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Wang SW, Wang C, Cheng YM, Chen CY, Hsieh TH, Wang CC, Kao JH. Genetic predisposition of metabolic dysfunction-associated steatotic liver disease: a population-based genome-wide association study. Hepatol Int 2025:10.1007/s12072-024-10769-0. [PMID: 39755997 DOI: 10.1007/s12072-024-10769-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 12/06/2024] [Indexed: 01/07/2025]
Abstract
BACKGROUND/PURPOSE Although metabolic dysfunction-associated steatotic liver disease (MASLD) has been proposed to replace the diagnosis of non-alcoholic fatty liver disease (NAFLD) with new diagnostic criteria since 2023, the genetic predisposition of MASLD remains to be explored. METHODS Participants with data of genome-wide association studies (GWAS) in the Taiwan Biobank database were collected. Patients with missing data, positive for HBsAg, anti-HCV, and alcohol drinking history were excluded. MASLD was defined if having hepatic steatosis on ultrasound, plus at least one of cardiometabolic criteria. The Taiwan biobank used two genetic chips during the period of data collection: Taiwan biobank version 1 (TWBv1) as the initial chip and TWBv2 specifically designed for the Taiwanese population. TWBv2 was used as test group and TWBv1 as validation group. NAFLD fibrosis score (NFS) was used to assess the degree of liver fibrosis, and carotid plaques on duplex ultrasound were employed for the diagnosis of atherosclerosis. RESULTS In a total of 16,407 (mean age 55.35 ± 10.41; 29.6% males) participants, 6722 (41.0%) had MASLD. Eleven single-nucleotide polymorphisms (SNP) were identified to be associated with MASLD. Their functions were exonic in two and intronic in nine. They were related to the PNALA3, and SAMM50 genes located on chromosome 22. The linkage disequilibrium showed a high correlation with each other. Four SNPs of PNALA3 and SAMM50 genes had increased risk of MASLD and higher levels of AST/ALT. In addition, there was no association of these two genes with glucose metabolism, but better lipid profiles in SAMM50. CONCLUSIONS This large GWAS study indicates that eleven SNPs of PNPLA3 and SAMM50 genes predispose the development of MASLD in Taiwanese population.
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Affiliation(s)
- Shao-Wen Wang
- Department of Education, Taipei Medical University-Shuang Ho Hospital, Ministry of Health and Welfare, New Taipei City, Taiwan
| | - Ching Wang
- National Yang Ming Chiao Tung University, Hsinchu City, Taiwan
| | - Yu-Ming Cheng
- Department of Gastroenterology and Hepatology, Tung's Taichung MetroHarbor Hospital, Taichung, Taiwan
| | - Chun-Yi Chen
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Tsung-Han Hsieh
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Chia-Chi Wang
- Department of Gastroenterology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, 289 Jianguo Rd., Xindian Area, New Taipei City, 23142, Taiwan.
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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Sato S, Iino C, Sasada T, Furusawa K, Yoshida K, Sawada K, Mikami T, Fukuda S, Nakaji S, Sakuraba H. A 4-year cohort study of the effects of PNPLA3 rs738409 genotypes on liver fat and fibrosis and gut microbiota in a non-fatty liver population. Environ Health Prev Med 2025; 30:17. [PMID: 40074353 PMCID: PMC11925709 DOI: 10.1265/ehpm.24-00365] [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: 03/14/2025] Open
Abstract
BACKGROUND Many factors are associated with the development and progression of liver fat and fibrosis; however, genetics and the gut microbiota are representative factors. Moreover, recent studies have indicated a link between host genes and the gut microbiota. This study investigated the effect of patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 (C > G), which has been reported to be most involved in the onset and progression of fatty liver, on liver fat and fibrosis in a cohort study related to gut microbiota in a non-fatty liver population. METHODS This cohort study included 214 participants from the health check-up project in 2018 and 2022 who had non-fatty liver with controlled attenuation parameter (CAP) values <248 dB/m by FibroScan and were non-drinkers. Changes in CAP values and liver stiffness measurement (LSM), liver-related items, and gut microbiota from 2018 to 2022 were investigated separately for PNPLA3 rs738409 CC, CG, and GG genotypes. RESULTS Baseline values showed no difference among the PNPLA3 rs738409 genotypes for any of the measurement items. From 2018 to 2022, the PNPLA3 rs738409 CG and GG genotype groups showed a significant increase in CAP and body mass index; no significant change was observed in the CC genotype group. LSM increased in all genotypes, but the rate of increase was highest in the GG genotype, followed by the CG and CC genotypes. Fasting blood glucose levels increased in all genotypes; however, HOMA-IR (Homeostasis Model Assessment of Insulin Resistance) increased significantly only in the GG genotype. HDL (high-density lipoprotein) and LDL (low-density lipoprotein) cholesterol levels significantly increased in all genotypes, whereas triglycerides did not show any significant changes in any genotype. As for the gut microbiota, the relative abundance of Feacalibacterium in the PNPLA3 rs738409 GG genotype decreased by 2% over 4 years, more than 2-fold compared to CC and GG genotypes. Blautia increased significantly in the CC group. CONCLUSION The results suggest that PNPLA3 G-allele carriers of non-fatty liver develop liver fat and fibrosis due to not only obesity and insulin resistance but also the deterioration of gut microbiota, which may require a relatively long course of time, even years.
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Affiliation(s)
- Satoshi Sato
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine
| | - Chikara Iino
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine
| | - Takafumi Sasada
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine
| | - Keisuke Furusawa
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine
| | - Kenta Yoshida
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine
| | - Kaori Sawada
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine
| | - Tatsuya Mikami
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine
| | - Shinsaku Fukuda
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine
| | - Shigeyuki Nakaji
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine
| | - Hirotake Sakuraba
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine
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Sato S, Iino C, Sasada T, Soma G, Furusawa K, Yoshida K, Sawada K, Mikami T, Fukuda S, Nakaji S, Sakuraba H. An epidemiological study on the factors including genetic polymorphism influencing ALT >30 U/L and liver fibrosis progression in metabolic dysfunction-associated steatotic liver disease among the general population. JGH Open 2024; 8:e70043. [PMID: 39713746 PMCID: PMC11659511 DOI: 10.1002/jgh3.70043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 09/29/2024] [Accepted: 10/07/2024] [Indexed: 12/24/2024]
Abstract
Background and Aim Identifying the factors contributing to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), a lifestyle-related disease, is crucial for preventing future liver-related deaths. This study aimed to epidemiologically investigate factors, including single-nucleotide polymorphisms (SNPs) associated with alanine aminotransferase (ALT) levels >30 U/L and potential risk factors for liver fibrosis, in a general population cohort of patients with MASLD. Methods Among 1059 participants in the health checkup project, 228 who were diagnosed with MASLD were analyzed. Liver fat content and stiffness were measured using FibroScan, and 13 SNPs associated with non-alcoholic fatty liver disease (NAFLD) were measured in addition to other clinical parameters. Results In the multivariate analysis, male sex, younger age, and high triglyceride levels were significant risk factors for ALT levels >30 U/L (P-value < 0.05). Furthermore, among the 13 SNPs measured, only the GG genotypes of patatin-like phospholipase domain-containing 3 gene (PNPLA3) rs738409 and rs2896019 were significant risk factors for ALT levels >30 U/L (P-value 0.004 and 0.007). The GG genotypes of PNPLA3 rs738409 and rs2896019 had higher FibroScan-aspartate aminotransferase (FAST) and APRI scores than the CC + CG and TT + TG genotypes (P-value < 0.05). In addition, multivariate analysis revealed that the GG genotypes of rs738409 and rs2896019 were significant risk factors independent of cardiovascular metabolic risk for patients with MASLD (P-value 0.038 and 0.021). Conclusion An individualized treatment approach is warranted for patients with MASLD due to the influence of various factors on its progression, including genetic factors and lifestyle diseases.
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Affiliation(s)
- Satoshi Sato
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Chikara Iino
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Takafumi Sasada
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Go Soma
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Keisuke Furusawa
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Kenta Yoshida
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Kaori Sawada
- Department of Preemptive MedicineHirosaki University Graduate School of MedicineHirosakiJapan
| | - Tatsuya Mikami
- Department of Preemptive MedicineHirosaki University Graduate School of MedicineHirosakiJapan
| | - Shinsaku Fukuda
- Department of Preemptive MedicineHirosaki University Graduate School of MedicineHirosakiJapan
| | - Shigeyuki Nakaji
- Department of Preemptive MedicineHirosaki University Graduate School of MedicineHirosakiJapan
| | - Hirotake Sakuraba
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
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Gancheva S, Roden M, Castera L. Diabetes as a risk factor for MASH progression. Diabetes Res Clin Pract 2024; 217:111846. [PMID: 39245423 DOI: 10.1016/j.diabres.2024.111846] [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: 07/24/2024] [Revised: 08/28/2024] [Accepted: 09/03/2024] [Indexed: 09/10/2024]
Abstract
Non-alcoholic (now: metabolic) steatohepatitis (MASH) is the progressive inflammatory form of metabolic dysfunction-associated steatotic liver disease (MASLD), which often coexists and mutually interacts with type 2 diabetes (T2D), resulting in worse hepatic and cardiovascular outcomes. Understanding the intricate mechanisms of diabetes-related MASH progression is crucial for effective therapeutic strategies. This review delineates the multifaceted pathways involved in this interplay and explores potential therapeutic implications. The synergy between adipose tissue, gut microbiota, and hepatic alterations plays a pivotal role in disease progression. Adipose tissue dysfunction, particularly in the visceral depot, coupled with dysbiosis in the gut microbiota, exacerbates hepatic injury and insulin resistance. Hepatic lipid accumulation, oxidative stress, and endoplasmic reticulum stress further potentiate inflammation and fibrosis, contributing to disease severity. Dietary modification with weight reduction and exercise prove crucial in managing T2D-related MASH. Additionally, various well-known but also novel anti-hyperglycemic medications exhibit potential in reducing liver lipid content and, in some cases, improving MASH histology. Therapies targeting incretin receptors show promise in managing T2D-related MASH, while thyroid hormone receptor-β agonism has proven effective as a treatment of MASH and fibrosis.
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Affiliation(s)
- Sofiya Gancheva
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich-Heine University, Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München-Neuherberg, Germany
| | - Michael Roden
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich-Heine University, Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München-Neuherberg, Germany.
| | - Laurent Castera
- Department of Hepatology, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France; Université Paris-Cité, INSERM UMR 1149, Centre de Recherche sur l'Inflammation Paris, Montmartre, Paris, France.
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Sato S, Iino C, Sasada T, Soma G, Furusawa K, Yoshida K, Sawada K, Mikami T, Nakaji S, Sakuraba H, Fukuda S. Epidemiological Study on the Interaction between the PNPLA3 (rs738409) and Gut Microbiota in Metabolic Dysfunction-Associated Steatotic Liver Disease. Genes (Basel) 2024; 15:1172. [PMID: 39336763 PMCID: PMC11430940 DOI: 10.3390/genes15091172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 08/31/2024] [Accepted: 09/02/2024] [Indexed: 09/30/2024] Open
Abstract
Many factors are associated with the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD); however, genetics and gut microbiota are representative factors. Recent studies have highlighted the link between host genes and the gut microbiota. Although there have been many studies on the separate effects of single nucleotide polymorphisms (SNPs) and gut bacteria on MASLD, few epidemiological studies have examined how SNPs and gut bacteria interact in the development and progression of MASLD. This study aimed to investigate the association between PNPLA3 rs738409, a representative MASLD-related SNP, and gut bacteria in MASLD using a cross-sectional study of the general population. The 526 participants (318 normal and 208 MASLD groups) were grouped into the PNPLA3 rs738409 SNP, CC, CG, and GG genotypes, and the differences in the gut microbiota were investigated in each group. The PNPLA3 rs738409 CC and CG genotypes were associated with decreased Blautia and Ruminococcaceae in the MASLD group. They were negatively correlated with controlled attenuation parameter levels, body mass index, serum blood glucose, and triglycerides. In contrast, there was no association between the normal and MASLD groups and the gut bacteria in the PNPLA3 rs738409, the GG genotype group. This finding implies that dietary interventions and probiotics may be more effective in preventing and treating MASLD in individuals with the PNPLA3 rs738409 CC and CG genotypes. In contrast, their efficacy may be limited in those with the GG genotype.
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Affiliation(s)
- Satoshi Sato
- Department of Gastroenterology, Hematology, and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Chikara Iino
- Department of Gastroenterology, Hematology, and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Takafumi Sasada
- Department of Gastroenterology, Hematology, and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Go Soma
- Department of Gastroenterology, Hematology, and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Keisuke Furusawa
- Department of Gastroenterology, Hematology, and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Kenta Yoshida
- Department of Gastroenterology, Hematology, and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Kaori Sawada
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Tatsuya Mikami
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Shigeyuki Nakaji
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Hirotake Sakuraba
- Department of Gastroenterology, Hematology, and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Shinsaku Fukuda
- Department of Gastroenterology, Hematology, and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
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Koch RL, Stanton JB, McClatchy S, Churchill GA, Craig SW, Williams DN, Johns ME, Chase KR, Thiesfeldt DL, Flynt JC, Pazdro R. Discovery of genomic loci for liver health and steatosis reveals overlap with glutathione redox genetics. Redox Biol 2024; 75:103248. [PMID: 38917671 PMCID: PMC11254179 DOI: 10.1016/j.redox.2024.103248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 05/27/2024] [Accepted: 06/18/2024] [Indexed: 06/27/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition in the United States, encompassing a wide spectrum of liver pathologies including steatosis, steatohepatitis, fibrosis, and cirrhosis. Despite its high prevalence, there are no medications currently approved by the Food and Drug Administration for the treatment of NAFLD. Recent work has suggested that NAFLD has a strong genetic component and identifying causative genes will improve our understanding of the molecular mechanisms contributing to NAFLD and yield targets for future therapeutic investigations. Oxidative stress is known to play an important role in NAFLD pathogenesis, yet the underlying mechanisms accounting for disturbances in redox status are not entirely understood. To better understand the relationship between the glutathione redox system and signs of NAFLD in a genetically-diverse population, we measured liver weight, serum biomarkers aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and graded liver pathology in a large cohort of Diversity Outbred mice. We compared hepatic endpoints to those of the glutathione redox system previously measured in the livers and kidneys of the same mice, and we screened for statistical and genetic associations using the R/qtl2 software. We discovered several novel genetic loci associated with markers of liver health, including loci that were associated with both liver steatosis and glutathione redox status. Candidate genes within each locus point to possible new mechanisms underlying the complex relationship between NAFLD and the glutathione redox system, which could have translational implications for future studies targeting NAFLD pathology.
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Affiliation(s)
- Rebecca L Koch
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - James B Stanton
- Department of Pathology, University of Georgia, Athens, GA, USA, 30602
| | | | | | - Steven W Craig
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - Darian N Williams
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - Mallory E Johns
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - Kylah R Chase
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - Dana L Thiesfeldt
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - Jessica C Flynt
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - Robert Pazdro
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602.
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Habib S. Team players in the pathogenesis of metabolic dysfunctions-associated steatotic liver disease: The basis of development of pharmacotherapy. World J Gastrointest Pathophysiol 2024; 15:93606. [PMID: 39220834 PMCID: PMC11362842 DOI: 10.4291/wjgp.v15.i4.93606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 05/14/2024] [Accepted: 07/23/2024] [Indexed: 08/22/2024] Open
Abstract
Nutrient metabolism is regulated by several factors. Social determinants of health with or without genetics are the primary regulator of metabolism, and an unhealthy lifestyle affects all modulators and mediators, leading to the adaptation and finally to the exhaustion of cellular functions. Hepatic steatosis is defined by presence of fat in more than 5% of hepatocytes. In hepatocytes, fat is stored as triglycerides in lipid droplet. Hepatic steatosis results from a combination of multiple intracellular processes. In a healthy individual nutrient metabolism is regulated at several steps. It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component. Several hormones, peptides, and genes have been described that participate in nutrient metabolism. Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP. As of now several publications have revealed very intricate regulation of nutrient metabolism, where most of the regulatory factors are tied to each other bidirectionally, making it difficult to comprehend chronological sequence of events. Insulin hormone is the primary regulator of all nutrients' metabolism both in prandial and fasting states. Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes; metabolic, inflammation and repair, and cell growth and regeneration. Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands, adiponectin, leptin, and adiponutrin. Insulin hormone has direct effect on these final modulators. Whereas blood glucose level, serum lipids, incretin hormones, bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle. The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) that help us understand the disease natural course, risk stratification, role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine. PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states; MASLD, cardiovascular disease and cancer. More than 1000 publications including original research and review papers were reviewed.
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Affiliation(s)
- Shahid Habib
- Department of Hepatology, Liver Institute PLLC, Tucson, AZ 85712, United States
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Habib S. Metabolic dysfunction-associated steatotic liver disease heterogeneity: Need of subtyping. World J Gastrointest Pathophysiol 2024; 15:92791. [PMID: 38845820 PMCID: PMC11151879 DOI: 10.4291/wjgp.v15.i2.92791] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 04/04/2024] [Accepted: 04/24/2024] [Indexed: 05/23/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread global disease with significant health burden. Unhealthy lifestyle, obesity, diabetes mellitus (DM), insulin resistance, and genetics have been implicated in the pathogenesis of MASLD. A significant degree of heterogeneity exists among each of above-mentioned risk factors. Heterogeneity of these risk factors translates into the heterogeneity of MASLD. On the other hand, MASLD can itself lead to insulin resistance and DM. Such heterogeneity makes it difficult to assess the natural course of an individual with MASLD in clinical practice. At present MASLD is considered as one disease despite the variability of etiopathogenic processes, and we lack the consensus definitions of unique subtypes of MASLD. In this review, pathogenic processes of MASLD are discussed and a need of subtyping is recommended.
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Affiliation(s)
- Shahid Habib
- Department of Hepatology, Liver Institute PLLC, Tucson, AZ 85716, United States
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Castillejo-López C, Bárcenas-Walls JR, Cavalli M, Larsson A, Wadelius C. A regulatory element associated to NAFLD in the promoter of DIO1 controls LDL-C, HDL-C and triglycerides in hepatic cells. Lipids Health Dis 2024; 23:48. [PMID: 38365720 PMCID: PMC10870585 DOI: 10.1186/s12944-024-02029-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 01/22/2024] [Indexed: 02/18/2024] Open
Abstract
BACKGROUND Genome-wide association studies (GWAS) have identified genetic variants linked to fat metabolism and related traits, but rarely pinpoint causative variants. This limitation arises from GWAS not considering functional implications of noncoding variants that can affect transcription factor binding and potentially regulate gene expression. The aim of this study is to investigate a candidate noncoding functional variant within a genetic locus flagged by a GWAS SNP associated with non-alcoholic fatty liver disease (NAFLD), a condition characterized by liver fat accumulation in non-alcohol consumers. METHODS CRISPR-Cas9 gene editing in HepG2 cells was used to modify the regulatory element containing the candidate functional variant linked to NAFLD. Global gene expression in mutant cells was assessed through RT-qPCR and targeted transcriptomics. A phenotypic assay measured lipid droplet accumulation in the CRISPR-Cas9 mutants. RESULTS The candidate functional variant, rs2294510, closely linked to the NAFLD-associated GWAS SNP rs11206226, resided in a regulatory element within the DIO1 gene's promoter region. Altering this element resulted in changes in transcription factor binding sites and differential expression of candidate target genes like DIO1, TMEM59, DHCR24, and LDLRAD1, potentially influencing the NAFLD phenotype. Mutant HepG2 cells exhibited increased lipid accumulation, a hallmark of NAFLD, along with reduced LDL-C, HDL-C and elevated triglycerides. CONCLUSIONS This comprehensive approach, that combines genome editing, transcriptomics, and phenotypic assays identified the DIO1 promoter region as a potential enhancer. Its activity could regulate multiple genes involved in the NAFLD phenotype or contribute to defining a polygenic risk score for enhanced risk assessment in NAFLD patients.
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Affiliation(s)
- Casimiro Castillejo-López
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 08 , Uppsala, Sweden, Box 815, Husargatan 3, BMC
| | - José Ramón Bárcenas-Walls
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 08 , Uppsala, Sweden, Box 815, Husargatan 3, BMC
| | - Marco Cavalli
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 08 , Uppsala, Sweden, Box 815, Husargatan 3, BMC
| | - Anders Larsson
- Department of Medical Sciences, Clinical Chemistry, Uppsala University Hospital, 751 85, Uppsala, Sweden
| | - Claes Wadelius
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 08 , Uppsala, Sweden, Box 815, Husargatan 3, BMC.
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Koh JH, Wang M, Suzuki H, Muthiah M, Ng CH, Huang DQ. NAFLD and NAFLD-related HCC in Asia: Burden and Surveillance. J Clin Exp Hepatol 2024; 14:101213. [PMID: 38076360 PMCID: PMC10701133 DOI: 10.1016/j.jceh.2023.06.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 06/30/2023] [Indexed: 06/21/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is rapidly emerging as a leading etiology of chronic liver disease (CLD) in Asia. The increasing incidence of NAFLD is projected to drive a surge in NAFLD-related hepatocellular carcinoma (HCC). A notable characteristic of NAFLD-HCC is its capacity for development in individuals without cirrhosis in more than a third of patients. Most practice guidelines recommend biannual ultrasound screening for patients with cirrhosis. In cases of severe limitations to ultrasound visualisation, cross-sectional abdominal imaging may be warranted. Improved strategies for HCC risk stratification are required for people with NAFLD but without cirrhosis. In this Review, we discuss the evolving trends of NAFLD and HCC in Asia, and implications for surveillance.
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Affiliation(s)
- Jia H. Koh
- Department of Medicine, National University Hospital, Singapore, Singapore
| | - Meng Wang
- Department of Medicine, National University Hospital, Singapore, Singapore
| | - Hiroyuki Suzuki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Mark Muthiah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Cheng H. Ng
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Daniel Q. Huang
- NAFLD Research Center, University of California at San Diego, USA
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11
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Chayama K, Hiramatsu A, Shima T, Itoh Y, Yamaguchi K, Nakajima T, Hoshikawa K, Kawamura Y, Akuta N, Ito K, Kawanaka M, Sakamoto M, Harada K, Goto Y, Nakayama T, Kumada H, Okanoue T. Impact of fibrosis on liver-related event incidence in nonalcoholic fatty liver disease: A multicenter observational study. Hepatol Res 2023; 53:1169-1184. [PMID: 37534742 DOI: 10.1111/hepr.13950] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 07/26/2023] [Accepted: 07/31/2023] [Indexed: 08/04/2023]
Abstract
AIM There are few reports on the prognosis of liver-related events in Japanese patients with nonalcoholic fatty liver disease (NAFLD). We undertook an observational study to compare the prognosis between fibrotic and nonfibrotic groups in Japanese NAFLD patients. METHODS Prognosis in 393 NAFLD patients who underwent liver biopsy between April 2013 and April 2015 at multiple centers were investigated. The time to onset of liver-related events, cardiovascular events, development of extrahepatic cancers, and death were compared between the pathologically fibrotic nonalcoholic steatohepatitis (NASH) group and nonalcoholic fatty liver (NAFL) + nonfibrotic NASH group. A similar analysis was carried out based on the fibrotic classification diagnosed using four noninvasive fibrosis prediction models. RESULTS The mean age and body mass index at the time of liver biopsy was 55.7 years old and 28.04 kg/m2 , respectively The cumulative incidence of liver-related events at 1080 days after liver biopsy was 5.79% in the pathologically fibrotic NASH group and 0% in the NAFL + nonfibrotic NASH group, with a significant difference (p = 0.0334). The cumulative incidence of liver-related events was significantly higher in the positive group for the prediction model than in the negative group in all four models (all p values were <0.0001). There was no significant difference between the pathologically fibrotic NASH group and NAFL + nonfibrotic NASH group in terms of cumulative incidence of cardiovascular events, development of extrahepatic cancers, and death. CONCLUSIONS The incidence of liver-related events was significantly higher in the fibrotic NASH group than that of the NAFL + nonfibrotic NASH group in Japanese NAFLD patients.
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Affiliation(s)
- Kazuaki Chayama
- Collaborative Research Laboratory of Medical Innovation, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology, Hiroshima Memorial Hospital, Hiroshima, Japan
| | - Toshihide Shima
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita, Japan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kanji Yamaguchi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tomoaki Nakajima
- Department of Hepatology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Kyoko Hoshikawa
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Japan
| | | | - Norio Akuta
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Kiyoaki Ito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Japan
| | - Miwa Kawanaka
- Department of General Internal Medicine 2, Kawasaki Medical Center, Kawasaki Medical School, Okayama, Japan
| | - Michiie Sakamoto
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Yoshihito Goto
- Department of Health Informatics, Kyoto University School of Public Health, Kyoto, Japan
| | - Takeo Nakayama
- Department of Health Informatics, Kyoto University School of Public Health, Kyoto, Japan
| | | | - Takeshi Okanoue
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita, Japan
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12
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Sadeghianpour Z, Cheraghian B, Farshchi HR, Asadi-Lari M. Non-alcoholic fatty liver disease and socioeconomic determinants in an Iranian cohort study. BMC Gastroenterol 2023; 23:350. [PMID: 37814220 PMCID: PMC10561474 DOI: 10.1186/s12876-023-02964-4] [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: 03/01/2023] [Accepted: 09/19/2023] [Indexed: 10/11/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is widespread worldwide. On the other hand, social inequality and socioeconomic status (SES) can affect all aspects of health. Therefore, this study aimed to investigate the relationship between SES indicators and NAFLD. METHODS This was a cross-sectional study using data from the registration phase of the Hoveyzeh Cohort Study, which included 10,009 individuals aged 35-70 years from May 2016 to August 2018. Fatty liver disease was determined based on Fatty Liver Index (FLI). The crude and adjusted odds ratios were calculated by logistic regression analysis to estimate associations between the fatty liver index and SES after controlling the potential confounders. RESULTS According to the FLI index, there were 2,006 people with fatty liver (28%) and 5,246 people without fatty liver (72%). Several 4496 people (62%) were women. The chi-square test showed significant relationships between the educational level and skill level (P < 0.001), the wealth index (P < 0.001), and Townsend Index (P < 0.001) with fatty liver index. In multivariable analysis, after adjustment for age, sex, physical activity, smoking, type of residence, calorie intake, dyslipidemia, skill level, and diabetes, the wealth index (p < 0.001) was positively associated with the fatty liver index. Besides, a reverse and significant association was seen between the Townsend index and the fatty liver index(p < 0.001). In contrast, no significant associations were seen between gender and educational level with the fatty liver index. CONCLUSIONS A more vulnerable SES is associated with NAFLD. Fatty liver index and socioeconomic indicators can be powerful monitoring tools to monitor health differences in diagnosing NAFLD.
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Affiliation(s)
- Zahra Sadeghianpour
- Department of Epidemiology, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Bahman Cheraghian
- Department of Biostatistics and Epidemiology, Alimentary Tract Research Center, Clinical Sciences Research Institute, School of Public Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hamid Reza Farshchi
- MRC/ARUK Centre for Musculoskeletal Ageing Research, National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, NG7 2UH, UK
| | - Mohsen Asadi-Lari
- Department of Epidemiology, School of Public Health, Iran University of Medical Sciences, Tehran, Iran.
- Oncopathology Research Centre, Iran University of Medical Sciences, Tehran, Iran.
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13
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Ito T, Morooka H, Takahashi H, Fujii H, Iwaki M, Hayashi H, Toyoda H, Oeda S, Hyogo H, Kawanaka M, Morishita A, Munekage K, Kawata K, Tsutsumi T, Sawada K, Maeshiro T, Tobita H, Yoshida Y, Naito M, Araki A, Arakaki S, Kawaguchi T, Noritake H, Ono M, Masaki T, Yasuda S, Tomita E, Yoneda M, Tokushige A, Ishigami M, Kamada Y, Ueda S, Aishima S, Sumida Y, Nakajima A, Okanoue T. Identification of clinical phenotypes associated with poor prognosis in patients with nonalcoholic fatty liver disease via unsupervised machine learning. J Gastroenterol Hepatol 2023; 38:1832-1839. [PMID: 37596843 DOI: 10.1111/jgh.16326] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 07/22/2023] [Accepted: 08/01/2023] [Indexed: 08/20/2023]
Abstract
BACKGROUND AND AIMS Both fibrosis status and body weight are important for assessing prognosis in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to identify population clusters for specific clinical outcomes based on fibrosis-4 (FIB-4) index and body mass index (BMI) using an unsupervised machine learning method. METHODS We conducted a multicenter study of 1335 biopsy-proven NAFLD patients from Japan. Using the Gaussian mixture model to divide the cohort into clusters based on FIB-4 index and BMI, we investigated prognosis for these clusters. RESULTS The cohort consisted of 223 cases (16.0%) with advanced fibrosis (F3-4) as assessed from liver biopsy. Median values of BMI and FIB-4 index were 27.3 kg/m2 and 1.67. The patients were divided into four clusters by Bayesian information criterion, and all-cause mortality was highest in cluster d, followed by cluster b (P = 0.001). Regarding the characteristics of each cluster, clusters d and b presented a high FIB-4 index (median 5.23 and 2.23), cluster a presented the lowest FIB-4 index (median 0.78), and cluster c was associated with moderate FIB-4 level (median 1.30) and highest BMI (median 34.3 kg/m2 ). Clusters a and c had lower mortality rates than clusters b and d. However, all-cause of death in clusters a and c was unrelated to liver disease. CONCLUSIONS Our clustering approach found that the FIB-4 index is an important predictor of mortality in NAFLD patients regardless of BMI. Additionally, non-liver-related diseases were identified as the causes of death in NAFLD patients with low FIB-4 index.
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Affiliation(s)
- Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hikaru Morooka
- Department of Emergency and Critical Care Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | | | - Hideki Fujii
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Michihiro Iwaki
- Division of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hideki Hayashi
- Department of Gastroenterology and Hepatology, Gifu Municipal Hospital, Gifu, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Satoshi Oeda
- Liver Center, Saga University Hospital, Saga, Japan
- Department of Laboratory Medicine, Saga University Hospital, Saga, Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology, JA Hiroshima Kouseiren General Hospital, Hiroshima, Japan
- Hyogo Life Care Clinic Hiroshima, Hiroshima, Japan
| | - Miwa Kawanaka
- Department of General Internal Medicine 2, Kawasaki Medical Center, Kawasaki Medical School, Okayama, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Takamatsu, Japan
| | - Kensuke Munekage
- Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan
| | - Kazuhito Kawata
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Tsubasa Tsutsumi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Koji Sawada
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Japan
| | - Tatsuji Maeshiro
- First Department of Internal Medicine, University of the Ryukyus Hospital, Okinawa, Japan
| | - Hiroshi Tobita
- Division of Hepatology, Shimane University Hospital, Izumo, Japan
| | - Yuichi Yoshida
- Department of Gastroenterology and Hepatology, Suita Municipal Hospital, Osaka, Japan
| | - Masafumi Naito
- Department of Gastroenterology and Hepatology, Suita Municipal Hospital, Osaka, Japan
| | - Asuka Araki
- Division of Hepatology, Shimane University Hospital, Izumo, Japan
| | - Shingo Arakaki
- First Department of Internal Medicine, University of the Ryukyus Hospital, Okinawa, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Hidenao Noritake
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Masafumi Ono
- Division of Innovative Medicine for Hepatobiliary and Pancreatology, Faculty of Medicine, Kagawa University, Takamatsu, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Takamatsu, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Eiichi Tomita
- Department of Gastroenterology and Hepatology, Gifu Municipal Hospital, Gifu, Japan
| | - Masato Yoneda
- Division of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Akihiro Tokushige
- Department of Cardiovascular Medicine and Hypertension, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshihiro Kamada
- Department of Advanced Metabolic Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Shinichiro Ueda
- Department of Clinical Pharmacology and Therapeutics, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Shinichi Aishima
- Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga, Japan
| | - Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Japan
| | - Atsushi Nakajima
- Division of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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14
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Seko Y, Yamaguchi K, Shima T, Iwaki M, Takahashi H, Kawanaka M, Tanaka S, Mitsumoto Y, Yoneda M, Nakajima A, Fjellström O, Blau JE, Carlsson B, Okanoue T, Itoh Y. The greater impact of PNPLA3 polymorphism on liver-related events in Japanese non-alcoholic fatty liver disease patients: A multicentre cohort study. Liver Int 2023; 43:2210-2219. [PMID: 37470077 DOI: 10.1111/liv.15678] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 06/25/2023] [Accepted: 07/06/2023] [Indexed: 07/21/2023]
Abstract
BACKGROUND & AIMS PNPLA3 rs738409 has been associated with an increased risk of liver-related events in patients with non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the epidemiology of NAFLD and the impact of PNPLA3 on prognosis in Japan. METHODS A longitudinal multicentre cohort study, the JAGUAR study, includes 1550 patients with biopsy-proven NAFLD in Japan. We performed genetic testing and evaluated outcomes from this cohort. Liver-related events were defined as hepatocellular carcinoma (HCC) and decompensated liver cirrhosis events. RESULTS During follow-up (median [range], 7.1 [1.0-24.0] years), 80 patients developed HCC, 104 developed liver-related events, and 59 died of any cause. The 5-year rate of liver-related events for each single-nucleotide polymorphism was 0.5% for CC, 3.8% for CG, and 5.8% for GG. Liver-related deaths were the most common (n = 28); only three deaths were due to cardiovascular disease. Multivariate analysis identified carriage of PNPLA3 CG/GG (hazard ratio [HR] 16.04, p = .006) and FIB-4 index >2.67 (HR 10.70, p < .01) as predictors of liver-related event development. No HCC or liver-related death was found among patients with PNPLA3 CC. There was a significantly increased risk of HCC, liver-related events, and mortality for CG/GG versus CC, but no difference between the CG and GG genotypes. CONCLUSIONS In Japanese individuals, the main cause of death from NAFLD is liver-related death. The greater risk of liver-related events incurred by PNPLA3 G allele was shown in Japan. Risk stratification for NAFLD in Japan is best accomplished by integrating PNPLA3 with the FIB-4 index.
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Affiliation(s)
- Yuya Seko
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kanji Yamaguchi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Toshihide Shima
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita, Japan
| | - Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | | | - Miwa Kawanaka
- General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama, Japan
| | - Saiyu Tanaka
- Center for Digestive and Liver Diseases, Nara City Hospital, Nara, Japan
| | - Yasuhide Mitsumoto
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Ola Fjellström
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Jenny E Blau
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | - Björn Carlsson
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Takeshi Okanoue
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita, Japan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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15
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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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16
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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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17
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Akuta N, Kawamura Y, Fujiyama S, Nakamichi K, Saegusa E, Ogura H, Kato M, Doi E, Inoue N, Sezaki H, Hosaka T, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Suzuki Y, Kumada H, Suzuki F. Treatment efficacy of diet and exercise program for fatty liver and pretreatment predictors. Hepatol Res 2023. [PMID: 36891614 DOI: 10.1111/hepr.13897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 01/13/2023] [Accepted: 02/27/2023] [Indexed: 03/10/2023]
Abstract
AIMS Both diet and exercise counseling are recommended for patients with fatty liver, including nonalcoholic fatty liver disease (NAFLD), to achieve weight loss goals. However, data evaluating treatment efficacy are limited. METHODS The subjects of this retrospective cohort study were 186 consecutive Japanese cases with fatty liver diagnosed by abdominal ultrasonography. Treatment efficacy and predictive factors of "Hospitalization Program for Improvement Purpose for Fatty Liver" as a combined diet and aerobic and resistance exercise program were evaluated according to the hospitalization group (153 cases) or the no hospitalization group (33 cases). To balance the confounding biases, treatment efficacy was evaluated using propensity score-matched analysis. In the hospitalization group, a diet of 25-30 kcal/kg multiplied by ideal body weight (BW) daily and aerobic and resistance exercise (exercise intensity of 4-5 metabolic equivalents daily, respectively) were performed for 6 days. RESULTS In liver function tests and BW at 6 months compared with baseline, the rates of decrease of the hospitalization group (24 cases) were significantly higher than those of the no hospitalization group (24 cases), using propensity score-matched analysis. In markers of glycolipid metabolism and ferritin levels, the rates of the hospitalization group were not different from those of the no hospitalization group. In the hospitalization group (153 cases), multivariate regression analysis identified the etiology of non-NAFLD, the presence of diabetes mellitus, and large waist circumference as independent predictors of decreased rates of hemoglobin A1c levels. CONCLUSION The diet and exercise program for fatty liver improved liver function tests and BW. Further study should be performed to develop a feasible and suitable program.
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Affiliation(s)
- Norio Akuta
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Yusuke Kawamura
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Shunichiro Fujiyama
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | | | - Eiji Saegusa
- Department of Rehabilitation, Toranomon Hospital, Tokyo, Japan
| | - Hidetoshi Ogura
- Department of Rehabilitation, Toranomon Hospital, Tokyo, Japan
| | - Masaki Kato
- Department of Rehabilitation, Toranomon Hospital, Tokyo, Japan
| | - Etsuko Doi
- Department of Nutrition, Toranomon Hospital, Tokyo, Japan
| | - Naoko Inoue
- Department of Nutrition, Toranomon Hospital, Tokyo, Japan
| | - Hitomi Sezaki
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Tetsuya Hosaka
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | | | - Satoshi Saitoh
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Yasuji Arase
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Kenji Ikeda
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Yoshiyuki Suzuki
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Hiromitsu Kumada
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Fumitaka Suzuki
- Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
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18
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Yamamoto R, Takeshita Y, Tsujiguchi H, Kannon T, Sato T, Hosomichi K, Suzuki K, Kita Y, Tanaka T, Goto H, Nakano Y, Yamashita T, Kaneko S, Tajima A, Nakamura H, Takamura T. Nutrigenetic interaction between apolipoprotein C3 polymorphism and fat intake in people with non-alcoholic fatty liver disease. Curr Dev Nutr 2023. [DOI: 10.1016/j.cdnut.2023.100051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2023] Open
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Hu R, Yang X, He X, Song G. The relationship between NAFLD and retinol-binding protein 4 - an updated systematic review and meta-analysis. Lipids Health Dis 2023; 22:8. [PMID: 36670387 PMCID: PMC9862531 DOI: 10.1186/s12944-022-01771-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 12/31/2022] [Indexed: 01/22/2023] Open
Abstract
PURPOSE Retinol-binding protein 4 (RBP4) has been considered to be related to metabolic related diseases, such as hyperuricemia, obesity, and diabetes mellitus. However, whether nonalcoholic fatty liver disease (NAFLD) is related to RBP4 is unclear. Previous studies on the relationship between NAFLD and RBP4 levels have yielded inconsistent results. Hence, this meta-analysis was aimed to clarify whether circulating RBP4 levels are in relation to the risk of NAFLD. METHODS A meta-analysis was performed by applying observational studies to evaluate circulating RBP4 levels and NAFLD. Eligible studies published up to September 23, 2022, were searched in Embase, PubMed, and Cochrane databases. RESULTS In this study, 17 cross-sectional studies involving 8423 participants were included. Results from a random effects model showed that circulating RBP4 levels were higher in NAFLD patients than non-NAFLD (standardized mean difference (SMD) 0.28; 95% confidence intervals (CI): 0.11-0.46, I2: 89.8%). This association was confirmed in the Yellow race. However, no significant association was noted in the Caucasian race. After excluding the morbidly obese Population from the weight loss study (n = 2), the results of the comparison remained largely unchanged (SMD 0.28; 95% CI: 0.10-0.47, I2: 90.8%). Remarkable publication bias was not found. Although considerable heterogeneity was observed among the studies, no potential sources of heterogeneity were found in the subgroup analysis. Diagnostic methods for NAFLD were determined to be a potential source of statistical heterogeneity in meta-regression. CONCLUSION The findings provide evidence that NAFLD patients exhibit higher levels of circulating RBP4 compared with controls, but high heterogeneity was observed. Thus, a high RBP4 level is probably a potential risk factor for NAFLD. To confirm the causal link between NAFLD and RBP4 level of causality, further prospective cohort studies are needed.
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Affiliation(s)
- Rui Hu
- grid.256883.20000 0004 1760 8442Department of Internal Medicine, Hebei Medical University, Shijiazhuang, 050017 Hebei People’s Republic of China ,grid.440208.a0000 0004 1757 9805Endocrinology Department, Hebei General Hospital, Shijiazhuang, 050051 Hebei People’s Republic of China
| | - Xiaoyue Yang
- grid.256883.20000 0004 1760 8442Department of Internal Medicine, Hebei Medical University, Shijiazhuang, 050017 Hebei People’s Republic of China ,grid.440208.a0000 0004 1757 9805Endocrinology Department, Hebei General Hospital, Shijiazhuang, 050051 Hebei People’s Republic of China
| | - Xiaoyu He
- grid.256883.20000 0004 1760 8442Department of Internal Medicine, Hebei Medical University, Shijiazhuang, 050017 Hebei People’s Republic of China ,grid.440208.a0000 0004 1757 9805Endocrinology Department, Hebei General Hospital, Shijiazhuang, 050051 Hebei People’s Republic of China
| | - Guangyao Song
- Endocrinology Department, Hebei General Hospital, Shijiazhuang, 050051, Hebei, People's Republic of China.
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Chen Y, Yan X, Wang T, Deng H, Deng X, Xu F, Liang H. PNPLA3 148M/M Is More Susceptible to Palmitic Acid-Induced Endoplasmic Reticulum Stress-Associated Apoptosis in HepG2 Cells. Int J Endocrinol 2023; 2023:2872408. [PMID: 36825197 PMCID: PMC9943609 DOI: 10.1155/2023/2872408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 11/16/2022] [Accepted: 11/22/2022] [Indexed: 02/16/2023] Open
Abstract
BACKGROUND Patatin-like phospholipase domain-containing 3 (PNPLA3) is a major susceptibility gene for nonalcoholic fatty liver disease (NAFLD), and its rs738409 (I148M) polymorphism is associated with the occurrence and progression of NAFLD. Endoplasmic reticulum (ER) stress-related hepatocyte lipoapoptosis contributes to the progress of NAFLD. PNPLA3 is also known as a member of the calcium-independent phospholipase A2ε family, which can hydrolyze fatty acids to generate lysophosphatidylcholine (LPC) that induces ER stress-related hepatocyte lipoapoptosis. Whether the PNPLA3 risk genotype 148M/M is involved in more severe ER stress-associated lipoapoptosis is unclear. METHODS A PNPLA3148I knock-in HepG2 cell model was constructed based on HepG2 expressing PNPLA3 148M/M using the Cas9/sgRNA system. PNPLA3 148M/M, I/M, and I/I cells were treated with 0.3 mM palmitic acid (PA) for 24 h to induce lipid deposition. Cellular lipid deposition was detected by oil red staining. Apoptosis was observed by TUNEL. LPC was determined by ELISA, and the expression of PNPLA3, the ER stress marker Bip, molecules involved in the ER stress PERK/elF-2a pathway, and its downstream C/EBP homologous protein (CHOP)-mediated apoptotic pathway were detected by western blot. RESULTS The results showed no difference in PNPLA3 basal expression and basal hepatocyte lipid content between the three genotypes of cells. Lipid deposition and apoptosis were more severe in PNPLA3 148M/M and 148I/M cells than in I/I cells after PA treatment. PA-induced upregulation of protein expression of Bip, ER stress-responsive PERK pathway molecules p-PERK, p-eIF2α, CHOP, and CHOP-associated apoptotic molecules PUMA and Bax were more pronounced in PNPLA3 148M/M cells than in PNPLA3 148I/I cells. The basal LPC levels and the PA-treated increase of LPC levels in the cell culture supernatants did not differ between the three genotypic cells. CONCLUSION PNPLA3 148M/M cells were more susceptible to PA-induced lipid deposition and ER stress-related apoptosis than 148I/I cells, and the proapoptotic susceptibility of PNPLA3 148M/M is independent of LPC.
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Affiliation(s)
- Yunzhi Chen
- Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
- Guangdong Provincial People's Hospital, Guangzhou 510080, China
| | - Xuemei Yan
- Department of Endocrinology and Metabolism, Joint Service Support Force 903 Hospital, Hangzhou 310005, China
| | - Tian Wang
- Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
| | - Hongrong Deng
- Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
| | - Xiaojie Deng
- Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
| | - Fen Xu
- Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
| | - Hua Liang
- Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
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21
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Shah PA, Patil R, Harrison SA. NAFLD-related hepatocellular carcinoma: The growing challenge. Hepatology 2023; 77:323-338. [PMID: 35478412 PMCID: PMC9970023 DOI: 10.1002/hep.32542] [Citation(s) in RCA: 99] [Impact Index Per Article: 49.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/15/2022] [Accepted: 02/17/2022] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a common cause of cancer-related mortality and morbidity worldwide. With the obesity pandemic, NAFLD-related HCC is contributing to the burden of disease exponentially. Genetic predisposition and clinical risk factors for NAFLD-related HCC have been identified. Cirrhosis is a well-known and major risk factor for NAFLD-related HCC. However, the occurrence of NAFLD-related HCC in patients without cirrhosis is increasingly recognized and poses a significant challenge regarding cancer surveillance. It is of paramount importance to develop optimal risk stratification scores and models to identify subsets of the population at high risk so they can be enrolled in surveillance programs. In this review, we will discuss the risks and prediction models for NAFLD-related HCC.
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Affiliation(s)
- Pir Ahmad Shah
- Department of Internal Medicine, University of Texas Health Science Center, San Antonio, Texas, USA
| | - Rashmee Patil
- South Texas Research Institute, Edinburg, Texas, USA
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22
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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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23
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Pansa CC, Molica LR, Moraes KCM. Non-alcoholic fatty liver disease establishment and progression: genetics and epigenetics as relevant modulators of the pathology. Scand J Gastroenterol 2022; 58:521-533. [PMID: 36426638 DOI: 10.1080/00365521.2022.2148835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) results from metabolic dysfunctions that affect more than one-third of the world population. Over the last decades, scientific investigations have clarified many details on the pathology establishment and development; however, effective therapeutics approaches are still evasive. In addition, studies demonstrated that NAFLD establishment and progression are related to several etiologies. Recently, genetics and epigenetics backgrounds have emerged as relevant elements to the pathology onset, and, hence, deserve deep investigation to clarify molecular details on NAFLD signaling, which may be correlated with population behavior. Thus, to minimize the global problem, public health and public policies should take advantage of studies on NAFLD over the next following decades. METHODS In this context, we have performed a selective literature review focusing on biochemistry of lipid metabolism, genetics, epigenetics, and the ethnicity as strong elements that drive NAFLD establishment. RESULTS Considering the etiological agents that acts on NAFLD development and progression, the genetics and the epigenetics emerged as relevant factors. Genetics acts as a powerful element in the establishment and progression of the NAFLD. Over the last decades, details concerning genes and their polymorphisms, as well as epigenetics, have been considered relevant elements in the systems biology of diseases, and their effects on NAFLD should be considered in-depth, as well as the ethnicity, clarifying whether people are susceptible to liver diseases. Moreover, the endemicity and social problems of hepatic disfunction are far to be solved, which require a combined effort of various sectors of society. CONCLUSION Hence, the elements presented and discussed in this short review demonstrated their relevance to the physiological control of NAFLD, opening perspectives for research to develop new strategy to treat fatty liver diseases.
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Affiliation(s)
- Camila Cristiane Pansa
- Departamento de Biologia Geral e Aplicada, Cellular Signalling and Gene Expression Laboratory, Universidade Estadual Paulista "Júlio de Mesquita Filho", Instituto de Biociências, Rio Claro, Brazil
| | - Letícia Ramos Molica
- Departamento de Biologia Geral e Aplicada, Cellular Signalling and Gene Expression Laboratory, Universidade Estadual Paulista "Júlio de Mesquita Filho", Instituto de Biociências, Rio Claro, Brazil
| | - Karen C M Moraes
- Departamento de Biologia Geral e Aplicada, Cellular Signalling and Gene Expression Laboratory, Universidade Estadual Paulista "Júlio de Mesquita Filho", Instituto de Biociências, Rio Claro, Brazil
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24
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Kimura M, Iguchi T, Iwasawa K, Dunn A, Thompson WL, Yoneyama Y, Chaturvedi P, Zorn AM, Wintzinger M, Quattrocelli M, Watanabe-Chailland M, Zhu G, Fujimoto M, Kumbaji M, Kodaka A, Gindin Y, Chung C, Myers RP, Subramanian GM, Hwa V, Takebe T. En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH. Cell 2022; 185:4216-4232.e16. [PMID: 36240780 PMCID: PMC9617783 DOI: 10.1016/j.cell.2022.09.031] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 08/01/2022] [Accepted: 09/23/2022] [Indexed: 11/07/2022]
Abstract
Genotype-phenotype associations for common diseases are often compounded by pleiotropy and metabolic state. Here, we devised a pooled human organoid-panel of steatohepatitis to investigate the impact of metabolic status on genotype-phenotype association. En masse population-based phenotypic analysis under insulin insensitive conditions predicted key non-alcoholic steatohepatitis (NASH)-genetic factors including the glucokinase regulatory protein (GCKR)-rs1260326:C>T. Analysis of NASH clinical cohorts revealed that GCKR-rs1260326-T allele elevates disease severity only under diabetic state but protects from fibrosis under non-diabetic states. Transcriptomic, metabolomic, and pharmacological analyses indicate significant mitochondrial dysfunction incurred by GCKR-rs1260326, which was not reversed with metformin. Uncoupling oxidative mechanisms mitigated mitochondrial dysfunction and permitted adaptation to increased fatty acid supply while protecting against oxidant stress, forming a basis for future therapeutic approaches for diabetic NASH. Thus, "in-a-dish" genotype-phenotype association strategies disentangle the opposing roles of metabolic-associated gene variant functions and offer a rich mechanistic, diagnostic, and therapeutic inference toolbox toward precision hepatology. VIDEO ABSTRACT.
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Affiliation(s)
- Masaki Kimura
- Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Takuma Iguchi
- Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Kentaro Iwasawa
- Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Andrew Dunn
- Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Wendy L Thompson
- Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Yosuke Yoneyama
- Institute of Research, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan
| | - Praneet Chaturvedi
- Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Aaron M Zorn
- Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Michelle Wintzinger
- Division of Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Mattia Quattrocelli
- Division of Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
| | - Miki Watanabe-Chailland
- NMR-Based Metabolomics Core Facility, Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Gaohui Zhu
- Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Masanobu Fujimoto
- Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Meenasri Kumbaji
- Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Asuka Kodaka
- Communication Design Center, Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan
| | | | | | - Robert P Myers
- Gilead Sciences, Foster City, CA 94404, USA; The Liver Company, Inc., Palo Alto, CA 94303, USA
| | - G Mani Subramanian
- Gilead Sciences, Foster City, CA 94404, USA; The Liver Company, Inc., Palo Alto, CA 94303, USA
| | - Vivian Hwa
- Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Takanori Takebe
- Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Institute of Research, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan; Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Communication Design Center, Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan.
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25
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Ivashkin VT, Maevskaya MV, Zharkova MS, Kotovskaya YV, Tkacheva ON, Troshina EA, Shestakova MV, Maev IV, Breder VV, Gheivandova NI, Doshchitsin VL, Dudinskaya EN, Ershova EV, Kodzoeva KB, Komshilova KA, Korochanskaya NV, Mayorov AY, Mishina EE, Nadinskaya MY, Nikitin IG, Pogosova NV, Tarzimanova AI, Shamkhalova MS. Clinical Practice Guidelines of the Russian Scientific Liver Society, Russian Gastroenterological Association, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians and National Society for Preventive Cardiology on Diagnosis and Treatment of Non-Alcoholic Liver Disease. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2022; 32:104-140. [DOI: 10.22416/1382-4376-2022-32-4-104-140] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Aim:present clinical guidelines, aimed at general practitioners, gastroenterologists, cardiologists, endocrinologists, comprise up-to-date methods of diagnosis and treatment of non-alcoholic fatty liver disease.Key points.Nonalcoholic fatty liver disease, the most wide-spread chronic liver disease, is characterized by accumulation of fat by more than 5 % of hepatocytes and presented by two histological forms: steatosis and nonalcoholic steatohepatitis. Clinical guidelines provide current views on pathogenesis of nonalcoholic fatty liver disease as a multisystem disease, methods of invasive and noninvasive diagnosis of steatosis and liver fibrosis, principles of nondrug treatment and pharmacotherapy of nonalcoholic fatty liver disease and associated conditions. Complications of nonalcoholic fatty liver disease include aggravation of cardiometabolic risks, development of hepatocellular cancer, progression of liver fibrosis to cirrhotic stage.Conclusion.Progression of liver disease can be avoided, cardiometabolic risks can be reduced and patients' prognosis — improved by the timely recognition of diagnosis of nonalcoholic fatty liver disease and associated comorbidities and competent multidisciplinary management of these patients.
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Affiliation(s)
| | | | | | - Yu. V. Kotovskaya
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
| | - O. N. Tkacheva
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
| | | | | | - I. V. Maev
- Yevdokimov Moscow State University of Medicine and Dentistry
| | - V. V. Breder
- Blokhin National Medical Research Center of Oncology
| | | | | | - E. N. Dudinskaya
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
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26
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Fukushima M, Miyaaki H, Sasaki R, Haraguchi M, Miuma S, Hara T, Soyama A, Hidaka M, Eguchi S, Nakao K. Most Cases of Cryptogenic Cirrhosis May be Nonobese Nonalcoholic Steatohepatitis-Risk Factors of Liver Steatosis After Liver Transplantation for Cryptogenic Cirrhosis: A Retrospective Study. Intern Med 2022; 62:1415-1423. [PMID: 36171128 DOI: 10.2169/internalmedicine.0514-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Aim The course of cryptogenic cirrhosis (CC) after liver transplantation (LT) is unknown. We therefore clarified the natural course post-LT for CC and investigated the etiology of CC. Methods Eighteen patients who underwent LT for CC were included. To rule out the possibility of NASH in patients with CC, those with a history of obesity or liver steatosis found pretransplantation were excluded. A liver biopsy was performed one year after LT and annually thereafter. Results Liver steatosis and steatohepatitis were identified in 61% and 39% of patients after LT, respectively, with a median time to the onset of 12 and 27 months, respectively. There were no other pathological findings such as liver allograft rejection, autoimmune hepatitis, or primary biliary cholangitis. The body mass index after LT (28.5 vs. 22.4 kg/m2; P=0.002) and mean muscle attenuation at the time of LT were significantly higher (33.3 vs. 25.8 Hounsfield units, P=0.03) and the postoperative hospitalization period shorter (50 vs. 102 days; P=0.02) in the steatosis group than in the non-steatosis group. Recipients were significantly younger in the steatohepatitis subgroup than in the simple steatosis subgroup (55.0 vs. 63.5 years old; P=0.04). Conclusions Despite excluding CC patients with a history of obesity, we observed that patients with CC had a high prevalence of steatosis after LT than those without CC. Young patients with a favorable postoperative course were noted to have a high risk of NASH after LT for CC. Patients with CC may represent cases of non-obese NASH.
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Affiliation(s)
- Masanori Fukushima
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Hisamitsu Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Ryu Sasaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Masafumi Haraguchi
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Satoshi Miuma
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Takanobu Hara
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Akihiko Soyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Masaaki Hidaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Japan
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Nakatsuka T, Tateishi R, Koike K. Changing clinical management of NAFLD in Asia. Liver Int 2022; 42:1955-1968. [PMID: 34459096 DOI: 10.1111/liv.15046] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/30/2021] [Accepted: 08/21/2021] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, affecting approximately 25% of the world's population. Recently, because of the sedentary lifestyle and overnutrition resulting from urbanisation, the burden of NAFLD has rapidly increased in many Asian countries. Currently, the prevalence of NAFLD in Asia is approximately 30%, as is the case in many Western countries. In Asia, the prevalence and presentation of NAFLD vary widely across regions because of the substantial diversity in race, socioeconomic status and living environment. Furthermore, the dual aetiology of fatty liver, particularly with viral hepatitis in Asia, makes it complex and challenging to manage. Because Asians are likely to have central adiposity and insulin resistance, approximately 7%-20% of non-obese Asians with body mass indexes of less than 25 kg/m2 are estimated to have NAFLD. Accumulating evidence indicates that NAFLD is associated with various extrahepatic comorbidities such as cardiovascular disease, chronic kidney disease, malignancy, in addition to liver-specific complications. Therefore, NAFLD should be managed as a multisystem disease in conjunction with metabolic syndrome. Lifestyle modification remains the basis of NAFLD management, but few patients can achieve adequate weight loss and maintain it long term. While various pharmacological agents are in phase 3 trials for steatohepatitis, Asian patients are underrepresented in most trials. This article reviews the epidemiological trends, clinical features, optimal assessment and current management practices for NAFLD in Asia.
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Affiliation(s)
- Takuma Nakatsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
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28
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Qiao M, Yang JH, Zhu Y, Hu JP. Association of sorting and assembly machinery component 50 homolog gene polymorphisms with nonalcoholic fatty liver disease susceptibility. Medicine (Baltimore) 2022; 101:e29958. [PMID: 35866791 PMCID: PMC9302252 DOI: 10.1097/md.0000000000029958] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Sorting and assembly machinery component 50 homolog (SAMM50) gene single-nucleotide polymorphisms (SNPs) have been connected with the susceptibility of nonalcoholic fatty liver disease (NAFLD), but with inconsistent results across the current evidence. The present work was schemed to explore the association between SAMM50 gene SNPs and NAFLD vulnerability via meta-analysis. METHODS PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang were retrieved for eligible literature previous to June 10, 2021. The odds ratios (ORs) of the dichotomic variables and the standardized mean difference of quantitative variables with corresponding 95% confidence intervals (95% CIs) were computed to evaluate the strength of the associations. The quality of included studies was assessed using Newcastle-Ottawa Scale (NOS). RESULTS In total, 8 case-control studies encompassing 6297 NAFLD patients and 7306 disease-free controls in this meta-analysis. Ultimately, this analysis included 8, 6, and 5 studies for rs2143571, rs3761472, and rs738491 polymorphisms respectively. The pooled data revealed that the 3 polymorphisms had conspicuous associations with NAFLD susceptibility: rs2143571, A vs. G, OR=1.51, 95% CI, 1.37-1.66, P < .01; rs3761472, A vs. G, OR=1.50, 95% CI, 1.35-1.67, P < .01; rs738491, A vs. G, OR=1.51, 95% CI, 1.40-1.63, P < .01. CONCLUSION This meta-analysis suggests that rs2143571, rs3761472, and rs738491 polymorphisms of the SAMM50 gene are appreciably associated with augmented risk of NAFLD vulnerability. It will provide the latest evidence to support the susceptibility of SAMM50 gene polymorphisms and NAFLD, and provide strategies for the prevention and treatment of NAFLD.
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Affiliation(s)
- Ming Qiao
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Jian-hua Yang
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Yi Zhu
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Jun-ping Hu
- College of Pharmacy, Xinjiang Medical University, Urumqi, China
- * Correspondence: Jun-ping Hu, College of Pharmacy, Xinjiang Medical University, 137 Liyushan Avenue, Xinshi District, Urumqi, Xinjiang 830017, China (e-mail: )
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Zhao W, Mori H, Tomiga Y, Tanaka K, Perveen R, Mine K, Inadomi C, Yoshioka W, Kubotsu Y, Isoda H, Kuwashiro T, Oeda S, Akiyama T, Zhao Y, Ozaki I, Nagafuchi S, Kawaguchi A, Aishima S, Anzai K, Takahashi H. HSPA8 Single-Nucleotide Polymorphism Is Associated with Serum HSC70 Concentration and Carotid Artery Atherosclerosis in Nonalcoholic Fatty Liver Disease. Genes (Basel) 2022; 13:genes13071265. [PMID: 35886046 PMCID: PMC9323248 DOI: 10.3390/genes13071265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 07/01/2022] [Accepted: 07/14/2022] [Indexed: 11/29/2022] Open
Abstract
There is an association between nonalcoholic fatty liver disease (NAFLD) and atherosclerosis, but the genetic risk of atherosclerosis in NAFLD remains unclear. Here, a single-nucleotide polymorphism (SNP) of the heat shock 70 kDa protein 8 (HSPA8) gene was analyzed in 123 NAFLD patients who had been diagnosed using a liver biopsy, and the NAFLD phenotype including the maximum intima–media thickness (Max-IMT) of the carotid artery was investigated. Patients with the minor allele (A/G or G/G) of rs2236659 showed a lower serum heat shock cognate 71 kDa protein concentration than those with the major A/A allele. Compared with the patients with the major allele, those with the minor allele showed a higher prevalence of hypertension and higher Max-IMT in men. No significant associations between the HSPA8 genotype and hepatic pathological findings were identified. In decision-tree analysis, age, sex, liver fibrosis, and HSPA8 genotype were individually associated with severe carotid artery atherosclerosis (Max-IMT ≥ 1.5 mm). Noncirrhotic men aged ≥ 65 years were most significantly affected by the minor allele of HSPA8. To predict the risk of atherosclerosis and cardiovascular disease, HSPA8 SNP genotyping might be useful, particularly for older male NAFLD patients.
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Affiliation(s)
- Wenli Zhao
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
- Liver Center, Saga University Hospital Faculty of Medicine, Saga University, Saga 849-8501, Japan; (H.I.); (S.O.)
| | - Hitoe Mori
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Yuki Tomiga
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Kenichi Tanaka
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Rasheda Perveen
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Keiichiro Mine
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
- Division of Mucosal Immunology, Research Center for Systems Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
| | - Chika Inadomi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Wataru Yoshioka
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Yoshihito Kubotsu
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Hiroshi Isoda
- Liver Center, Saga University Hospital Faculty of Medicine, Saga University, Saga 849-8501, Japan; (H.I.); (S.O.)
| | - Takuya Kuwashiro
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Satoshi Oeda
- Liver Center, Saga University Hospital Faculty of Medicine, Saga University, Saga 849-8501, Japan; (H.I.); (S.O.)
| | - Takumi Akiyama
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Ye Zhao
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250014, China;
| | - Iwata Ozaki
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
- Health Administration Centre, Saga Medical School, Saga University, Saga 849-8501, Japan
| | - Seiho Nagafuchi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Atsushi Kawaguchi
- Education and Research Center for Community Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan;
| | - Shinichi Aishima
- Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga 849-8501, Japan;
| | - Keizo Anzai
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
- Liver Center, Saga University Hospital Faculty of Medicine, Saga University, Saga 849-8501, Japan; (H.I.); (S.O.)
- Correspondence:
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Mitsala A, Tsalikidis C, Romanidis K, Pitiakoudis M. Non-Alcoholic Fatty Liver Disease and Extrahepatic Cancers: A Wolf in Sheep’s Clothing? Curr Oncol 2022; 29:4478-4510. [PMID: 35877216 PMCID: PMC9325209 DOI: 10.3390/curroncol29070356] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/23/2022] [Accepted: 06/23/2022] [Indexed: 12/02/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is now considered the main driver and leading cause of chronic liver disease globally. The umbrella term NAFLD describes a range of liver conditions closely related to insulin resistance, metabolic syndrome, diabetes mellitus, obesity, and dyslipidemia. At the same time, several malignancies, including hepatocellular carcinoma and colorectal cancer, are considered to be common causes of death among patients with NAFLD. At first, our review herein aims to investigate the role of NAFLD in developing colorectal neoplasms and adenomatous polyps based on the current literature. We will also explore the connection and the missing links between NAFLD and extrahepatic cancers. Interestingly, any relationship between NAFLD and extrahepatic malignancies could be attributable to several shared metabolic risk factors. Overall, obesity, insulin resistance, metabolic syndrome, and related disorders may increase the risk of developing cancer. Therefore, early diagnosis of NAFLD is essential for preventing the progression of the disease and avoiding its severe complications. In addition, cancer screening and early detection in these patients may improve survival and reduce any delays in treatment.
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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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Potential Therapeutic Targets and Promising Agents for Combating NAFLD. Biomedicines 2022; 10:biomedicines10040901. [PMID: 35453652 PMCID: PMC9032837 DOI: 10.3390/biomedicines10040901] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 01/25/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is a growing cause of liver cirrhosis and liver cancer worldwide because of the global increases in obesity, dyslipidemia, hypertension, and type 2 diabetes mellitus. Contrary to the advancements in therapies for viral hepatitis, effective treatments remain unestablished for patients with NAFLD. NAFLD, including NASH, is characterized by steatosis, inflammation, hepatic necrosis, and fibrosis. Despite our understanding of its pathophysiology, there are currently no effective treatments for NAFLD. In this review, we provide an update on the known pathophysiological mechanisms involved in the development of NAFLD and the role of hepatic stellate cells, and summarize the potential therapeutic agents, including natural products, for NAFLD.
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Squalene through Its Post-Squalene Metabolites Is a Modulator of Hepatic Transcriptome in Rabbits. Int J Mol Sci 2022; 23:ijms23084172. [PMID: 35456988 PMCID: PMC9031321 DOI: 10.3390/ijms23084172] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/08/2022] [Accepted: 04/08/2022] [Indexed: 02/04/2023] Open
Abstract
Squalene is a natural bioactive triterpene and an important intermediate in the biosynthesis of sterols. To assess the effect of this compound on the hepatic transcriptome, RNA-sequencing was carried out in two groups of male New Zealand rabbits fed either a diet enriched with 1% sunflower oil or the same diet with 0.5% squalene for 4 weeks. Hepatic lipids, lipid droplet area, squalene, and sterols were also monitored. The Squalene administration downregulated 9 transcripts and upregulated 13 transcripts. The gene ontology of transcripts fitted into the following main categories: transporter of proteins and sterols, lipid metabolism, lipogenesis, anti-inflammatory and anti-cancer properties. When the results were confirmed by RT-qPCR, rabbits receiving squalene displayed significant hepatic expression changes of LOC100344884 (PNPLA3), GCK, TFCP2L1, ASCL1, ACSS2, OST4, FAM91A1, MYH6, LRRC39, LOC108176846, GLT1D1 and TREH. A squalene-enriched diet increased hepatic levels of squalene, lanosterol, dihydrolanosterol, lathosterol, zymostenol and desmosterol. Strong correlations were found among specific sterols and some squalene-changed transcripts. Incubation of the murine AML12 hepatic cell line in the presence of lanosterol, dihydrolanosterol, zymostenol and desmosterol reproduced the observed changes in the expressions of Acss2, Fam91a1 and Pnpla3. In conclusion, these findings indicate that the squalene and post-squalene metabolites play important roles in hepatic transcriptional changes required to protect the liver against malfunction.
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Youssef SS, Abbas EAER, Youness RA, Elemeery MN, Nasr AS, Seif S. PNPLA3 and IL 28B signature for predicting susceptibility to chronic hepatitis C infection and fibrosis progression. Arch Physiol Biochem 2022; 128:483-489. [PMID: 31793339 DOI: 10.1080/13813455.2019.1694039] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Association studies identified genetic polymorphisms as predictive risk factors of rapid fibrosis progression in chronic hepatitis C (CHC). This study aims to assess the impact of IL28B rs8099917 polymorphism on CHC genotype 4 (G4) susceptibility and liver fibrosis progression individually; and in combination with PNPLA3 rs738409. PATIENTS AND METHODS IL28B rs8099917 and PNPLA3 rs738409 were genotyped in 150 Egyptian CHC patients and 175 healthy controls using real-time PCR. RESULTS IL28B rs8099917 genotype distribution significantly differs in healthy individuals versus CHC patients (p = .018); and in low versus advanced fibrosis IL28B (p = .013). The haplotype CC -GG (PNPLA3-IL28B) is considered a high-risk signature for susceptibility to CHC infection. Similarly, GG-GG (PNPLA3-IL28B) is considered a high-risk signature for higher degree of fibrosis. CONCLUSION IL28B rs8099917 and PNPLA3 rs738409 introduce genetic signature to identify patients at higher risk for CHC susceptibility and fibrosis progression in CHC G4.
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Affiliation(s)
- Samar Samir Youssef
- Microbial Biotechnology Department, Genetic Engineering and Biotechnology Division, National Research Centre, Dokki, Egypt
| | - Eman Abd El Razek Abbas
- Microbial Biotechnology Department, Genetic Engineering and Biotechnology Division, National Research Centre, Dokki, Egypt
| | - Rana Ahmed Youness
- Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Moustafa Nouh Elemeery
- Microbial Biotechnology Department, Genetic Engineering and Biotechnology Division, National Research Centre, Dokki, Egypt
- Département de Neurosciences, CRCHUM, Université de Montréal, Montréal, Quebec, Canada
| | - Amal Soliman Nasr
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Sameh Seif
- National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
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Maevskaya M, Kotovskaya Y, Ivashkin V, Tkacheva O, Troshina E, Shestakova M, Breder V, Geyvandova N, Doschitsin V, Dudinskaya E, Ershova E, Kodzoeva K, Komshilova K, Korochanskaya N, Mayorov A, Mishina E, Nadinskaya M, Nikitin I, Pogosova N, Tarzimanova A, Shamkhalova M. The National Consensus statement on the management of adult patients with non-alcoholic fatty liver disease and main comorbidities. TERAPEVT ARKH 2022; 94:216-253. [PMID: 36286746 DOI: 10.26442/00403660.2022.02.201363] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Indexed: 12/15/2022]
Abstract
The National Consensus was prepared with the participation of the National Medical Association for the Study of the Multimorbidity, Russian Scientific Liver Society, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians, National Society for Preventive Cardiology, Professional Foundation for the Promotion of Medicine Fund PROFMEDFORUM.
The aim of the multidisciplinary consensus is a detailed analysis of the course of non-alcoholic fatty liver disease (NAFLD) and the main associated conditions. The definition of NAFLD is given, its prevalence is described, methods for diagnosing its components such as steatosis, inflammation and fibrosis are described.
The association of NAFLD with a number of cardio-metabolic diseases (arterial hypertension, atherosclerosis, thrombotic complications, type 2 diabetes mellitus (T2DM), obesity, dyslipidemia, etc.), chronic kidney disease (CKD) and the risk of developing hepatocellular cancer (HCC) were analyzed. The review of non-drug methods of treatment of NAFLD and modern opportunities of pharmacotherapy are presented.
The possibilities of new molecules in the treatment of NAFLD are considered: agonists of nuclear receptors, antagonists of pro-inflammatory molecules, etc. The positive properties and disadvantages of currently used drugs (vitamin E, thiazolidinediones, etc.) are described. Special attention is paid to the multi-target ursodeoxycholic acid (UDCA) molecule in the complex treatment of NAFLD as a multifactorial disease. Its anti-inflammatory, anti-oxidant and cytoprotective properties, the ability to reduce steatosis an independent risk factor for the development of cardiovascular pathology, reduce inflammation and hepatic fibrosis through the modulation of autophagy are considered.
The ability of UDCA to influence glucose and lipid homeostasis and to have an anticarcinogenic effect has been demonstrated. The Consensus statement has advanced provisions for practitioners to optimize the diagnosis and treatment of NAFLD and related common pathogenetic links of cardio-metabolic diseases.
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Lee KJ, Moon JS, Kim NY, Ko JS. Effects of PNPLA3, TM6SF2 and SAMM50 on the development and severity of non-alcoholic fatty liver disease in children. Pediatr Obes 2022; 17:e12852. [PMID: 34490745 DOI: 10.1111/ijpo.12852] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 08/09/2021] [Accepted: 08/16/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Although genetic variants of PNPLA3, TM6SF2 and SAMM50 have been reported to increase the risk of non-alcoholic fatty liver disease (NAFLD), no pediatric studies have evaluated the association between SAMM50 and NAFLD. OBJECTIVE This study aimed to investigate the risk factors, including genetic variants, of pediatric NAFLD. METHODS NAFLD was defined as the presence of hepatic steatosis on ultrasound. We included 228 patients with NAFLD (body mass index-Z [BMI-Z] = 2.51 ± 1.01) and 225 controls (BMI-Z = 0.22 ± 1.48). We genotyped four variants of PNPLA3 (rs738409), TM6SF2 (rs58542926) and SAMM50 (rs2073080 and rs3761472) by TaqMan allelic discrimination. The pediatric NAFLD fibrosis score, aspartate transaminase (AST)/platelet ratio index and fibrosis-4 score were used to evaluate the degree of fibrosis. We calculated the genetic risk score for additive effects according to the sum of risk alleles. RESULTS The mean age was 12.6 ± 3.5 years. The four genetic variants, male sex and BMI-Z, independently increased susceptibility to NAFLD. These four variants, in addition to fasting insulin and triglycerides, remained significant risk factors with higher odds ratios in children with overweight. These variants increased the alanine aminotransferase (ALT) level and three fibrosis scores independently. As the genetic risk score increased, AST, ALT and the fibrosis scores increased independently. CONCLUSION PNPLA3, TM6SF2 and SAMM50 are associated with the development and severity of pediatric NAFLD. The impact of genetic variants is greater in children with overweight. The four genetic variants have synergetic effects on the severity of pediatric NAFLD.
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Affiliation(s)
- Kyung Jae Lee
- Department of Pediatrics, Hallym University College of Medicine, Chuncheon, South Korea
| | - Jin Soo Moon
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, South Korea
| | - Nan Young Kim
- Hallym Institute of Translational Genomics & Bioinformatics, Hallym University Medical Center, Anyang, Republic of Korea
| | - Jae Sung Ko
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, South Korea
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Fairfield CJ, Drake TM, Pius R, Bretherick AD, Campbell A, Clark DW, Fallowfield JA, Hayward C, Henderson NC, Joshi PK, Mills NL, Porteous DJ, Ramachandran P, Semple RK, Shaw CA, Sudlow CL, Timmers PR, Wilson JF, Wigmore SJ, Harrison EM, Spiliopoulou A. Genome-Wide Association Study of NAFLD Using Electronic Health Records. Hepatol Commun 2022; 6:297-308. [PMID: 34535985 PMCID: PMC8793997 DOI: 10.1002/hep4.1805] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 07/04/2021] [Indexed: 12/20/2022] Open
Abstract
Genome-wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co-existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta-analysis using available summary association statistics. Six risk loci were identified (P < 5*10-8 ) (apolipoprotein E [APOE], patatin-like phospholipase domain containing 3 [PNPLA3, transmembrane 6 superfamily member 2 [TM6SF2], glucokinase regulator [GCKR], mitochondrial amidoxime reducing component 1 [MARC1], and tribbles pseudokinase 1 [TRIB1]). All loci retained significance in sensitivity analyses without co-existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta-analysis. Rs429358 (P = 2.17*10-11 ) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95% confidence interval 0.78-0.90] and homozygotes 0.64 [0.50-0.79]). Conclusion: This GWAS replicates six known NAFLD-susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches.
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Affiliation(s)
- Cameron J. Fairfield
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Thomas M. Drake
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Riinu Pius
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Andrew D. Bretherick
- MRC Human Genetics UnitInstitute of Genetics and CancerUniversity of EdinburghEdinburghScotland
| | - Archie Campbell
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
- Centre for Genomic and Experimental MedicineInstitute of Genetics & Molecular MedicineUniversity of EdinburghEdinburghScotland
- Health Data Research UKUniversity of EdinburghEdinburghScotland
| | - David W. Clark
- Centre for Global Health ResearchUsher InstituteUniversity of EdinburghEdingburghScotland
| | - Jonathan A. Fallowfield
- Centre for Inflammation ResearchQueen’s Medical Research InstituteUniversity of EdinburghEdingburghScotland
| | - Caroline Hayward
- MRC Human Genetics UnitInstitute of Genetics and CancerUniversity of EdinburghEdinburghScotland
| | - Neil C. Henderson
- Centre for Inflammation ResearchQueen’s Medical Research InstituteUniversity of EdinburghEdingburghScotland
| | - Peter K. Joshi
- Centre for Global Health ResearchUsher InstituteUniversity of EdinburghEdingburghScotland
| | - Nicholas L. Mills
- Centre for Cardiovascular ScienceQueen’s Medical Research InstituteUniversity of EdinburghEdingburghScotland
| | - David J. Porteous
- Centre for Genomic and Experimental MedicineInstitute of Genetics & Molecular MedicineUniversity of EdinburghEdinburghScotland
| | - Prakash Ramachandran
- Centre for Inflammation ResearchQueen’s Medical Research InstituteUniversity of EdinburghEdingburghScotland
| | - Robert K. Semple
- Centre for Cardiovascular ScienceQueen’s Medical Research InstituteUniversity of EdinburghEdingburghScotland
| | - Catherine A. Shaw
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Cathie L.M. Sudlow
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Paul R.H.J. Timmers
- MRC Human Genetics UnitInstitute of Genetics and CancerUniversity of EdinburghEdinburghScotland
- Centre for Global Health ResearchUsher InstituteUniversity of EdinburghEdingburghScotland
| | - James F. Wilson
- MRC Human Genetics UnitInstitute of Genetics and CancerUniversity of EdinburghEdinburghScotland
- Centre for Global Health ResearchUsher InstituteUniversity of EdinburghEdingburghScotland
| | - Stephen J. Wigmore
- Department of Clinical SurgeryDivision of Health SciencesUniversity of EdinburghEdingburghScotland
| | - Ewen M. Harrison
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
- Department of Clinical SurgeryDivision of Health SciencesUniversity of EdinburghEdingburghScotland
| | - Athina Spiliopoulou
- Centre for Global Health ResearchUsher InstituteUniversity of EdinburghEdingburghScotland
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Kamada Y, Takahashi H, Shimizu M, Kawaguchi T, Sumida Y, Fujii H, Seko Y, Fukunishi S, Tokushige K, Nakajima A, Okanoue T. Clinical practice advice on lifestyle modification in the management of nonalcoholic fatty liver disease in Japan: an expert review. J Gastroenterol 2021; 56:1045-1061. [PMID: 34718870 DOI: 10.1007/s00535-021-01833-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 10/01/2021] [Indexed: 02/04/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases worldwide, including in Japan. The Japanese Society of Gastroenterology (JSGE) and the Japanese Society of Hepatology (JSH) have established the Japanese NAFLD/NASH guidelines in 2014 and revised these guidelines in 2020. As described in these guidelines, weight reduction by diet and/or exercise therapy is important for the treatment of NAFLD patients. The I148M single nucleotide polymorphism (rs738409 C > G) of PNPLA3 (patatin-like phospholipase domain-containing 3 protein) is widely known to be associated with the occurrence and progression of NAFLD. In the Japanese, the ratio of PNPLA3 gene polymorphisms found is approximately 20%, which is higher than that found in Westerners. In addition, the ratio of lean NAFLD patients is also higher in Japan than in Western countries. Therefore, the method for lifestyle guidance for the NAFLD patients in Japan would be different from that for the people in Western countries. The problems in the treatment of NAFLD patients include alcohol consumption and sarcopenia. Therefore, guidelines that can help clinicians treat Japanese patients with NAFLD are needed. In this expert review, we summarize evidence-based interventions for lifestyle modification (diet, exercise, alcohol, and sarcopenia) for the treatment of patients with NAFLD, especially from Japan and Asian countries.
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Affiliation(s)
- Yoshihiro Kamada
- Department of Advanced Metabolic Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.
| | - Hirokazu Takahashi
- Department of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, 840-8502, Japan
| | - Masahito Shimizu
- Department of Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, 830-0011, Japan
| | - Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, 480-1195, Japan
| | - Hideki Fujii
- Department of Premier Preventive Medicine, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan
| | - Yuya Seko
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Shinya Fukunishi
- Premier Departmental Research of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, 569-8686, Japan
| | - Katsutoshi Tokushige
- Department of Internal Medicine, Institute of Gastroenterology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, 3-9, Fuku-ura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Takeshi Okanoue
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, 1-2 Kawazonocho, Suita, Osaka, 564-0013, Japan
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Pal P, Palui R, Ray S. Heterogeneity of non-alcoholic fatty liver disease: Implications for clinical practice and research activity. World J Hepatol 2021; 13:1584-1610. [PMID: 34904031 PMCID: PMC8637673 DOI: 10.4254/wjh.v13.i11.1584] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 07/29/2021] [Accepted: 10/14/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a heterogeneous condition with a wide spectrum of clinical presentations and natural history and disease severity. There is also substantial inter-individual variation and variable response to a different therapy. This heterogeneity of NAFLD is in turn influenced by various factors primarily demographic/dietary factors, metabolic status, gut microbiome, genetic predisposition together with epigenetic factors. The differential impact of these factors over a variable period of time influences the clinical phenotype and natural history. Failure to address heterogeneity partly explains the sub-optimal response to current and emerging therapies for fatty liver disease. Consequently, leading experts across the globe have recently suggested a change in nomenclature of NAFLD to metabolic-associated fatty liver disease (MAFLD) which can better reflect current knowledge of heterogeneity and does not exclude concomitant factors for fatty liver disease (e.g. alcohol, viral hepatitis, etc.). Precise identification of disease phenotypes is likely to facilitate clinical trial recruitment and expedite translational research for the development of novel and effective therapies for NAFLD/MAFLD.
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Affiliation(s)
- Partha Pal
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad 500082, India
| | - Rajan Palui
- Department of Endocrinology, The Mission Hospital, Durgapur 713212, West Bengal, India
| | - Sayantan Ray
- Department of Endocrinology, Jagannath Gupta Institute of Medical Sciences and Hospital, Kolkata 700137, West Bengal, India
- Diabetes and Endocrinology, Apollo Clinic, Ballygunge, Kolkata 700019, West Bengal, India
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Roe JD, Garcia LA, Klimentidis YC, Coletta DK. Association of PNPLA3 I148M with Liver Disease Biomarkers in Latinos. Hum Hered 2021; 86:21-27. [PMID: 34749354 DOI: 10.1159/000520734] [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: 05/17/2021] [Accepted: 11/03/2021] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Liver disease accounts for approximately 2 million deaths per year worldwide. The majority of liver diseases are due to complications of cirrhosis, viral hepatitis, and hepatocellular carcinoma. Increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) may indicate liver disease. Moreover, there are additional noninvasive liver fibrosis indices that help to estimate liver damage, including AST-to-ALT ratio, AST-to-platelet ratio index (APRI), fibrosis-4 (FIB-4) score, and nonalcoholic fatty liver disease (NAFLD) fibrosis score. The aims of the present study were to (1) perform an association analysis of the patatin-like phospholipase domain containing 3 (PNPLA3) I148M (rs738409) variant with ALT, AST, and various liver fibrosis indices, and (2) determine whether there are gender-related differences in these associations. METHODS We obtained demographic, anthropometric, and metabolic phenotypes from Latino adult participants (n = 503, 64% female, 36.4 ± 0.5 years) from the Arizona Insulin Resistance (AIR) registry. SNP genotyping of I148M was performed using the TaqMan allelic discrimination assay. We used linear regression for the association analyses of the genotypes with ALT, AST, and the various liver fibrosis indices. We included genotype, age, body mass index, and alcohol status in the linear regression model. RESULTS The variant I148M was in Hardy-Weinberg equilibrium, with genotype distribution: non-risk CC 118, heterozygous CG 246, and risk GG 139. The G allele was significantly associated with increased ALT and AST levels (p = 7.8 × 10-7 and p = 9.7 × 10-6, respectively). Moreover, we showed that the G allele was significantly associated with higher APRI (p = 3.7 × 10-7) and FIB-4 score (p = 4.1 × 10-3). When we analyzed the data by gender, we observed similar significant trends for ALT, AST, and APRI (all, p < 0.01). In females, the G allele was significantly associated with increased FIB-4 score (p = 6.9 × 10-3), which was not observed in the males (p > 0.05). There was no association of the I148M variant with AST/ALT ratio nor NAFLD risk score, whether analyzed in all adults or by gender. DISCUSSION/CONCLUSION Our findings provide additional evidence of an association of PNPLA3 I148M with several liver disease biomarkers in male and female Latinos residing in the Southwest of the United States.
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Affiliation(s)
- Jonathan D Roe
- Department of Physiology, College of Medicine, University of Arizona, Tucson, Arizona, USA
| | - Luis A Garcia
- Department of Medicine, Division of Endocrinology, College of Medicine, University of Arizona, Tucson, Arizona, USA.,Center for Disparities in Diabetes Obesity, and Metabolism, University of Arizona, Tucson, Arizona, USA
| | - Yann C Klimentidis
- Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona, USA
| | - Dawn K Coletta
- Department of Physiology, College of Medicine, University of Arizona, Tucson, Arizona, USA.,Department of Medicine, Division of Endocrinology, College of Medicine, University of Arizona, Tucson, Arizona, USA.,Center for Disparities in Diabetes Obesity, and Metabolism, University of Arizona, Tucson, Arizona, USA
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Tokushige K, Ikejima K, Ono M, Eguchi Y, Kamada Y, Itoh Y, Akuta N, Yoneda M, Iwasa M, Yoneda M, Otsuka M, Tamaki N, Kogiso T, Miwa H, Chayama K, Enomoto N, Shimosegawa T, Takehara T, Koike K. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis 2020. Hepatol Res 2021; 51:1013-1025. [PMID: 34533266 DOI: 10.1111/hepr.13688] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 06/30/2021] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become a serious public health issue not only in Western countries but also in Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis (NASH) is a progressive form of disease that often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma (HCC). While a definite diagnosis of NASH requires liver biopsy to confirm the presence of hepatocyte ballooning, hepatic fibrosis is the most important prognostic factor in NAFLD. With so many NAFLD patients, it is essential to have an effective screening method for NAFLD with hepatic fibrosis. As HCC with non-viral liver disease has increased markedly in Japan, effective screening and surveillance of HCC are also urgently needed. The most common death etiology in NAFLD patients is cardiovascular disease event. Gastroenterologists must, therefore, pay close attention to CVD when examining NAFLD patients. In the updated guidelines, we propose screening and follow-up methods for hepatic fibrosis, HCC, and CVD in NAFLD patients. Several drug trials are ongoing for NAFLD/NASH therapy, however, there is currently no specific drug therapy for NAFLD/NASH. In addition to vitamin E and thiazolidinedione derivatives, recent trials have focused on sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) analogues, and effective therapies are expected to be developed. These practical guidelines for NAFLD/NASH were established by the Japanese Society of Gastroenterology in conjunction with the Japan Society of Hepatology. Clinical evidence reported internationally between 1983 and October 2018 was collected, and each clinical and background question was evaluated using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system. This English summary pro- vides the core essentials of these clinical practice guidelines, which include the definition and concept, screening systems for hepatic fibrosis, HCC and CVD, and current therapies for NAFLD/NASH in Japan.
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Affiliation(s)
- Katsutoshi Tokushige
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan.,Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Kenichi Ikejima
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Masafumi Ono
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Yuichiro Eguchi
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Yoshihiro Kamada
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Yoshito Itoh
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Norio Akuta
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Masato Yoneda
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Motoh Iwasa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Masashi Yoneda
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Motoyuki Otsuka
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Nobuharu Tamaki
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Tomomi Kogiso
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | | | - Nobuyuki Enomoto
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
| | | | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan
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Wang J, Conti DV, Bogumil D, Sheng X, Noureddin M, Wilkens LR, Le Marchand L, Rosen HR, Haiman CA, Setiawan VW. Association of Genetic Risk Score With NAFLD in An Ethnically Diverse Cohort. Hepatol Commun 2021; 5:1689-1703. [PMID: 34558842 PMCID: PMC8485887 DOI: 10.1002/hep4.1751] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 05/03/2021] [Indexed: 12/15/2022] Open
Abstract
Most genetic studies of nonalcoholic fatty liver disease (NAFLD) have been conducted in Whites. In this large and ethnically diverse cohort, we assessed the transportability of previously identified genetic variants for NAFLD, built a genetic risk score (GRS), and examined its association with NAFLD risk in multiple ethnic groups. Thirty previously identified genome-wide association studies (GWAS) variants (P < 5 × 10-8 ) and 17 other variants associated with NAFLD were examined in a nested case-control study of NAFLD (1,448 cases/8,444 controls) in this multi-ethnic cohort study. We then built a GRS using 11 independent single-nucleotide polymorphisms from these prior studies and examined its association with NAFLD by cirrhosis status across multiple ethnic groups. Of the 30 GWAS SNPs, 20 (67%) were replicated (P < 0.05) in the pooled multi-ethnic population. The highest percentage of replication was seen in Latinos (43%), followed by Japanese Americans (37%), Whites (17%), and Native Hawaiians and African Americans (≤10%). Several genetic variants, including those in PNPLA3 (patatin-like phospholipase domain containing 3), HSD17B13 (hydroxysteroid 17-beta dehydrogenase 13), TM6SF2 (transmembrane 6 superfamily member 2), GATAD2A (GATA zinc finger domain containing 2A), GCKR (glucokinase regulator), SUGP1 (SURP and G-patch domain containing 1), MBOAT7 (membrane bound O-acyltransferase domain containing 7), TRIB1 (tribbles pseudokinase 1), SAMM50 (sorting and assembly machinery component), and ERLIN1 (ER lipid raft associated 1)-CHUK (component of inhibitor of nuclear factor kappa B kinase complex)-CWF19L1 (CWF19 like cell cycle control factor 1) gene cluster, were replicated in at least two ethnic groups. An 11-SNP weighted GRS was associated with NAFLD risk in the multi-ethnic population (odds ratio [OR] per SD increase = 1.41; 95% confidence interval [CI] = 1.32-1.50), as well as in each ethnic group (OR ranged from 1.30 in African Americans to 1.52 in Latinos). The GRS-NAFLD association was stronger for NAFLD with cirrhosis (OR = 1.67; 95% CI = 1.46-1.92) compared to NAFLD without cirrhosis (OR = 1.37; 95% CI = 1.28-1.46) (P heterogeneity = 0.003). Conclusion: In this ethnically diverse cohort, we replicated several key genetic variants for NAFLD and showed the utility of GRS based on the risk alleles for NAFLD risk stratification in multiple ethnic groups.
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Affiliation(s)
- Jun Wang
- Department of Preventive MedicineKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
| | - David V. Conti
- Department of Preventive MedicineKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
- Center for Genetic EpidemiologyKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
- Norris Comprehensive Cancer CenterKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
| | - David Bogumil
- Department of Preventive MedicineKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
| | - Xin Sheng
- Department of Preventive MedicineKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
| | - Mazen Noureddin
- Division of Gastroenterology and HepatologyDepartment of MedicineCedars‐Sinai Medical CenterLos AngelesCAUSA
| | - Lynne R. Wilkens
- Epidemiology ProgramUniversity of Hawaii Cancer CenterHonoluluHIUSA
| | - Loic Le Marchand
- Epidemiology ProgramUniversity of Hawaii Cancer CenterHonoluluHIUSA
| | - Hugo R. Rosen
- Department of MedicineKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
| | - Christopher A. Haiman
- Department of Preventive MedicineKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
- Center for Genetic EpidemiologyKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
- Norris Comprehensive Cancer CenterKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
| | - Veronica Wendy Setiawan
- Department of Preventive MedicineKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
- Center for Genetic EpidemiologyKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
- Norris Comprehensive Cancer CenterKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
- Department of MedicineKeck School of Medicine of University of Southern CaliforniaLos AngelesCAUSA
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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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Pafili K, Roden M. Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans. Mol Metab 2021; 50:101122. [PMID: 33220492 PMCID: PMC8324683 DOI: 10.1016/j.molmet.2020.101122] [Citation(s) in RCA: 174] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/30/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) comprises hepatic alterations with increased lipid accumulation (steatosis) without or with inflammation (nonalcoholic steatohepatitis, NASH) and/or fibrosis in the absence of other causes of liver disease. NAFLD is developing as a burgeoning health challenge, mainly due to the worldwide obesity and diabetes epidemics. SCOPE OF REVIEW This review summarizes the knowledge on the pathogenesis underlying NAFLD by focusing on studies in humans and on hypercaloric nutrition, including effects of saturated fat and fructose, as well as adipose tissue dysfunction, leading to hepatic lipotoxicity, abnormal mitochondrial function, and oxidative stress, and highlights intestinal dysbiosis. These mechanisms are discussed in the context of current treatments targeting metabolic pathways and the results of related clinical trials. MAJOR CONCLUSIONS Recent studies have provided evidence that certain conditions, for example, the severe insulin-resistant diabetes (SIRD) subgroup (cluster) and the presence of an increasing number of gene variants, seem to predispose for excessive risk of NAFLD and its accelerated progression. Recent clinical trials have been frequently unsuccessful in halting or preventing NAFLD progression, perhaps partly due to including unselected cohorts in later stages of NAFLD. On the basis of this literature review, this study proposed screening in individuals with the highest genetic or acquired risk of disease progression, for example, the SIRD subgroup, and developing treatment concepts targeting the earliest pathophysiolgical alterations, namely, adipocyte dysfunction and insulin resistance.
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Affiliation(s)
- Kalliopi Pafili
- Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Düsseldorf, Germany; German Center for Diabetes Research, München-Neuherberg, Germany
| | - Michael Roden
- Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Düsseldorf, Germany; German Center for Diabetes Research, München-Neuherberg, Germany; Division of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
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Salari N, Darvishi N, Mansouri K, Ghasemi H, Hosseinian-Far M, Darvishi F, Mohammadi M. Association between PNPLA3 rs738409 polymorphism and nonalcoholic fatty liver disease: a systematic review and meta-analysis. BMC Endocr Disord 2021; 21:125. [PMID: 34147109 PMCID: PMC8214766 DOI: 10.1186/s12902-021-00789-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 06/10/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a common disorder that is known to be the leading cause of chronic liver disease worldwide. This study aims to systematically review and meta-analyze the association between PNPLA3 rs738409 polymorphism and non-alcoholic fatty liver. METHODS Following a systematic review and meta-analysis method, articles without any time limitation, were extracted from SID, MagIran, IranDoc, Scopus, Embase, Web of Science (WoS), PubMed and ScienceDirect international databases. Random effects model was used for analysis, and heterogeneity of studies was investigated considering the I2 index and using Comprehensive Meta-Analysis software. RESULTS The odds ratio of CC genotype in patients with non-alcoholic fatty liver demonstrates the protective effect of CC genotype with the ratio of 0.52, whereas CG genotype presents an increasing effect of CG genotype with the ratio of 0.19, and GG genotype also showed an increasing effect of GG genotype with the ratio of 1.05. Moreover, CG + GG genotypes as a single group demostrated an odds rartio of 0.88. CONCLUSION This meta-analysis highlights that people with CC genotype has 52% lower chance of developing non-alcoholic fatty liver disease, and those with CG genotype had 19% higher risk of developing non-alcoholic fatty liver. Those with GG genotype were 105% more likely to develop non-alcoholic fatty liver than others. Moreover, those present in a population with CG + GG genotypes were 88% more likely to have non-alcoholic fatty liver disease.
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Affiliation(s)
- Nader Salari
- Department of Biostatistics, School of Health, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Niloufar Darvishi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Kamran Mansouri
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hooman Ghasemi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Melika Hosseinian-Far
- Department of Food Science & Technology, Faculty of Agriculture, Ferdowsi University of Mashhad (FUM), Kermanshah, Iran
| | - Fateme Darvishi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Masoud Mohammadi
- Department of Nursing, School of Nursing and Midwifery, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Diagnosis and management of secondary causes of steatohepatitis. J Hepatol 2021; 74:1455-1471. [PMID: 33577920 DOI: 10.1016/j.jhep.2021.01.045] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 01/09/2021] [Accepted: 01/25/2021] [Indexed: 02/06/2023]
Abstract
The term non-alcoholic fatty liver disease (NAFLD) was originally coined to describe hepatic fat deposition as part of the metabolic syndrome. However, a variety of rare hereditary liver and metabolic diseases, intestinal diseases, endocrine disorders and drugs may underlie, mimic, or aggravate NAFLD. In contrast to primary NAFLD, therapeutic interventions are available for many secondary causes of NAFLD. Accordingly, secondary causes of fatty liver disease should be considered during the diagnostic workup of patients with fatty liver disease, and treatment of the underlying disease should be started to halt disease progression. Common genetic variants in several genes involved in lipid handling and metabolism modulate the risk of progression from steatosis to fibrosis, cirrhosis and hepatocellular carcinoma development in NAFLD, alcohol-related liver disease and viral hepatitis. Hence, we speculate that genotyping of common risk variants for liver disease progression may be equally useful to gauge the likelihood of developing advanced liver disease in patients with secondary fatty liver disease.
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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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Kawanaka M, Nishino K, Morimoto Y, Ishii K, Tanikawa T, Urata N, Suehiro M, Sasai T, Haruma K, Kawamoto H. Progression from Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis Cirrhosis Confirmed by Liver Histology after 14 Years. Intern Med 2021; 60:1397-1401. [PMID: 33281161 PMCID: PMC8170238 DOI: 10.2169/internalmedicine.6118-20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
A 44-year-old patient progressed from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) cirrhosis. She was diagnosed with NAFL via a liver biopsy. At 56 years old, she was diagnosed with NASH stage 3 via a second liver biopsy. One year later, she was diagnosed with NASH cirrhosis via a third liver biopsy. This is the first study to report the gradual deterioration of liver histology shown via three liver biopsies and fibrosis markers in a patient who progressed from NAFL to NASH cirrhosis. Following menopause, it is necessary to be aware of the rapid development of liver fibrosis.
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Affiliation(s)
- Miwa Kawanaka
- Department of General Internal Medicine2, Kawasaki Medical Center, Kawasaki Medical School, Japan
| | - Ken Nishino
- Department of General Internal Medicine2, Kawasaki Medical Center, Kawasaki Medical School, Japan
| | - Yumiko Morimoto
- Department of General Internal Medicine2, Kawasaki Medical Center, Kawasaki Medical School, Japan
| | - Katsunori Ishii
- Department of General Internal Medicine2, Kawasaki Medical Center, Kawasaki Medical School, Japan
| | - Tomohiro Tanikawa
- Department of General Internal Medicine2, Kawasaki Medical Center, Kawasaki Medical School, Japan
| | - Noriyo Urata
- Department of General Internal Medicine2, Kawasaki Medical Center, Kawasaki Medical School, Japan
| | - Mitsuhiko Suehiro
- Department of General Internal Medicine2, Kawasaki Medical Center, Kawasaki Medical School, Japan
| | - Takako Sasai
- Department of General Internal Medicine2, Kawasaki Medical Center, Kawasaki Medical School, Japan
| | - Ken Haruma
- Department of General Internal Medicine2, Kawasaki Medical Center, Kawasaki Medical School, Japan
| | - Hirofumi Kawamoto
- Department of General Internal Medicine2, Kawasaki Medical Center, Kawasaki Medical School, Japan
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Seko Y, Yamaguchi K, Tochiki N, Yano K, Takahashi A, Okishio S, Kataoka S, Okuda K, Umemura A, Moriguchi M, Itoh Y. The Effect of Genetic Polymorphism in Response to Body Weight Reduction in Japanese Patients with Nonalcoholic Fatty Liver Disease. Genes (Basel) 2021; 12:628. [PMID: 33922278 PMCID: PMC8145113 DOI: 10.3390/genes12050628] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 04/11/2021] [Accepted: 04/21/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND weight loss as a result of lifestyle intervention is effective when treating non-alcoholic fatty liver disease (NAFLD). We estimated the effects of PNPLA3 rs738409 and HSD17B13 rs6834314 variants in response to diet therapy in Japanese patients with NAFLD. METHODS we analyzed the correlation between the change in liver stiffness and change in body weight in 140 patients administered diet therapy for 1-year, according to PNPLA3 and HSD17B13 genotypes. RESULTS the bodyweight (BW) reduction rate was greater in patients with the PNPLA3 genotype CC than CG and GG (p = 0.035). Change in liver stiffness measurement (LSM) was significantly associated with a change in BW in PNPLA3 CG/GG (r = 0.279/0.381), but not in PNPLA3 CC (p = 0.187). Change in LSM was correlated with change in BW only in patients with HSD17B13 AG/GG (r = 0.425), but not the AA genotype (p = 0.069). A multivariate analysis identified that a change in LSM was correlated with a change in BW in carriers of HSD17B13 AG/GG (B = 3.043, p = 0.032), but not HSD17B13 AA. The change in LSM of patients with a BW reduction of more than 7% (0.50) was significantly greater than that of patients with a BW reduction of less than 7% (0.83) (p = 0.038). CONCLUSIONS in Japanese patients with NAFLD, HSD17B13 rs6834314 polymorphism is associated with the change in LSM by lifestyle intervention. The approach, including genetic assessments, may contribute to the establishment of appropriate therapeutic strategies to treat NAFLD.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Yoshito Itoh
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (Y.S.); (K.Y.); (N.T.); (K.Y.); (A.T.); (S.O.); (S.K.); (K.O.); (A.U.); (M.M.)
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50
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Wegermann K, Garrett ME, Zheng J, Coviello A, Moylan CA, Abdelmalek MF, Chow S, Guy CD, Diehl AM, Ashley‐Koch A, Suzuki A. Sex and Menopause Modify the Effect of Single Nucleotide Polymorphism Genotypes on Fibrosis in NAFLD. Hepatol Commun 2021; 5:598-607. [PMID: 33860118 PMCID: PMC8034580 DOI: 10.1002/hep4.1668] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 11/30/2020] [Accepted: 12/07/2020] [Indexed: 12/29/2022] Open
Abstract
The development of fibrosis in nonalcoholic fatty liver disease (NAFLD) is influenced by genetics, sex, and menopausal status, but whether genetic susceptibility to fibrosis is influenced by sex and reproductive status is unclear. Our aim was to identify metabolism-related single nucleotide polymorphisms (SNPs), whose effect on NAFLD fibrosis is significantly modified by sex and menopausal status. We performed a cross-sectional, proof-of-concept study of 616 patients in the Duke NAFLD Clinical Database and Biorepository. The primary outcome was nonalcoholic steatohepatitis-Clinical Research Network (NASH-CRN) fibrosis stage. Menopause status was self-reported; age 51 years was used as a surrogate for menopause in patients with missing menopause data. The Metabochip was used to obtain 98,359 SNP genotypes in known metabolic pathway genes for each patient. We used additive genetic models to characterize sex and menopause-specific effects of SNP genotypes on NAFLD fibrosis stage. In the main effects analysis, none of the SNPs were associated with fibrosis at P < 0.05 after correcting for multiple comparisons. Twenty-five SNPs significantly interacted with sex/menopause to affect fibrosis stage (interaction P < 0.0001). After removal of loci in linkage disequilibrium, 10 independent loci were identified. Six were in the following genes: KCNIP4 (potassium voltage-gated channel interacting protein 4), PSORS1C1 (psoriasis susceptibility 1 candidate 1), KLHL8 (Kelch-like family member 8), GLRA1 (glycine receptor alpha 1), NOTCH2 (notch receptor 2), and PRKCH (protein kinase C eta), and four SNPs were intergenic. In stratified models, four SNPs were significant in premenopausal and postmenopausal women, three only in postmenopausal women, two in men and postmenopausal women, and one only in premenopausal women. Conclusion: We identified 10 loci with a significant sex/menopause interaction with respect to fibrosis. None of these SNPs were significant in all sex/menopause groups, suggesting modulation of genetic susceptibility to fibrosis by sex and menopause status. Future studies of genetic predictors of NAFLD progression should account for sex and menopause.
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Affiliation(s)
- Kara Wegermann
- Division of GastroenterologyDepartment of MedicineDuke UniversityDurhamNCUSA
| | | | - Jiayin Zheng
- Public Health Sciences DivisionFred Hutchinson Cancer Research CenterSeattleWAUSA
| | - Andrea Coviello
- Division of EndocrinologyDepartment of MedicineDuke UniversityDurhamNCUSA
| | - Cynthia A. Moylan
- Division of GastroenterologyDepartment of MedicineDuke UniversityDurhamNCUSA
- Department of MedicineDurham Veterans Affairs Medical CenterDurhamNCUSA
| | - Manal F. Abdelmalek
- Division of GastroenterologyDepartment of MedicineDuke UniversityDurhamNCUSA
| | - Shein‐Chung Chow
- Department of Biostatistics and BioinformaticsDuke UniversityDurhamNCUSA
| | | | - Anna Mae Diehl
- Division of GastroenterologyDepartment of MedicineDuke UniversityDurhamNCUSA
| | | | - Ayako Suzuki
- Division of GastroenterologyDepartment of MedicineDuke UniversityDurhamNCUSA
- Department of MedicineDurham Veterans Affairs Medical CenterDurhamNCUSA
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