- Institute of Laboratory Animal Science, University of Zurich, 8952 Schlieren, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University of Zurich, 8091 Zurich, Switzerland
| | - Thorsten Buch
- Institute of Laboratory Animal Science, University of Zurich, 8952 Schlieren, Switzerland
| | - Andrej Shevchenko
- Max Plank Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
| | - Jochen Hampe
- Department of Gastroenterology and Hepatology, Universitätsklinikum Dresden, 01304 Dresden, Germany; Center for Regenerative Therapies, TU Dresden, 01307 Dresden, Germany
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University of Zurich, 8091 Zurich, Switzerland
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33
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Ahmad MI, Khan MU, Kodali S, Shetty A, Bell SM, Victor D. Hepatocellular Carcinoma Due to Nonalcoholic Fatty Liver Disease: Current Concepts and Future Challenges. J Hepatocell Carcinoma 2022; 9:477-496. [PMID: 35673598 PMCID: PMC9167599 DOI: 10.2147/jhc.s344559] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 05/14/2022] [Indexed: 12/24/2022] Open
Abstract
Obesity has been labeled as the global pandemic of the 21st century, resulting from a sedentary lifestyle and caloric excess. Nonalcoholic fatty liver disease (NAFLD), characterized by excessive hepatic steatosis, is strongly associated with obesity and metabolic syndrome and is estimated to be present in one-quarter of the world population, making it the most common cause of the chronic liver disease (CLD). NAFLD spectrum varies from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. The burden of NAFLD has been predicted to increase in the coming decades resulting in increased rates of decompensated cirrhosis, hepatocellular carcinoma (HCC), and liver-related deaths. In the current review, we describe the pathophysiology of NAFLD and NASH, risk factors associated with disease progression, related complications, and mortality. Later, we have discussed the changing epidemiology of HCC, with NAFLD emerging as the most common cause of CLD and HCC. We have also addressed the risk factors of HCC development in the NAFLD population (including demographic, metabolic, genetic, dietary, and lifestyle factors), presentation of NAFLD-associated HCC, its prognosis, and the issue of HCC development in non-cirrhotic NAFLD. Lastly, the problems related to HCC screening in the NAFLD population, the remaining challenges, and future directions, especially the need to identify the high-risk individuals, will be discussed. We will conclude the review by summarizing the clinical evidence for treating fibrosis and preventing HCC in those at risk with NAFLD-associated HCC.
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Affiliation(s)
- Muhammad Imran Ahmad
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital Houston, Houston, TX, USA
| | - Muhammad Umair Khan
- Department of Gastroenterology and Hepatology, Hamad Medical Corporation, Doha, Qatar
- ECPE- Executive and Continuing Professional Education, Harvard T.H Chan School of Public Health, Boston, MA, 02115-5810, USA
| | - Sudha Kodali
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital Houston, Houston, TX, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX, USA
| | - Akshay Shetty
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital Houston, Houston, TX, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX, USA
| | - S Michelle Bell
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX, USA
| | - David Victor
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital Houston, Houston, TX, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX, USA
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Whitfield JB, Schwantes-An TH, Darlay R, Aithal GP, Atkinson SR, Bataller R, Botwin G, Chalasani NP, Cordell HJ, Daly AK, Day CP, Eyer F, Foroud T, Gleeson D, Goldman D, Haber PS, Jacquet JM, Liang T, Liangpunsakul S, Masson S, Mathurin P, Moirand R, McQuillin A, Moreno C, Morgan MY, Mueller S, Müllhaupt B, Nagy LE, Nahon P, Nalpas B, Naveau S, Perney P, Pirmohamed M, Seitz HK, Soyka M, Stickel F, Thompson A, Thursz MR, Trépo E, Morgan TR, Seth D. A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers. J Hepatol 2022; 76:275-282. [PMID: 34656649 PMCID: PMC8803006 DOI: 10.1016/j.jhep.2021.10.005] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 09/06/2021] [Accepted: 10/05/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Only a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk. METHODS Three cohorts (GenomALC-1: n = 1,690, GenomALC-2: n = 3,037, UK Biobank: relevant n = 6,898) with a history of heavy alcohol consumption (≥80 g/day (men), ≥50 g/day (women), for ≥10 years) were included. Cases were participants with alcohol-related cirrhosis. Controls had a history of similar alcohol consumption but no evidence of liver disease. Risk scores were computed from up to 8 genetic loci identified previously as associated with alcohol-related cirrhosis and 3 clinical risk factors. Score performance for the stratification of alcohol-related cirrhosis risk was assessed and compared across the alcohol-related liver disease spectrum, including hepatocellular carcinoma (HCC). RESULTS A combination of 3 single nucleotide polymorphisms (SNPs) (PNPLA3:rs738409, SUGP1-TM6SF2:rs10401969, HSD17B13:rs6834314) and diabetes status best discriminated cirrhosis risk. The odds ratios (ORs) and (95% CIs) between the lowest (Q1) and highest (Q5) score quintiles of the 3-SNP score, based on independent allelic effect size estimates, were 5.99 (4.18-8.60) (GenomALC-1), 2.81 (2.03-3.89) (GenomALC-2), and 3.10 (2.32-4.14) (UK Biobank). Patients with diabetes and high risk scores had ORs of 14.7 (7.69-28.1) (GenomALC-1) and 17.1 (11.3-25.7) (UK Biobank) compared to those without diabetes and with low risk scores. Patients with cirrhosis and HCC had significantly higher mean risk scores than patients with cirrhosis alone (0.76 ± 0.06 vs. 0.61 ± 0.02, p = 0.007). Score performance was not significantly enhanced by information on additional genetic risk variants, body mass index or coffee consumption. CONCLUSIONS A risk score based on 3 genetic risk variants and diabetes status enables the stratification of heavy drinkers based on their risk of cirrhosis, allowing for the provision of earlier preventative interventions. LAY SUMMARY Excessive chronic drinking leads to cirrhosis in some people, but so far there is no way to identify those at high risk of developing this debilitating disease. We developed a genetic risk score that can identify patients at high risk. The risk of cirrhosis is increased >10-fold with just two risk factors - diabetes and a high genetic risk score. Risk assessment using this test could enable the early and personalised management of this disease in high-risk patients.
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Affiliation(s)
- John B Whitfield
- Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Queensland 4029, Australia.
| | - Tae-Hwi Schwantes-An
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis IN, USA
| | - Rebecca Darlay
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom
| | - Guruprasad P Aithal
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals and the University of Nottingham, Nottingham NG7 2UH, United Kingdom
| | - Stephen R Atkinson
- Department of Metabolism, Digestion & Reproduction, Imperial College London, UK
| | - Ramon Bataller
- Center for Liver Diseases, University of Pittsburgh Medical Center, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA
| | - Greg Botwin
- Department of Veterans Affairs, VA Long Beach Healthcare System, 5901 East Seventh Street, Long Beach, CA 90822, USA; F. Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California CA 90048, USA
| | - Naga P Chalasani
- Department of Medicine, Indiana University, Indianapolis, Indiana, IN 46202-5175, USA
| | - Heather J Cordell
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom
| | - Ann K Daly
- Faculty of Medical Sciences, Newcastle University Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom
| | - Christopher P Day
- Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom
| | - Florian Eyer
- Division of Clinical Toxicology, Department of Internal Medicine 2, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
| | - Tatiana Foroud
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis IN, USA
| | - Dermot Gleeson
- Liver Unit, Sheffield Teaching Hospitals, AO Floor Robert Hadfield Building, Northern General Hospital, Sheffied S5 7AU, UK
| | - David Goldman
- Laboratory of Neurogenetics, NIAAA, Rockville, MD 20852, USA
| | - Paul S Haber
- Drug Health Services, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia; Faculty of Medicine and Health, the University of Sydney, Sydney, NSW 2006, Australia
| | | | - Tiebing Liang
- Department of Medicine, Indiana University, Indianapolis, Indiana, IN 46202-5175, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University and Roudebush Veterans Administration Medical Center, Indianapolis, USA
| | - Steven Masson
- Faculty of Medical Sciences, Newcastle University Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom
| | - Philippe Mathurin
- CHRU de Lille, Hôpital Claude Huriez, Rue M. Polonovski CS 70001, 59 037 Lille Cedex, France
| | - Romain Moirand
- Univ Rennes, INRA, INSERM, CHU Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer), F-35000 Rennes, France
| | - Andrew McQuillin
- Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London WC1E 6DE, UK
| | - Christophe Moreno
- CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
| | - Marsha Y Morgan
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London NW3 2PF, UK
| | - Sebastian Mueller
- Department of Internal Medicine, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Zeppelinstraße 11-33, 69121 Heidelberg, Germany
| | - Beat Müllhaupt
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, CH-8901 Zurich, Switzerland
| | - Laura E Nagy
- Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio, OH 44195, USA
| | - Pierre Nahon
- Service d'Hépatologie, APHP Hôpital Avicenne et Université Paris 13, Bobigny, France; University Paris 13, Bobigny, France; Inserm U1162 Génomique fonctionnelle des tumeurs solides, Paris, France
| | - Bertrand Nalpas
- Service Addictologie, CHRU Caremeau, 30029 Nîmes, France; DISC, Inserm, 75013 Paris, France
| | - Sylvie Naveau
- Hôpital Antoine-Béclère, 157 Rue de la Porte de Trivaux, 92140 Clamart, France
| | - Pascal Perney
- Hôpital Universitaire Caremeau, Place du Pr. Robert Debre, 30029 Nîmes, France
| | - Munir Pirmohamed
- MRC Centre for Drug Safety Science and Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GL, UK
| | - Helmut K Seitz
- Department of Internal Medicine, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Zeppelinstraße 11-33, 69121 Heidelberg, Germany
| | - Michael Soyka
- Psychiatric Hospital University of Munich, Nussbaumsstr.7, 80336 Munich, Germany; Privatklinik Meiringen, Willigen, CH 3860 Meiringen, Switzerland
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, CH-8901 Zurich, Switzerland
| | - Andrew Thompson
- MRC Centre for Drug Safety Science and Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GL, UK; Health Analytics, Lane Clark & Peacock LLP, London, UK
| | - Mark R Thursz
- Department of Metabolism, Digestion & Reproduction, Imperial College London, UK
| | - Eric Trépo
- CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
| | - Timothy R Morgan
- Department of Veterans Affairs, VA Long Beach Healthcare System, 5901 East Seventh Street, Long Beach, CA 90822, USA; Department of Medicine, University of California, Irvine, USA
| | - Devanshi Seth
- Drug Health Services, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia; Faculty of Medicine and Health, the University of Sydney, Sydney, NSW 2006, Australia; Centenary Institute of Cancer Medicine and Cell Biology, the University of Sydney, Sydney, NSW 2006, Australia.
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Burlone ME, Bellan M, Barbaglia MN, Mocchetti G, Mallela VR, Minisini R, Rigamonti C, Pirisi M. HSD17B13 and other liver fat-modulating genes predict development of hepatocellular carcinoma among HCV-positive cirrhotics with and without viral clearance after DAA treatment. Clin J Gastroenterol 2022; 15:301-309. [PMID: 35098490 DOI: 10.1007/s12328-021-01578-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 12/17/2021] [Indexed: 12/02/2022]
Abstract
BACKGROUND Genetic predisposition to accumulate liver fat (expressed by a polygenic risk score, GRS, based on the number of at-risk alleles of PNPLA3, TM6SF2, MBOAT7 and GCKR) may influence the probability of developing hepatocellular carcinoma (HCC) after hepatitis C treatment. Whether this holds true taking into account carriage of the HSD17B13:TA splice variant, also affecting lipogenesis, and achievement of viral clearance (SVR), is unknown. METHODS PNPLA3, TM6SF2, MBOAT7, GCKR and HSD17B13 variants were determined in a cohort of 328 cirrhotic patients free of HCC before starting treatment with direct acting antivirals (DAA). RESULTS SVR in the study cohort was 96%. At the end of follow-up, N = 21 patients had been diagnosed an HCC; none of the genes included in the GRS was individually associated with HCC development. However, in a Cox proportional hazards model, a GRS > 0.457 predicted HCC independently of sex, diabetes, albumin, INR and FIB4. The fit of the model improved adding treatment outcome and carriage of the HSD17B13:TA splice variant, with sex, GRS > 0.457, HSD17B13:TA splice variant and failure to achieve an SVR (hazard ratio = 6.75, 4.24, 0.24 and 7.7, respectively) being independent predictors of HCC. CONCLUSION Our findings confirm that genes modulating liver fat and lipogenesis are important risk factors for HCC development among cirrhotics C treated with DAA.
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Affiliation(s)
- Michela E Burlone
- Internal Medicine, Azienda Ospedaliero-Universitaria "Maggiore Della Carità", Novara, Italy
| | - Mattia Bellan
- Internal Medicine, Azienda Ospedaliero-Universitaria "Maggiore Della Carità", Novara, Italy
- Department of Translational Medicine (DiMeT), Università del Piemonte Orientale, Novara, Italy
| | - Matteo N Barbaglia
- Department of Translational Medicine (DiMeT), Università del Piemonte Orientale, Novara, Italy
| | - Ginevra Mocchetti
- Department of Translational Medicine (DiMeT), Università del Piemonte Orientale, Novara, Italy
| | - Venkata R Mallela
- Department of Translational Medicine (DiMeT), Università del Piemonte Orientale, Novara, Italy
| | - Rosalba Minisini
- Department of Translational Medicine (DiMeT), Università del Piemonte Orientale, Novara, Italy
| | - Cristina Rigamonti
- Internal Medicine, Azienda Ospedaliero-Universitaria "Maggiore Della Carità", Novara, Italy
- Department of Translational Medicine (DiMeT), Università del Piemonte Orientale, Novara, Italy
| | - Mario Pirisi
- Internal Medicine, Azienda Ospedaliero-Universitaria "Maggiore Della Carità", Novara, Italy.
- Department of Translational Medicine (DiMeT), Università del Piemonte Orientale, Novara, Italy.
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Schnabl B, Arteel GE, Stickel F, Hengstler J, Vartak N, Ghallab A, Dooley S, Li Y, Schwabe RF. Liver specific, systemic and genetic contributors to alcohol-related liver disease progression. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:36-44. [PMID: 35042252 PMCID: PMC8941985 DOI: 10.1055/a-1714-9330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Alcohol-related liver disease (ALD) impacts millions of patients worldwide each year and the numbers are increasing. Disease stages range from steatosis via steatohepatitis and fibrosis to cirrhosis, severe alcohol-associated hepatitis and liver cancer. ALD is usually diagnosed at an advanced stage of progression with no effective therapies. A major research goal is to improve diagnosis, prognosis and also treatments for early ALD. This however needs prioritization of this disease for financial investment in basic and clinical research to more deeply investigate mechanisms and identify biomarkers and therapeutic targets for early detection and intervention. Topics of interest are communication of the liver with other organs of the body, especially the gut microbiome, the individual genetic constitution, systemic and liver innate inflammation, including bacterial infections, as well as fate and number of hepatic stellate cells and the composition of the extracellular matrix in the liver. Additionally, mechanical forces and damaging stresses towards the sophisticated vessel system of the liver, including the especially equipped sinusoidal endothelium and the biliary tract, work together to mediate hepatocytic import and export of nutritional and toxic substances, adapting to chronic liver disease by morphological and functional changes. All the aforementioned parameters contribute to the outcome of alcohol use disorder and the risk to develop advanced disease stages including cirrhosis, severe alcoholic hepatitis and liver cancer. In the present collection, we summarize current knowledge on these alcohol-related liver disease parameters, excluding the aspect of inflammation, which is presented in the accompanying review article by Lotersztajn and colleagues.
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Affiliation(s)
- Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, United States
- Department of Medicine, VA San Diego Healthcare System, San Diego, United States
| | - Gavin E Arteel
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, United States
- Pittsburgh Liver Research Center, Pittsburgh, United States
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Jan Hengstler
- Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors, TU Dortmund University, Dortmund, Germany
| | - Nachiket Vartak
- Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors, TU Dortmund University, Dortmund, Germany
| | - Ahmed Ghallab
- Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors, TU Dortmund University, Dortmund, Germany
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | - Steven Dooley
- Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Yujia Li
- Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Robert F Schwabe
- Department of Medicine, Columbia University, New York, United States
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Understanding the Role of the Gut Microbiome and Microbial Metabolites in Non-Alcoholic Fatty Liver Disease: Current Evidence and Perspectives. Biomolecules 2021; 12:biom12010056. [PMID: 35053205 PMCID: PMC8774162 DOI: 10.3390/biom12010056] [Citation(s) in RCA: 159] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/24/2021] [Accepted: 12/30/2021] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. NAFLD begins as a relatively benign hepatic steatosis which can evolve to non-alcoholic steatohepatitis (NASH); the risk of cirrhosis and hepatocellular carcinoma (HCC) increases when fibrosis is present. NAFLD represents a complex process implicating numerous factors—genetic, metabolic, and dietary—intertwined in a multi-hit etiopathogenetic model. Recent data have highlighted the role of gut dysbiosis, which may render the bowel more permeable, leading to increased free fatty acid absorption, bacterial migration, and a parallel release of toxic bacterial products, lipopolysaccharide (LPS), and proinflammatory cytokines that initiate and sustain inflammation. Although gut dysbiosis is present in each disease stage, there is currently no single microbial signature to distinguish or predict which patients will evolve from NAFLD to NASH and HCC. Using 16S rRNA sequencing, the majority of patients with NAFLD/NASH exhibit increased numbers of Bacteroidetes and differences in the presence of Firmicutes, resulting in a decreased F/B ratio in most studies. They also present an increased proportion of species belonging to Clostridium, Anaerobacter, Streptococcus, Escherichia, and Lactobacillus, whereas Oscillibacter, Flavonifaractor, Odoribacter, and Alistipes spp. are less prominent. In comparison to healthy controls, patients with NASH show a higher abundance of Proteobacteria, Enterobacteriaceae, and Escherichia spp., while Faecalibacterium prausnitzii and Akkermansia muciniphila are diminished. Children with NAFLD/NASH have a decreased proportion of Oscillospira spp. accompanied by an elevated proportion of Dorea, Blautia, Prevotella copri, and Ruminococcus spp. Gut microbiota composition may vary between population groups and different stages of NAFLD, making any conclusive or causative claims about gut microbiota profiles in NAFLD patients challenging. Moreover, various metabolites may be involved in the pathogenesis of NAFLD, such as short-chain fatty acids, lipopolysaccharide, bile acids, choline and trimethylamine-N-oxide, and ammonia. In this review, we summarize the role of the gut microbiome and metabolites in NAFLD pathogenesis, and we discuss potential preventive and therapeutic interventions related to the gut microbiome, such as the administration of probiotics, prebiotics, synbiotics, antibiotics, and bacteriophages, as well as the contribution of bariatric surgery and fecal microbiota transplantation in the therapeutic armamentarium against NAFLD. Larger and longer-term prospective studies, including well-defined cohorts as well as a multi-omics approach, are required to better identify the associations between the gut microbiome, microbial metabolites, and NAFLD occurrence and progression.
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Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study. Lancet Oncol 2021; 23:161-171. [PMID: 34902334 DOI: 10.1016/s1470-2045(21)00603-3] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 10/03/2021] [Accepted: 10/15/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Hepatocellular carcinoma is a frequent consequence of alcohol-related liver disease, with variable incidence among heavy drinkers. We did a genome-wide association study (GWAS) to identify common genetic variants for alcohol-related hepatocellular carcinoma. METHODS We conducted a two-stage case-control GWAS in a discovery cohort of 2107 unrelated European patients with alcohol-related liver disease aged 20-92 years recruited between Oct 22, 1993, and March 12, 2017. Cases were patients with alcohol-related hepatocellular carcinoma diagnosed by imaging or histology. Controls were patients with alcohol-related liver disease without hepatocellular carcinoma. We used an additive logistic regression model adjusted for the first ten principal components to assess genetic variants associated with alcohol-related hepatocellular carcinoma. We did another analysis with adjustment for age, sex, and liver fibrosis. New candidate associations (p<1 × 10-6) and variants previously associated with alcohol-related hepatocellular carcinoma were evaluated in a validation cohort of 1933 patients with alcohol-related liver disease aged 29-92 years recruited between July 21, 1995, and May 2, 2019. We did a meta-analysis of the two case-control cohorts. FINDINGS The discovery cohort included 775 cases and 1332 controls. Of 7 962 325 variants assessed, we identified WNT3A-WNT9A (rs708113; p=1·11 × 10-8) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10-10), PNPLA3 (rs738409; p=9·29 × 10-7), and HSD17B13 (rs72613567; p=2·49 × 10-4). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10-3), TM6SF2 (rs58542926; p=4·06 × 10-5), and PNPLA3 (rs738409; p=1·17 × 10-4). All three variants reached GWAS significance in the meta-analysis: WNT3A-WNT9A (odds ratio 0·73, 95% CI 0·66-0·81; p=3·93 × 10-10), TM6SF2 (1·77, 1·52-2·07; p=3·84×10-13), PNPLA3 (1·34, 1·22-1·47; p=7·30 × 10-10). Adjustment for clinical covariates yielded similar results. We observed an additive effect of at-risk alleles on alcohol-related hepatocellular carcinoma. WNT3A-WNT9A rs708113 was not associated with liver fibrosis. INTERPRETATION WNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt-β-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis. FUNDING Ligue Nationale contre le Cancer, Bpifrance, INSERM, AFEF, CARPEM, Labex OncoImmunology, and Agence Nationale de la Recherche.
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Dongiovanni P, Meroni M, Longo M, Fargion S, Fracanzani AL. Genetics, Immunity and Nutrition Boost the Switching from NASH to HCC. Biomedicines 2021; 9:1524. [PMID: 34829753 PMCID: PMC8614742 DOI: 10.3390/biomedicines9111524] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/20/2021] [Accepted: 10/22/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading contributor to the global burden of chronic liver diseases. The phenotypic umbrella of NAFLD spans from simple and reversible steatosis to nonalcoholic steatohepatitis (NASH), which may worsen into cirrhosis and hepatocellular carcinoma (HCC). Notwithstanding, HCC may develop also in the absence of advanced fibrosis, causing a delayed time in diagnosis as a consequence of the lack of HCC screening in these patients. The precise event cascade that may precipitate NASH into HCC is intricate and it entails diverse triggers, encompassing exaggerated immune response, endoplasmic reticulum (ER) and oxidative stress, organelle derangement and DNA aberrancies. All these events may be accelerated by both genetic and environmental factors. On one side, common and rare inherited variations that affect hepatic lipid remodeling, immune microenvironment and cell survival may boost the switching from steatohepatitis to liver cancer, on the other, diet-induced dysbiosis as well as nutritional and behavioral habits may furtherly precipitate tumor onset. Therefore, dietary and lifestyle interventions aimed to restore patients' health contribute to counteract NASH progression towards HCC. Even more, the combination of therapeutic strategies with dietary advice may maximize benefits, with the pursuit to improve liver function and prolong survival.
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Affiliation(s)
- Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
| | - Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| | - Silvia Fargion
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
| | - Anna Ludovica Fracanzani
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
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Pinyol R, Torrecilla S, Wang H, Montironi C, Piqué-Gili M, Torres-Martin M, Wei-Qiang L, Willoughby CE, Ramadori P, Andreu-Oller C, Taik P, Lee YA, Moeini A, Peix J, Faure-Dupuy S, Riedl T, Schuehle S, Oliveira CP, Alves VA, Boffetta P, Lachenmayer A, Roessler S, Minguez B, Schirmacher P, Dufour JF, Thung SN, Reeves HL, Carrilho FJ, Chang C, Uzilov AV, Heikenwalder M, Sanyal A, Friedman SL, Sia D, Llovet JM. Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J Hepatol 2021; 75:865-878. [PMID: 33992698 DOI: 10.1016/j.jhep.2021.04.049] [Citation(s) in RCA: 138] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies. METHODS We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n = 53 NASH-HCC; n = 74 NASH) and whole exome sequencing (n = 52 NASH-HCC) data were compared to HCCs of other aetiologies (n = 184). Three NASH-HCC mouse models were analysed by RNA-seq/expression-array (n = 20). Activin A receptor type 2A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays. RESULTS Mutational profiling of NASH-HCC tumours revealed TERT promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% vs. 3%, p <0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs. 2% in viral/alcohol-HCC, p = 0.03). Tumour mutational burden was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 vs. 0.94 mutations/megabase; p <0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/TGF-β proliferation subclass tumours (42% vs. 26%, p = 0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of an immunosuppressive cancer field. In 3 murine models of NASH-HCC, key features of human NASH-HCC were preserved. CONCLUSIONS NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature. LAY SUMMARY The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH) is increasing globally, but its molecular traits are not well characterised. In this study, we uncovered higher rates of ACVR2A mutations (10%) - a potential tumour suppressor - and the presence of a novel mutational signature that characterises NASH-related HCC.
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Affiliation(s)
- Roser Pinyol
- Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Sara Torrecilla
- Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | | | - Carla Montironi
- Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Marta Piqué-Gili
- Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Miguel Torres-Martin
- Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain; Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Leow Wei-Qiang
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
| | - Catherine E Willoughby
- Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Pierluigi Ramadori
- Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany
| | - Carmen Andreu-Oller
- Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain; Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | | | - Youngmin A Lee
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Department of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Agrin Moeini
- Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Judit Peix
- Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Suzanne Faure-Dupuy
- Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany
| | - Tobias Riedl
- Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany
| | - Svenja Schuehle
- Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany
| | - Claudia P Oliveira
- Departments of Gastroenterology and Pathology, University of São Paulo - School of Medicine, São Paulo, Brazil
| | - Venancio A Alves
- Departments of Gastroenterology and Pathology, University of São Paulo - School of Medicine, São Paulo, Brazil
| | - Paolo Boffetta
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Anja Lachenmayer
- Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, CH-3010, Bern, Switzerland
| | | | - Beatriz Minguez
- Liver Unit, Vall d´Hebron Hospital Universitari, Liver Diseases Research Group, Vall d´Hebron Institut of Research (VHIR), Vall d´Hebron Hospital Campus. CIBERehd, Universitat Autonoma de Barcelona, Barcelona, Catalonia, Spain
| | | | - Jean-François Dufour
- Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, CH-3010, Bern, Switzerland
| | - Swan N Thung
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Helen L Reeves
- Newcastle University Translational and Clinical Research Institute and Newcastle University Centre for Cancer, Medical School, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK; Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
| | - Flair J Carrilho
- Departments of Gastroenterology and Pathology, University of São Paulo - School of Medicine, São Paulo, Brazil
| | - Charissa Chang
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Andrew V Uzilov
- Sema4, Stamford, Connecticut, USA; Department of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany
| | - Arun Sanyal
- Divisions of Gastroenterology and Hepatology, Virginia Commonwealth University, Richmond, VA, USA
| | - Scott L Friedman
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Daniela Sia
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Josep M Llovet
- Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain; Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain.
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Meroni M, Longo M, Tria G, Dongiovanni P. Genetics Is of the Essence to Face NAFLD. Biomedicines 2021; 9:1359. [PMID: 34680476 PMCID: PMC8533437 DOI: 10.3390/biomedicines9101359] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 09/27/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. It is closely related to obesity, insulin resistance (IR) and dyslipidemia so much so it is considered the hepatic manifestation of the Metabolic Syndrome. The NAFLD spectrum extends from simple steatosis to nonalcoholic steatohepatitis (NASH), a clinical condition which may progress up to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). NAFLD is a complex disease whose pathogenesis is shaped by both environmental and genetic factors. In the last two decades, several heritable modifications in genes influencing hepatic lipid remodeling, and mitochondrial oxidative status have been emerged as predictors of progressive hepatic damage. Among them, the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, the Transmembrane 6 superfamily member 2 (TM6SF2) p.E167K and the rs641738 membrane bound-o-acyltransferase domain-containing 7 (MBOAT7) polymorphisms are considered the most robust modifiers of NAFLD. However, a forefront frontier in the study of NAFLD heritability is to postulate score-based strategy, building polygenic risk scores (PRS), which aggregate the most relevant genetic determinants of NAFLD and biochemical parameters, with the purpose to foresee patients with greater risk of severe NAFLD, guaranteeing the most highly predictive value, the best diagnostic accuracy and the more precise individualized therapy.
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Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
- Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, 20122 Milano, Italy
| | - Giada Tria
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
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Bianco C, Tavaglione F, Romeo S, Valenti L. Genetic risk scores and personalization of care in fatty liver disease. Curr Opin Pharmacol 2021; 61:6-11. [PMID: 34537584 DOI: 10.1016/j.coph.2021.08.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 08/03/2021] [Accepted: 08/10/2021] [Indexed: 12/18/2022]
Abstract
Nonalcoholic fatty liver disease is the leading cause of chronic liver disease. Genetic predisposition, lifestyle, and metabolic comorbidities concur to nonalcoholic fatty liver disease development and progression to nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. Improvement in risk stratification and development of effective therapies for nonalcoholic steatohepatitis are key unmet clinical needs. Knowledge emerging from genomics could meet this need. A polygenic risk score (PRS) is calculated by summing the number of trait-associated alleles carried by an individual, which can be weighted by their effect size on the trait and captures the individual's genetic risk to develop a disease. In this review, we focalize on the potential use of PRSs for disease detection at an early stage and stratification of the risk of progression to severe forms. PRSs may represent robust instruments to implement targeted prevention programs, hepatocellular carcinoma surveillance in at-risk individuals, and to develop precision medicine therapeutic approaches.
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Affiliation(s)
- Cristiana Bianco
- Precision Medicine - Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Federica Tavaglione
- Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Clinical Medicine and Hepatology Unit, Department of Internal Medicine and Geriatrics, Campus Bio-Medico University, Rome, Italy
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Science, Magna Graecia University, Catanzaro, Italy
| | - Luca Valenti
- Precision Medicine - Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università Degli Studi di Milano, Milan, Italy.
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43
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Morgan MY, Sharma M, Atkinson SR. Genetic and Environmental Susceptibility to Alcoholic Hepatitis. Clin Liver Dis 2021; 25:517-535. [PMID: 34229837 DOI: 10.1016/j.cld.2021.04.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Constitutional, environmental, and genetic risk factors influence the development of alcohol-related cirrhosis. The amount of alcohol consumed and whether excessive drinking continues after the identification of pre-cirrhotic liver damage are key risk factors. Female sex, ethnicity, obesity, coffee consumption, cigarette smoking, and exposure to other causes of liver injury also influence the risk of disease development. More recently several genetic loci have been robustly associated with the risk for developing significant alcohol-related liver disease. It remains unclear whether additional risk factors are involved in the development of the clinical syndrome of alcoholic hepatitis, but the genetic evidence is suggestive.
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Affiliation(s)
- Marsha Y Morgan
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College, Rowland Hill Street, Hampstead, London NW3 2PF, UK.
| | - Moksh Sharma
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College, Rowland Hill Street, Hampstead, London NW3 2PF, UK
| | - Stephen R Atkinson
- Department of Metabolism, Digestion and Reproduction, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
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Abstract
PURPOSE OF REVIEW To summarize recent evidence demonstrating increased cardiovascular disease (CVD) risk, and how CVD risk may be reduced, in patients with nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS NAFLD is a multisystem disease, defined by a spectrum of liver fat-associated conditions extending from simple steatosis, to inflammation, fibrosis and cirrhosis. NAFLD not only increases the risk of liver morbidity and mortality but also increases the risk of CVD morbidity and mortality and is associated with recognized CVD risk factors such as hypertension, atherogenic dyslipidaemia, type 2 diabetes mellitus and chronic kidney disease. Evidence suggests that the liver fibrosis stage may be a strong CVD risk factor. Lifestyle measures (e.g. weight loss and increased physical activity) are effective in improving CVD risk factors. Hypoglycaemic agents, such as the peroxisome proliferator-activated receptor gamma agonist pioglitazone and the glucagon-like peptide-1 receptor agonist liraglutide, reduce cardiovascular risk and may improve liver histology. Statin and antihypertensive treatments are well tolerated and currently it is unclear whether novel antifibrotic drugs will reduce CVD risk. SUMMARY Assessment and treatment of increased cardiovascular risk is important in patients with NAFLD. If not contra-indicated, pioglitazone or a glucagon-like peptide 1 agonist should be considered and may benefit both CVD risk and early liver disease.
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Affiliation(s)
- Michael P Johnston
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, Scotland
| | - Janisha Patel
- Department of Hepatology, University Hospital Southampton
| | - Christopher D Byrne
- Nutrition and Metabolism, Faculty of Medicine, University of Southampton
- National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK
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45
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Barcena-Varela M, Lujambio A. The Endless Sources of Hepatocellular Carcinoma Heterogeneity. Cancers (Basel) 2021; 13:2621. [PMID: 34073538 PMCID: PMC8198457 DOI: 10.3390/cancers13112621] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 05/20/2021] [Accepted: 05/21/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) represents a global health problem. The incidence keeps increasing and current therapeutic options confer limited benefits to the patients. Tumor heterogeneity plays a central role in this context, limiting the availability of predictive biomarkers and complicating the criteria used to choose the most suitable therapeutic option. HCC heterogeneity occurs at different levels: within the population (inter-patient heterogeneity) and within tumors from the same patient (intra-patient and intra-tumor heterogeneity). Experts in the field have made many efforts to classify the patients based on clinicopathological characteristics and molecular signatures; however, there is still much work ahead to be able to integrate the extra-tumor heterogeneity that emerges from the complexity of the tumor microenvironment, which plays a critical role in the pathogenesis of the disease and therapy responses. In this review, we summarize tumor intrinsic and extrinsic sources of heterogeneity of the most common etiologies of HCC and summarize the most recent discoveries regarding the evolutionary trajectory of liver cancer cells and the influence of tumor-extrinsic factors such as the microbiome and the host immune system. We further highlight the potential of novel high-throughput methodologies to contribute to a better understanding of this devastating disease and to the improvement of the clinical management of patients.
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Affiliation(s)
- Marina Barcena-Varela
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Amaia Lujambio
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Loomba R, Friedman SL, Shulman GI. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell 2021; 184:2537-2564. [PMID: 33989548 DOI: 10.1016/j.cell.2021.04.015] [Citation(s) in RCA: 1135] [Impact Index Per Article: 283.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/21/2021] [Accepted: 04/09/2021] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide. Its more advanced subtype, nonalcoholic steatohepatitis (NASH), connotes progressive liver injury that can lead to cirrhosis and hepatocellular carcinoma. Here we provide an in-depth discussion of the underlying pathogenetic mechanisms that lead to progressive liver injury, including the metabolic origins of NAFLD, the effect of NAFLD on hepatic glucose and lipid metabolism, bile acid toxicity, macrophage dysfunction, and hepatic stellate cell activation, and consider the role of genetic, epigenetic, and environmental factors that promote fibrosis progression and risk of hepatocellular carcinoma in NASH.
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Affiliation(s)
- Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
| | - Scott L Friedman
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Gerald I Shulman
- Departments of Internal Medicine and Cellular & Molecular Physiology, Yale Diabetes Research Center, Yale School of Medicine, New Haven, CT 06520, USA.
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Liu SY, Tsai IT, Hsu YC. Alcohol-Related Liver Disease: Basic Mechanisms and Clinical Perspectives. Int J Mol Sci 2021; 22:5170. [PMID: 34068269 PMCID: PMC8153142 DOI: 10.3390/ijms22105170] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 05/07/2021] [Accepted: 05/12/2021] [Indexed: 12/12/2022] Open
Abstract
Alcohol-related liver disease (ALD) refers to the liver damage occurring due to excessive alcohol consumption and involves a broad spectrum of diseases that includes liver steatosis, steatohepatitis, hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The progression of ALD is mainly associated with the amount and duration of alcohol usage; however, it is also influenced by genetic, epigenetic, and environmental factors. The definite diagnosis of ALD is based on a liver biopsy, although several non-invasive diagnostic tools and serum biomarkers have emerging roles in the early detection of ALD. While alcohol abstinence and nutritional support remain the cornerstone of ALD treatment, growing evidence has revealed that the therapeutic agents that target oxidative stress or gut-liver axis, inflammatory response inhibition, and liver regeneration enhancement also play a role in ALD management. Furthermore, microRNAs modulation and mesenchymal stem cell-based therapy have emerging potential as ALD therapeutic options. This review summarizes the updated understanding of the pathophysiology, diagnosis, and novel therapeutic approaches for ALD.
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Affiliation(s)
- Szu-Yi Liu
- Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan; (S.-Y.L.); (I.-T.T.)
| | - I-Ting Tsai
- Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan; (S.-Y.L.); (I.-T.T.)
- School of Medicine for International Student, I-Shou University, Kaohsiung 82445, Taiwan
| | - Yin-Chou Hsu
- Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan; (S.-Y.L.); (I.-T.T.)
- School of Medicine for International Student, I-Shou University, Kaohsiung 82445, Taiwan
- School of Chinese Medicine for Post Baccalaureate, I-Shou University, Kaohsiung 82445, Taiwan
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48
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Zhang X, Wu M, Liu Z, Yuan H, Wu X, Shi T, Chen X, Zhang T. Increasing prevalence of NAFLD/NASH among children, adolescents and young adults from 1990 to 2017: a population-based observational study. BMJ Open 2021; 11:e042843. [PMID: 33947727 PMCID: PMC8098935 DOI: 10.1136/bmjopen-2020-042843] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE To describe the prevalence and variations of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) among children and adolescents (CADs) and young adults (YADs). DESIGN A population-based observational study. SETTING Annual cases and prevalence of NAFLD/NASH from 1990 to 2017, by sex, region and country were collected from the Global Burden of Disease database. MAIN OUTCOME MEASURES The estimated annual percentage change, which was calculated by a regression line, was used to quantify the temporal trends in NAFLD/NASH burden among young people at the global, regional and national levels. RESULTS Globally, NAFLD/NASH incidence increased from 19.34 million in 1990 to 29.49 million in 2017 among CADs, with an annual increase of 1.35%. Additionally, in YADs, the number of cases and NAFLD/NASH prevalence significantly increased during this period, independent of sex and region. The greatest NAFLD/NASH increase was in North Africa and the Middle East. Almost all countries showed an increasing trend from 1990 to 2017, with the most pronounced increase observed in the developed regions. CONCLUSIONS The epidemiology of NAFLD/NASH in young people has changed considerably over the last three decades. Both the prevalence and number of cases have increased irrespective of sex, age and region. This phenomenon can result in a predictable increase in chronic liver disease burden in the near future. Understanding the prevalence of NAFLD/NASH and its variations is of paramount importance to develop strategies to implement public health policy.
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Affiliation(s)
- Xin Zhang
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
| | - Mingshan Wu
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
| | - Zhenqiu Liu
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
- Human Phenome Institute, Fudan University, Shanghai, China
| | - Huangbo Yuan
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
| | - Xuefu Wu
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
| | - Tingting Shi
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
| | - Xingdong Chen
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
- Human Phenome Institute, Fudan University, Shanghai, China
| | - Tiejun Zhang
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
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Bianco C, Casirati E, Malvestiti F, Valenti L. Genetic predisposition similarities between NASH and ASH: Identification of new therapeutic targets. JHEP Rep 2021; 3:100284. [PMID: 34027340 PMCID: PMC8122117 DOI: 10.1016/j.jhepr.2021.100284] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 03/09/2021] [Accepted: 03/15/2021] [Indexed: 12/12/2022] Open
Abstract
Fatty liver disease can be triggered by a combination of excess alcohol, dysmetabolism and other environmental cues, which can lead to steatohepatitis and can evolve to acute/chronic liver failure and hepatocellular carcinoma, especially in the presence of shared inherited determinants. The recent identification of the genetic causes of steatohepatitis is revealing new avenues for more effective risk stratification. Discovery of the mechanisms underpinning the detrimental effect of causal mutations has led to some breakthroughs in the comprehension of the pathophysiology of steatohepatitis. Thanks to this approach, hepatocellular fat accumulation, altered lipid droplet remodelling and lipotoxicity have now taken centre stage, while the role of adiposity and gut-liver axis alterations have been independently validated. This process could ignite a virtuous research cycle that, starting from human genomics, through omics approaches, molecular genetics and disease models, may lead to the development of new therapeutics targeted to patients at higher risk. Herein, we also review how this knowledge has been applied to: a) the study of the main PNPLA3 I148M risk variant, up to the stage of the first in-human therapeutic trials; b) highlight a role of MBOAT7 downregulation and lysophosphatidyl-inositol in steatohepatitis; c) identify IL-32 as a candidate mediator linking lipotoxicity to inflammation and liver disease. Although this precision medicine drug discovery pipeline is mainly being applied to non-alcoholic steatohepatitis, there is hope that successful products could be repurposed to treat alcohol-related liver disease as well.
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Key Words
- AA, arachidonic acid
- ASH, alcoholic steatohepatitis
- DAG, diacylglycerol
- DNL, de novo lipogenesis
- ER, endoplasmic reticulum
- FFAs, free fatty acids
- FGF19, fibroblast growth factor 19
- FLD, fatty liver disease
- FXR, farnesoid X receptor
- GCKR, glucokinase regulator
- GPR55, G protein-coupled receptor 55
- HCC, hepatocellular carcinoma
- HFE, homeostatic iron regulator
- HSC, hepatic stellate cells
- HSD17B13, hydroxysteroid 17-beta dehydrogenase 13
- IL-, interleukin-
- IL32
- LDs, lipid droplets
- LPI, lysophosphatidyl-inositol
- MARC1, mitochondrial amidoxime reducing component 1
- MBOAT7
- MBOAT7, membrane bound O-acyltransferase domain-containing 7
- NASH, non-alcoholic steatohepatitis
- PNPLA3
- PNPLA3, patatin like phospholipase domain containing 3
- PPAR, peroxisome proliferator-activated receptor
- PRS, polygenic risk score
- PUFAs, polyunsaturated fatty acids
- SREBP, sterol response element binding protein
- TAG, triacylglycerol
- TNF-α, tumour necrosis factor-α
- alcoholic liver disease
- cirrhosis
- fatty liver disease
- genetics
- interleukin-32
- non-alcoholic fatty liver disease
- precision medicine
- steatohepatitis
- therapy
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Affiliation(s)
- Cristiana Bianco
- Precision Medicine - Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Elia Casirati
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Francesco Malvestiti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Luca Valenti
- Precision Medicine - Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
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Pirola CJ, Salatino A, Sookoian S. Pleiotropy within gene variants associated with nonalcoholic fatty liver disease and traits of the hematopoietic system. World J Gastroenterol 2021; 27:305-320. [PMID: 33584064 PMCID: PMC7852588 DOI: 10.3748/wjg.v27.i4.305] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/19/2020] [Accepted: 12/28/2020] [Indexed: 02/06/2023] Open
Abstract
Genome-wide association studies of complex diseases, including nonalcoholic fatty liver disease (NAFLD), have demonstrated that a large number of variants are implicated in the susceptibility of multiple traits — a phenomenon known as pleiotropy that is increasingly being explored through phenome-wide association studies. We focused on the analysis of pleiotropy within variants associated with hematologic traits and NAFLD. We used information retrieved from large public National Health and Nutrition Examination Surveys, Genome-wide association studies, and phenome-wide association studies based on the general population and explored whether variants associated with NAFLD also present associations with blood cell-related traits. Next, we applied systems biology approaches to assess the potential biological connection/s between genes that predispose affected individuals to NAFLD and nonalcoholic steatohepatitis, and genes that modulate hematological-related traits—specifically platelet count. We reasoned that this analysis would allow the identification of potential molecular mediators that link NAFLD with platelets. Genes associated with platelet count are most highly expressed in the liver, followed by the pancreas, heart, and muscle. Conversely, genes associated with NAFLD presented high expression levels in the brain, lung, spleen, and colon. Functional mapping, gene prioritization, and functional analysis of the most significant loci (P < 1 × 10-8) revealed that loci involved in the genetic modulation of platelet count presented significant enrichment in metabolic and energy balance pathways. In conclusion, variants in genes influencing NAFLD exhibit pleiotropic associations with hematologic traits, particularly platelet count. Likewise, significant enrichment of related genes with variants influencing platelet traits was noted in metabolic-related pathways. Hence, this approach yields novel mechanistic insights into NAFLD pathogenesis.
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Affiliation(s)
- Carlos Jose Pirola
- Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
- Institute of Medical Research A Lanari, University of Buenos Aires, School of Medicine, Ciudad Autónoma de Buenos Aires, Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
| | - Adrian Salatino
- Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
- Institute of Medical Research A Lanari, University of Buenos Aires, School of Medicine, Ciudad Autónoma de Buenos Aires, Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
| | - Silvia Sookoian
- Institute of Medical Research A Lanari, University of Buenos Aires, School of Medicine, Ciudad Autónoma de Buenos Aires, Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
- Department of Clinical and Molecular Hepatology, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
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