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Norden-Krichmar TM, Rotroff D, Schwantes-An TH, Bataller R, Goldman D, Nagy LE, Liangpunsakul S. Genomic approaches to explore susceptibility and pathogenesis of alcohol use disorder and alcohol-associated liver disease. Hepatology 2025; 81:1595-1606. [PMID: 37796138 PMCID: PMC10985049 DOI: 10.1097/hep.0000000000000617] [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: 05/24/2023] [Accepted: 08/13/2023] [Indexed: 10/06/2023]
Abstract
Excessive alcohol use is a major risk factor for the development of an alcohol use disorder (AUD) and contributes to a wide variety of other medical illnesses, including alcohol-associated liver disease (ALD). Both AUD and ALD are complex and causally interrelated diseases, and multiple factors other than alcohol consumption are implicated in the disease pathogenesis. While the underlying pathophysiology of AUD and ALD is complex, there is substantial evidence for a genetic susceptibility of both diseases. Current genome-wide association studies indicate that the genes associated with clinical AUD only poorly overlap with the genes identified for heavy drinking and, in turn, neither overlap with the genes identified for ALD. Uncovering the main genetic factors will enable us to identify molecular drivers underlying the pathogenesis, discover potential targets for therapy, and implement patient care early in disease progression. In this review, we described multiple genomic approaches and their implications to investigate the susceptibility and pathogenesis of both AUD and ALD. We concluded our review with a discussion of the knowledge gaps and future research on genomic studies in these 2 diseases.
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Affiliation(s)
| | - Daniel Rotroff
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH
| | - Tae-Hwi Schwantes-An
- Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN
| | - Ramon Bataller
- Liver Unit, Institut of Digestive and Metabolic Diseases, Hospital Clinic, Barcelona, Spain
- Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS)
| | - David Goldman
- Laboratory of Neurogenetics and Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD
| | - Laura E. Nagy
- Center for Liver Disease Research, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
- Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indianapolis, IN
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
- Roudebush Veterans Administration Medical Center, Indianapolis, IN
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2
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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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3
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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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Roberts LR. Surveillance for Hepatocellular Carcinoma. Clin Liver Dis 2025; 29:17-31. [PMID: 39608955 DOI: 10.1016/j.cld.2024.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2024]
Abstract
This article reviews surveillance for the detection of early stage hepatocellular carcinoma, covering the rationale for surveillance, optimal selection of persons needing surveillance, methods and frequency of screening, strategies for addressing barriers to surveillance, and trends for future improvement in surveillance leading to more effective cancer control and improved patient outcomes. The importance of integrating liver cancer surveillance as a core component of national public health programs is emphasized. The impact of emerging technologies for identifying persons at risk, stratifying individual risk to improve the cost-effectiveness of surveillance programs, and improving the performance, accessibility, and convenience of surveillance are discussed.
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Affiliation(s)
- Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, 200 First Street Southwest, Rochester, MN 55905, USA.
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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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Li LN, Li WW, Xiao LS, Lai WN. Lactylation signature identifies liver fibrosis phenotypes and traces fibrotic progression to hepatocellular carcinoma. Front Immunol 2024; 15:1433393. [PMID: 39257588 PMCID: PMC11383765 DOI: 10.3389/fimmu.2024.1433393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 07/31/2024] [Indexed: 09/12/2024] Open
Abstract
Introduction Precise staging and classification of liver fibrosis are crucial for the hierarchy management of patients. The roles of lactylation are newly found in the progression of liver fibrosis. This study is committed to investigating the signature genes with histone lactylation and their connection with immune infiltration among liver fibrosis with different phenotypes. Methods Firstly, a total of 629 upregulated and 261 downregulated genes were screened out of 3 datasets of patients with liver fibrosis from the GEO database and functional analysis confirmed that these differentially expressed genes (DEGs) participated profoundly in fibrosis-related processes. After intersecting with previously reported lactylation-related genes, 12 DEGs related to histone lactylation were found and narrowed down to 6 core genes using R algorithms, namely S100A6, HMGN4, IFI16, LDHB, S100A4, and VIM. The core DEGs were incorporated into the Least absolute shrinkage and selection operator (LASSO) model to test their power to distinguish the fibrotic stage. Results Advanced fibrosis presented a pattern of immune infiltration different from mild fibrosis, and the core DEGs were significantly correlated with immunocytes. Gene set and enrichment analysis (GSEA) results revealed that core DEGs were closely linked to immune response and chemokine signaling. Samples were classified into 3 clusters using the LASSO model, followed by gene set variation analysis (GSVA), which indicated that liver fibrosis can be divided into status featuring lipid metabolism reprogramming, immunity immersing, and intermediate of both. The regulatory networks of the core genes shared several transcription factors, and certain core DEGs also presented dysregulation in other liver fibrosis and idiopathic pulmonary fibrosis (IPF) cohorts, indicating that lactylation may exert comparable functions in various fibrotic pathology. Lastly, core DEGs also exhibited upregulation in HCC. Discussion Lactylation extensively participates in the pathological progression and immune infiltration of fibrosis. Lactylation and related immune infiltration could be a worthy focus for the investigation of HCC developed from liver fibrosis.
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Affiliation(s)
- Lin-Na Li
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Wen-Wen Li
- Guangzhou Wondfo Health Science and Technology Co., Ltd, Guangzhou, China
| | - Lu-Shan Xiao
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wei-Nan Lai
- Department of Rheumatology and Immunology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Urias E, Tedesco NR, Burkholder DA, Moran IJ, Miller MJ, Jasty VSJ, Patil S, Zoellner S, Wijarnpreecha K, Chen VL. PNPLA3 risk allele is associated with risk of hepatocellular carcinoma but not decompensation in compensated cirrhosis. Hepatol Commun 2024; 8:e0441. [PMID: 38780253 PMCID: PMC11124711 DOI: 10.1097/hc9.0000000000000441] [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: 01/31/2024] [Accepted: 03/03/2024] [Indexed: 05/25/2024] Open
Abstract
BACKGROUND The PNPLA3-rs738409-G, TM6SF2-rs58542926-T, and HSD17B13-rs6834314-A polymorphisms have been associated with cirrhosis, hepatic decompensation, and HCC. However, whether they remain associated with HCC and decompensation in people who already have cirrhosis remains unclear, which limits the clinical utility of genetics in risk stratification as HCC is uncommon in the absence of cirrhosis. We aimed to characterize the effects of PNPLA3, TM6SF2, and HSD17B13 genotype on hepatic decompensation, HCC, and liver-related mortality or liver transplant in patients with baseline compensated cirrhosis. METHODS We conducted a single-center retrospective study of patients in the Michigan Genomics Initiative who underwent genotyping. The primary predictors were PNPLA3, TM6SF2, and HSD17B13 genotypes. Primary outcomes were either hepatic decompensation, HCC, or liver-related mortality/transplant. We conducted competing risk Fine-Gray analyses on our cohort. RESULTS We identified 732 patients with baseline compensated cirrhosis. During follow-up, 50% of patients developed decompensation, 13% developed HCC, 24% underwent liver transplant, and 27% died. PNPLA3-rs738409-G genotype was associated with risk of incident HCC: adjusted subhazard hazard ratio 2.42 (1.40-4.17), p=0.0015 for PNPLA3-rs738409-GG vs. PNPLA3-rs738409-CC genotype. The 5-year cumulative incidence of HCC was higher in PNPLA3-rs738409-GG carriers than PNPLA3-rs738409-CC/-CG carriers: 15.6% (9.0%-24.0%) vs. 7.4% (5.2%-10.0%), p<0.001. PNPLA3 genotype was not associated with decompensation or the combined outcome of liver-related mortality or liver transplant. TM6SF2 and HSD17B13 genotypes were not associated with decompensation or HCC. CONCLUSIONS The PNPLA3-rs738409-G allele is associated with an increased risk of HCC among patients with baseline compensated cirrhosis. People with cirrhosis and PNPLA3-rs738409-GG genotype may warrant more intensive HCC surveillance.
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Affiliation(s)
- Esteban Urias
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Nicholas R. Tedesco
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Daniel A. Burkholder
- Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Houston, Texas, USA
| | - Isabel J. Moran
- Michigan State University College of Medicine, East Lansing, Michigan, USA
| | - Matthew J. Miller
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Venkata Sai J. Jasty
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Snehal Patil
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA
| | - Sebastian Zoellner
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA
| | - Karn Wijarnpreecha
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Arizona College of Medicine—Phoenix, Phoenix, Arizona, USA
| | - Vincent L. Chen
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
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Konkwo C, Chowdhury S, Vilarinho S. Genetics of liver disease in adults. Hepatol Commun 2024; 8:e0408. [PMID: 38551385 PMCID: PMC10984672 DOI: 10.1097/hc9.0000000000000408] [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: 11/12/2023] [Accepted: 01/30/2024] [Indexed: 04/02/2024] Open
Abstract
Chronic liver disease stands as a significant global health problem with an estimated 2 million annual deaths across the globe. Combining the use of next-generation sequencing technologies with evolving knowledge in the interpretation of genetic variation across the human genome is propelling our understanding, diagnosis, and management of both rare and common liver diseases. Here, we review the contribution of risk and protective alleles to common forms of liver disease, the rising number of monogenic diseases affecting the liver, and the role of somatic genetic variants in the onset and progression of oncological and non-oncological liver diseases. The incorporation of genomic information in the diagnosis and management of patients with liver disease is driving the beginning of a new era of genomics-informed clinical hepatology practice, facilitating personalized medicine, and improving patient care.
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Affiliation(s)
- Chigoziri Konkwo
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
| | - Shanin Chowdhury
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Silvia Vilarinho
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
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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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Germani G, D’Arcangelo F, Grasso M, Burra P. Advances and Controversies in Acute Alcohol-Related Hepatitis: From Medical Therapy to Liver Transplantation. Life (Basel) 2023; 13:1802. [PMID: 37763206 PMCID: PMC10532507 DOI: 10.3390/life13091802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/10/2023] [Accepted: 08/18/2023] [Indexed: 09/29/2023] Open
Abstract
Alcohol-related hepatitis (AH) is a clinical syndrome characterized by recent-onset jaundice in the context of alcohol consumption. In patients with severe AH "unresponsive" to steroid therapy, mortality rates exceed 70% within six months. According to European and American guidelines, liver transplantation (LT) may be considered in highly selected patients who do not respond to medical therapy. The aim of this narrative review is to summarize current knowledge from medical therapy to liver transplantation in acute alcohol-related hepatitis. Due to the impossibility to guarantee six-month abstinence, LT for AH is controversial. Principal concerns are related to organ scarcity in the subset of stigma of "alcohol use disorder" (AUD) and the risk of relapse to alcohol use after LT. Return to alcohol use after LT is a complex issue that cannot be assessed as a yes/no variable with heterogeneous results among studies. In conclusion, present data indicate that well-selected patients have excellent outcomes, with survival rates of up to 100% at 24 and 36 months after LT. Behavioral therapy, ongoing psychological support, and strong family support seem essential to improve long-term outcomes after LT and reduce the risk in relapse of alcohol use.
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Affiliation(s)
- Giacomo Germani
- Multivisceral Transplant Unit, Azienda Ospedale—Università Padova, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy
| | - Francesca D’Arcangelo
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale—Università Padova, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy; (F.D.); (M.G.); (P.B.)
| | - Marco Grasso
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale—Università Padova, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy; (F.D.); (M.G.); (P.B.)
| | - Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale—Università Padova, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy; (F.D.); (M.G.); (P.B.)
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11
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Niu X, Zhu L, Xu Y, Zhang M, Hao Y, Ma L, Li Y, Xing H. Global prevalence, incidence, and outcomes of alcohol related liver diseases: a systematic review and meta-analysis. BMC Public Health 2023; 23:859. [PMID: 37170239 PMCID: PMC10173666 DOI: 10.1186/s12889-023-15749-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 04/25/2023] [Indexed: 05/13/2023] Open
Abstract
BACKGROUND Alcohol related liver disease (ARLD) is one of the major chronic liver diseases worldwide. This review aimed to describe the global prevalence, incidence, and outcomes of ARLD. METHODS Medline, Embase, The Cochrane Library, and China National Knowledge Infrastructure (CNKI) were searched from inception to May 31, 2022. The language was restricted to English or Chinese. According to the criteria, articles describing the basic characteristics of the population were selected. Two reviewers extracted the data independently. RESULTS A total of 372 studies were identified: 353 were used for prevalence analysis, 7 were used for incidence analysis, and 114 were used to for outcome analysis. The prevalence of ARLD worldwide was 4.8%. The prevalence in males was 2.9%, which was higher than female (0.5%). Among the ethnic groups, the percentage was highest in Caucasians (68.9%). Alcoholic liver cirrhosis comprised the highest proportion in the disease spectrum of ARLD at 32.9%. The prevalence of ascites in ARLD population was highest (25.1%). The ARLD population who drinking for > 20 years accounted for 54.8%, and the average daily alcohol intake was 146.6 g/d. About 59.5% of ARLD patients were current or former smokers, and 18.7% were complicated with hepatitis virus infection. The incidence was 0.208/1000 person-years. The overall mortality was 23.9%, and the liver-related mortality was 21.6%. CONCLUSION The global prevalence of ARLD was 4.8% and was affected by sex, region, drinking years, and other factors. Therefore, removing the factors causing a high disease prevalence is an urgent requisite. TRIAL REGISTRATION PROSPERO Nr: CRD42021286192.
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Affiliation(s)
- Xuanxuan Niu
- Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, 100015 China
| | - Lin Zhu
- Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, 100015 China
| | - Yifan Xu
- Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, 100015 China
| | - Menghan Zhang
- Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, 100015 China
| | - Yanxu Hao
- Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, 100015 China
| | - Lei Ma
- Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, 100015 China
| | - Yan Li
- Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, 100015 China
| | - Huichun Xing
- Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, 100015 China
- Peking University Ditan Teaching Hospital, Beijing, 100015 China
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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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13
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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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14
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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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15
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Tandoh KZ, Quaye O. Genetic associations in chronic hepatitis B infection: toward developing polygenic risk scores. Future Microbiol 2022; 17:541-549. [PMID: 35332782 DOI: 10.2217/fmb-2021-0176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Chronic hepatitis B (CHB) infection results in multiple clinical phenotypes of varying severity. One of the critical gaps in CHB management is the lack of a genetic-based tool to aid existing hepatocellular carcinoma and cirrhosis risk stratification models for patients with active CHB. Such individual predictive models for CHB are plagued by an inherent limitation of discriminatory power that clearly indicates the need for their improvement. In this article, we highlight genetic association studies in CHB that identified HLA and cytokine genetic susceptibility loci to CHB. We advance the position that translating CHB genetic susceptibility loci into polygenic risk scores will be a welcome addendum to the current arsenal of CHB outcome predictive models. We conclude with comments on hurdles that future research efforts should address within the research enclave of CHB and advocate for increased genetic data representation from sub-Saharan Africa.
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Affiliation(s)
- Kwesi Z Tandoh
- Department of Biochemistry, West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), Cell & Molecular Biology, College of Basic & Applied Sciences, University of Ghana, Accra, Ghana
| | - Osbourne Quaye
- Department of Biochemistry, West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), Cell & Molecular Biology, College of Basic & Applied Sciences, University of Ghana, Accra, Ghana
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16
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Zelber-Sagi S, Noureddin M, Shibolet O. Lifestyle and Hepatocellular Carcinoma What Is the Evidence and Prevention Recommendations. Cancers (Basel) 2021; 14:cancers14010103. [PMID: 35008267 PMCID: PMC8750465 DOI: 10.3390/cancers14010103] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/20/2021] [Accepted: 12/22/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary The increasing public health burden of Hepatocellular carcinoma (HCC) emphasizes the importance of defining important modifiable risk factors. In the following review, we will discuss the evidence for the relation of major lifestyle risk factors, mostly from large population-based studies. Generally, it is has been shown that healthy lifestyle habits, including minimizing obesity, eating a healthy diet, avoidance of smoking and alcohol, and increasing physical activity, have the potential to prevent HCC. Dietary composition is important beyond obesity. Consumption of n-3 polyunsaturated fatty acids, as well as fish and poultry, vegetables and fiber, are inversely associated with HCC, while red meat, saturated fat, cholesterol and sugar are related to increased risk. Data from multiple studies clearly show a beneficial effect for physical activity in reducing the risk of HCC. Smoking and alcohol can lead to liver fibrosis and liver cancer and jointly lead to an even greater risk. Abstract The increasing burden of hepatocellular carcinoma (HCC) emphasizes the unmet need for primary prevention. Lifestyle measures appear to be important modifiable risk factors for HCC regardless of its etiology. Lifestyle patterns, as a whole and each component separately, are related to HCC risk. Dietary composition is important beyond obesity. Consumption of n-3 polyunsaturated fatty acids, as well as fish and poultry, are inversely associated with HCC, while red meat, saturated fat, and cholesterol are related to increased risk. Sugar consumption is associated with HCC risk, while fiber and vegetable intake is protective. Data from multiple studies clearly show a beneficial effect for physical activity in reducing the risk of HCC. However, the duration, mode and intensity of physical activity needed are yet to be determined. There is evidence that smoking can lead to liver fibrosis and liver cancer and has a synergistic effect with alcohol drinking. On the other hand, an excessive amount of alcohol by itself has been associated with increased risk of HCC directly (carcinogenic effect) or indirectly (liver fibrosis and cirrhosis progression. Large-scale intervention studies testing the effect of comprehensive lifestyle interventions on HCC prevention among diverse cohorts of liver disease patients are greatly warranted.
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Affiliation(s)
- Shira Zelber-Sagi
- School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa 3498838, Israel
- Department of Gastroenterology & Hepatology, Tel Aviv Medical Center, Tel Aviv 6423906, Israel;
- Correspondence: ; Tel.: +972-54-4634440; Fax: +972-3-5446086
| | - Mazen Noureddin
- Karsh Division of Gastroenterology and Hepatology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - Oren Shibolet
- Department of Gastroenterology & Hepatology, Tel Aviv Medical Center, Tel Aviv 6423906, Israel;
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6697801, Israel
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17
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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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18
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Xiang H, Wu Z, Wang J, Wu T. Research progress, challenges and perspectives on PNPLA3 and its variants in Liver Diseases. J Cancer 2021; 12:5929-5937. [PMID: 34476007 PMCID: PMC8408107 DOI: 10.7150/jca.57951] [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: 01/07/2021] [Accepted: 07/26/2021] [Indexed: 12/02/2022] Open
Abstract
The human patatin-like phospholipase domain-containing 3 gene (PNPLA3) is highly expressed in liver and adipose tissue and encodes a transmembrane polypeptide chain containing 481 amino acids. The I148M variant of PNPLA3 is a single nucleotide polymorphism, which is related to a variety of liver and cardiovascular diseases and their complications (such as non-alcoholic fatty liver disease, liver fibrosis, coronary artery disease). This review mainly describes the pathophysiological effects of PNPLA3 and its variants, and their roles in the progression of liver disease and its complications.
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Affiliation(s)
- Hongjiao Xiang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zecheng Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Junmin Wang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tao Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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19
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Nahon P, Allaire M, Nault JC, Paradis V. Characterizing the mechanism behind the progression of NAFLD to hepatocellular carcinoma. Hepat Oncol 2020; 7:HEP36. [PMID: 33680428 PMCID: PMC7907968 DOI: 10.2217/hep-2020-0017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 09/11/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) developed in non-alcoholic fatty liver disease (NAFLD) individuals presents substantial clinical and biological characteristics, which remain to be elucidated. Its occurrence in noncirrhotic patients raises issues regarding surveillance strategies, which cannot be considered as cost-effective given the high prevalence of obesity and metabolic syndrome, and furthermore delineates specific oncogenic process that could be targeted in the setting of primary or secondary prevention. In this context, the identification of a genetic heterogeneity modulating HCC risk as well as specific biological pathways have been made possible through genome-wide association studies, development of animal models and in-depth analyses of human samples at the pathological and genomic levels. These advances must be confirmed and pursued to pave the way for personalized management of NAFLD-related HCC.
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Affiliation(s)
- Pierre Nahon
- APHP, Service d’Hépatologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Bondy
- Inserm, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d’Hématologie, Paris, France
- Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, Bobigny, France
| | - Manon Allaire
- APHP, Service d’Hépatologie, GH Pitié-Salpêtrière, Paris, France
- Université de Paris, Centre de recherche sur l’inflammation, Inserm-UMR1149, 75018 Paris, France
| | - Jean-Charles Nault
- APHP, Service d’Hépatologie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Bondy
- Inserm, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d’Hématologie, Paris, France
- Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, Bobigny, France
| | - Valérie Paradis
- APHP, Service d’Anatomopathologie, Hôpital Beaujon, Clichy, France
- Université de Paris, CNRS, Centre de Recherche sur l’Inflammation (CRI), Paris F-75890, France
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20
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Meroni M, Longo M, Dongiovanni P. Genetic and metabolic factors: the perfect combination to treat metabolic associated fatty liver disease. EXPLORATION OF MEDICINE 2020; 1:218-243. [DOI: 10.37349/emed.2020.00015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 06/20/2020] [Indexed: 01/04/2025] Open
Abstract
The prevalence of nonalcoholic or more recently re-defined metabolic associated fatty liver disease (MAFLD) is rapidly growing worldwide. It is characterized by hepatic fat accumulation exceeding 5% of liver weight not attributable to alcohol consumption. MAFLD refers to an umbrella of conditions ranging from simple steatosis to nonalcoholic steatohepatitis which may finally progress to cirrhosis and hepatocellular carcinoma. MAFLD is closely related to components of the metabolic syndrome and to environmental factors. In addition to the latter, genetic predisposition plays a key role in MAFLD pathogenesis and strictly contributes to its progressive forms. The candidate genes which have been related to MAFLD hereditability are mainly involved in lipids remodeling, lipid droplets assembly, lipoprotein packaging and secretion, de novo lipogenesis, and mitochondrial redox status. In the recent years, it has emerged the opportunity to translate the genetics into clinics by aggregating the genetic variants mostly associated with MAFLD in polygenic risk scores. These scores might be used in combination with metabolic factors to identify those patients at higher risk to develop more severe liver disease and to schedule an individual therapeutic approach.
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Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milano, Italy
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milano, Italy
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy
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21
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The landscape of gene mutations in cirrhosis and hepatocellular carcinoma. J Hepatol 2020; 72:990-1002. [PMID: 32044402 DOI: 10.1016/j.jhep.2020.01.019] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 01/16/2020] [Accepted: 01/21/2020] [Indexed: 12/13/2022]
Abstract
Chronic liver disease and primary liver cancer are a massive global problem, with a future increase in incidences predicted. The most prevalent form of primary liver cancer, hepatocellular carcinoma, occurs after years of chronic liver disease. Mutations in the genome are a causative and defining feature of all cancers. Chronic liver disease, mostly at the cirrhotic stage, causes the accumulation of progressive mutations which can drive cancer development. Within the liver, a Darwinian process selects out dominant clones with selected driver mutations but also leaves a trail of passenger mutations which can be used to track the evolution of a tumour. Understanding what causes specific mutations and how they combine with one another to form cancer is a question at the heart of understanding, preventing and tackling liver cancer. Herein, we review the landscape of gene mutations in cirrhosis, especially those paving the way toward hepatocellular carcinoma development, that have been characterised by recent studies capitalising on technological advances in genomic sequencing. With these insights, we are beginning to understand how cancers form in the liver, particularly on the background of chronic liver disease. This knowledge may soon lead to breakthroughs in the way we detect, diagnose and treat this devastating disease.
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22
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Interplay of PNPLA3 and HSD17B13 Variants in Modulating the Risk of Hepatocellular Carcinoma among Hepatitis C Patients. Gastroenterol Res Pract 2020; 2020:4216451. [PMID: 32382265 PMCID: PMC7196159 DOI: 10.1155/2020/4216451] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 03/10/2020] [Accepted: 03/18/2020] [Indexed: 02/07/2023] Open
Abstract
A single-nucleotide polymorphism causing a C to G change in the PNPLA3 gene (rs738409) is associated with disease severity and development of hepatocellular carcinoma (HCC) in nonalcoholic fatty liver disease; the insertion variant rs72613567:TA of the 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13) mitigates this detrimental effect. Our aim was to evaluate if the same holds true in chronic hepatitis C virus infection (HCV). With a case control retrospective study design, we selected 110 patients who developed HCC on a background of HCV infection, matching each patient for sex and age (±30 months) to three HCV-infected, non-HCC patients. All participants underwent genotyping for PNPLA3 and HSD17B13 gene variants. Both univariate and multivariate analyses of risk factors for advanced disease and HCC were performed. Carriage of PNPLA3 G∗ allele was associated with a trend of progressively more severe liver disease, from mild fibrosis to significant fibrosis, cirrhosis, and HCC (p = 0.007). When the HSD17B13:TA status of these patients was taken into account, the abovementioned trend was strengthened among HSD17B13 major allele homozygotes and completely blunted among carriers of the minor allele (p = 0.0003 and 0.953, respectively). In a conditional logistic regression model including diabetes and AST to platelet ratio index among predictor variables, the unfavourable genetic profile characterized by the coexistence of the PNPLA3 minor allele and HSD17B13 major allele (vs. all other possible combinations) was an independent risk factor for HCC (OR = 2.00, 95% CI: 1.23-3.26) together with a history of alcohol abuse. In conclusion, carriage of the combination PNPLA3 minor allele and HSD17B13 major allele may represent a risk factor for HCC among HCV-infected patients. The interplay between the two genes may explain some of the controversy on this topic and may be exploited to stratify HCC risk in hepatitis C.
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23
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Dong XC. PNPLA3-A Potential Therapeutic Target for Personalized Treatment of Chronic Liver Disease. Front Med (Lausanne) 2019; 6:304. [PMID: 31921875 PMCID: PMC6927947 DOI: 10.3389/fmed.2019.00304] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 12/02/2019] [Indexed: 01/10/2023] Open
Abstract
Patatin-like phospholipase domain-containing protein 3 (PNPLA3) is a lipid droplet-associated protein that has been shown to have hydrolase activity toward triglycerides and retinyl esters. The first evidence of PNPLA3 being associated with fatty liver disease was revealed by a genome-wide association study (GWAS) of Hispanic, African American, and European American individuals in the Dallas Heart Study back in 2008. Since then, numerous GWAS reports have shown that PNPLA3 rs738409[G] (148M) variant is associated with hepatic triglyceride accumulation (steatosis), inflammation, fibrosis, cirrhosis, and even hepatocellular carcinoma regardless of etiologies including alcohol- or obesity-related and others. The frequency of PNPLA3(148M) variant ranges from 17% in African Americans, 23% in European Americans, to 49% in Hispanics in the Dallas Heart Study. Due to high prevalence of obesity and alcohol consumption in modern societies, the PNPLA3(148M) gene variant and environment interaction poses a serious concern for public health, especially chronic liver diseases including alcohol-related liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). Therefore, PNPLA3(148M) variant is a potential therapeutic target for chronic liver disease in the rs738409 allele carriers. Currently, there is no approved drug specifically targeting the PNPLA3(148M) variant yet. With additional mechanistic studies, novel therapeutic strategies are expected to be developed for the treatment of the PNPLA3(148M) variant-associated chronic liver diseases in the near future.
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Affiliation(s)
- Xiaocheng Charlie Dong
- Center for Diabetes and Metabolic Diseases, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
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Pocha C, Xie C. Hepatocellular carcinoma in alcoholic and non-alcoholic fatty liver disease-one of a kind or two different enemies? Transl Gastroenterol Hepatol 2019; 4:72. [PMID: 31728429 DOI: 10.21037/tgh.2019.09.01] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 08/22/2019] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular cancer (HCC) is a cancer with an overall poor prognosis and an alarming globally rising incidence. While viral etiology of chronic liver disease and HCC is down-trending, alcohol and excess calorie intake have emerged as major culprits. Alcohol related liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) share similar pathogenetic mechanism of hepatic injury and in promoting development of HCC; yet some genetic and epigenetic features are distinct and may promise clinical utility. Population based intervention are urgently needed to reduce alcohol use and improve metabolic factors such as obesity and diabetes. The goal is to identify at-risk patients, to link these patients to care and to provide effective management of chronic liver disease and HCC. This review focuses on the epidemiology, pathophysiology including genetic and epigenetic altercation as well as clinical aspects of ALD and NAFLD associated HCC.
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Affiliation(s)
- Christine Pocha
- Avera McKennnan Hospital and University Medical Center, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA.,Department of Gastroenterology and Hepatology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Chencheng Xie
- Avera McKennnan Hospital and University Medical Center, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA.,Department of Gastroenterology and Hepatology, Thomas Jefferson University, Philadelphia, PA, USA
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25
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Yang J, Trépo E, Nahon P, Cao Q, Moreno C, Letouzé E, Imbeaud S, Bayard Q, Gustot T, Deviere J, Bioulac-Sage P, Calderaro J, Ganne-Carrié N, Laurent A, Blanc JF, Guyot E, Sutton A, Ziol M, Zucman-Rossi J, Nault JC. A 17-Beta-Hydroxysteroid Dehydrogenase 13 Variant Protects From Hepatocellular Carcinoma Development in Alcoholic Liver Disease. Hepatology 2019; 70:231-240. [PMID: 30908678 DOI: 10.1002/hep.30623] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Accepted: 03/05/2019] [Indexed: 01/10/2023]
Abstract
Recently, a loss of function variant (rs72613567) in 17-beta-hydroxysteroid dehydrogenase 13 (HSD17B13) has been identified as protective of nonalcoholic (NAFLD) and alcoholic liver disease (ALD). However, the role of this single-nucleotide polymorphism (SNP) in the development of hepatocellular carcinoma (HCC) is currently unknown. A total of 3,315 European patients with HCC (n = 1,109) or without HCC, but with chronic liver disease (CLD; n = 2,206), from four centers were analyzed either by whole-exome sequencing (WES; exploratory cohort, 285 HCC) or genotyped for HSD17B13 rs72613567 (validation cohort, 824 HCC and all CLD). We included a control group of 33,337 healthy European individuals from the Exome Aggregation Consortium. We compared distribution of genotype using the chi-square test and logistic regression. In the exploratory cohort analyzed by WES, frequency of the TA allele of HSD17B13 rs72613567 was significantly decreased in HCC patients compared to healthy controls (P = 1.52 × 10-06 ). In the validation cohort, frequency of TA allele carriers was also decreased in patients with CLD and without HCC (39%) compared to healthy individuals (47%; P < 0.0001). The protective effect of the TA allele of HSD17B13 rs72613567 was identified in patients with ALD (odds ratio [OR] = 0.73; 95% confidence interval [CI], 0.65-0.82; P < 0.0001), NAFLD (OR = 0.64; 95% CI, 0.49-0.83; P = 0.0007), and hepatitis C (OR = 0.71; 95% CI, 0.60-0.85; P = 0.0002). In patients with ALD, the proportion of TA allele carriers with HCC was significantly lower (32%) than in CLD patients without HCC (40%), even after adjustment for age, sex, and fibrosis (OR = 0.64; 95% CI, 0.46-0.87; P = 0.005). Conclusion: The HSD17B13 rs72613567 loss of function variant is protective of HCC development in patients with ALD.
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Affiliation(s)
- Jie Yang
- Cordeliers Research Center, Sorbonne University, Inserm, USPC, Paris Descartes University, Paris Diderot University, Paris 13 University, Functional Genomics of Solid Tumors Laboratory, Paris, France
| | - Eric Trépo
- Cordeliers Research Center, Sorbonne University, Inserm, USPC, Paris Descartes University, Paris Diderot University, Paris 13 University, Functional Genomics of Solid Tumors Laboratory, Paris, France
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, University clinics of Bruxelles Erasme Hospital, Free University of Bruxelles, Bruxelles, Belgium
| | - Pierre Nahon
- Cordeliers Research Center, Sorbonne University, Inserm, USPC, Paris Descartes University, Paris Diderot University, Paris 13 University, Functional Genomics of Solid Tumors Laboratory, Paris, France
- Liver unit, Jean Verdier Hospital, Paris-Seine-Saint-Denis University Hospital, Assistance-Publique Paris Hospitals, Bondy, France
- Paris 13 University, Sorbonne Paris Cité, Paris, France
| | - Qian Cao
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Christophe Moreno
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, University clinics of Bruxelles Erasme Hospital, Free University of Bruxelles, Bruxelles, Belgium
| | - Eric Letouzé
- Cordeliers Research Center, Sorbonne University, Inserm, USPC, Paris Descartes University, Paris Diderot University, Paris 13 University, Functional Genomics of Solid Tumors Laboratory, Paris, France
| | - Sandrine Imbeaud
- Cordeliers Research Center, Sorbonne University, Inserm, USPC, Paris Descartes University, Paris Diderot University, Paris 13 University, Functional Genomics of Solid Tumors Laboratory, Paris, France
| | - Quentin Bayard
- Cordeliers Research Center, Sorbonne University, Inserm, USPC, Paris Descartes University, Paris Diderot University, Paris 13 University, Functional Genomics of Solid Tumors Laboratory, Paris, France
| | - Thierry Gustot
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, University clinics of Bruxelles Erasme Hospital, Free University of Bruxelles, Bruxelles, Belgium
| | - Jacques Deviere
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, University clinics of Bruxelles Erasme Hospital, Free University of Bruxelles, Bruxelles, Belgium
| | - Paulette Bioulac-Sage
- Bordeaux university, UMR1053 Bordeaux Research in Translational Oncology, BaRITOn, Bordeaux, France
- Department of Pathology, Pellegrin Hospital, Bordeaux CHU, Bordeaux, France
| | - Julien Calderaro
- Department of Pathology, Henri Mondor Hospital; Paris Est Créteil University, Inserm U955, Team 18, Mondor Institute for Biomedical Research, Créteil, France
| | - Nathalie Ganne-Carrié
- Cordeliers Research Center, Sorbonne University, Inserm, USPC, Paris Descartes University, Paris Diderot University, Paris 13 University, Functional Genomics of Solid Tumors Laboratory, Paris, France
- Liver unit, Jean Verdier Hospital, Paris-Seine-Saint-Denis University Hospital, Assistance-Publique Paris Hospitals, Bondy, France
- Paris 13 University, Sorbonne Paris Cité, Paris, France
| | - Alexis Laurent
- Department of Hepatobiliary Surgery, Henri Mondor Hospital, Créteil; Paris Est Créteil University, Inserm U955, Team 18, Mondor Institute for Biomedical Research, Créteil, France
| | - Jean Frédéric Blanc
- Department of Gastroenterology, Magellan Medical and Surgical Center, Haut-Lévêque hospital, CHU of Bordeaux, Bordeaux, France
| | - Erwan Guyot
- Department of Biochemistry, Jean Verdier Hospital, Paris-Seine-Saint-Denis University Hospital, Assistance-Publique Paris Hospitals, Bondy, France
- INSERM U1148 LVTS, UFR SMBH, Paris 13 University, PRES Paris Sorbonne Cité, Bobigny, France
| | - Angela Sutton
- Department of Biochemistry, Jean Verdier Hospital, Paris-Seine-Saint-Denis University Hospital, Assistance-Publique Paris Hospitals, Bondy, France
- INSERM U1148 LVTS, UFR SMBH, Paris 13 University, PRES Paris Sorbonne Cité, Bobigny, France
| | - Marianne Ziol
- Cordeliers Research Center, Sorbonne University, Inserm, USPC, Paris Descartes University, Paris Diderot University, Paris 13 University, Functional Genomics of Solid Tumors Laboratory, Paris, France
- Paris 13 University, Sorbonne Paris Cité, Paris, France
- Biological Resource Center (BB-0033-00027), Paris-Seine-Saint-Denis University Hospital, Assistance-Publique Paris Hospitals, Bondy, France
| | - Jessica Zucman-Rossi
- Cordeliers Research Center, Sorbonne University, Inserm, USPC, Paris Descartes University, Paris Diderot University, Paris 13 University, Functional Genomics of Solid Tumors Laboratory, Paris, France
- European Georges Pompidou Hospital, Assistance-Publique Paris Hospitals, Paris, France
| | - Jean-Charles Nault
- Cordeliers Research Center, Sorbonne University, Inserm, USPC, Paris Descartes University, Paris Diderot University, Paris 13 University, Functional Genomics of Solid Tumors Laboratory, Paris, France
- Liver unit, Jean Verdier Hospital, Paris-Seine-Saint-Denis University Hospital, Assistance-Publique Paris Hospitals, Bondy, France
- Paris 13 University, Sorbonne Paris Cité, Paris, France
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Abstract
Prediction of future hepatocellular carcinoma (HCC) risk in the sizable chronic liver disease population is an urgent unmet need to enable regular HCC screening for early detection. Germline deoxyribonucleic acid polymorphisms likely represent etiology-specific host factors that determine HCC susceptibility, including single nucleotide polymorphisms in EGF, IFNL3, MICA, and TLL1 in hepatitis C with or without active viral infection, and PNPLA3, TM6SF2, and MBOAT7 in metabolic liver diseases. Transcriptome-based prognostic liver signature in diseased liver tissue has been associated with long-term HCC risk in viral and metabolic etiologies. Transcriptomic signatures of hepatic injury and specific cell type such as aggregated lymphocytes also predict HCC development. Circulating factors such as proteins and their chemical modification, nucleotides, and metabolites may serve for less-invasive assessment of short- or long-term HCC risk. These biomarkers will enable individual HCC risk-based personalized clinical management for cost-effective early HCC detection and improvement of patient survival.
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Matsushita H, Takaki A. Alcohol and hepatocellular carcinoma. BMJ Open Gastroenterol 2019; 6:e000260. [PMID: 31139422 PMCID: PMC6505979 DOI: 10.1136/bmjgast-2018-000260] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 01/04/2019] [Accepted: 01/12/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Alcohol is classified as a Group 1 carcinogen by the International Agency for Research on Cancer because it induces hepatocellular carcinoma (among other cancers) in humans. An excessive alcohol intake may result in fatty liver, acute/chronic hepatitis, and cirrhosis and eventually lead to hepatocellular carcinoma. It has been reported that alcohol abuse increases the relative risk of hepatocellular carcinoma by 3- to 10-fold. AIM AND METHODS To clarify the known mechanisms of alcohol-related carcinogenesis, we searched Pubmed using the terms alcohol and immune mechanism, alcohol and cancer, and immune mechanism and cancer and summarized the articles as a qualitative review. RESULTS From a clinical perspective, it is well known that alcohol interacts with other factors, such as smoking, viral hepatitis, and diabetes, leading to an increased risk of hepatocellular carcinoma. There are several possible mechanisms through which alcohol may induce liver carcinogenicity, including the mutagenic effects of acetaldehyde and the production of ROS due to the excessive hepatic deposition of iron. Furthermore, it has been reported that alcohol accelerates hepatitis C virus-induced liver tumorigenesis through TLR4 signaling. Despite intense investigations to elucidate the mechanisms, they remain poorly understood. CONCLUSION This review summarizes the recent findings of clinical and pathological studies that have investigated the carcinogenic effects of alcohol in the liver.
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Affiliation(s)
- Hiroshi Matsushita
- Department of Gastroenterology and Hepatology, Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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Huang Z, Guo X, Zhang G, Liang L, Nong B. Correlation between PNPLA3 rs738409 polymorphism and hepatocellular carcinoma: a meta-analysis of 10,330 subjects. Int J Biol Markers 2019; 34:117-122. [PMID: 30852978 DOI: 10.1177/1724600818812471] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE The correlation between patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphism and hepatocellular carcinoma was investigated by several pilot studies, but the results of these studies were controversial. Therefore, we performed this study to better assess the relationship between PNPLA3 rs738409 polymorphism and the likelihood of hepatocellular carcinoma. METHODS Eligible studies were searched in PubMed, Medline, EMBASE, and Web of Science. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the relationship between PNPLA3 rs738409 polymorphism and hepatocellular carcinoma. RESULTS A total of 17 studies with 10,330 participants were analyzed. A significant association with the likelihood of hepatocellular carcinoma was detected for the PNPLA3 rs738409 polymorphism in dominant (P = 0.0001; OR 0.66; 95% CI 0.53, 0.82), recessive (P < 0.0001; OR 2.32; 95% CI 1.76, 3.06) and allele (P < 0.0001; OR 0.64; 95% CI 0.53, 0.77) comparisons. Further subgroup analyses revealed that the PNPLA3 rs738409 polymorphism was significantly associated with the likelihood of hepatocellular carcinoma in Caucasians (dominant model: P < 0.0001, OR 0.57, 95% CI 0.45, 0.71; recessive model: P < 0.0001, OR 2.74, 95% CI 2.02, 3.71; allele model: P < 0.0001, OR 0.56, 95% CI 0.46, 0.67). However, no positive results were detected in Asians. CONCLUSIONS Our findings indicated that the PNPLA3 rs738409 polymorphism may serve as a potential biological marker of hepatocellular carcinoma in Caucasians.
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Affiliation(s)
- Zongsheng Huang
- Department of Gastroenterology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Xianwen Guo
- Department of Gastroenterology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Guo Zhang
- Department of Gastroenterology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Liexin Liang
- Department of Gastroenterology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Bing Nong
- Department of Gastroenterology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
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Yang J, Trépo E, Nahon P, Cao Q, Moreno C, Letouzé E, Imbeaud S, Gustot T, Deviere J, Debette S, Amouyel P, Bioulac-Sage P, Calderaro J, Ganne-Carrié N, Laurent A, Blanc JF, Guyot E, Sutton A, Ziol M, Zucman-Rossi J, Nault JC. PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases. Int J Cancer 2019; 144:533-544. [PMID: 30289982 DOI: 10.1002/ijc.31910] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 08/30/2018] [Accepted: 09/10/2018] [Indexed: 01/10/2023]
Abstract
Few single nucleotide polymorphisms (SNPs) have been reproducibly associated with hepatocellular carcinoma (HCC). Our aim was to test the association between nine SNPs and HCC occurrence. SNPs in genes linked to HCC (DEPDC5, GRIK1, KIF1B, STAT4, MICA, DLC1, DDX18) or to liver damage (PNPLA3-rs738409, TM6SF2-rs58542926) in GWAS were genotyped in discovery cohorts including 1,020 HCC, 2,021 controls with chronic liver disease and 2,484 healthy individuals and replication was performed in prospective cohorts of cirrhotic patients with alcoholic liver disease (ALD, n = 249) and hepatitis C (n = 268). In the discovery cohort, PNPLA3 and TM6SF2 SNPs were associated with HCC (OR = 1.67 [CI95%:1.16-2.40], p = 0.005; OR = 1.45 [CI95%:1.08-1.94], p = 0.01) after adjustment for fibrosis, age, gender and etiology. In contrast, STAT4-rs7574865 was associated with HCC only in HBV infected patients (p = 0.03) and the other tested SNP were not linked with HCC risk. PNPLA3 and TM6SF2 variants were independently associated with HCC in patients with ALD (OR = 3.91 [CI95%:2.52-6.06], p = 1.14E-09; OR = 1.79 [CI95%:1.25-2.56], p = 0.001) but not with other etiologies. PNPLA3 SNP was also significantly associated with HCC developed on a nonfibrotic liver (OR = 2.19 [CI95%:1.22-3.92], p = 0.007). The association of PNPLA3 and TM6SF2 with HCC risk was confirmed in the prospective cohort with ALD. A genetic score including PNPLA3 and TM6SF2 minor alleles showed a progressive significant increased risk of HCC in ALD patients. In conclusion, PNPLA3-rs738409 and TM6SF2-rs58542926 are inherited risk variants of HCC development in patients with ALD in a dose dependent manner. The link between PNPLA3 and HCC on nonfibrotic liver suggests a direct role in liver carcinogenesis.
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Affiliation(s)
- Jie Yang
- Inserm UMR-1162, Génomique fonctionnelle des Tumeurs solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France
| | - Eric Trépo
- Inserm UMR-1162, Génomique fonctionnelle des Tumeurs solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Cliniques Universitaires de Bruxelles Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Pierre Nahon
- Inserm UMR-1162, Génomique fonctionnelle des Tumeurs solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France
- Liver unit, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, 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
| | - Qian Cao
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Christophe Moreno
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Cliniques Universitaires de Bruxelles Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Eric Letouzé
- Inserm UMR-1162, Génomique fonctionnelle des Tumeurs solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France
| | - Sandrine Imbeaud
- Inserm UMR-1162, Génomique fonctionnelle des Tumeurs solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France
| | - Thierry Gustot
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Cliniques Universitaires de Bruxelles Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Jacques Deviere
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Cliniques Universitaires de Bruxelles Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Stéphanie Debette
- Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Bordeaux, France
- CHU de Bordeaux, Department of Neurology, Bordeaux, France
| | - Philippe Amouyel
- University of Lille, Institut National de la Santé et de la Recherche Médicale, CHU Lille, Institut Pasteur de Lille, Lille, France
| | - Paulette Bioulac-Sage
- Univ. Bordeaux, UMR1053 Bordeaux Research in Translational Oncology, Bordeaux, France
- Service de Pathologie, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France
| | - Julien Calderaro
- Service d'anatomopathologie, Hôpital Henri Mondor, Créteil
- Université Paris Est Créteil, Inserm U955, Team 18, Institut Mondor de Recherche Biomédicale, France
| | - Nathalie Ganne-Carrié
- Inserm UMR-1162, Génomique fonctionnelle des Tumeurs solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France
- Liver unit, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, 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
| | - Alexis Laurent
- Service de chirurgie digestive, Hôpital Henri Mondor, Créteil
- Université Paris Est Créteil, Institut Mondor de Recherche Biomédicale, France
| | - Jean Frédéric Blanc
- Service Hépato-Gastroentérologie et oncologie digestive, Centre Medico-Chirurgical Magellan, Hôpital Haut-Lévêque, CHU de Bordeaux, Bordeaux, France
| | - Erwan Guyot
- Laboratoire de biochimie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France
- INSERM U1148 LVTS, UFR SMBH, Université Paris 13, PRES Paris Sorbonne Cité, Bobigny, France
| | - Angela Sutton
- Laboratoire de biochimie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France
- INSERM U1148 LVTS, UFR SMBH, Université Paris 13, PRES Paris Sorbonne Cité, Bobigny, France
| | - Marianne Ziol
- Inserm UMR-1162, Génomique fonctionnelle des Tumeurs solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, 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 Ressources Biologiques (BB-0033-00027) Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France
| | - Jessica Zucman-Rossi
- Inserm UMR-1162, Génomique fonctionnelle des Tumeurs solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France
- Hôpital Europeen Georges Pompidou, Paris, France
| | - Jean-Charles Nault
- Inserm UMR-1162, Génomique fonctionnelle des Tumeurs solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France
- Liver unit, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, 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
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Ganne-Carrié N, Nahon P. Hepatocellular carcinoma in the setting of alcohol-related liver disease. J Hepatol 2019; 70:284-293. [PMID: 30658729 DOI: 10.1016/j.jhep.2018.10.008] [Citation(s) in RCA: 248] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 10/01/2018] [Accepted: 10/08/2018] [Indexed: 01/27/2023]
Abstract
Alcohol-related liver disease is the most prevalent type of chronic liver disease worldwide, accounting for 30% of hepatocellular carcinoma (HCC) cases and HCC-specific deaths. Alcohol has been associated with an increased risk of several malignancies, this risk starting at doses as low as 10 g/1 unit/day. The carcinogenic process includes direct acetaldehyde toxicity through the formation of protein and DNA adducts, an increased production of reactive oxygen species, changes to lipid peroxidation and metabolism, inflammation and an impaired immune response and modifications to DNA methylation. A high annual incidence of HCC has been observed in large European cohorts of patients with alcoholic cirrhosis, reaching 2.9%, with numerous host factors modulating this risk (age, gender, liver failure, genetic polymorphisms affecting oncogenic pathways). Because of impaired surveillance and poor patient compliance, HCC is often detected late in patients with chronic liver disease of alcoholic aetiology. This delay in detection, which is frequently made in the context of advanced liver cirrhosis rather than in surveillance programmes, results in more advanced HCC that is less amenable to curative treatment. Consequently, patients with alcohol-related HCC generally have a worse prognosis than those with non-alcoholic HCC.
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Affiliation(s)
- Nathalie Ganne-Carrié
- AP-HP, Hôpital Jean Verdier, Liver Unit, Bondy, France; University Paris 13, Sorbonne Paris Cité, "équipe labellisée Ligue Contre le Cancer", F-93000 Bobigny, France; INSERM UMR-1162: Functional Genomics of Solid Tumours, F-75010 Paris, France.
| | - Pierre Nahon
- AP-HP, Hôpital Jean Verdier, Liver Unit, Bondy, France; University Paris 13, Sorbonne Paris Cité, "équipe labellisée Ligue Contre le Cancer", F-93000 Bobigny, France; INSERM UMR-1162: Functional Genomics of Solid Tumours, F-75010 Paris, France
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31
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Abstract
Hepatocellular carcinoma (HCC) is associated with chronic inflammation and fibrosis arising from different etiologies, including hepatitis B and C and alcoholic and nonalcoholic fatty liver diseases. The inflammatory cytokines tumor necrosis factor-α and interleukin-6 and their downstream targets nuclear factor kappa B (NF-κB), c-Jun N-terminal kinase (JNK), and signal transducer and activator of transcription 3 drive inflammation-associated HCC. Further, while adaptive immunity promotes immune surveillance to eradicate early HCC, adaptive immune cells, such as CD8+ T cells, Th17 cells, and B cells, can also stimulate HCC development. Thus, the role of the hepatic immune system in HCC development is a highly complex topic. This review highlights the role of cytokine signals, NF-κB, JNK, innate and adaptive immunity, and hepatic stellate cells in HCC and discusses whether these pathways could be therapeutic targets. The authors will also discuss cholangiocarcinoma and liver metastasis because biliary inflammation and tumor-associated stroma are essential for cholangiocarcinoma development and because primary tumor-derived inflammatory mediators promote the formation of a "premetastasis niche" in the liver.
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Affiliation(s)
- Yoon Mee Yang
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - So Yeon Kim
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Ekihiro Seki
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
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Meroni M, Longo M, Rametta R, Dongiovanni P. Genetic and Epigenetic Modifiers of Alcoholic Liver Disease. Int J Mol Sci 2018; 19:E3857. [PMID: 30513996 PMCID: PMC6320903 DOI: 10.3390/ijms19123857] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 10/31/2018] [Accepted: 11/28/2018] [Indexed: 12/12/2022] Open
Abstract
Alcoholic liver disease (ALD), a disorder caused by excessive alcohol consumption is a global health issue. More than two billion people consume alcohol in the world and about 75 million are classified as having alcohol disorders. ALD embraces a wide spectrum of hepatic lesions including steatosis, alcoholic steatohepatitis (ASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). ALD is a complex disease where environmental, genetic, and epigenetic factors contribute to its pathogenesis and progression. The severity of alcohol-induced liver disease depends on the amount, method of usage and duration of alcohol consumption as well as on age, gender, presence of obesity, and genetic susceptibility. Genome-wide association studies and candidate gene studies have identified genetic modifiers of ALD that can be exploited as non-invasive biomarkers, but which do not completely explain the phenotypic variability. Indeed, ALD development and progression is also modulated by epigenetic factors. The premise of this review is to discuss the role of genetic variants and epigenetic modifications, with particular attention being paid to microRNAs, as pathogenic markers, risk predictors, and therapeutic targets in ALD.
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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.
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy.
| | - Raffaela Rametta
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy.
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy.
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Yamamoto K, Kogiso T, Taniai M, Hashimoto E, Tokushige K. Differences in the genetic backgrounds of patients with alcoholic liver disease and non-alcoholic fatty liver disease. JGH OPEN 2018; 3:17-24. [PMID: 30834336 PMCID: PMC6386744 DOI: 10.1002/jgh3.12097] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 08/20/2018] [Accepted: 08/25/2018] [Indexed: 12/23/2022]
Abstract
Background and Aim Alcoholic liver disease (ALD) and non‐alcoholic fatty liver disease (NAFLD) have common hepatic histological features, but few studies have compared the genomic backgrounds of these two diseases. Here, we compared the genetic differences between ALD and NAFLD. Methods This study enrolled 318 Japanese patients with ALD (n = 118; male, 86%; median age, 62 years; liver cirrhosis, 58%; hepatocellular carcinoma [HCC], 31%) and NAFLD (n = 200; male, 55%; age, 61 years; cirrhosis, 19%; HCC, 12%). The genotype frequencies of 10 single nucleotide polymorphisms (SNPs) were analyzed. Results The ADH1B genotype GG and ALDH2 genotype GG were observed more frequently, and the percentage of patients with the MTP genotype GG was lower in ALD compared with NAFLD patients (ADH1B, 16 vs 4%; ALDH2 84 vs 44%; MTP 62 vs 72%, respectively; all P < 0.01). Comparing noncirrhosis to cirrhosis, the frequency of the potassium voltage‐gated channel subfamily Q member 1 (KCNQ1) genotype TT and adrenoceptor beta 3 (ADRB3) genotype TT was increased significantly in ALD‐related cirrhosis. In contrast, the patatin‐like phospholipase 3 (PNPLA3) genotype CC was decreased significantly in NAFLD‐related cirrhosis. A comparison of patients with and without HCC demonstrated that the KCNQ1 genotype TT was increased significantly in both HCC groups. In addition, associations between the KCNJ15 genotype GG and ALD‐HCC and the G allele of PNPLA3 and NAFLD‐HCC were identified. Conclusions SNPs in genes related to ethanol and lipid metabolism clearly differed between patients with ALD and NAFLD. KCNQ1 might affect the progression and hepatocarcinogenesis in both ALD and NAFLD.
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Affiliation(s)
- Kuniko Yamamoto
- Institute of Gastroenterology, Department of Internal Medicine Tokyo Women's Medical University Tokyo Japan
| | - Tomomi Kogiso
- Institute of Gastroenterology, Department of Internal Medicine Tokyo Women's Medical University Tokyo Japan
| | - Makiko Taniai
- Institute of Gastroenterology, Department of Internal Medicine Tokyo Women's Medical University Tokyo Japan
| | - Etsuko Hashimoto
- Institute of Gastroenterology, Department of Internal Medicine Tokyo Women's Medical University Tokyo Japan
| | - Katsutoshi Tokushige
- Institute of Gastroenterology, Department of Internal Medicine Tokyo Women's Medical University Tokyo Japan
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Barbara M, Scott A, Alkhouri N. New insights into genetic predisposition and novel therapeutic targets for nonalcoholic fatty liver disease. Hepatobiliary Surg Nutr 2018; 7:372-381. [PMID: 30498712 DOI: 10.21037/hbsn.2018.08.05] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the United States affecting 80-100 million Americans. NAFLD encompasses a spectrum of diseases ranging from excess liver fat (nonalcoholic fatty liver or NAFL), to necro-inflammation (nonalcoholic steatohepatitis or NASH), to fibrosis/ cirrhosis, and malignant transformation (hepatocellular carcinoma). Susceptibility to NAFLD is highly variable and it remains unclear why some patients with NAFLD exhibit NASH, whereas patients with known risk factors have NAFL only. The reasons for this variability can be a partially attributed to differences in genetic background. In the last decade, there have been multiple genome wide association studies, which have enriched our understanding of the genetic basis of NAFLD. The I148M PNPLA3 (patatin-like phospholipase domain-containing protein 3) variant has been identified as the major common genetic determinant of NAFLD. Variants with moderate effect size like TM6SF2, MBOAT7 and GCKR have also been shown to have a significant contribution. New research has uncovered major pathways leading to disease development and progression; therefore, multiple medications are being developed and tested for the treatment of advanced NAFLD. These agents target metabolic mechanisms as well as inflammation and fibrosis pathways. Several randomized clinical trials (RCTs) are evaluating the efficacy of these novel agents on histological improvement of disease severity and decreasing liver-related outcomes. FDA-approved medications for NASH and NASH-related fibrosis are expected by 2020.
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Affiliation(s)
- Mary Barbara
- Department of Medicine, University of Texas (UT) Health San Antonio, San Antonio, TX, USA
| | | | - Naim Alkhouri
- Department of Medicine, University of Texas (UT) Health San Antonio, San Antonio, TX, USA.,Texas Liver Institute, San Antonio, TX, USA
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Yen YH, Tsai MC, Wu CK, Chang KC, Hung CH, Chiu KW, Lu SN, Wang JH, Chen CH, Kee KM, Kuo YH, Tseng PL, Lin MT, Huang CM, Lin JT, Hu TH. Association between PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma in Asian chronic hepatitis C patients: A longitudinal study. J Formos Med Assoc 2018; 117:833-840. [PMID: 29089161 DOI: 10.1016/j.jfma.2017.10.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 09/08/2017] [Accepted: 10/16/2017] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND/PURPOSE Prdevious meta-analyses assess whether or not patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 C > G) was associated with increased risk of hepatocellular carcinoma (HCC) in Caucasians patients with hepatitis C virus (HCV)-related cirrhosis, these meta-analyses did not provide firm conclusions. Only one cross-sectional study involving Asian patients has previously been conducted to explore this issue. We aim to investigate this in a longitudinal cohort of Asian chronic hepatitis C (CHC) patients. METHODS We consecutively enrolled 1011 CHC patients who underwent liver biopsy before initiating interferon-based therapy. These patients were followed-up and screened for HCC up to a median of 6.9 years. The influence of rs738409 (GG) genotype on the occurrence of HCC was assessed using the Kaplan-Meier method, then according to the multivariate Cox model. RESULTS During follow-up, 143 (14.1%) patients developed HCC. rs738409 (GG) genotype was not associated with time-to-HCC development on multivariate Cox regression (P = 0.634). When considering the occurrence of these events over time, rs738409 (GG) genotype did not influence the risk of HCC development (log-rank = 0.12). Among 261 patients with liver cirrhosis, rs738409 (GG) genotype was not associated with time-to-HCC development on multivariate Cox regression (P = 0.737). When considering the occurrence of these events over time, rs738409 (GG) genotype did not influence the risk of HCC development (log-rank = 0.72). CONCLUSION In this longitudinal study with liver biopsy to stage liver fibrosis, we affirm there is no influence of the rs738409 (GG) genotype on the occurrence of HCC in Asian CHC patients, including cirrhotic patients.
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Affiliation(s)
- Yi-Hao Yen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung, Taiwan
| | - Ming-Chao Tsai
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung, Taiwan
| | - Cheng-Kun Wu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung, Taiwan
| | - Kuo-Chin Chang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung, Taiwan
| | - King-Wah Chiu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung, Taiwan
| | - Kwong-Ming Kee
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung, Taiwan
| | - Yuan-Hung Kuo
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung, Taiwan
| | - Po-Lin Tseng
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung, Taiwan
| | - Ming-Tsung Lin
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung, Taiwan
| | - Chao-Min Huang
- Department of Biological Sciences, National Sun Yat-sen University, 70 Lienhai Rd., Kaohsiung 80424, Taiwan
| | - Jung-Ting Lin
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung, Taiwan.
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Thursz M, Gual A, Lackner C, Mathurin P, Moreno C, Spahr L, Sterneck M, Cortez-Pinto H. EASL Clinical Practice Guidelines: Management of alcohol-related liver disease. J Hepatol 2018; 69:154-181. [PMID: 29628280 DOI: 10.1016/j.jhep.2018.03.018] [Citation(s) in RCA: 574] [Impact Index Per Article: 82.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 03/20/2018] [Indexed: 12/12/2022]
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Seko Y, Yamaguchi K, Mizuno N, Okuda K, Takemura M, Taketani H, Hara T, Umemura A, Nishikawa T, Moriguchi M, Yasui K, Kamaguchi M, Nishioji K, Mochizuki N, Kobayashi M, Mori K, Tanaka S, Matsuura K, Tanaka Y, Itoh Y. Combination of PNPLA3 and TLL1 polymorphism can predict advanced fibrosis in Japanese patients with nonalcoholic fatty liver disease. J Gastroenterol 2018; 53:438-448. [PMID: 28744823 DOI: 10.1007/s00535-017-1372-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Accepted: 07/19/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND Hepatic fibrosis is an independent risk factor for mortality and liver-related events in patients with nonalcoholic fatty liver disease (NAFLD). PNPLA3 rs738409 has been associated with fibrosis in viral and non-viral hepatitis. TLL1 rs17047200 also has been associated with developing hepatocellular carcinoma probably via hepatic fibrogenesis. We estimated the impact of these genetic polymorphisms on hepatic fibrosis in Japanese patients with NAFLD. METHODS We analyzed the association between these genetic variants and the backgrounds of 817 individuals who received health checkups (health check cohort) from 2012 to 2014. Then, we investigated the relationship between genetic variants and liver histology in 258 consecutive patients with biopsy-proven NAFLD in Japan (NAFLD cohort) from 2012 to 2017 (UMIN000027399). RESULTS The prevalence of PNPLA3 CG/GG in the NAFLD cohort was higher than that in the health check cohort (p < 0.001). The prevalence of patients with advanced fibrosis (stages 3-4) was higher for PNPLA3 genotype CG/GG than CC (p = 0.048) and for TLL1 genotype AT/TT than AA (p = 0.044). The high-risk group which had at least two risk alleles of these variants was more likely to have advanced fibrosis (p = 0.004). Multivariate analysis identified body mass index [odds ratio (OR) 1.123, serum AST (OR 1.037, p = 0.004], serum albumin (OR 0.247, p = 0.032), and genetic high risk (OR 2.632, p = 0.026) as predictors of advanced fibrosis. CONCLUSIONS In Japanese patients with NAFLD, individuals with risk alleles of PNPLA3 and TLL1 may have a risk of advanced fibrosis.
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Affiliation(s)
- Yuya Seko
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Kanji Yamaguchi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Naoki Mizuno
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Keiichiro Okuda
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Masashi Takemura
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Hiroyoshi Taketani
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Tasuku Hara
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Atsushi Umemura
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Taichiro Nishikawa
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Michihisa Moriguchi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Kohichiroh Yasui
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan
| | - Mai Kamaguchi
- Health Care Division, Kyoto Second Red Cross Hospital, Kyoto, Kyoto, Japan
| | - Kenichi Nishioji
- Health Care Division, Kyoto Second Red Cross Hospital, Kyoto, Kyoto, Japan
| | - Naomi Mochizuki
- Health Care Division, Kyoto Second Red Cross Hospital, Kyoto, Kyoto, Japan
| | - Masao Kobayashi
- Health Care Division, Kyoto Second Red Cross Hospital, Kyoto, Kyoto, Japan
| | - Kojiroh Mori
- Center for Digestive and Liver Diseases, Nara City Hospital, Nara, Japan
| | - Saiyu Tanaka
- Center for Digestive and Liver Diseases, Nara City Hospital, Nara, Japan
| | - Kentaro Matsuura
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yoshito Itoh
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan.
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Fujiwara N, Friedman SL, Goossens N, Hoshida Y. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol 2018; 68:526-549. [PMID: 28989095 PMCID: PMC5818315 DOI: 10.1016/j.jhep.2017.09.016] [Citation(s) in RCA: 520] [Impact Index Per Article: 74.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 09/24/2017] [Accepted: 09/25/2017] [Indexed: 01/27/2023]
Abstract
Patients who develop chronic fibrotic liver disease, caused by viral or metabolic aetiologies, are at a high risk of developing hepatocellular carcinoma (HCC). Even after complete HCC tumour resection or ablation, the carcinogenic tissue microenvironment in the remnant liver can give rise to recurrent de novo HCC tumours, which progress into incurable, advanced-stage disease in most patients. Thus, early detection and prevention of HCC development is, in principle, the most impactful strategy to improve patient prognosis. However, a "one-size-fits-all" approach to HCC screening for early tumour detection, as recommended by clinical practice guidelines, is utilised in less than 20% of the target population, and the performance of screening modalities, including ultrasound and alpha-fetoprotein, is suboptimal. Furthermore, optimal screening strategies for emerging at-risk patient populations, such as those with chronic hepatitis C after viral cure, or those with non-cirrhotic, non-alcoholic fatty liver disease remain controversial. New HCC biomarkers and imaging modalities may improve the sensitivity and specificity of HCC detection. Clinical and molecular HCC risk scores will enable precise HCC risk prediction followed by tailoured HCC screening of individual patients, maximising cost-effectiveness and optimising allocation of limited medical resources. Several aetiology-specific and generic HCC chemoprevention strategies are evolving. Epidemiological and experimental studies have identified candidate chemoprevention targets and therapies, including statins, anti-diabetic drugs, and selective molecular targeted agents, although their clinical testing has been limited by the lengthy process of cancer development that requires long-term, costly studies. Individual HCC risk prediction is expected to overcome the challenge by enabling personalised chemoprevention, targeting high-risk patients for precision HCC prevention and substantially improving the dismal prognosis of HCC.
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Affiliation(s)
- Naoto Fujiwara
- Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, USA; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Japan
| | - Scott L Friedman
- Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, USA
| | - Nicolas Goossens
- Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland
| | - Yujin Hoshida
- Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, USA.
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Lim HW, Bernstein DE. Risk Factors for the Development of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis, Including Genetics. Clin Liver Dis 2018; 22:39-57. [PMID: 29128060 DOI: 10.1016/j.cld.2017.08.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease is emerging as the most common cause of chronic liver disease worldwide. This trend is, in part, secondary, to the growing incidence of obesity, type 2 diabetes, and metabolic syndrome. Other risk factors include age, gender, race/ethnicity, genetic predisposition, and polycystic ovarian disease. With the introduction of genome-wide association studies, genetic mutations contributing to inherited susceptibility to steatosis have been identified, which hold keys to future improvement in diagnosis and management. This article expands on the aforementioned risk factors and summarizes the current available data on genetic and environmental factors associated with this common entity.
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Affiliation(s)
- Huei-Wen Lim
- Department of Internal Medicine, Northwell Health, 400 Community Drive, Manhasset, NY 11030, USA
| | - David E Bernstein
- Department of Gastroenterology and Hepatology, Northwell Health, Center for Liver Diseases, 400 Community Drive, Manhasset, NY 11030, USA.
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Matsuura K, Tanaka Y. Host genetic variations associated with disease progression in chronic hepatitis C virus infection. Hepatol Res 2018; 48:127-133. [PMID: 29235266 DOI: 10.1111/hepr.13042] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Revised: 12/04/2017] [Accepted: 12/05/2017] [Indexed: 12/19/2022]
Abstract
Treatment with recently developed interferon-free oral regimens combining direct-acting antiviral agents (DAAs) results in the elimination of hepatitis C virus (HCV) in almost all chronic hepatitis C (CHC) patients. In the era of DAAs, surveillance of hepatocellular carcinoma (HCC) after eradication of HCV by anti-HCV therapy is particularly important. As is well known, an advanced state of hepatic fibrosis is the major risk factor for developing HCC. Therefore, an increased understanding of various factors associated with disease progression and development of HCC in CHC patients is essential for implementing personalized treatment and surveillance of disease progression and HCC. Recent genome-wide association studies (GWAS) have identified several host genetic variants influencing treatment efficacy or clinical course in HCV infection. This review focuses on these host genetic variations recently identified, mainly by GWAS, which are associated with the clinical course of chronic HCV infection, especially disease progression and hepatocarcinogenesis.
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Affiliation(s)
- Kentaro Matsuura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Rausch V, Mueller S. Suppressed Fat Mobilization Due to PNPLA3 rs738409 -Associated Liver Damage in Heavy Drinkers: The Liver Damage Feedback Hypothesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1032:153-172. [PMID: 30362098 DOI: 10.1007/978-3-319-98788-0_12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PNPLA3 variant rs738409 has been identified as important progression factor in patients with ALD and NAFLD, the most common liver diseases worldwide. These findings point towards similarities between metabolism of alcohol and fat with regard to the PNPLA3 gene. However, despite many efforts, neither the mechanisms of PNPLA3-related liver damage nor the physiological role of PNPLA3 are fully understood. Based on a large monocentric cohort of Caucasian heavy drinkers we could recently provide evidence that PNPLA3 GG primarily correlated with signs of liver damage (steatohepatitis, ballooning) but less with steatosis. Moreover, upon alcohol withdrawal, PNPLA3 GG carriers showed a delayed inflammation-associated resolution of liver stiffness. In line with the histological findings, hepatic fat content as quantified by CAP (controlled attenuation parameter) did not depend on PNPLA3 status and decreased equally in all genotypes by ca. 30 dB/m during alcohol withdrawal. Preliminary additional analysis from this large cohort indicates that PNPLA3 GG carriers (8.2%) drink significantly less high percentage beverages (23% vs 55%, p < 0.001) but show no metabolic phenotype such as increased weight, BMI or diabetes. On the molecular level, key molecules, important for lipolysis and flow of free fatty acids to the liver were drastically reduced in G carriers. These included the liver-synthesized serum ApoA1, the LD-associated protein perilipin5 and the recently identified hepato-protective transcriptional cofactor transducin beta-like-related 1 (TBLR1). Based on these findings, we here introduce the liver damage feedback hypothesis. Accordingly, PNPLA3-mediated liver damage (e.g. by enhanced metabolic activity) suppresses the mobilization of fat towards the liver at various levels (reduced serum lipid flux to the liver and fat mobilization from peripheric adipose tissues, suppressed hepatocyte fat release and avoidance of high percentage alcohol beverages). Finally, the liver damage feedback hypothesis identifies a novel and central role of liver damage on systemic fat homeostasis, which has not been appreciated so far.
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Affiliation(s)
- Vanessa Rausch
- Center for Alcohol Research, University Hospital Heidelberg and Salem Medical Center, Heidelberg, Germany.
| | - Sebastian Mueller
- Department of Internal Medicine, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Heidelberg, Germany
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Interaction and joint effect of ALT and chronic liver disease on liver cancer in type 2 diabetes patients. Oncotarget 2017; 8:103851-103863. [PMID: 29262605 PMCID: PMC5732771 DOI: 10.18632/oncotarget.21804] [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: 04/05/2017] [Accepted: 09/20/2017] [Indexed: 12/02/2022] Open
Abstract
Background This study examined whether serum alanine transaminase (ALT) and chronic liver diseases were interactively, jointly, or independently associated with hepatocellular carcinoma (HCC) risk in type 2 diabetic patients. Materials and Methods A retrospective cohort study was conducted in 46,369 Chinese type 2 diabetic patients, aged 30 and older, in National Diabetes Care Management Program in 2002-2004. These data were analyzed by multivariate Cox proportional hazards models. Results Mean follow-up period was 8.20 years. Multivariate-adjusted hazard ratios of HCC were 2.85 (95% confidence interval, CI: 2.45–3.31), 3.80 (3.04–4.76), and 3.89 (3.08–4.91) for patients with a level of ALT 40–80, 80–120, and >120 U/L, respectively, compared with patients with a level of ALT < 40 U/L after multivariable adjustment. Significant hazard ratios of HCC for patients with a level of ALT ≥ 40 U/L and alcoholic liver damage, nonalcoholic fatty liver disease, liver cirrhosis, hepatitis B virus and hepatitis C virus infection, or any one of these chronic liver diseases compared with patients with ALT level < 40 U/L and no counterpart comorbidity were observed. Significant effect modifications were observed between ALT level with liver cirrhosis and HBV. Conclusions Results suggest significant effect modification and joint associations of ALT ≥ 40 U/L and chronic liver diseases. Diabetes care should provide lifestyle or treatment interventions to manage ALT level, liver cirrhosis and hepatitis B virus infection for reducing burden of HCC.
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Nahon P, Nault JC. Constitutional and functional genetics of human alcohol-related hepatocellular carcinoma. Liver Int 2017; 37:1591-1601. [PMID: 28296015 DOI: 10.1111/liv.13419] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 03/08/2017] [Indexed: 02/13/2023]
Abstract
Exploration of the constitutional genetics of hepatocellular carcinoma (HCC) has identified numerous variants associated with a higher risk of liver cancer in alcoholic cirrhotic patients. Although Genome-Wide Association studies have not been carried out in the field of alcohol-related HCC, common single nucleotide polymorphisms conferring a small increase in the risk of liver cancer risk have been identified and shown to modulate ethanol metabolism, inflammation, oxidative stress, iron or lipid metabolism. Specific patterns of gene mutations including CTNNB1, TERT, ARID1A and SMARCA2 exist in alcohol-related HCC. Moreover, a specific mutational process observed at the nucleotide level by next generation sequencing has revealed cooperation between alcohol and tobacco in the development of HCC. Combining this genetic information with epidemiological and clinical data that might define specific HCC risk classes and refine surveillance strategies needs to be assessed in large prospective cohorts of patients with alcoholic cirrhosis.
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Affiliation(s)
- Pierre Nahon
- AP-HP, Hôpital Jean Verdier, Service d'Hépatologie, Bondy, France.,Université Paris 13, Bobigny, France.,Inserm UMR-1162, "Functional Genetics of Solid Tumours", Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Oncoimmunology, Equipe labellisée Ligue contre le Cancer, Paris, France
| | - Jean-Charles Nault
- AP-HP, Hôpital Jean Verdier, Service d'Hépatologie, Bondy, France.,Université Paris 13, Bobigny, France.,Inserm UMR-1162, "Functional Genetics of Solid Tumours", Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Oncoimmunology, Equipe labellisée Ligue contre le Cancer, Paris, France
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Mehta N, Dodge JL, Roberts JP, Hirose R, Yao FY. Misdiagnosis of hepatocellular carcinoma in patients receiving no local-regional therapy prior to liver transplant: An analysis of the Organ Procurement and Transplantation Network explant pathology form. Clin Transplant 2017; 31. [PMID: 28881064 DOI: 10.1111/ctr.13107] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2017] [Indexed: 12/13/2022]
Abstract
Patients with T1 hepatocellular carcinoma (HCC) are not eligible for Model for End Stage Liver Disease (MELD) exception for liver transplant (LT) in part due to a high rate of misdiagnosis (no HCC on explant). The likelihood of misdiagnosis for T2 HCC and factors associated with misdiagnosis are unknown. We analyzed the Organ Procurement and Transplantation Network database including 5664 adults who underwent LT from 2012 to 2015 with MELD exception for T2 HCC, and searched for no evidence of HCC in the explant pathology file. We focused on those (n = 324) receiving no local-regional therapy (LRT) to evaluate the probability of no HCC found in explant. Median waiting time was short at 1.7 months, and 35 (11%) had no HCC on explant. On multivariable logistic regression, factors associated with no HCC on explant were age <50 (OR: 17.3, P < .001), non-HCV (OR: 5.4, P = .001), and alpha-fetoprotein <10 (OR: 2.9, P = .04). Tumor size and number were not different between groups. The proportion of misdiagnosis did not change significantly after implementation of Liver Imaging Reporting and Data System (LI-RADS) for HCC diagnosis. CONCLUSION The rate of misdiagnosis was 11% among T2 HCC patients who underwent LT without receiving LRT prior to LT and did not change significantly after implementation of LI-RADS. More efforts are needed to eliminate unnecessary LT for patients without HCC.
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Affiliation(s)
- Neil Mehta
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA, USA
| | - Jennifer L Dodge
- Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, CA, USA
| | - John P Roberts
- Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, CA, USA
| | - Ryutaro Hirose
- Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, CA, USA
| | - Francis Y Yao
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA, USA.,Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, CA, USA
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45
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Seko Y, Sumida Y, Tanaka S, Mori K, Taketani H, Ishiba H, Hara T, Okajima A, Umemura A, Nishikawa T, Yamaguchi K, Moriguchi M, Kanemasa K, Yasui K, Imai S, Shimada K, Itoh Y. Development of hepatocellular carcinoma in Japanese patients with biopsy-proven non-alcoholic fatty liver disease: Association between PNPLA3 genotype and hepatocarcinogenesis/fibrosis progression. Hepatol Res 2017; 47:1083-1092. [PMID: 27862719 DOI: 10.1111/hepr.12840] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 10/30/2016] [Accepted: 11/07/2016] [Indexed: 12/13/2022]
Abstract
AIM Some patients with non-alcoholic fatty liver disease (NAFLD) develop hepatocellular carcinoma (HCC). Patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 (encoding the I148M variant) has been associated with advanced fibrosis and HCC. We determined the risk factors for HCC, including the PNPLA3 rs738409 polymorphism, in Japanese patients with biopsy-proven NAFLD. METHODS In this retrospective cohort study, we analyzed hepatocarcinogenesis in 238 patients. PNPLA3 rs738409 genotype was determined by allelic discrimination in 130 patients. Among them, 86 patients who were followed up for >5 years and without liver cirrhosis were analyzed to clarify the relationship between PNPLA3 genotype and long-term changes in biomarkers. RESULTS Of 238 patients, PNPLA3 genotype frequencies were: CC, 0.14; CG, 0.46; and GG, 0.40. During a follow-up period of 6.1 years, 10 patients (4.2%) with non-alcoholic steatohepatitis developed HCC. The cumulative rate of HCC was 1.9% at the end of the 5th year and 8.3% at the end of the 10th year. Multivariate analysis identified PNPLA3 genotype GG (hazard ratio, 6.36; P = 0.019) and fibrosis stage (fibrosis stage 3/4; hazard ratio, 24.4; P = 0.011) as predictors of HCC development. In the long follow-up cohort, a larger reduction in platelet count was found in the GG group (P = 0.032) despite a larger reduction in alanine aminotransferase (P = 0.023) compared to that in the CC/CG group. CONCLUSIONS In Japanese patients with NAFLD, severe fibrosis and PNPLA3 GG genotype were predictors of HCC development, independent of other known risk factors. Patients with the PNPLA3 GG genotype have the potential for a decreased platelet count, even when alanine aminotransferase levels are well controlled.
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Affiliation(s)
- Yuya Seko
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto
| | - Yoshio Sumida
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto
| | - Saiyu Tanaka
- Center for Digestive and Liver Diseases, Nara City Hospital, Nara
| | - Kojiroh Mori
- Center for Digestive and Liver Diseases, Nara City Hospital, Nara
| | - Hiroyoshi Taketani
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto
| | - Hiroshi Ishiba
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto
| | - Tasuku Hara
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto
| | - Akira Okajima
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto
| | - Atsushi Umemura
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto
| | - Taichiro Nishikawa
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto
| | - Kanji Yamaguchi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto
| | - Michihisa Moriguchi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto
| | | | - Kohichiroh Yasui
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto
| | - Shunsuke Imai
- Department of Pathology, Nara City Hospital, Nara, Japan
| | - Keiji Shimada
- Department of Pathology, Nara City Hospital, Nara, Japan
| | - Yoshito Itoh
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto
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Ramadori P, Cubero FJ, Liedtke C, Trautwein C, Nevzorova YA. Alcohol and Hepatocellular Carcinoma: Adding Fuel to the Flame. Cancers (Basel) 2017; 9:cancers9100130. [PMID: 28946672 PMCID: PMC5664069 DOI: 10.3390/cancers9100130] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 09/15/2017] [Accepted: 09/19/2017] [Indexed: 02/06/2023] Open
Abstract
Primary tumors of the liver represent the fifth most common type of cancer in the world and the third leading cause of cancer-related death. Case-control studies from different countries report that chronic ethanol consumption is associated with an approximately 2-fold increased odds ratio for hepatocellular carcinoma (HCC). Despite the substantial epidemiologic data in humans demonstrating that chronic alcohol consumption is a major risk factor for HCC development, the pathways causing alcohol-induced liver cancer are poorly understood. In this overview, we summarize the epidemiological evidence for the association between alcohol and liver cancer, review the genetic, oncogenic, and epigenetic factors that drive HCC development synergistically with ethanol intake and discuss the essential molecular and metabolic pathways involved in alcohol-induced liver tumorigenesis.
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Affiliation(s)
- Pierluigi Ramadori
- Department of Internal Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany.
| | - Francisco Javier Cubero
- Department of Immunology, Complutense University School of Medicine, Madrid 28040, Spain.
- 13 de Octubre Health Research Institute (imas12), Madrid 28041, Spain.
| | - Christian Liedtke
- Department of Internal Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany.
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany.
| | - Yulia A Nevzorova
- Department of Internal Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany.
- Department of Animal Physiology II, Faculty of Biology, Complutense University, Madrid 28040, Spain.
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47
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Atkinson SR, Way MJ, McQuillin A, Morgan MY, Thursz MR. Homozygosity for rs738409:G in PNPLA3 is associated with increased mortality following an episode of severe alcoholic hepatitis. J Hepatol 2017; 67:120-127. [PMID: 28161471 DOI: 10.1016/j.jhep.2017.01.018] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 01/11/2017] [Accepted: 01/13/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Carriage of rs738409:G in PNPLA3 is associated with an increased risk of developing alcohol-related cirrhosis and has a significant negative effect on survival. Short-term mortality in patients with severe alcoholic hepatitis is high; drinking behaviour is a major determinant of outcome in survivors. The aim of this study was to determine whether carriage of rs738409:G has an additional detrimental effect on survival in this patient group. METHODS Genotyping was undertaken in 898 cases with severe alcoholic hepatitis, recruited through the UK Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial, and 1188 White British/Irish alcohol dependent controls with no liver injury, recruited via University College London. Subsequent drinking behaviour was classified, in cases surviving ≥90days, as abstinent or drinking. The relationship between rs738409 genotype, drinking behaviour and survival was explored. RESULTS The frequency of rs738409:G was significantly higher in cases than controls (29.5% vs. 18.9%; p=2.15×10-15; odds ratio 1.80 [95% confidence interval (CI) 1.55-2.08]). Case-mortality at days 28, 90 and 450 was 16%, 25% and 41% respectively. There was no association between rs738409:G and 28-day mortality. Mortality in the 90 to 450-day period was higher in survivors who subsequently resumed drinking (hazard ratio [HR] 2.77, 95% CI 1.79-4.29; p<0.0001) and in individuals homozygous for rs738409:G (HR 1.69, 95% CI 1.02-2.81, p=0.04). CONCLUSION Homozygosity for rs738409:G in PNPLA3 confers significant additional risk of medium-term mortality in patients with severe alcoholic hepatitis. Rs738409 genotype may be taken into account when considering treatment options for these patients. LAY SUMMARY Individuals misusing alcohol who carry a particular variant of the gene PNPLA3 are more at risk of developing severe alcoholic hepatitis, a condition with a poor chance of survival. The longer-term outcome in people with this condition who survive the initial illness is strongly influenced by their ability to remain abstinent from alcohol. However, carriers of this gene variant are less likely to survive even if they are able to stop drinking completely. Knowing if someone carries this gene variant could influence the way in which they are managed. Clinical trial numbers: EudraCT reference number: 2009-013897-42; ISRCTN reference number: ISRCTN88782125. CLINICAL TRIAL NUMBERS EudraCT reference number: 2009-013897-42; ISRCTN reference number: ISRCTN88782125.
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Affiliation(s)
- Stephen R Atkinson
- Department of Hepatology, Division of Surgery and Cancer, Imperial College London, UK.
| | - Michael J Way
- UCL Institute for Liver and Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK; Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK
| | - Andrew McQuillin
- Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK
| | - Marsha Y Morgan
- UCL Institute for Liver and Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Mark R Thursz
- Department of Hepatology, Division of Surgery and Cancer, Imperial College London, UK
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Goossens N, Bian CB, Hoshida Y. Tailored algorithms for hepatocellular carcinoma surveillance: Is one-size-fits-all strategy outdated? CURRENT HEPATOLOGY REPORTS 2017; 16:64-71. [PMID: 28337405 PMCID: PMC5358664 DOI: 10.1007/s11901-017-0336-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
PURPOSE OF REVIEW Current clinical practice guidelines recommend regular hepatocellular carcinoma (HCC) surveillance with biannual ultrasound with or without serum alpha-fetoprotein uniformly applied to all patients with cirrhosis. However, clinical implementation of this one-size-fits-all strategy has been challenging as evidenced by very low application rate below 20% due to various reasons, including suboptimal performance of the surveillance modalities. RECENT FINDINGS Newly emerging imaging techniques such as abbreviated MRI (AMRI) and molecular HCC risk biomarkers have increasingly become available for clinical evaluation and implementation. These technologies may have a potential to reshape HCC surveillance by enabling tailored strategies. This would involve performing optimized surveillance tests according to individual HCC risk, and allocating limited medical resources for HCC surveillance based on cost-effectiveness. SUMMARY Tailored HCC surveillance could lead to achievement of precision HCC care and substantial improvement of the current dismal patient prognosis.
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Affiliation(s)
- Nicolas Goossens
- Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
- Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland
| | - C. Billie Bian
- Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Yujin Hoshida
- Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
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Huang CF, Huang CY, Yeh ML, Wang SC, Chen KY, Ko YM, Lin CC, Tsai YS, Tsai PC, Lin ZY, Chen SC, Dai CY, Huang JF, Chuang WL, Yu ML. Genetics Variants and Serum Levels of MHC Class I Chain-related A in Predicting Hepatocellular Carcinoma Development in Chronic Hepatitis C Patients Post Antiviral Treatment. EBioMedicine 2017; 15:81-89. [PMID: 27998720 PMCID: PMC5233818 DOI: 10.1016/j.ebiom.2016.11.031] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 11/25/2016] [Accepted: 11/28/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND/AIMS The genome-wide association study has shown that MHC class I chain-related A (MICA) genetic variants were associated with hepatitis C virus (HCV) related hepatocellular carcinoma (HCC). The impact of the genetic variants and its serum levels on post-treatment cohort is elusive [corrected]. METHODS MICA rs2596542 genotype and serum MICA (sMICA) levels were evaluated in 705 patients receiving antiviral therapy. RESULTS Fifty-eight (8·2%) patients developed HCC, with a median follow-up period of 48·2 months (range: 6–129 months). The MICA A allele was associated with a significantly increased risk of HCC development in cirrhotic non-SVR patients but not in patients of non-cirrhotic and/or with SVR. For cirrhotic non-SVR patients, high sMICA levels (HR/CI: 5·93/1·86–26·38, P = 0·002) [corrected] and the MICA rs2596542 A allele (HR/CI: 4·37/1·52–12·07, P = 0·002) were independently associated with HCC development. The risk A allele or GG genotype with sMICA > 175 ng/mL provided the best accuracy (79%) and a negative predictive value of 100% in predicting HCC. CONCLUSIONS Cirrhotic patients who carry MICA risk alleles and those without risk alleles but with high sMICA levels possessed the highest risk of HCC development once they failed antiviral therapy.
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Affiliation(s)
- Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine,College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Occupational Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Cing-Yi Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine,College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shu-Chi Wang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Kuan-Yu Chen
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yu-Min Ko
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-Chih Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Shan Tsai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Pei-Chien Tsai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine,College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shinn-Cherng Chen
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine,College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine,College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Occupational Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine,College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine,College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine,College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-Sen University, Taiwan; Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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Nonalcoholic fatty liver disease in Asia: emerging perspectives. J Gastroenterol 2017; 52:164-174. [PMID: 27637587 DOI: 10.1007/s00535-016-1264-3] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 09/06/2016] [Indexed: 02/07/2023]
Abstract
As in the West, nonalcoholic fatty liver disease (NAFLD) is the commonest chronic liver disease in Asia, with a prevalence higher than 40 % in some countries. The risk factors for NAFLD development are similar to those in Western countries, including increased body mass index, diabetes, insulin resistance, and metabolic syndrome. NAFLD in Asians is associated with different extrahepatic manifestations involving the cardiovascular, gastrointestinal, and renal systems. A considerable proportion of Asians with NAFLD are described as having "lean" NAFLD. Present in approximately 20 % of the Asian population, lean NAFLD is closely linked with insulin resistance, diabetes, and other metabolic complications, but its association with disease progression to nonalcoholic steatohepatitis and cirrhosis remains to be defined. There is emerging evidence of the interactions of NAFLD with hepatitis B virus and hepatitis C virus infection in Asia. Unlike in Western countries, NAFLD constitutes only a minority of cirrhosis and hepatocellular carcinoma cases in Asia. Possible explanations are the lower prevalence of obesity and the overwhelming problem of viral hepatitis in Asia. With aging of the obesity cohort in Asia, NAFLD-related liver complications are expected to increase.
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