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Buchynskyi M, Oksenych V, Kamyshna I, Vari SG, Kamyshnyi A. Genetic Predictors of Comorbid Course of COVID-19 and MAFLD: A Comprehensive Analysis. Viruses 2023; 15:1724. [PMID: 37632067 PMCID: PMC10459448 DOI: 10.3390/v15081724] [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: 07/06/2023] [Revised: 07/26/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) and its potential impact on the severity of COVID-19 have gained significant attention during the pandemic. This review aimed to explore the genetic determinants associated with MAFLD, previously recognized as non-alcoholic fatty liver disease (NAFLD), and their potential influence on COVID-19 outcomes. Various genetic polymorphisms, including PNPLA3 (rs738409), GCKR (rs780094), TM6SF2 (rs58542926), and LYPLAL1 (rs12137855), have been investigated in relation to MAFLD susceptibility and progression. Genome-wide association studies and meta-analyses have revealed associations between these genetic variants and MAFLD risk, as well as their effects on lipid metabolism, glucose regulation, and liver function. Furthermore, emerging evidence suggests a possible connection between these MAFLD-associated polymorphisms and the severity of COVID-19. Studies exploring the association between indicated genetic variants and COVID-19 outcomes have shown conflicting results. Some studies observed a potential protective effect of certain variants against severe COVID-19, while others reported no significant associations. This review highlights the importance of understanding the genetic determinants of MAFLD and its potential implications for COVID-19 outcomes. Further research is needed to elucidate the precise mechanisms linking these genetic variants to disease severity and to develop gene profiling tools for the early prediction of COVID-19 outcomes. If confirmed as determinants of disease severity, these genetic polymorphisms could aid in the identification of high-risk individuals and in improving the management of COVID-19.
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Affiliation(s)
- Mykhailo Buchynskyi
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, 46001 Ternopil, Ukraine
| | - Valentyn Oksenych
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway
| | - Iryna Kamyshna
- Department of Medical Rehabilitation, I. Horbachevsky Ternopil National Medical University, 46001 Ternopil, Ukraine
| | - Sandor G. Vari
- International Research and Innovation in Medicine Program, Cedars–Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Aleksandr Kamyshnyi
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, 46001 Ternopil, Ukraine
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Sohal A, Chaudhry H, Kowdley KV. Genetic Markers Predisposing to Nonalcoholic Steatohepatitis. Clin Liver Dis 2023; 27:333-352. [PMID: 37024211 DOI: 10.1016/j.cld.2023.01.006] [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: 04/08/2023]
Abstract
The growing prevalence of nonalcoholic fatty liver disease (NAFLD) has sparked interest in understanding genetics and epigenetics associated with the development and progression of the disease. A better understanding of the genetic factors related to progression will be beneficial in the risk stratification of patients. These genetic markers can also serve as potential therapeutic targets in the future. In this review, we focus on the genetic markers associated with the progression and severity of NAFLD.
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Affiliation(s)
- Aalam Sohal
- Liver Institute Northwest, 3216 Northeast 45th Place Suite 212, Seattle, WA 98105, USA
| | - Hunza Chaudhry
- Department of Internal Medicine, UCSF Fresno, 155 North Fresno Street, Fresno, CA 93722, USA
| | - Kris V Kowdley
- Liver Institute Northwest, 3216 Northeast 45th Place Suite 212, Seattle, WA 98105, USA; Elson S. Floyd College of Medicine, Washington State University, WA, USA.
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Sulaiman SA, Dorairaj V, Adrus MNH. Genetic Polymorphisms and Diversity in Nonalcoholic Fatty Liver Disease (NAFLD): A Mini Review. Biomedicines 2022; 11:106. [PMID: 36672614 PMCID: PMC9855725 DOI: 10.3390/biomedicines11010106] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 12/13/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common liver disease with a wide spectrum of liver conditions ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The prevalence of NAFLD varies across populations, and different ethnicities have specific risks for the disease. NAFLD is a multi-factorial disease where the genetics, metabolic, and environmental factors interplay and modulate the disease's development and progression. Several genetic polymorphisms have been identified and are associated with the disease risk. This mini-review discussed the NAFLD's genetic polymorphisms and focusing on the differences in the findings between the populations (diversity), including of those reports that did not show any significant association. The challenges of genetic diversity are also summarized. Understanding the genetic contribution of NAFLD will allow for better diagnosis and management explicitly tailored for the various populations.
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Affiliation(s)
- Siti Aishah Sulaiman
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Jalan Yaa’cob Latiff, Cheras, Kuala Lumpur 56000, Malaysia; (V.D.); (M.N.H.A.)
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Holmer M, Ekstedt M, Nasr P, Zenlander R, Wester A, Tavaglione F, Romeo S, Kechagias S, Stål P, Hagström H. Effect of common genetic variants on the risk of cirrhosis in non-alcoholic fatty liver disease during 20 years of follow-up. Liver Int 2022; 42:2769-2780. [PMID: 36166317 PMCID: PMC9828463 DOI: 10.1111/liv.15438] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 09/11/2022] [Accepted: 09/25/2022] [Indexed: 01/20/2023]
Abstract
BACKGROUND AND AIMS Several genotypes associate with a worse histopathological profile in patients with non-alcoholic fatty liver disease (NAFLD). Whether genotypes impact long-term outcomes is unclear. We investigated the importance of PNPLA3, TM6SF2, MBOAT7 and GCKR genotype for the development of severe outcomes in NAFLD. METHOD DNA samples were collected from 546 patients with NAFLD. Advanced fibrosis was diagnosed by liver biopsy or elastography. Non-alcoholic steatohepatitis (NASH) was histologically defined. Additionally, 5396 controls matched for age, sex and municipality were identified from population-based registers. Events of severe liver disease and all-cause mortality were collected from national registries. Hazard ratios (HRs) adjusted for age, sex, body mass index and type 2 diabetes were estimated with Cox regression. RESULTS In NAFLD, the G/G genotype of PNPLA3 was associated with a higher prevalence of NASH at baseline (odds ratio [OR] 3.67, 95% CI = 1.66-8.08), but not with advanced fibrosis (OR 1.81, 95% CI = 0.79-4.14). After up to 40 years of follow-up, the PNPLA3 G/G genotype was associated with a higher rate of severe liver disease (adjusted hazard ratio [aHR] 2.27, 95% CI = 1.15-4.47) compared with the C/C variant. NAFLD patients developed cirrhosis at a higher rate than controls (aHR 9.00, 95% CI = 6.85-11.83). The PNPLA3 G/G genotype accentuated this rate (aHR 23.32, 95% = CI 9.14-59.47). Overall mortality was not affected by any genetic variant. CONCLUSION The PNPLA3 G/G genotype is associated with an increased rate of cirrhosis in NAFLD. Our results suggest that assessment of the PNPLA3 genotype is of clinical relevance in patients with NAFLD to individualize monitoring and therapeutic strategies.
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Affiliation(s)
- Magnus Holmer
- Division of Liver and Pancreatic disease, Department of Upper GIKarolinska University HospitalStockholmSweden,Department of Medicine, HuddingeKarolinska InstitutetStockholmSweden
| | - Mattias Ekstedt
- Department of Gastroenterology and Hepatology, Department of Health, Medicine, and Caring SciencesLinköping UniversityLinköpingSweden
| | - Patrik Nasr
- Department of Medicine, HuddingeKarolinska InstitutetStockholmSweden,Department of Gastroenterology and Hepatology, Department of Health, Medicine, and Caring SciencesLinköping UniversityLinköpingSweden
| | - Robin Zenlander
- Department of Medicine, HuddingeKarolinska InstitutetStockholmSweden
| | - Axel Wester
- Department of Medicine, HuddingeKarolinska InstitutetStockholmSweden
| | - Federica Tavaglione
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg LaboratoryUniversity of GothenburgGothenburgSweden
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg LaboratoryUniversity of GothenburgGothenburgSweden,Department of CardiologySahlgrenska University HospitalGothenburgSweden
| | - Stergios Kechagias
- Department of Gastroenterology and Hepatology, Department of Health, Medicine, and Caring SciencesLinköping UniversityLinköpingSweden
| | - Per Stål
- Division of Liver and Pancreatic disease, Department of Upper GIKarolinska University HospitalStockholmSweden,Department of Medicine, HuddingeKarolinska InstitutetStockholmSweden
| | - Hannes Hagström
- Division of Liver and Pancreatic disease, Department of Upper GIKarolinska University HospitalStockholmSweden,Department of Medicine, HuddingeKarolinska InstitutetStockholmSweden,Clinical Epidemiology Unit, Department of Medicine, SolnaKarolinska InstitutetStockholmSweden
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The additive effect of genetic and metabolic factors in the pathogenesis of nonalcoholic fatty liver disease. Sci Rep 2022; 12:17608. [PMID: 36266438 PMCID: PMC9584936 DOI: 10.1038/s41598-022-22729-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 10/18/2022] [Indexed: 01/13/2023] Open
Abstract
Both genetic and metabolic factors influence the pathology of nonalcoholic fatty liver disease (NAFLD). The aim of this retrospective study was to evaluate the impact of these factors at each stage of disease. We analysed the impact of obesity, diabetes mellitus and genetic risk factors (alleles of PNPLA3 or HSD17B13) on nonalcoholic steatohepatitis (NASH), significant fibrosis (stage ≥ 2) and advanced fibrosis (stage ≥ 3) in 346 patients. Genetic high risk was defined as having at least 2 risk alleles. The median age was 59 years, median body mass index was 27.1 kg/m2, and 46.8% had diabetes mellitus. Obesity was a risk factor for NASH, significant fibrosis, and advanced fibrosis. Diabetes mellitus increased the risk of NASH. Genetic risk increased the risk of significant and advanced fibrosis. Odds ratios for NASH, significant fibrosis and advanced fibrosis increased with the number of genetic and metabolic risk factors. The patients with both metabolic and genetic risks had an odds ratio of 12.30 for NASH, 5.50 for significant fibrosis, and 6.25 for advanced fibrosis. Factors strongly impact on the pathology of NAFLD differed according to the fibrosis stages. Synergistic effects were observed between genetic and metabolic factors at all stages.
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Kawaguchi T, Tsutsumi T, Nakano D, Torimura T. MAFLD: Renovation of clinical practice and disease awareness of fatty liver. Hepatol Res 2022; 52:422-432. [PMID: 34472683 DOI: 10.1111/hepr.13706] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/15/2021] [Accepted: 08/17/2021] [Indexed: 12/11/2022]
Abstract
Recently, international expert panels have proposed a new definition of fatty liver: metabolic dysfunction-associated fatty liver disease (MAFLD). MAFLD is not just a simple renaming of non-alcoholic fatty liver disease (NAFLD). The unique feature of MAFLD is the inclusion of metabolic dysfunctions, which are high-risk factors for events. In addition, MAFLD is independent of alcohol intake and the co-existing causes of liver disease. This new concept of MAFLD may have a widespread impact on patients, medical doctors, medical staff, and various stakeholders regarding fatty liver. Thus, MAFLD may renovate clinical practice and disease awareness of fatty liver. In this review, we introduce the definition of and rationale for MAFLD. We further describe representative cases showing how the diagnostic processes differ between MAFLD and NAFLD. We also summarize recent studies comparing MAFLD with NAFLD and discuss the impact of MAFLD on clinical trials, Japanese populations, and disease awareness.
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Affiliation(s)
- Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Tsubasa Tsutsumi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Dan Nakano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
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Luo F, Oldoni F, Das A. TM6SF2: A Novel Genetic Player in Nonalcoholic Fatty Liver and Cardiovascular Disease. Hepatol Commun 2022; 6:448-460. [PMID: 34532996 PMCID: PMC8870032 DOI: 10.1002/hep4.1822] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 08/13/2021] [Accepted: 08/25/2021] [Indexed: 12/11/2022] Open
Abstract
Transmembrane 6 superfamily member 2 (TM6SF2) is located on chromosome 19 (19p12) and encodes for a protein of undetermined function. Genetic studies have reported the association between a nonsynonymous variant in TM6SF2 (E167K, rs58542926) with hepatic triglyceride content and its impact on the cardiovascular system. Clinical and epidemiological studies have confirmed the role of TM6SF2 in the development of nonalcoholic fatty liver disease (NAFLD). Recently, TM6SF2 was also shown to play an important role in promoting hepatic fibrosis and hepatocellular cancer in mouse models. This review aims to capture the physiological role of TM6SF2 in the regulation of lipid metabolism and its involvement in cardiometabolic diseases.
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Affiliation(s)
- Fei Luo
- Department of Cardiovascular MedicineThe Second Xiangya Hospital of Central South UniversityChangshaChina
- Department of Molecular GeneticsUniversity of Texas Southwestern Medical CenterDallasTXUSA
| | - Federico Oldoni
- Department of Molecular GeneticsUniversity of Texas Southwestern Medical CenterDallasTXUSA
| | - Avash Das
- Department of Molecular GeneticsUniversity of Texas Southwestern Medical CenterDallasTXUSA
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Xue WY, Zhang L, Liu CM, Gao Y, Li SJ, Huai ZY, Dai J, Wang YY. Research progress on the relationship between TM6SF2 rs58542926 polymorphism and non-alcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2022; 16:97-107. [PMID: 35057689 DOI: 10.1080/17474124.2022.2032661] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION nonalcoholic fatty liver disease is a common liver disease with a global average prevalence of about 25%. In addition to the incidence of NAFLD being related to obesity, diabetes, hyperlipidemia, etc., genetic factors also have an important impact on the incidence of NAFLD. AREAS COVERED Current experimental results and clinical studies show that the transmembrane 6 superfamily member 2 (TM6SF2) gene plays an important role in the pathogenesis of NAFLD. The research on genetic polymorphism of TM6SF2 gene mainly focuses on rs58542926 locus (rs58542926 c.449 C > T, p. Glu167Lys, E167K). The Mutations of this site might increase the risk of NAFLD in carriers. EXPERT OPINION The mutation of this site causes the disorder of triglyceride metabolism in the liver, which leads to the deposition of a large amount of lipids in the liver, and further induces the incidence of NAFLD. With the study of the mechanism of TM6SF2 gene polymorphism in the pathogenesis of NAFLD, it is helpful to understand the molecular mechanism of the pathogenesis of NAFLD, which has a great value for the treatment of NAFLD.
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Affiliation(s)
- Wan-Ying Xue
- School of Life Sciences, Bengbu Medical College, Bengbu, Anhui, China
| | - Li Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Chuan-Miao Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Yu Gao
- School of Life Sciences, Bengbu Medical College, Bengbu, Anhui, China
| | - Shu-Jing Li
- School of Life Sciences, Bengbu Medical College, Bengbu, Anhui, China
| | - Zi-You Huai
- School of Life Sciences, Bengbu Medical College, Bengbu, Anhui, China
| | - Jing Dai
- School of Life Sciences, Bengbu Medical College, Bengbu, Anhui, China
| | - Yuan-Yuan Wang
- School of Life Sciences, Bengbu Medical College, Bengbu, Anhui, China
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Li XY, Liu Z, Li L, Wang HJ, Wang H. TM6SF2 rs58542926 is related to hepatic steatosis, fibrosis and serum lipids both in adults and children: A meta-analysis. Front Endocrinol (Lausanne) 2022; 13:1026901. [PMID: 36353245 PMCID: PMC9637980 DOI: 10.3389/fendo.2022.1026901] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 10/12/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND AND AIMS Findings about the associations between transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 and nonalcoholic fatty liver disease have not been consistently replicated, particularly in steatosis and fibrosis. The present study aimed to investigate the associations between the rs58542926T allele and the spectrum of NAFLD and its related metabolic phenotypes. METHODS Systematic literature research was performed to analyse the associations between rs58542926 and the spectrum of NAFLD and its related metabolic phenotypes. A random effects meta-analysis with a dominant genetic model was applied. RESULTS Data from 123,800 individuals across 44 studies were included in the current meta-analysis.rs58542926 T allele was associated with an increased risk of NAFLD in both adults (OR=1.62; 95% CI: 1.40, 1.86) and children (OR=2.87; 95% CI: 1.85, 4.46). Children had a stronger association with NAFLD (P=0.01). rs58542926 T allele was also positively associated with steatosis progression (mean difference=0.22; 95% CI: 0.05, 0.39) and fibrosis stage (OR=1.50; 95% CI: 1.20, 1.88) in adults. The TM6SF2 rs58542926 T allele was positively associated with ALT in both adults and children (both P<0.01) and only with higher AST in adults (P<0.01). The rs58542926 T allele was negatively associated with serum total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides (TGs) in both adults and children (all P<0.01).The serum level of TG was much lower in adults than in children (P<0.01). CONCLUSION TM6SF2 rs58542926 is involved in the entire spectrum of NAFLD and its related metabolic phenotype, and differences in serum lipid levels were observed between adults and children. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021288163.
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Affiliation(s)
- Xue-Ying Li
- Department of Maternal and Child Health, School of Public Health, Peking University, Beijing, China
| | - Zheng Liu
- Department of Maternal and Child Health, School of Public Health, Peking University, Beijing, China
| | - Li Li
- Department of Endocrinology and Metabolism, Ningbo First Hospital, Ningbo, China
| | - Hai-Jun Wang
- Department of Maternal and Child Health, School of Public Health, Peking University, Beijing, China
| | - Hui Wang
- Department of Maternal and Child Health, School of Public Health, Peking University, Beijing, China
- *Correspondence: Hui Wang,
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Okanoue T, Sakamoto M, Harada K, Inagaki M, Totsuka N, Hashimoto G, Kumada H. Efficacy and safety of apararenone (MT-3995) in patients with nonalcoholic steatohepatitis: A randomized controlled study. Hepatol Res 2021; 51:943-956. [PMID: 34260795 DOI: 10.1111/hepr.13695] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/24/2021] [Accepted: 07/01/2021] [Indexed: 12/30/2022]
Abstract
AIM To evaluate the efficacy, safety, and tolerability of apararenone 10 mg/day in patients with nonalcoholic steatohepatitis (NASH). METHODS In this multicenter, randomized, double-blind, placebo-controlled phase II study, patients received apararenone 10 mg or placebo once daily for 72 weeks. The primary efficacy end-point was percent change in serum alanine aminotransferase (ALT) from baseline to 24 weeks after randomization. Secondary efficacy end-points included changes in liver fibrosis markers. Adverse drug reactions (ADRs) and serum potassium levels were evaluated. RESULTS Forty-eight patients were randomly assigned to treatment (placebo, 23; apararenone, 25). The percent change in ALT at 24 weeks was -3.0% and -13.7% with placebo and apararenone, respectively (p = 0.308). The apararenone group showed greater reductions from baseline in fibrosis markers (type IV collagen 7S and procollagen-3 N-terminal peptide) and noninvasive tests of fibrosis (enhanced liver fibrosis score and Fibrosis-4 index) at all time points versus placebo. The percentage of patients with improvement of 1 point or more in fibrosis stage/without nonalcoholic fatty liver disease activity score worsening was 41.7% with apararenone and 26.1% with placebo (p = 0.203). Adverse drug reactions were reported in three (13.0%) and three (12.5%) patients in the placebo and apararenone groups, respectively. Serum potassium levels increased in the apararenone group during the study and decreased to near baseline after the end of treatment. CONCLUSIONS In patients with NASH, apararenone 10 mg/day for 72 weeks was effective in decreasing ALT levels, improved multiple potential fibrosis markers, and was safe and well tolerated. Pathological findings showed anti-inflammatory and antifibrotic effects of apararenone.
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Affiliation(s)
- Takeshi Okanoue
- Department of Gastroenterology, Saiseikai Suita Hospital, Osaka, Japan
| | - Michiie Sakamoto
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Masaya Inagaki
- Data Science Department, Ikuyaku, Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Naoko Totsuka
- Clinical Research and Development II Department, Ikuyaku, Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Gaia Hashimoto
- Clinical Research and Development II Department, Ikuyaku, Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
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Akkiz H, Taskin E, Karaogullarindan U, Delik A, Kuran S, Kutlu O. The influence of RS738409 I148M polymorphism of patatin-like phospholipase domain containing 3 gene on the susceptibility of non-alcoholic fatty liver disease. Medicine (Baltimore) 2021; 100:e25893. [PMID: 34106646 PMCID: PMC8133255 DOI: 10.1097/md.0000000000025893] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 04/21/2021] [Indexed: 01/14/2023] Open
Abstract
We aimed to elucidate the frequency of polymorphic genotypes and alleles of patatin-like phospholipase domain containing 3 rs738409 polymorphism and its possible associations with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis in a cohort from Turkey.We enrolled 200 patients diagnosed with NAFLD and genotyped for rs738409 I148M polymorphism by real-time polymerase chain reaction, particularly by melting curve analysis. SPSS analysis software was used for statistical significance. Continuous variable values were expressed as mean ± standard deviation. Significant statistical level was chosen as p = 0.05.Our results demonstrate in a cohort from Turkey that rs738409 C > G polymorphism (I148M) of patatin-like phospholipase domain containing 3 gene is significantly able to affect individuals to have NAFLD in unadjusted regression model.Consistent with the previous studies in other populations, our study group showed a significantly higher risk of having NAFLD in unadjusted regression model but not in the adjusted model indicating that non-genetic factors such as age and sex may be responsible for the association. However, independent studies need to validate our findings with a larger group of NAFLD patients, as well as in different ethnic cohorts.
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Affiliation(s)
- Hikmet Akkiz
- Cukurova University, Medical Faculty, Department of Gastroenterology, Adana
| | - Emre Taskin
- Karabuk University, Medical Faculty, Department of Medical Biology and Genetics, Karabuk
| | | | - Anil Delik
- Cukurova University, Faculty of Natural and Applied Science, Department of Biology, Adana
| | - Sedef Kuran
- Cukurova University, Medical Faculty, Department of Gastroenterology, Adana
| | - Ozlem Kutlu
- Sabanci University Nanotechnology Research and Application Center, Istanbul, Turkey
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Campos-Murguía A, Ruiz-Margáin A, González-Regueiro JA, Macías-Rodríguez RU. Clinical assessment and management of liver fibrosis in non-alcoholic fatty liver disease. World J Gastroenterol 2020; 26:5919-5943. [PMID: 33132645 PMCID: PMC7584064 DOI: 10.3748/wjg.v26.i39.5919] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 05/24/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is among the most frequent etiologies of cirrhosis worldwide, and it is associated with features of metabolic syndrome; the key factor influencing its prognosis is the progression of liver fibrosis. This review aimed to propose a practical and stepwise approach to the evaluation and management of liver fibrosis in patients with NAFLD, analyzing the currently available literature. In the assessment of NAFLD patients, it is important to identify clinical, genetic, and environmental determinants of fibrosis development and its progression. To properly detect fibrosis, it is important to take into account the available methods and their supporting scientific evidence to guide the approach and the sequential selection of the best available biochemical scores, followed by a complementary imaging study (transient elastography, magnetic resonance elastography or acoustic radiation force impulse) and finally a liver biopsy, when needed. To help with the selection of the most appropriate method a Fagan's nomogram analysis is provided in this review, describing the diagnostic yield of each method and their post-test probability of detecting liver fibrosis. Finally, treatment should always include diet and exercise, as well as controlling the components of the metabolic syndrome, +/- vitamin E, considering the presence of sleep apnea, and when available, allocate those patients with advanced fibrosis or high risk of progression into clinical trials. The final end of this approach should be to establish an opportune diagnosis and treatment of liver fibrosis in patients with NAFLD, aiming to decrease/stop its progression and improve their prognosis.
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Affiliation(s)
- Alejandro Campos-Murguía
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Astrid Ruiz-Margáin
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - José A González-Regueiro
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Ricardo U Macías-Rodríguez
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
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James G, Reisberg S, Lepik K, Galwey N, Avillach P, Kolberg L, Mägi R, Esko T, Alexander M, Waterworth D, Loomis AK, Vilo J. An exploratory phenome wide association study linking asthma and liver disease genetic variants to electronic health records from the Estonian Biobank. PLoS One 2019; 14:e0215026. [PMID: 30978214 PMCID: PMC6461350 DOI: 10.1371/journal.pone.0215026] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 03/25/2019] [Indexed: 12/22/2022] Open
Abstract
The Estonian Biobank, governed by the Institute of Genomics at the University of Tartu (Biobank), has stored genetic material/DNA and continuously collected data since 2002 on a total of 52,274 individuals representing ~5% of the Estonian adult population and is increasing. To explore the utility of data available in the Biobank, we conducted a phenome-wide association study (PheWAS) in two areas of interest to healthcare researchers; asthma and liver disease. We used 11 asthma and 13 liver disease-associated single nucleotide polymorphisms (SNPs), identified from published genome-wide association studies, to test our ability to detect established associations. We confirmed 2 asthma and 5 liver disease associated variants at nominal significance and directionally consistent with published results. We found 2 associations that were opposite to what was published before (rs4374383:AA increases risk of NASH/NAFLD, rs11597086 increases ALT level). Three SNP-diagnosis pairs passed the phenome-wide significance threshold: rs9273349 and E06 (thyroiditis, p = 5.50x10-8); rs9273349 and E10 (type-1 diabetes, p = 2.60x10-7); and rs2281135 and K76 (non-alcoholic liver diseases, including NAFLD, p = 4.10x10-7). We have validated our approach and confirmed the quality of the data for these conditions. Importantly, we demonstrate that the extensive amount of genetic and medical information from the Estonian Biobank can be successfully utilized for scientific research.
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Affiliation(s)
- Glen James
- AstraZeneca, Global Medical Affairs, Cambridge, United Kingdom
| | - Sulev Reisberg
- Institute of Computer Science, University of Tartu, Tartu, Estonia
- STACC, Tartu, Estonia
- Quretec, Tartu, Estonia
| | - Kaido Lepik
- Institute of Computer Science, University of Tartu, Tartu, Estonia
| | - Nicholas Galwey
- GlaxoSmithKline, Research and Development, Stevenage, United Kingdom
| | - Paul Avillach
- Department of Biomedical Informatics, Harvard Medical School, Boston, United States of America
- Department of Medical Informatics, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Liis Kolberg
- Institute of Computer Science, University of Tartu, Tartu, Estonia
| | - Reedik Mägi
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Tõnu Esko
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Myriam Alexander
- GlaxoSmithKline, Research and Development, Stevenage, United Kingdom
| | - Dawn Waterworth
- GlaxoSmithKline, Genetics, Collegeville, PA, United States of America
| | - A. Katrina Loomis
- Pfizer Worldwide Research and Development, Groton, CT, United States of America
| | - Jaak Vilo
- Institute of Computer Science, University of Tartu, Tartu, Estonia
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Basyte-Bacevice V, Skieceviciene J, Valantiene I, Sumskiene J, Petrenkiene V, Kondrackiene J, Petrauskas D, Lammert F, Kupcinskas J. TM6SF2 and MBOAT7 Gene Variants in Liver Fibrosis and Cirrhosis. Int J Mol Sci 2019; 20:ijms20061277. [PMID: 30875804 PMCID: PMC6470827 DOI: 10.3390/ijms20061277] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 03/06/2019] [Accepted: 03/09/2019] [Indexed: 02/07/2023] Open
Abstract
Previous large-scale genetic studies identified single nucleotide polymorphisms (SNPs) of the TM6SF2 and MBOAT7 genes as risk factors for alcoholic liver cirrhosis and non-alcoholic fatty liver disease. In this study, we tried to evaluate the association between TM6SF2 variant rs58542926 and MBOAT7 variant rs641738 and the risk of hepatic fibrosis or liver cirrhosis of different etiology. In parallel, we also aimed to evaluate whether these two SNPs modify the effects of the PNPLA3 rs738409 risk variant for the development of hepatic fibrosis and liver cirrhosis. The study was conducted at the Department of Gastroenterology, Lithuanian University of Health Sciences Hospital, and included 334 patients with liver cirrhosis, 128 patients with liver fibrosis, and 550 controls. SNPs were genotyped by quantitative PCR, using TaqMan allelic discrimination assays. Overall, TM6SF2 rs58542926 as well as MBOAT7rs641738 were not linked to hepatic fibrosis, alcohol or hepatitis C virus induced liver cirrhosis in an Eastern European population. These genetic variations also did not mediate the effect of PNPLA3 rs738409 SNP for liver developing liver fibrosis or liver cirrhosis.
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Affiliation(s)
- Viktorija Basyte-Bacevice
- Department of Gastroenterology, Lithuanian University of Health Sciences, LT-50009 Kaunas, Lithuania.
| | - Jurgita Skieceviciene
- Institute for Digestive Research, Lithuanian University of Health Sciences, LT-50009 Kaunas, Lithuania.
| | - Irena Valantiene
- Department of Gastroenterology, Lithuanian University of Health Sciences, LT-50009 Kaunas, Lithuania.
- Institute for Digestive Research, Lithuanian University of Health Sciences, LT-50009 Kaunas, Lithuania.
| | - Jolanta Sumskiene
- Department of Gastroenterology, Lithuanian University of Health Sciences, LT-50009 Kaunas, Lithuania.
| | - Vitalija Petrenkiene
- Department of Gastroenterology, Lithuanian University of Health Sciences, LT-50009 Kaunas, Lithuania.
| | - Jurate Kondrackiene
- Department of Gastroenterology, Lithuanian University of Health Sciences, LT-50009 Kaunas, Lithuania.
| | - Dalius Petrauskas
- Department of Gastroenterology, Lithuanian University of Health Sciences, LT-50009 Kaunas, Lithuania.
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, 66421 Homburg, Germany.
| | - Juozas Kupcinskas
- Department of Gastroenterology, Lithuanian University of Health Sciences, LT-50009 Kaunas, Lithuania.
- Institute for Digestive Research, Lithuanian University of Health Sciences, LT-50009 Kaunas, Lithuania.
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Li Z, Lin M, Liu C, Chen Z, Wang D, Shi X, Yang S, Li XJ. The rs4686434 variant in the fetuin B (FETUB) locus is associated with intrahepatic triglyceride content in obese Chinese adults. J Diabetes 2018; 10:916-925. [PMID: 29671945 DOI: 10.1111/1753-0407.12774] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 04/07/2018] [Accepted: 04/14/2018] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND This study explored associations of genetic variants in the fetuin B (FETUB) locus with intrahepatic triglyceride (IHTG) content. METHODS Four tagging single-nucleotide polymorphisms (SNPs) of the FETUB locus and patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 and transmembrane 6 super family member 2 (TM6SF2) rs58542926 were genotyped in 418 obese Chinese adults in whom serum FETUB and IHTG were measured. RESULTS Subjects carrying the minor G allele for FETUB rs4686434 (AG/GG) had lower serum FETUB levels (mean [±SD] 3.89 ± 1.36 vs 4.22 ± 1.46 μg/mL; P = 0.021) and IHTG content (12.7 ± 9.4% vs 14.6 ± 9.8%; P = 0.045) than their controls (AA), whereas IHTG content was higher in those carrying the minor G allele for PNPLA3 rs738409 (CG/GG) than in their controls (CC; 14.5 ± 10.1% vs 12.0 ± 8.6%; P = 0.012). After adjusting for potential confounders, IHTG content was lower in carriers of the minor G allele for FETUB rs4686434 (AG/GG vs AA, β -2.27 ± 0.91, P = 0.012), but was higher in carriers of the minor G allele for PNPLA3 rs738409 (CG/GG vs CC, β 2.65 ± 0.97, P = 0.006). There was a significant joint effect between FETUB rs4686434 and PNPLA3 rs738409 on IHTG content, with increasing genetic risk score (counting the risk allele of A in rs4686434 and G in rs738409) being associated with higher IHTG content (β 1.85 ± 0.48, P <0.001). CONCLUSIONS Carrying the minor G allele for FETUB rs4686434 was significantly associated with decreased IHTG content and may affect hepatic triglyceride accumulation in individuals at high risk of non-alcoholic fatty liver disease.
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Affiliation(s)
- Zhibin Li
- Xiamen Diabetes Institute, The First Affiliated Hospital, Xiamen University, Xiamen, China
- Epidemiology Research Unit, The First Affiliated Hospital, Xiamen University, Xiamen, China
| | - Mingzhu Lin
- Department of Endocrinology and Diabetes, The First Affiliated Hospital, Xiamen University, Xiamen, China
| | - Changqin Liu
- Department of Endocrinology and Diabetes, The First Affiliated Hospital, Xiamen University, Xiamen, China
- Department of Endocrinology and Diabetes, The Teaching Hospital of Fujian Medical University, Xiamen, China
| | - Zheng Chen
- Department of Endocrinology and Diabetes, The First Affiliated Hospital, Xiamen University, Xiamen, China
| | - Dongmei Wang
- School of Medicine, Xiamen University, Xiamen, China
| | - Xiulin Shi
- Department of Endocrinology and Diabetes, The First Affiliated Hospital, Xiamen University, Xiamen, China
| | - Shuyu Yang
- Xiamen Diabetes Institute, The First Affiliated Hospital, Xiamen University, Xiamen, China
- Department of Endocrinology and Diabetes, The First Affiliated Hospital, Xiamen University, Xiamen, China
| | - Xue-Jun Li
- Xiamen Diabetes Institute, The First Affiliated Hospital, Xiamen University, Xiamen, China
- Department of Endocrinology and Diabetes, The First Affiliated Hospital, Xiamen University, Xiamen, China
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Koo BK, Joo SK, Kim D, Bae JM, Park JH, Kim JH, Kim W. Additive effects of PNPLA3 and TM6SF2 on the histological severity of non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2018; 33:1277-1285. [PMID: 29193269 DOI: 10.1111/jgh.14056] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 11/08/2017] [Accepted: 11/20/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM We investigated the effects of PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7-TMC4 rs641738 variants on metabolic phenotypes and their combined effects on the histological severity of non-alcoholic fatty liver disease (NAFLD). METHODS We genotyped rs738409, rs58542926, and rs641738 in biopsy-proven NAFLD patients (n = 416) and healthy controls (n = 109). Homeostasis model assessment of insulin resistance and adipose tissue insulin resistance were calculated. RESULTS The rs738409 and rs58542926 variants, but not rs641738, were associated not only with non-alcoholic steatohepatitis (NASH) (odds ratio [OR], 2.00; 95% confidence interval [CI], 1.46-2.73 and OR, 1.91; 95% CI, 1.04-3.51) but also with significant fibrosis (≥ F2) (OR, 1.53; 95% CI, 1.11-2.11 and OR, 1.88; 95% CI, 1.02-3.46) in NAFLD, even after adjustment for metabolic risk factors. Of both variants, only rs738409 was associated with homeostasis model assessment of insulin resistance and adipose tissue insulin resistance even in healthy controls (P = 0.046 and 0.002, respectively) as well as in the entire study cohort (P = 0.016 and 0.048, respectively). PNPLA3 and TM6SF2 risk variants additively increased the risk of NASH and significant fibrosis (OR per risk allele, 2.03; 95% CI, 1.50-2.73 and 1.61; 95% CI, 1.19-2.17). Even in subjects with low insulin resistance, the risk of NASH or significant fibrosis increased as the number of risk alleles increased (P = 0.008 and 0.020, respectively). CONCLUSIONS PNPLA3 and TM6SF2 determine the risk of NASH and significant fibrosis, even after adjustment for insulin resistance, and exert an additive effect on NASH and significant fibrosis.
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Affiliation(s)
- Bo Kyung Koo
- Division of Endocrinology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Sae Kyung Joo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Donghee Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
| | - Jeong Mo Bae
- Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Jeong Hwan Park
- Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Jung Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Won Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
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Benedict M, Zhang X. Non-alcoholic fatty liver disease: An expanded review. World J Hepatol 2017; 9:715-732. [PMID: 28652891 PMCID: PMC5468341 DOI: 10.4254/wjh.v9.i16.715] [Citation(s) in RCA: 497] [Impact Index Per Article: 62.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 02/08/2017] [Accepted: 04/18/2017] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses the simple steatosis to more progressive steatosis with associated hepatitis, fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. NAFLD is a growing epidemic, not only in the United States, but worldwide in part due to obesity and insulin resistance leading to liver accumulation of triglycerides and free fatty acids. Numerous risk factors for the development of NAFLD have been espoused with most having some form of metabolic derangement or insulin resistance at the core of its pathophysiology. NAFLD patients are at increased risk of liver-related as well as cardiovascular mortality, and NAFLD is rapidly becoming the leading indication for liver transplantation. Liver biopsy remains the gold standard for definitive diagnosis, but the development of noninvasive advanced imaging, biochemical and genetic tests will no doubt provide future clinicians with a great deal of information and opportunity for enhanced understanding of the pathogenesis and targeted treatment. As it currently stands several medications/supplements are being used in the treatment of NAFLD; however, none seem to be the "magic bullet" in curtailing this growing problem yet. In this review we summarized the current knowledge of NAFLD epidemiology, risk factors, diagnosis, pathogenesis, pathologic changes, natural history, and treatment in order to aid in further understanding this disease and better managing NAFLD patients.
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Affiliation(s)
- Mark Benedict
- Mark Benedict, Xuchen Zhang, Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, United States
| | - Xuchen Zhang
- Mark Benedict, Xuchen Zhang, Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, United States
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18
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Miyaaki H, Nakao K. Significance of genetic polymorphisms in patients with nonalcoholic fatty liver disease. Clin J Gastroenterol 2017; 10:201-207. [PMID: 28290069 DOI: 10.1007/s12328-017-0732-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Accepted: 03/02/2017] [Indexed: 12/16/2022]
Abstract
Because of recent advances in genetic research such as genome-wide association studies, the underlying genetic mechanisms of nonalcoholic fatty liver disease (NAFLD) pathophysiology have been elucidated. Here, we present a review of the current literature on the impact of genetic polymorphisms in patients with NAFLD. These genetic polymorphisms, which regulate lipid metabolism, glucose metabolism, and the renin-angiotensin system, are involved in NAFLD onset, steatosis, inflammation, fibrosis, and hepatocellular carcinoma (HCC). Among these genetic polymorphisms, many studies and meta-analyses have demonstrated that position 148 (rs738409 C/G) of the patatin-like phospholipase domain-containing protein (PNPLA3) is a genetic factor associated with NAFLD pathophysiological features, such as hepatic fat level, hepatic inflammation, fibrosis, and HCC. However, the impact of genetic polymorphisms on NAFLD pathophysiology appears to differ among ethnic groups. Therefore, further studies with larger sample sizes are needed for each ethnic group.
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Affiliation(s)
- Hisamitsu Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
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19
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A multi-component classifier for nonalcoholic fatty liver disease (NAFLD) based on genomic, proteomic, and phenomic data domains. Sci Rep 2017; 7:43238. [PMID: 28266614 PMCID: PMC5339694 DOI: 10.1038/srep43238] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Accepted: 01/20/2017] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of conditions that include steatohepatitis and fibrosis that are thought to emanate from hepatic steatosis. Few robust biomarkers or diagnostic tests have been developed for hepatic steatosis in the setting of obesity. We have developed a multi-component classifier for hepatic steatosis comprised of phenotypic, genomic, and proteomic variables using data from 576 adults with extreme obesity who underwent bariatric surgery and intra-operative liver biopsy. Using a 443 patient training set, protein biomarker discovery was performed using the highly multiplexed SOMAscan® proteomic assay, a set of 19 clinical variables, and the steatosis predisposing PNPLA3 rs738409 single nucleotide polymorphism genotype status. The most stable markers were selected using a stability selection algorithm with a L1-regularized logistic regression kernel and were then fitted with logistic regression models to classify steatosis, that were then tested against a 133 sample blinded verification set. The highest area under the ROC curve (AUC) for steatosis of PNPLA3 rs738409 genotype, 8 proteins, or 19 phenotypic variables was 0.913, whereas the final classifier that included variables from all three domains had an AUC of 0.935. These data indicate that multi-domain modeling has better predictive power than comprehensive analysis of variables from a single domain.
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20
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Kawamura Y, Ikeda K, Arase Y, Fujiyama S, Hosaka T, Kobayashi M, Saitoh S, Sezaki H, Akuta N, Suzuki F, Suzuki Y, Kumada H. New Discriminant Method for Identifying the Aggressive Disease Phenotype of Non-alcoholic Fatty Liver Disease. Intern Med 2017; 56. [PMID: 28626169 PMCID: PMC5505899 DOI: 10.2169/internalmedicine.56.7830] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Objective To detect the aggressive phenotype (AP) of non-alcoholic fatty liver disease (NAFLD) based on the initial laboratory data and clinical characteristics. Methods We enrolled 144 patients with histologically proven NAFLD. For the first analysis, 24 NAFLD patients underwent repeat biopsy to establish a discriminant formula for predicting the AP of NAFLD (D-APN). The AP was defined by NAFLD that had been maintained or progressed to a fibrotic stage beyond stage 2. In the second analysis, we analyzed the distribution of the AP in each stage of disease and the incidence of the PNPLA3 rs738409 GG genotype in AP in 120 other patients. Results After the analysis, the following function was found to discriminate the disease phenotype: z=0.150×body mass index (kg/m2)+0.085×age (years)+1.112×ln (AST) (IU/L)+0.127×ln (m-AST)-12.96. A positive result indicates the AP of NAFLD. The discriminant functions had a positive predictive value of 94% and a negative predictive value of 71%. The distribution of the AP and the incidence of the PNPLA3 GG genotype in the AP in each stage of the disease among the 120 patients were as follows: non-alcoholic fatty liver, 30%/33%; non-alcoholic steatohepatitis (NASH) stage 1, 53%/26%; stage 2, 71%/70%; stage 3, 92%/57%; and stage 4, 93%/64%; there was a significant increase in the incidence of the AP as the disease progressed (p<0.001). Conclusion The new discriminant formula was useful for predicting disease progression potential in NAFLD patients and the incidence of the PNPLA3 GG genotype was elevated according to the distribution of AP.
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Affiliation(s)
- Yusuke Kawamura
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Kenji Ikeda
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Yasuji Arase
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Shunichiro Fujiyama
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Tetsuya Hosaka
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Masahiro Kobayashi
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Satoshi Saitoh
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Hitomi Sezaki
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Norio Akuta
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Fumitaka Suzuki
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Yoshiyuki Suzuki
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Hiromitsu Kumada
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
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Akuta N, Kawamura Y, Suzuki F, Saitoh S, Arase Y, Fujiyama S, Sezaki H, Hosaka T, Kobayashi M, Suzuki Y, Kobayashi M, Ikeda K, Kumada H. Analysis of association between circulating miR-122 and histopathological features of nonalcoholic fatty liver disease in patients free of hepatocellular carcinoma. BMC Gastroenterol 2016; 16:141. [PMID: 27955628 PMCID: PMC5153912 DOI: 10.1186/s12876-016-0557-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 12/07/2016] [Indexed: 01/17/2023] Open
Abstract
Background The association between circulating microRNA-122 (miR-122) and histopathological features of nonalcoholic fatty liver disease (NAFLD) remains unclear. Methods The association of serum miR-122 levels with histopathological features of NAFLD (steatosis, ballooning, lobular inflammation, and stage, as histological components of nonalcoholic steatohepatitis) was examined in serial liver biopsies from 36 hepatocellular carcinoma (HCC)-free Japanese patients with histopathologically-proven NAFLD. The median interval between first and second liver biopsies was 4.6 years. Results In patients who showed improvement of histopathological scores (steatosis, ballooning, and stage), serum miR-122 levels were significantly lower at second biopsy than first biopsy. In patients who showed no improvement, the changes at second biopsy were not different from those at first biopsy. There were significant and strong associations between serum miR-122 ratio (ratio of level at second biopsy to that at first biopsy) and changes in histopathological scores (of steatosis, lobular inflammation, and stage). There were also significant and strong associations between serum miR-122 ratio and changes in other clinical parameters, including aspartate aminotransferase and alanine aminotransferase. Conclusions Longitudinal examination of serial liver biopsies showed the association of serum miR-122 with histopathological features of HCC-free NAFLD patients. Electronic supplementary material The online version of this article (doi:10.1186/s12876-016-0557-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Norio Akuta
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan.
| | - Yusuke Kawamura
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan
| | - Fumitaka Suzuki
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan
| | - Satoshi Saitoh
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan
| | - Yasuji Arase
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan
| | - Shunichiro Fujiyama
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan
| | - Hitomi Sezaki
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan
| | - Tetsuya Hosaka
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan
| | - Masahiro Kobayashi
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan
| | - Yoshiyuki Suzuki
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan
| | | | - Kenji Ikeda
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan
| | - Hiromitsu Kumada
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan
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Salameh H, Hanayneh MA, Masadeh M, Naseemuddin M, Matin T, Erwin A, Singal AK. PNPLA3 as a Genetic Determinant of Risk for and Severity of Non-alcoholic Fatty Liver Disease Spectrum. J Clin Transl Hepatol 2016; 4:175-191. [PMID: 27777887 PMCID: PMC5075002 DOI: 10.14218/jcth.2016.00009] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 05/10/2016] [Accepted: 05/23/2016] [Indexed: 12/15/2022] Open
Abstract
Background and Aims:Patatin-like phospholipase domain protein 3 (PNPLA3) polymorphisms (rs738409 C>G) are associated with non-alcoholic fatty liver disease (NAFLD). We performed a systematic review and meta-analysis to examine the association of PNPLA3 polymorphisms with the spectrum and severity of this disease. Methods: Studies evaluating the association between the PNPLA3 polymorphism spectrum (fatty liver, steatohepatitis, cirrhosis, and hepatocellular carcinoma) and NAFLD were included. Pooled data are reported as odds ratios (ORs) with 95% confidence intervals. Results: Of 393 potentially relevant studies, 35 on NAFLD were included in the analysis. Compared to healthy controls, the pooled ORs for rs738409 CG and GG compared to CC among patients with non-alcoholic fatty liver (NAFL) were 1.46 (1.16-1.85) and 2.76 (2.30-3.13), and were 1.75 (1.24-2.46) and 4.44 (2.92-6.76) among patients with non-alcoholic steatohepatitis respectively. The respective ORs for CG and GG compared to the CC genotype were 2.35 (0.90-6.13) and 5.05 (1.47-17.29) when comparing non-alcoholic hepatocellular carcinoma to NAFL patients. Among the NAFLD patients, the ORs for G allele frequency when comparing steatosis grade 2-3 to grade 0-1 NAFL, when comparing the NAFLD activity score of ≥ 4 to score ≤ 3, when comparing NASH to NAFLD, when comparing the presence of lobular inflammation to absence, and when comparing the presence of hepatocyte ballooning to absence were 2.33 (1.43-3.80), 1.80 (1.36-2.37), 1.66 (1.42-1.94), 1.58 (1.19-2.10), and 2.63 (1.87-3.69) respectively. Subgroup analysis based on ethnicity showed similar results. Conclusions:PNPLA3 polymorphisms have strong association with the risk for and severity of NAFLDs. PNPLA3 polymorphism plays an evolving role in diagnosis and treatment decisions in patients with NAFLD.
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Affiliation(s)
- Habeeb Salameh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA
| | - Muhannad Al Hanayneh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA
| | - Maen Masadeh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
| | | | - Tasnia Matin
- Department of Internal Medicine, University of Alabama, Birmingham, AL, USA
| | - Angelika Erwin
- Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Ashwani K. Singal
- Division of Gastroenterology and Hepatology, University of Alabama, Birmingham, AL, USA
- *Correspondence to: Ashwani Kumar Singal, Division of Gastroenterology and Hepatology, University of Alabama, 1808 7 Ave S BDB 351, Birmingham, AL 35294-0012, USA. Tel: +1-205-934-5623, Fax: +1-205-975-0961, E-mail:
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Ravi Kanth VV, Sasikala M, Sharma M, Rao PN, Reddy DN. Genetics of non-alcoholic fatty liver disease: From susceptibility and nutrient interactions to management. World J Hepatol 2016; 8:827-837. [PMID: 27458502 PMCID: PMC4945502 DOI: 10.4254/wjh.v8.i20.827] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 05/04/2016] [Accepted: 06/14/2016] [Indexed: 02/06/2023] Open
Abstract
Genetics plays an important role in determining the susceptibility of an individual to develop a disease. Complex, multi factorial diseases of modern day (diabetes, cardiovascular disease, hypertension and obesity) are a result of disparity between the type of food consumed and genes, suggesting that food which does not match the host genes is probably one of the major reasons for developing life style diseases. Non-alcoholic fatty liver is becoming a global epidemic leading to substantial morbidity. While various genotyping approaches such as whole exome sequencing using next generation sequencers and genome wide association studies have identified susceptibility loci for non-alcoholic fatty liver disease (NAFLD) including variants in patatin-like phospholipase domain containing 3 and transmembrane 6 superfamily member 2 genes apart from others; nutrient based studies emphasized on a combination of vitamin D, E and omega-3 fatty acids to manage fatty liver disease. However majority of the studies were conducted independent of each other and very few studies explored the interactions between the genetic susceptibility and nutrient interactions. Identifying such interactions will aid in optimizing the nutrition tailor made to an individual's genetic makeup, thereby aiding in delaying the onset of the disease and its progression. The present topic focuses on studies that identified the genetic susceptibility for NAFLD, nutritional recommendations, and their interactions for better management of NAFLD.
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Affiliation(s)
- Vishnubhotla Venkata Ravi Kanth
- Vishnubhotla Venkata Ravi Kanth, Mitnala Sasikala, Asian Healthcare Foundation, a Research Wing of Asian Institute of Gastroenterology, Hyderabad 500082, Telangana, India
| | - Mitnala Sasikala
- Vishnubhotla Venkata Ravi Kanth, Mitnala Sasikala, Asian Healthcare Foundation, a Research Wing of Asian Institute of Gastroenterology, Hyderabad 500082, Telangana, India
| | - Mithun Sharma
- Vishnubhotla Venkata Ravi Kanth, Mitnala Sasikala, Asian Healthcare Foundation, a Research Wing of Asian Institute of Gastroenterology, Hyderabad 500082, Telangana, India
| | - Padaki Nagaraja Rao
- Vishnubhotla Venkata Ravi Kanth, Mitnala Sasikala, Asian Healthcare Foundation, a Research Wing of Asian Institute of Gastroenterology, Hyderabad 500082, Telangana, India
| | - Duvvuru Nageshwar Reddy
- Vishnubhotla Venkata Ravi Kanth, Mitnala Sasikala, Asian Healthcare Foundation, a Research Wing of Asian Institute of Gastroenterology, Hyderabad 500082, Telangana, India
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Impact of circulating miR-122 for histological features and hepatocellular carcinoma of nonalcoholic fatty liver disease in Japan. Hepatol Int 2016; 10:647-56. [PMID: 27074850 DOI: 10.1007/s12072-016-9729-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 03/21/2016] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIM Relationships between circulating microRNA-122 (miR-122) and histological features of nonalcoholic fatty liver disease (NAFLD) are unclear. METHODS The impact of serum miR-122 levels for histological features and hepatocellular carcinoma (HCC) was investigated in 305 Japanese patients with histological proven NAFLD. Twenty-three patients were with HCC at the time of diagnosis of NAFLD, and four patients developed HCC during the follow-up. The cross-sectional or longitudinal evaluations were performed to investigate the impact for HCC. RESULTS Serum miR-122 levels (calibrated relative to the median levels of patients) partly affected severity of steatosis, ballooning, lobular inflammation, and stage. Multivariate analysis identified HCC and/or histological components of NASH as morphological factors that independently influenced serum miR-122 levels at the diagnosis of NAFLD. There was a strong correlation between serum miR-122 levels and AST, ALT levels. In cross-sectional evaluation, serum miR-122 levels of patients without HCC were significantly higher than those with HCC in patients of stage 3 but not stage 4. In longitudinal evaluation of one patient with follow-up time of 25 years, from the diagnosis of NAFLD until HCC, serum miR-122 levels had already tended to decrease before the progression of fibrosis stage. CONCLUSIONS HCC and/or histological components of NASH affected serum miR-122 levels, independently. In longitudinal evaluation of HCC patients, serum miR-122 levels had already tended to decrease before the progression of fibrosis stage. Further prospective studies are needed to investigate the impact of serum miR-122 for histological features and hepatocarcinogenesis of NAFLD.
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Bidirectional Relationships and Disconnects between NAFLD and Features of the Metabolic Syndrome. Int J Mol Sci 2016; 17:367. [PMID: 26978356 PMCID: PMC4813227 DOI: 10.3390/ijms17030367] [Citation(s) in RCA: 107] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 03/02/2016] [Accepted: 03/07/2016] [Indexed: 12/19/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents a wide spectrum of liver disease from simple steatosis, to steatohepatitis, (both with and without liver fibrosis), cirrhosis and end-stage liver failure. NAFLD also increases the risk of hepatocellular carcinoma (HCC) and both HCC and end stage liver disease may markedly increase risk of liver-related mortality. NAFLD is increasing in prevalence and is presently the second most frequent indication for liver transplantation. As NAFLD is frequently associated with insulin resistance, central obesity, dyslipidaemia, hypertension and hyperglycaemia, NAFLD is often considered the hepatic manifestation of the metabolic syndrome. There is growing evidence that this relationship between NAFLD and metabolic syndrome is bidirectional, in that NAFLD can predispose to metabolic syndrome features, which can in turn exacerbate NAFLD or increase the risk of its development in those without a pre-existing diagnosis. Although the relationship between NAFLD and metabolic syndrome is frequently bidirectional, recently there has been much interest in genotype/phenotype relationships where there is a disconnect between the liver disease and metabolic syndrome features. Such potential examples of genotypes that are associated with a dissociation between liver disease and metabolic syndrome are patatin-like phospholipase domain-containing protein-3 (PNPLA3) (I148M) and transmembrane 6 superfamily member 2 protein (TM6SF2) (E167K) genotypes. This review will explore the bidirectional relationship between metabolic syndrome and NAFLD, and will also discuss recent insights from studies of PNPLA3 and TM6SF2 genotypes that may give insight into how and why metabolic syndrome features and liver disease are linked in NAFLD.
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