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Di Sessa A, Zarrilli S, Forcina G, Frattolillo V, Camponesco O, Migliaccio C, Ferrara S, Umano GR, Cirillo G, Miraglia Del Giudice E, Marzuillo P. Role of metabolic dysfunction-associated steatotic liver disease and of its genetics on kidney function in childhood obesity. Int J Obes (Lond) 2025; 49:605-611. [PMID: 39521922 DOI: 10.1038/s41366-024-01674-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 10/29/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024]
Abstract
OBJECTIVES Evidence linked metabolic associated steatotic liver disease (MASLD) to kidney damage with the potential contribution of the I148M variant of the Patatin-like phospholipase containing domain 3 (PNPLA3) gene. We aimed at investigating the relationship of MASLD and of its genetics with kidney function in children with obesity. METHODS A comprehensive evaluation including genotyping for the I148M PNPLA3 polymorphism was performed in 1037 children with obesity. Fatty liver (FL) was assessed by liver ultrasound. According to MASLD criteria, subjects with obesity but without FL were included in group 1, while patients with obesity and FL (encompassing one MASLD criterion) were clustered into group 2. Group 3 included patients with obesity, FL, and metabolic dysregulation (encompassing >1 MASLD criterion). RESULTS Alanine transaminase levels significantly increased while estimated glomerular filtration rate (eGFR) significantly reduced from group 1 to 3. Group 3 showed a higher percentage of carriers of the I148M allele of the PNPLA3 gene compared to other groups (p < 0.0001). Carriers of group 2 and of group 3 showed reduced eGFR levels than noncarriers of group 2 (p = 0.04) and of group 3 (p = 0.02), respectively. A general linear model for eGFR variance in the study population showed an inverse association of eGFR with both MASLD and PNPLA3 genotypes (p = 0.011 and p = 0.02, respectively). An inverse association of eGFR with MASLD was also confirmed only in carriers (p = 0.006). CONCLUSIONS The coexistence of more than 1 MASLD criterion in children with obesity seems to adversely affect kidney function. The PNPLA3 I148M allele further impacts on this association.
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Affiliation(s)
- Anna Di Sessa
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy.
| | - Sarah Zarrilli
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Gianmario Forcina
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Vittoria Frattolillo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Ornella Camponesco
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Claudia Migliaccio
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Serena Ferrara
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giuseppina Rosaria Umano
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Grazia Cirillo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Emanuele Miraglia Del Giudice
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Pierluigi Marzuillo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
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Mantovani A, Targher G. PNPLA3 variation and kidney disease. Liver Int 2025; 45:e16010. [PMID: 38873992 DOI: 10.1111/liv.16010] [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: 04/29/2024] [Revised: 05/16/2024] [Accepted: 06/04/2024] [Indexed: 06/15/2024]
Abstract
Accumulating epidemiological evidence shows that the patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 G allele, which is the most robust genetic variant associated with greater susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD), is significantly associated with impaired kidney function in both adults and children, regardless of the presence of common renal risk factors, MASLD severity, and other potential confounders. Although some prospective studies have reported a significant association between the PNPLA3 rs738409 G allele and the increased risk of developing chronic kidney disease (CKD), the epidemiological evidence about a possible direct effect of the PNPLA3 rs738409 G allele on the risk of developing CKD is still limited. Experimentally, PNPLA3 is expressed in renal podocytes, pericytes, and proximal tubule cells, thus supporting the notion that the mutant PNPLA3 protein may play a role in developing renal steatosis and fibrosis. However, it cannot be ruled out that a part of the adverse effect of the PNPLA3 rs738409 G allele on kidney function may be driven by a direct impact of this genetic variant on the development and progression of MASLD. It is possible to hypothesize that identifying the PNPLA3 genotype might help identify individuals at higher risk of CKD and those at greater risk of advanced MASLD. In this narrative minireview, we summarize the current epidemiological data about the association between the PNPLA3 rs738409 G allele and the risk of CKD and abnormal albuminuria. We also briefly discuss the putative biological mechanisms underpinning this association and its potential and future clinical implications.
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Affiliation(s)
- Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Giovanni Targher
- Department of Medicine, University of Verona, Verona, Italy
- Metabolic Diseases Research Unit, IRCCS Sacro Cuore-Don Calabria Hospital, Negrar di Valpolicella, Italy
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Reid MV, Fredickson G, Mashek DG. Mechanisms coupling lipid droplets to MASLD pathophysiology. Hepatology 2024:01515467-990000000-01067. [PMID: 39475114 DOI: 10.1097/hep.0000000000001141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 10/17/2024] [Indexed: 01/03/2025]
Abstract
Hepatic steatosis, the buildup of neutral lipids in lipid droplets (LDs), is commonly referred to as metabolic dysfunction-associated steatotic liver disease when alcohol or viral infections are not involved. Metabolic dysfunction-associated steatotic liver disease encompasses simple steatosis and the more severe metabolic dysfunction-associated steatohepatitis, characterized by inflammation, hepatocyte injury, and fibrosis. Previously viewed as inert markers of disease, LDs are now understood to play active roles in disease etiology and have significant nonpathological and pathological functions in cell signaling and function. These dynamic properties of LDs are tightly regulated by hundreds of proteins that coat the LD surface, controlling lipid metabolism, trafficking, and signaling. The following review highlights various facets of LD biology with the primary goal of discussing key mechanisms through which LDs promote the development of advanced liver diseases, including metabolic dysfunction-associated steatohepatitis.
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Affiliation(s)
- Mari V Reid
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Gavin Fredickson
- Department of Integrated Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Douglas G Mashek
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Minnesota, Minneapolis, Minnesota, USA
- Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, Minnesota, USA
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Zhao J, Liu L, Cao YY, Gao X, Targher G, Byrne CD, Sun DQ, Zheng MH. MAFLD as part of systemic metabolic dysregulation. Hepatol Int 2024; 18:834-847. [PMID: 38594474 DOI: 10.1007/s12072-024-10660-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 02/11/2024] [Indexed: 04/11/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. In recent years, a new terminology and definition of metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed. Compared to the NAFLD definition, MAFLD better emphasizes the pathogenic role of metabolic dysfunction in the development and progression of this highly prevalent condition. Metabolic disorders, including overweight/obesity, type 2 diabetes mellitus (T2DM), atherogenic dyslipidemia and hypertension, are often associated with systemic organ dysfunctions, thereby suggesting that multiple organ damage can occur in MAFLD. Substantial epidemiological evidence indicates that MAFLD is not only associated with an increased risk of liver-related complications, but also increases the risk of developing several extra-hepatic diseases, including new-onset T2DM, adverse cardiovascular and renal outcomes, and some common endocrine diseases. We have summarized the current literature on the adverse effect of MAFLD on the development of multiple extrahepatic (cardiometabolic and endocrine) complications and examined the role of different metabolic pathways and organ systems in the progression of MAFLD, thus providing new insights into the role of MAFLD as a multisystem metabolic disorder. Our narrative review aimed to provide insights into potential mechanisms underlying the known associations between MAFLD and extrahepatic diseases, as part of MAFLD as a multisystem disease, in order to help focus areas for future drug development targeting not only liver disease but also the risk of extrahepatic complications.
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Affiliation(s)
- Jing Zhao
- Urologic Nephrology Center, Jiangnan University Medical Center, Wuxi, China
- Affiliated Wuxi Clinical College of Nantong University, Wuxi, China
- Wuxi No. 2 People's Hospital, Wuxi, China
| | - Lu Liu
- Urologic Nephrology Center, Jiangnan University Medical Center, Wuxi, China
- Affiliated Wuxi Clinical College of Nantong University, Wuxi, China
- Wuxi No. 2 People's Hospital, Wuxi, China
| | - Ying-Ying Cao
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang, China
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Giovanni Targher
- Department of Medicine, University of Verona, Verona, Italy
- Metabolic Diseases Research Unit, IRCCS Sacro Cuore-Don Calabria Hospital, Negrar di Valpolicella, Italy
| | - Christopher D Byrne
- Southampton National Institute for Health and Care Research Biomedical Research Centre, University Hospital Southampton, and University of Southampton, Southampton General Hospital, Southampton, UK
| | - Dan-Qin Sun
- Urologic Nephrology Center, Jiangnan University Medical Center, Wuxi, China.
- Affiliated Wuxi Clinical College of Nantong University, Wuxi, China.
- Wuxi No. 2 People's Hospital, Wuxi, China.
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang, China.
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Zaharia OP, Strassburger K, Knebel B, Binsch C, Kupriyanova Y, Möser C, Bódis K, Prystupa K, Yurchenko I, Mendez Cardenas DM, Schön M, Herder C, Al-Hasani H, Schrauwen-Hinderling V, Jandeleit-Dahm K, Wagner R, Roden M. Role of patatin-like phospholipase domain-containing 3 gene for decreasing kidney function in recently diagnosed diabetes mellitus. Diabetes Metab Syndr 2024; 18:103137. [PMID: 39427597 DOI: 10.1016/j.dsx.2024.103137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 09/12/2024] [Accepted: 10/08/2024] [Indexed: 10/22/2024]
Abstract
AIMS We examined the association of the G allele in the single-nucleotide polymorphism (SNP) rs738409 in the third exon of patatin-like phospholipase domain-containing 3 gene (PNPLA3) gene, with chronic kidney disease in diabetes endotypes. METHODS Participants with recent-onset diabetes (n = 707) from the prospective German Diabetes Study (GDS) underwent cluster assignment, detailed phenotyping, genotyping and magnetic resonance spectroscopy to quantify hepatocellular lipid content (HCL). RESULTS Severe insulin-resistant diabetes (SIRD) had the lowest glomerular filtration rates (eGFR) and highest HCL compared to severe insulin-deficient, moderate obesity-related, moderate age-related and severe autoimmune diabetes endotypes (all p < 0.05). HCL was negatively associated with eGFR (r = -0.287, p < 0.01) across all groups. Stratification by G-allele carrier status did not reveal any association between HCL and eGFR among the endotypes. However, the proportion of G-allele carriers increased from 44 % for eGFR >60 ml/min to 52 % for eGFR <60 ml/min (p < 0.05). CONCLUSIONS The PNPLA3 polymorphism may contribute to declining kidney function independently of liver lipids.
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Affiliation(s)
- Oana Patricia Zaharia
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich Heine University, Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München, Neuherberg, Germany
| | - Klaus Strassburger
- German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München, Neuherberg, Germany; Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | - Birgit Knebel
- German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München, Neuherberg, Germany; Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | - Christian Binsch
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich Heine University, Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München, Neuherberg, Germany
| | - Yuliya Kupriyanova
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München, Neuherberg, Germany
| | - Clara Möser
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich Heine University, Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München, Neuherberg, Germany
| | - Kálmán Bódis
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich Heine University, Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München, Neuherberg, Germany
| | - Katsiaryna Prystupa
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München, Neuherberg, Germany
| | - Iryna Yurchenko
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München, Neuherberg, Germany
| | - Dania Marel Mendez Cardenas
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München, Neuherberg, Germany
| | - Martin Schön
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich Heine University, Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München, Neuherberg, Germany
| | - Christian Herder
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich Heine University, Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München, Neuherberg, Germany
| | - Hadi Al-Hasani
- German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München, Neuherberg, Germany; Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | - Vera Schrauwen-Hinderling
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München, Neuherberg, Germany; Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Karin Jandeleit-Dahm
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München, Neuherberg, Germany; Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia
| | - Robert Wagner
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich Heine University, Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute 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 Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München, Neuherberg, Germany.
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Lonardo A. Association of NAFLD/NASH, and MAFLD/MASLD with chronic kidney disease: an updated narrative review. METABOLISM AND TARGET ORGAN DAMAGE 2024; 4. [DOI: 10.20517/mtod.2024.07] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) account for substantial financial burden worldwide. These alarming features call for enhanced efforts to prevent and manage the development and progression of CKD. Accumulating evidence supporting a causal role of NAFLD/MAFLD/MASLD-in CKD opens new horizons to achieve this aim. Recent epidemiological studies and meta-analyses exploring the association of NAFLD/MAFLD/MASLD with CKD and the characteristics of NAFLD/MAFLD/MASLD associated with the odds of incident CKD are discussed. The involved pathomechanisms, including the common soil hypothesis, genetics, gut dysbiosis, and portal hypertension, are examined in detail. Finally, lifestyle changes (diet and physical exercise), direct manipulation of gut microbiota, and drug approaches involving statins, renin-angiotensin-aldosterone system inhibitors, GLP-1 Receptor Agonists, Sodium-glucose cotransporter-2, pemafibrate, and vonafexor are examined within the context of prevention and management of CKD among those with NAFLD/MAFLD/MASLD. The evolving NAFLD/MAFLD/MASLD nomenclature may generate confusion among practicing clinicians and investigators. However, comparative studies investigating the pros and contra of different nomenclatures may identify the most useful definitions among NAFLD/MAFLD/MASLD and strategies to identify, prevent, and halt the onset and progression of CKD.
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Chen JF, Wu ZQ, Liu HS, Yan S, Wang YX, Xing M, Song XQ, Ding SY. Cumulative effects of excess high-normal alanine aminotransferase levels in relation to new-onset metabolic dysfunction-associated fatty liver disease in China. World J Gastroenterol 2024; 30:1346-1357. [PMID: 38596503 PMCID: PMC11000085 DOI: 10.3748/wjg.v30.i10.1346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/12/2024] [Accepted: 02/18/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND Within the normal range, elevated alanine aminotransferase (ALT) levels are associated with an increased risk of metabolic dysfunction-associated fatty liver disease (MAFLD). AIM To investigate the associations between repeated high-normal ALT measurements and the risk of new-onset MAFLD prospectively. METHODS A cohort of 3553 participants followed for four consecutive health examinations over 4 years was selected. The incidence rate, cumulative times, and equally and unequally weighted cumulative effects of excess high-normal ALT levels (ehALT) were measured. Cox proportional hazards regression was used to analyse the association between the cumulative effects of ehALT and the risk of new-onset MAFLD. RESULTS A total of 83.13% of participants with MAFLD had normal ALT levels. The incidence rate of MAFLD showed a linear increasing trend in the cumulative ehALT group. Compared with those in the low-normal ALT group, the multivariate adjusted hazard ratios of the equally and unequally weighted cumulative effects of ehALT were 1.651 [95% confidence interval (CI): 1.199-2.273] and 1.535 (95%CI: 1.119-2.106) in the third quartile and 1.616 (95%CI: 1.162-2.246) and 1.580 (95%CI: 1.155-2.162) in the fourth quartile, respectively. CONCLUSION Most participants with MAFLD had normal ALT levels. Long-term high-normal ALT levels were associated with a cumulative increased risk of new-onset MAFLD.
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Affiliation(s)
- Jing-Feng Chen
- Health Management Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zhuo-Qing Wu
- Institute of Systems Engineering, Dalian University of Technology, Dalian 116024, Liaoning Province, China
| | - Hao-Shuang Liu
- Health Management Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Su Yan
- Health Management Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - You-Xiang Wang
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Miao Xing
- School of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang 471003, Henan Province, China
| | - Xiao-Qin Song
- Health Management Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Su-Ying Ding
- Health Management Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
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Oh JH, Jun DW. Nonalcoholic fatty liver disease–related extrahepatic complications, associated outcomes, and their treatment considerations. METABOLIC STEATOTIC LIVER DISEASE 2024:101-122. [DOI: 10.1016/b978-0-323-99649-5.00007-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Mantovani A, Targher G. PNPLA3 rs738409 polymorphism and kidney dysfunction: an association beyond nonalcoholic fatty liver disease? METABOLISM AND TARGET ORGAN DAMAGE 2023; 3. [DOI: 10.20517/mtod.2023.24] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
This commentary is primarily devoted to a recent observational study by Mantovani and colleagues (Aliment Pharmacol Ther. 2023; 57: 1093-102) examining the adverse effect of the patatin-like phospholipase domain-containing protein-3 (PNPLA3 ) rs738409 G allele on the kidney function in a cohort of 1,144 middle-aged Italian individuals with metabolic dysfunction. In this study, the authors found that the PNPLA3 rs738409 G allele was significantly associated with lower levels of estimated glomerular filtrate rate (eGFR), even after adjusting for not only common anthropometric and cardiometabolic risk factors but also ethnicity, serum liver enzymes, use of drugs against dyslipidemia and chronic kidney disease polygenic risk score. Additionally, in a subgroup of 144 patients followed for a median of 17 months, the authors also found that the PNPLA3 rs738409 G allele was independently associated with a faster eGFR decline. Commenting on the cohort study by Mantovani et al ., we also summarized the rapidly expanding evidence linking the PNPLA3 rs738409 variant with the risk of kidney disease. Furthermore, we discussed the potential research implications of these findings.
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Nysather J, Kaya E, Manka P, Gudsoorkar P, Syn WK. Nonalcoholic Fatty Liver Disease and Chronic Kidney Disease Cross Talk. ADVANCES IN KIDNEY DISEASE AND HEALTH 2023; 30:315-335. [PMID: 37657879 DOI: 10.1053/j.akdh.2023.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 12/14/2022] [Accepted: 04/04/2023] [Indexed: 09/03/2023]
Abstract
Nonalcoholic fatty liver disease is a multisystem condition with effects beyond the liver. The identification of chronic kidney disease as an independent mediator of nonalcoholic fatty liver disease or associated entity with shared cardiometabolic risk factors remains controversial and continues to draw scientific interest. With increasing prevalence of nonalcoholic fatty liver disease and lack of Food and Drug Administration approved therapies, these shared cardiometabolic risk factors have drawn significant attention. In this article, we review shared pathophysiological mechanisms between nonalcoholic fatty liver disease and chronic kidney disease along with current treatment strategies that might be useful for both disease processes.
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Affiliation(s)
- Jacob Nysather
- Division of Nephrology and Kidney C.A.R.E. Program, University of Cincinnati, OH
| | - Eda Kaya
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus Bochum, Ruhr-University Bochum, Bochum, Germany
| | - Paul Manka
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus Bochum, Ruhr-University Bochum, Bochum, Germany
| | - Prakash Gudsoorkar
- Division of Nephrology and Kidney C.A.R.E. Program, University of Cincinnati, OH
| | - Wing-Kin Syn
- Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO; Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, Euskal Herriko Unibertsitatea/Universidad del País Vasco, Leioa, Spain.
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Sun DQ, Targher G, Byrne CD, Wheeler DC, Wong VWS, Fan JG, Tilg H, Yuan WJ, Wanner C, Gao X, Long MT, Kanbay M, Nguyen MH, Navaneethan SD, Yilmaz Y, Huang Y, Gani RA, Marzuillo P, Boursier J, Zhang H, Jung CY, Chai J, Valenti L, Papatheodoridis G, Musso G, Wong YJ, El-Kassas M, Méndez-Sánchez N, Sookoian S, Pavlides M, Duseja A, Holleboom AG, Shi J, Chan WK, Fouad Y, Yang J, Treeprasertsuk S, Cortez-Pinto H, Hamaguchi M, Romero-Gomez M, Al Mahtab M, Ocama P, Nakajima A, Dai C, Eslam M, Wei L, George J, Zheng MH. An international Delphi consensus statement on metabolic dysfunction-associated fatty liver disease and risk of chronic kidney disease. Hepatobiliary Surg Nutr 2023; 12:386-403. [PMID: 37351121 PMCID: PMC10282675 DOI: 10.21037/hbsn-22-421] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 02/01/2023] [Indexed: 08/27/2023]
Abstract
BACKGROUND With the rising global prevalence of fatty liver disease related to metabolic dysfunction, the association of this common liver condition with chronic kidney disease (CKD) has become increasingly evident. In 2020, the more inclusive term metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to replace the term non-alcoholic fatty liver disease (NAFLD). The observed association between MAFLD and CKD and our understanding that CKD can be a consequence of underlying metabolic dysfunction support the notion that individuals with MAFLD are at higher risk of having and developing CKD compared with those without MAFLD. However, to date, there is no appropriate guidance on CKD in individuals with MAFLD. Furthermore, there has been little attention paid to the link between MAFLD and CKD in the Nephrology community. METHODS AND RESULTS Using a Delphi-based approach, a multidisciplinary panel of 50 international experts from 26 countries reached a consensus on some of the open research questions regarding the link between MAFLD and CKD. CONCLUSIONS This Delphi-based consensus statement provided guidance on the epidemiology, mechanisms, management and treatment of MAFLD and CKD, as well as the relationship between the severity of MAFLD and risk of CKD, which establish a framework for the early prevention and management of these two common and interconnected diseases.
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Affiliation(s)
- Dan-Qin Sun
- Department of Nephrology, Jiangnan University Medical Center, Wuxi, China
- Affiliated Wuxi Clinical College of Nantong University, Wuxi, China
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Christopher D. Byrne
- Southampton National Institute for Health and Care Research Biomedical Research Centre, University Hospital Southampton, and Southampton General Hospital, University of Southampton, Southampton, UK
| | - David C. Wheeler
- Department of Renal Medicine, University College London, London, UK
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China
| | - Jian-Gao Fan
- Center for Fatty Liver, Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Wei-Jie Yuan
- Department of Nephrology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Christoph Wanner
- Division of Nephrology, Department of Medicine, Würzburg University Clinic, Würzburg, Germany
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Michelle T. Long
- Section of Gastroenterology, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA
| | - Mehmet Kanbay
- Division of Nephrology, Department of Medicine (M.K.), Koc University School of Medicine, Istanbul, Turkey
| | - Mindie H. Nguyen
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, CA, USA
- Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, CA, USA
| | - Sankar D. Navaneethan
- Section of Nephrology and Institute of Clinical and Translational Research, Baylor College of Medicine, and Michael E. DeBakey VA Medical Center, Houston, TX, USA
| | - Yusuf Yilmaz
- Department of Gastroenterology, School of Medicine, Marmara University, Istanbul, Turkey
- Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey
| | - Yuli Huang
- Department of Cardiology, Shunde Hospital, Southern Medical University, Foshan, China
| | - Rino A. Gani
- Division of Hepatobiliary, Department of Internal Medicine, Dr. Cipto Mangunkusumo National General Hospital, Medical Faculty Universitas Indonesia, Jakarta, Indonesia
| | - Pierluigi Marzuillo
- Department of Woman, Child and of General and Specialized Surgery, Università della Campania “Luigi Vanvitelli”, Napoli, Italy
| | - Jérôme Boursier
- HIFIH Laboratory, UPRES EA3859, Angers University, Angers, France
- Hepato-Gastroenterology and Digestive Oncology Department, Angers University Hospital, Angers, France
| | - Huijie Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chan-Young Jung
- Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Republic of Korea
| | - Jin Chai
- Cholestatic Liver Diseases Center, Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Università degli Studi di Milano, Milan, Italy
| | - George Papatheodoridis
- Department of Gastroenterology, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Giovanni Musso
- Emergency and Intensive Care Medicine, HUMANITAS Gradenigo Hospital;
| | - Yu-Jun Wong
- Department of Gastroenterology & Hepatology, Changi General Hospital, Singhealth, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
| | - Mohamed El-Kassas
- Department of Endemic Medicine, Faculty of Medicine, Helwan University, Cairo, Egypt
| | | | - Silvia Sookoian
- Clinical and Molecular Hepatology, Centro de Altos Estudios en Ciencias Humanas y de la Salud (CAECIHS), Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Michael Pavlides
- Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Adriaan G. Holleboom
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Junping Shi
- Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Wah-Kheong Chan
- Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Yasser Fouad
- Department of Gastroenterology, Hepatology and Endemic Medicine, Faculty of Medicine, Minia University, Minya, Egypt
| | - Junwei Yang
- Center for Kidney Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | | | - Helena Cortez-Pinto
- Clínica Universitária de Gastrenterologia, Laboratório de Nutrição, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Masahide Hamaguchi
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Manuel Romero-Gomez
- UCM Digestive Diseases, University Hospital Virgen del Rocio, Institute of Biomedicine of Seville (CSIC/HUVR/US), Ciberehd, University of Seville, Sevilla, Spain
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Ponsiano Ocama
- Department of Medicine, Makerere University of College of Health Sciences, Kampala, Uganda
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Chunsun Dai
- Center for Kidney Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | - Lai Wei
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
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Mantovani A, Zusi C, Csermely A, Taverna A, Cappelli D, Pagani M, Valenti L, Maffeis C, Targher G. Association between PNPLA3 rs738409 variant and 5-year estimated glomerular filtration rate decline in post-menopausal women with type 2 diabetes: A panel-data analysis. Nutr Metab Cardiovasc Dis 2023; 33:1093-1097. [PMID: 37208069 DOI: 10.1016/j.numecd.2023.03.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 02/26/2023] [Accepted: 03/05/2023] [Indexed: 05/21/2023]
Abstract
BACKGROUND AND AIMS Little is known about the relationship between patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 variant and decline in estimated glomerular filtration rate (eGFR) over time in individuals with type 2 diabetes (T2DM). METHODS AND RESULTS We enrolled an outpatient sample of 46 post-menopausal women with T2DM and preserved kidney function at baseline (in 2017), who were followed through 2022. eGFR and albuminuria were measured annually. Genotyping of PNPLA3 rs738409 was performed by TaqMan-based RT-PCR system. Overall, 25 (54.3%) patients had PNPLA3 rs738409 CC (homozygous wild-type) genotype and 21 had CG or GG genotypes. During the 5-year follow-up, the presence of rs738409 CG/GG genotypes was associated with faster eGFR decline (coefficient: -6.55; 95% CI -11.0 to -2.08; p = 0.004 by random-effects panel data analysis). This association remained significant even after adjustment for 5-year changes in age, hemoglobin A1c, hypertension status, albuminuria and use of sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists. CONCLUSIONS This pilot study suggests that in post-menopausal T2DM women with preserved kidney function at baseline, the risk allele (G) of PNPLA3 rs738409 is associated with a faster eGFR decline during a 5-year follow-up, independent of annual changes in common renal risk factors and use of certain glucose-lowering medications.
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Affiliation(s)
- Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy.
| | - Chiara Zusi
- Pediatric Diabetes and Metabolic Disorders Unit, Department of Surgical Sciences, Dentistry, Pediatrics and Gynaecology, University Hospital of Verona, Verona, Italy
| | - Alessandro Csermely
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Antonio Taverna
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Davide Cappelli
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Micol Pagani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Luca Valenti
- Precision Medicine - Biological Resource Center, Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Claudio Maffeis
- Pediatric Diabetes and Metabolic Disorders Unit, Department of Surgical Sciences, Dentistry, Pediatrics and Gynaecology, University Hospital of Verona, Verona, Italy
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
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Mantovani A, Pelusi S, Margarita S, Malvestiti F, Dell'Alma M, Bianco C, Ronzoni L, Prati D, Targher G, Valenti L. Adverse effect of PNPLA3 p.I148M genetic variant on kidney function in middle-aged individuals with metabolic dysfunction. Aliment Pharmacol Ther 2023; 57:1093-1102. [PMID: 36947711 DOI: 10.1111/apt.17477] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/01/2023] [Accepted: 03/09/2023] [Indexed: 03/24/2023]
Abstract
BACKGROUND The PNPLA3 p.I148M variant is the main genetic determinant of nonalcoholic fatty liver disease, and PNPLA3 silencing is being evaluated to treat this liver condition. Data suggest that the p.I148M variant predisposes to kidney damage, but the relative contribution to kidney function, compared to overall genetic susceptibility, is not defined. AIMS We aimed to assess the effect of PNPLA3 p.I148M on the estimated glomerular filtration rate (eGFR) in individuals with metabolic dysfunction. METHODS We included 1144 middle-aged individuals from the Liver-Bible-2022 cohort. Glomerular filtration rate (eGFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. The effect of PNPLA3 p.I148M on eGFRCKD-EPI levels was tested under additive genetic models adjusted for clinical predictors, ethnicity and a polygenic risk score of chronic kidney disease (PRS-CKD). In a subset of 144 individuals, we examined the effect of PNPLA3 p.I148M on eGFRCKD-EPI over a median follow-up of 17 months. RESULTS The p.I148M variant was associated with lower eGFRCKD-EPI levels (-1.24 mL/min/1.73 m2 per allele, 95% CI: -2.32 to -0.17; p = 0.023), independent of age, sex, height, waist circumference, systolic blood pressure, LDL-cholesterol, transaminases, fasting insulin, albuminuria, lipid-lowering drugs, ethnicity and PRS-CKD score. In the prospective evaluation, the p.I148M variant was independently associated with faster eGFRCKD-EPI decline (ΔeGFRCKD-EPI -3.57 mL/min/1.73 m2 per allele, 95% CI: -6.94 to -0.21; p = 0.037). CONCLUSIONS We found a detrimental impact of the PNPLA3 p.I148M variant on eGFRCKD-EPI levels in middle-aged individuals with metabolic dysfunction. This association was independent of established risk factors, ethnicity and genetic predisposition to CKD. PNPLA3 p.I148M silencing may protect against kidney damage progression in carriers.
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Affiliation(s)
- Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Serena Pelusi
- Precision Medicine Lab, Biological Resource Center - Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Sara Margarita
- Precision Medicine Lab, Biological Resource Center - Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Francesco Malvestiti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Michela Dell'Alma
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Cristiana Bianco
- Precision Medicine Lab, Biological Resource Center - Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Luisa Ronzoni
- Precision Medicine Lab, Biological Resource Center - Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Daniele Prati
- Precision Medicine Lab, Biological Resource Center - Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Luca Valenti
- Precision Medicine Lab, Biological Resource Center - Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
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Zhang H, Rios RS, Boursier J, Anty R, Chan WK, George J, Yilmaz Y, Wong VWS, Fan J, Dufour JF, Papatheodoridis G, Chen L, Schattenberg JM, Shi J, Xu L, Wong GLH, Lange NF, Papatheodoridi M, Mi Y, Zhou Y, Byrne CD, Targher G, Feng G, Zheng M. Hepatocyte apoptosis fragment product cytokeratin-18 M30 level and non-alcoholic steatohepatitis risk diagnosis: an international registry study. Chin Med J (Engl) 2023; 136:341-350. [PMID: 36848175 PMCID: PMC10106257 DOI: 10.1097/cm9.0000000000002603] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Indexed: 03/01/2023] Open
Abstract
BACKGROUND Liver biopsy for the diagnosis of non-alcoholic steatohepatitis (NASH) is limited by its inherent invasiveness and possible sampling errors. Some studies have shown that cytokeratin-18 (CK-18) concentrations may be useful in diagnosing NASH, but results across studies have been inconsistent. We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH. METHODS Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD), and in all patients, circulating CK-18 M30 levels were measured. Individuals with a NAFLD activity score (NAS) ≥5 with a score of ≥1 for each of steatosis, ballooning, and lobular inflammation were diagnosed as having definite NASH; individuals with a NAS ≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver (NAFL). RESULTS A total of 2571 participants were screened, and 1008 (153 with NAFL and 855 with NASH) were finally enrolled. Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL (mean difference 177 U/L; standardized mean difference [SMD]: 0.87 [0.69-1.04]). There was an interaction between CK-18 M30 levels and serum alanine aminotransferase, body mass index (BMI), and hypertension ( P < 0.001, P = 0.026 and P = 0.049, respectively). CK-18 M30 levels were positively associated with histological NAS in most centers. The area under the receiver operating characteristics (AUROC) for NASH was 0.750 (95% confidence intervals: 0.714-0.787), and CK-18 M30 at Youden's index maximum was 275.7 U/L. Both sensitivity (55% [52%-59%]) and positive predictive value (59%) were not ideal. CONCLUSION This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.
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Affiliation(s)
- Huai Zhang
- Department of Biostatistics and Medical Record, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Department of Hepatology, MAFLD Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Rafael S. Rios
- Department of Hepatology, MAFLD Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Jerome Boursier
- Service d’Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d’Angers, Angers, France
- Laboratoire HIFIH, UPRES EA3859, SFR ICAT 4208, Université d’Angers, Angers, France
| | - Rodolphe Anty
- Université Côte d’Azur, CHU, INSERM, U1065, C3M, 06204 Nice, France
| | - Wah-Kheong Chan
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | - Yusuf Yilmaz
- Department of Gastroenterology, School of Medicine, Marmara University, Istanbul, Turkey
- Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Jiangao Fan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200000, China
| | - Jean-François Dufour
- University Clinic for Visceral Surgery and Medicine, Inselspital, University Hospital Bern, Bern, Switzerland
- Graduate School for Health Sciences, University of Bern, Bern, Switzerland
| | - George Papatheodoridis
- Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital, of Athens “Laiko”, Athens, Greece
| | - Li Chen
- Department of Gastroenterology, Ruijin Hospital, Shanghai 200000, China
| | - Jörn M. Schattenberg
- Metabolic Liver Research Program I, Department of Medicine, University Medical Center Mainz, Mainz, Germany
| | - Junping Shi
- The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310000, China
| | - Liang Xu
- Tianjin Second People's Hospital, Tianjin 300000, China
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Naomi F. Lange
- University Clinic for Visceral Surgery and Medicine, Inselspital, University Hospital Bern, Bern, Switzerland
- Graduate School for Health Sciences, University of Bern, Bern, Switzerland
| | - Margarita Papatheodoridi
- Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital, of Athens “Laiko”, Athens, Greece
| | - Yuqiang Mi
- Tianjin Second People's Hospital, Tianjin 300000, China
| | - Yujie Zhou
- Department of Hepatology, MAFLD Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai 200000, China
| | - Christopher D. Byrne
- Southampton National Institute for Health and Care Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Gong Feng
- Xi’an Medical University, Xi’an, Shaanxi 710000, China
| | - Minghua Zheng
- Department of Hepatology, MAFLD Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang 325000, China
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Navadurong H, Prasoppokakorn T, Srisawat N, Chaiteerakij R, Komolmit P, Tangkijvanich P, Treeprasertsuk S. Urinary neutrophil gelatinase‐associated lipocalin: A novel biomarker for predicting chronic kidney disease in patients with nonalcoholic fatty liver disease. PORTAL HYPERTENSION & CIRRHOSIS 2022; 1:157-166. [DOI: 10.1002/poh2.32] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 09/30/2022] [Indexed: 01/03/2025]
Abstract
AbstractAimsNonalcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) are common diseases worldwide. Reports of a high prevalence of CKD in NAFLD patients have been documented. Urinary neutrophil gelatinase‐associated lipocalin (NGAL) is a reliable biomarker for renal dysfunction, and it is recommended for early detection of acute kidney injury (AKI) in cirrhotic patients. Currently, there is no evidence for using urine NGAL to predict CKD in NAFLD patients. We aim to determine the proportion of CKD and identify the predictive value of NGAL and other factors associated with CKD in these patients.MethodsA single‐center, cross‐sectional study was conducted between July 2018 and December 2019 in consecutive NAFLD patients diagnosed by transient elastography (TE) or liver biopsy at a tertiary care university hospital in Bangkok, Thailand. Advanced liver fibrosis is defined as fibrosis stages 3–4. The definition of CKD is estimated glomerular filtration rate (eGFR) <60 ml⋅min−1⋅1.73 m−2 based on the Kidney Disease Improving Global Outcomes (KDIGO) guideline 2012. Urine NGAL level was measured by enzyme linked immunosorbent assay technique.ResultsA total of 101 NAFLD patients were included with a mean age of 54 ± 16 years. Among these patients, 14 (13.9%), 13 (12.9%), and 32 (31.7%) had fibrosis stages 2, 3, and 4, respectively. Nine percent (9 of 101) of patients with NAFLD with a mean eGFR of 42.66 ± 17.42 ml⋅min−1⋅1.73 m−2. The statistically significant factors associated with CKD were a higher level of urine NGAL (55.1 [25.15–150.60] vs. 15.1 [9.67–25.15] ng/ml; p = 0.006), a higher level of TE (17.3 [6.85–46.20] vs. 7.7 [5.6–11.7] kPa; p = 0.038), and a presence of advanced fibrosis (77.8% vs. 40.7%; p = 0.041), compared to those without CKD. Urine NGAL was the only significant factor associated with CKD in NAFLD patients. The cutoff level of urine NGAL at 36.75 ng/ml showed odds ratio of 21.27 (95% CI: 3.97–113.82; p < 0.001) and 1.02 (95% CI: 1.00–1.04; p = 0.024) by univariate and multivariate analyses, respectively. The selected urine NGAL cutoff demonstrated a sensitivity and specificity of 77.8% and 85.9% for predicting CKD, respectively.ConclusionsThe proportion of CKD in NAFLD patients was 9% and the presence of advanced fibrosis was a significant risk factor associated with CKD. Additionally, urine NGAL was significantly associated with CKD in NAFLD patients using a cutoff level of 36.75 ng/ml for predicting CKD with acceptable sensitivity and specificity. A larger prospective cohort study is needed to validate our findings.
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Affiliation(s)
- Huttakan Navadurong
- Department of Medicine Division of Gastroenterology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society Bangkok Thailand
| | - Thaninee Prasoppokakorn
- Department of Medicine Division of Gastroenterology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society Bangkok Thailand
| | - Nattachai Srisawat
- Department of Medicine Division of Nephrology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society Bangkok Thailand
- Excellent Center for Critical Care Nephrology, King Chulalongkorn Memorial Hospital, Thai Red Cross Society Bangkok Thailand
| | - Roongruedee Chaiteerakij
- Department of Medicine Division of Gastroenterology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society Bangkok Thailand
| | - Piyawat Komolmit
- Department of Medicine Division of Gastroenterology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society Bangkok Thailand
- Liver Fibrosis and Cirrhosis Research Unit Chulalongkorn University Bangkok Thailand
| | - Pisit Tangkijvanich
- Department of Biochemistry and Liver Research Unit, Faculty of Medicine Chulalongkorn University Bangkok Thailand
| | - Sombat Treeprasertsuk
- Department of Medicine Division of Gastroenterology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society Bangkok Thailand
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Di Sessa A, Russo MC, Arienzo MR, Umano GR, Cozzolino D, Cirillo G, Guarino S, Miraglia Del Giudice E, Marzuillo P. PNPLA3 I148M Polymorphism Influences Renal Function in Children With Obesity and Prediabetes. J Ren Nutr 2022; 32:670-676. [PMID: 35121131 DOI: 10.1053/j.jrn.2022.01.007] [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: 08/12/2021] [Revised: 11/28/2021] [Accepted: 01/10/2022] [Indexed: 11/11/2022] Open
Abstract
OBJECTIVE Nonalcoholic fatty liver disease negatively impacts on renal function with the contribution of the I148 M variant in the patatin-like phospholipase-containing domain 3 (PNPLA3) gene. We hypothesized that children with prediabetes present with a lower estimated glomerular filtration rate (eGFR) than those with normal glucose tolerance (NGT) and that the 148M PNPLA3 allele could play a worsening role. We aimed evaluating the influence of the I148 M PNPLA3 polymorphism on the relationship between the eGFR and prediabetes in children with obesity. METHODS One thousand thirty-six children underwent to complete assessment and were genotyped for the I148 M PNPLA3 polymorphism. RESULTS Patients with prediabetes showed lower eGFR levels (171.03 ± 40.32 vs. 190.80 ± 41.71 mL/min/1.73 m2; P = .001) and higher prevalence of nonalcoholic fatty liver disease (80% vs. 59%; P = .003) than those with NGT. Children with prediabetes showed lower eGFR levels than those with NGT (150.97 ± 14.56 vs. 192.88 ± 40.09; P < .0001) among carriers of the PNPLA3 148M allele. This was not confirmed among patients homozygous for the PNPLA3 I148 allele. A general linear model for eGFR variance confirmed an inverse and significant association of the eGFR with prediabetes in patients carrying the 148M PNPLA3 allele but not in patients homozygous for the PNPLA3 I148 allele. CONCLUSIONS Prediabetes negatively affects renal function in children with obesity. This effect is heightened in patients carrying the PNPLA3 148M allele.
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Affiliation(s)
- Anna Di Sessa
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy.
| | - Maria Cecilia Russo
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Maria Rosaria Arienzo
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Giuseppina Rosaria Umano
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Domenico Cozzolino
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Grazia Cirillo
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Stefano Guarino
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Emanuele Miraglia Del Giudice
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Pierluigi Marzuillo
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
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17
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Lonardo A, Mantovani A, Targher G, Baffy G. Nonalcoholic Fatty Liver Disease and Chronic Kidney Disease: Epidemiology, Pathogenesis, and Clinical and Research Implications. Int J Mol Sci 2022; 23:13320. [PMID: 36362108 PMCID: PMC9654863 DOI: 10.3390/ijms232113320] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 10/25/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide, affecting up to ~30% of adult populations. NAFLD defines a spectrum of progressive liver conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma, which often occur in close and bidirectional associations with metabolic disorders. Chronic kidney disease (CKD) is characterized by anatomic and/or functional renal damage, ultimately resulting in a reduced glomerular filtration rate. The physiological axis linking the liver and kidneys often passes unnoticed until clinically significant portal hypertension, as a major complication of cirrhosis, becomes apparent in the form of ascites, refractory ascites, or hepatorenal syndrome. However, the extensive evidence accumulated since 2008 indicates that noncirrhotic NAFLD is associated with a higher risk of incident CKD, independent of obesity, type 2 diabetes, and other common renal risk factors. In addition, subclinical portal hypertension has been demonstrated to occur in noncirrhotic NAFLD, with a potential adverse impact on renal vasoregulation. However, the mechanisms underlying this association remain unexplored to a substantial extent. With this background, in this review we discuss the current evidence showing a strong association between NAFLD and the risk of CKD, and the putative biological mechanisms underpinning this association. We also discuss in depth the potential pathogenic role of the hepatorenal reflex, which may be triggered by subclinical portal hypertension and is a poorly investigated but promising research topic. Finally, we address emerging pharmacotherapies for NAFLD that may also beneficially affect the risk of developing CKD in individuals with NAFLD.
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Affiliation(s)
- Amedeo Lonardo
- Division of Internal Medicine, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, 37126 Verona, Italy
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, 37126 Verona, Italy
| | - Gyorgy Baffy
- Department of Medicine, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02130, USA
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18
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Theofilis P, Vordoni A, Kalaitzidis RG. Interplay between metabolic dysfunction-associated fatty liver disease and chronic kidney disease: Epidemiology, pathophysiologic mechanisms, and treatment considerations. World J Gastroenterol 2022; 28:5691-5706. [PMID: 36338895 PMCID: PMC9627426 DOI: 10.3748/wjg.v28.i39.5691] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/06/2022] [Accepted: 09/19/2022] [Indexed: 02/06/2023] Open
Abstract
The recently proposed nomenclature change from non-alcoholic fatty liver disease to metabolic dysfunction-associated fatty liver disease (MAFLD) has resulted in the reappraisal of epidemiological trends and associations with other chronic diseases. In this context, MAFLD appears to be tightly linked to incident chronic kidney disease (CKD). This association may be attributed to multiple shared risk factors including type 2 diabetes mellitus, arterial hypertension, obesity, dyslipidemia, and insulin resistance. Moreover, similarities in their molecular pathophysiologic mechanisms can be detected, since inflammation, oxidative stress, fibrosis, and gut dysbiosis are highly prevalent in these pathologic states. At the same time, lines of evidence suggest a genetic predisposition to MAFLD due to gene polymorphisms, such as the PNPLA3 rs738409 G allele polymorphism, which may also propagate renal dysfunction. Concerning their management, available treatment considerations for obesity (bariatric surgery) and novel antidiabetic agents (glucagon-like peptide 1 receptor agonists, sodium-glucose co-transporter 2 inhibitors) appear beneficial in preclinical and clinical studies of MAFLD and CKD modeling. Moreover, alternative approaches such as melatonin supplementation, farnesoid X receptor agonists, and gut microbiota modulation may represent attractive options in the future. With a look to the future, additional adequately sized studies are required, focusing on preventing renal complications in patients with MAFLD and the appropriate management of individuals with concomitant MAFLD and CKD.
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Affiliation(s)
- Panagiotis Theofilis
- Center for Nephrology “G. Papadakis,” General Hospital of Nikaia-Piraeus “Agios Panteleimon,” Nikaia 18454, Greece
| | - Aikaterini Vordoni
- Center for Nephrology “G. Papadakis,” General Hospital of Nikaia-Piraeus “Agios Panteleimon,” Nikaia 18454, Greece
| | - Rigas G Kalaitzidis
- Center for Nephrology “G. Papadakis,” General Hospital of Nikaia-Piraeus “Agios Panteleimon,” Nikaia 18454, Greece
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19
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Han E, Kim MK, Im SS, Jang BK, Kim HS. Non-alcoholic fatty liver disease and sarcopenia is associated with the risk of albuminuria independent of insulin resistance, and obesity. J Diabetes Complications 2022; 36:108253. [PMID: 35817677 DOI: 10.1016/j.jdiacomp.2022.108253] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 06/21/2022] [Accepted: 06/28/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND Although non-alcoholic fatty liver disease (NAFLD) is associated with metabolic disorders, its influence on albuminuria has not been determined. The aim of this study was to identify the relationship between NAFLD and albuminuria in the general Korean population. METHODS Data from the Korea National Health and Nutrition Examination Surveys (KNHANES) of 2008-2011 were analyzed (n = 1795). Albuminuria was defined as an albumin-to-creatinine ratio of ≥30 mg/g in random spot urine samples. NAFLD was defined as a fatty liver index (FLI) ≥60 or NAFLD liver fat score (LFS) > -0.64. RESULTS A total of 289 (16.1 %) subjects were classified as having albuminuria. Subjects with NAFLD exhibited a higher rate of albuminuria than subjects without NAFLD (crude odds ratios [ORs] = 2.60-2.95, all P < 0.001). Regardless of hypertension, insulin resistance, or obesity, the risk for albuminuria was higher in the NAFLD group than in the group without NAFLD (measured by either FLI or LFS; all P < 0.001). When subjects with NAFLD had sarcopenia, the risk of albuminuria further increased (OR = 4.33-4.64, all P < 0.001). Multiple logistic regression analyses also demonstrated that NAFLD was independently associated with albuminuria (OR = 2.58, 95 % confidence interval [CI] = 1.66-4.02, P < 0.001 for FLI, OR = 1.87, 95 % CI = 1.28-2.75, P = 0.001 for LFS). CONCLUSIONS NAFLD was associated with an increased risk of albuminuria in the general Korean population. This association was independent of hypertension, insulin resistance, chronic kidney disease, diabetes and obesity, and stronger in subjects with sarcopenia.
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Affiliation(s)
- Eugene Han
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Mi Kyung Kim
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Seung-Soon Im
- Department of Physiology, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Byoung Kuk Jang
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Hye Soon Kim
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea.
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20
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Zhang H, Zheng KI, Zhu PW, Chen SD, Li G, Ma HL, Tang LJ, Huang OY, Byrne CD, Targher G, Wang XD, Zheng MH. Lower serum copper concentrations are associated with higher prevalence of nonalcoholic steatohepatitis: a matched case-control study. Eur J Gastroenterol Hepatol 2022; 34:838-843. [PMID: 35694803 DOI: 10.1097/meg.0000000000002392] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND AND AIM Copper is an essential trace element involved in oxidative stress reactions and energy metabolism. While nonalcoholic fatty liver disease (NAFLD) is closely related to metabolic dysfunction, the role of copper in the development of simple steatosis (NAFL) and nonalcoholic steatohepatitis (NASH) is still unclear. We aimed to compare serum copper levels between patients with simple steatosis and those with NASH. METHODS AND RESULTS We studied 102 patients with biopsy-proven NASH (cases) and 102 NAFL controls, who were matched for age, sex, and residential city. Multivariable conditional logistic analysis was performed to explore associations between serum copper levels and the presence of NASH. Serum copper levels were significantly lower in patients with NASH than in those with matched NAFL controls (15.53 ± 2.41 μmol/l vs. 16.34 ± 3.23 μmol/l; P = 0.029). This intergroup difference in serum copper levels was more pronounced in men than in women. The per unit, per SD, and per doubling of serum copper levels were associated, respectively, with an approximately 20, 40, and 90% decrease in risk of having NASH, even after adjustment for potential confounding factors. CONCLUSION Lower serum copper concentrations are significantly associated with higher prevalence of NASH among biopsied-proven NAFLD patients, particularly in men.
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Affiliation(s)
- Huai Zhang
- Biostatistics and Medical Quality Management Office, The First Affiliated Hospital of Wenzhou Medical University
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Departments of
| | - Kenneth I Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Departments of
| | | | - Sui-Dan Chen
- Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Gang Li
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Departments of
| | - Hong-Lei Ma
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Departments of
| | - Liang-Jie Tang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Departments of
| | - Ou-Yang Huang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Departments of
| | - Christopher D Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Xiao-Dong Wang
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Departments of
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, China
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21
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Li G, Tang LJ, Zhu PW, Huang OY, Rios RS, Zheng KI, Chen SD, Ma HL, Targher G, Byrne CD, Pan XY, Zheng MH. PNPLA3 rs738409 C>G Variant Influences the Association Between Visceral Fat and Significant Fibrosis in Biopsy-proven Nonalcoholic Fatty Liver Disease. J Clin Transl Hepatol 2022; 10:439-448. [PMID: 35836754 PMCID: PMC9240254 DOI: 10.14218/jcth.2021.00286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/11/2021] [Accepted: 09/22/2021] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND AND AIMS Intra-abdominal visceral fat accumulation and patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 G/C gene polymorphism confer a greater susceptibility to nonalcoholic fatty liver disease (NAFLD). We examined whether the relationship between visceral fat accumulation and liver disease severity may be influenced by PNPLA3 rs738409 polymorphism. METHODS The variant of PNPLA3 rs738409 was genotyped within 523 Han individuals with biopsy-confirmed NAFLD. Visceral fat area (VFA) was measured by bioelectrical impedance. Significant liver fibrosis (SF), defined as stage F ≥2 on histology, was the outcome measure of interest. RESULTS The distribution of PNPLA3 genotypes was CC: 27.5%, CG: 48.2%, and GG: 24.3%. Higher VFA was associated with greater risk of having SF (adjusted-odds ratio [OR]: 1.03; 95% confidence interval [CI]: 1.02-1.04, p<0.05), independent of potential confounders. Among subjects with the same VFA level, the risk of SF was greater among carriers of the rs738409 G genotype than among those who did not. Stratified analysis showed that PNPLA3 rs738409 significantly influenced the association between VFA and SF. VFA remained significantly associated with SF only among the rs738409 G-allele carriers (adjusted-OR: 1.05; 95% CI: 1.03-1.08 for the GG group; and adjusted-OR:1.03; 95% CI: 1.01-1.04 for the GC group). There was a significant interaction between VFA and PNPLA3 rs738409 genotype (P interaction =0.004). CONCLUSIONS PNPLA3 rs738409 G allele has a moderate effect on the association between VFA and risk of SF in adult individuals with biopsy-proven NAFLD. Existence of the PNPLA3 rs738409 G allele and VFA interact to increase risk of SF.
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Affiliation(s)
- Gang Li
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Liang-Jie Tang
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Pei-Wu Zhu
- Department of Laboratory Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ou-Yang Huang
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Rafael S. Rios
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Kenneth I. Zheng
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Sui-Dan Chen
- Department of Pathology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hong-Lei Ma
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Christopher D. Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Xiao-Yan Pan
- Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang, China
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22
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Li G, Rios RS, Wang XX, Yu Y, Zheng KI, Huang OY, Tang LJ, Ma HL, Jin Y, Targher G, Byrne CD, Pan XY, Zheng MH. Sex influences the association between appendicular skeletal muscle mass to visceral fat area ratio and non-alcoholic steatohepatitis in patients with biopsy-proven non-alcoholic fatty liver disease. Br J Nutr 2022; 127:1613-1620. [PMID: 34176541 DOI: 10.1017/s0007114521002415] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Sarcopenic obesity is regarded as a risk factor for the progression and development of non-alcoholic fatty liver disease (NAFLD). Since male sex is a risk factor for NAFLD and skeletal muscle mass markedly varies between the sexes, we examined whether sex influences the association between appendicular skeletal muscle mass to visceral fat area ratio (SVR), that is, an index of skeletal muscle mass combined with abdominal obesity, and the histological severity of NAFLD. The SVR was measured by bioelectrical impedance in a cohort of 613 (M/F = 443/170) Chinese middle-aged individuals with biopsy-proven NAFLD. Multivariable logistic regression and subgroup analyses were used to test the association between SVR and the severity of NAFLD (i.e. non-alcoholic steatohepatitis (NASH) or NASH with the presence of any stage of liver fibrosis). NASH was identified by a NAFLD activity score ≥5, with a minimum score of 1 for each of its categories. The presence of fibrosis was classified as having a histological stage ≥1. The SVR was inversely associated with NASH in men (adjusted OR 0·62; 95 % CI 0·42, 0·92, P = 0·017 for NASH, adjusted OR 0·65; 95 % CI 0·43, 0·99, P = 0·043 for NASH with the presence of fibrosis), but not in women (1·47 (95 % CI 0·76, 2·83), P = 0·25 for NASH, and 1·45 (95 % CI 0·74, 2·83), P = 0·28 for NASH with the presence of fibrosis). There was a significant interaction for sex and SVR (Pinteraction = 0·017 for NASH and Pinteraction = 0·033 for NASH with the presence of fibrosis). Our findings show that lower skeletal muscle mass combined with abdominal obesity is strongly associated with the presence of NASH only in men.
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Affiliation(s)
- Gang Li
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou325000, People's Republic of China
| | - Rafael S Rios
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou325000, People's Republic of China
| | - Xin-Xin Wang
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Yue Yu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Kenneth I Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou325000, People's Republic of China
| | - Ou-Yang Huang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou325000, People's Republic of China
| | - Liang-Jie Tang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou325000, People's Republic of China
| | - Hong-Lei Ma
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou325000, People's Republic of China
| | - Yi Jin
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Christopher D Byrne
- Southampton National Institute for Health Research, Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Xiao-Yan Pan
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou325000, People's Republic of China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, People's Republic of China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, People's Republic of China
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23
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Kanbay M, Copur S, Demiray A, Sag AA, Covic A, Ortiz A, Tuttle KR. Fatty kidney: A possible future for chronic kidney disease research. Eur J Clin Invest 2022; 52:e13748. [PMID: 35040119 DOI: 10.1111/eci.13748] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 01/15/2022] [Accepted: 01/16/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND Metabolic syndrome is a growing twenty-first century pandemic associated with multiple clinical comorbidities ranging from cardiovascular diseases, non-alcoholic fatty liver disease and polycystic ovary syndrome to kidney dysfunction. A novel area of research investigates the concept of fatty kidney in the pathogenesis of chronic kidney disease, especially in patients with diabetes mellitus or metabolic syndrome. AIM To review the most updated literature on fatty kidney and provide future research, diagnostic and therapeutic perspectives on a disease increasingly affecting the contemporary world. MATERIALS AND METHOD We performed an extensive literature search through three databases including Embase (Elsevier) and the Cochrane Central Register of Controlled Trials (Wiley) and PubMed/Medline Web of Science in November 2021 by using the following terms and their combinations: 'fatty kidney', 'ectopic fat', 'chronic kidney disease', 'cardiovascular event', 'cardio-metabolic risk', 'albuminuria' and 'metabolic syndrome'. Each study has been individually assessed by the authors. RESULTS Oxidative stress and inflammation, Klotho deficiency, endoplasmic reticulum stress, mitochondrial dysfunction and disruption of cellular energy balance appear to be the main pathophysiological mechanisms leading to tissue damage following fat accumulation. Despite the lack of large-scale comprehensive studies in this novel field of research, current clinical trials demonstrate fatty kidney as an independent risk factor for the development of chronic kidney disease and cardiovascular events. CONCLUSION The requirement for future studies investigating the pathophysiology, clinical outcomes and therapeutics of fatty kidney is clear.
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Affiliation(s)
- Mehmet Kanbay
- Division of Nephrology, Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Atalay Demiray
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Alan A Sag
- Division of Vascular and Interventional Radiology, Department of Radiology, Duke University Medical Center, Durham, North Carolina, USA
| | - Adrian Covic
- Department of Nephrology, Grigore T. Popa' University of Medicine, Iasi, Romania
| | - Alberto Ortiz
- Department of Medicine, Universidad Autonoma de Madrid and IIS-Fundacion Jimenez Diaz, Madrid, Spain
| | - Kathherine R Tuttle
- Division of Nephrology, University of Washington, Seattle, Washington, USA.,Providence Medical Research Center, Providence Health Care, Spokane, Washington, USA
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Chen SD, Zhang H, Rios RS, Li YY, Zhu PW, Jin Y, Ma HL, Tang LJ, Li G, Huang OY, Zheng KI, Byrne CD, Targher G, Zheng MH. J-shaped relationship between serum zinc levels and the severity of hepatic necro-inflammation in patients with MAFLD. Nutr Metab Cardiovasc Dis 2022; 32:1259-1265. [PMID: 35260312 DOI: 10.1016/j.numecd.2022.01.035] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 01/07/2022] [Accepted: 01/31/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND AND AIMS Zinc is an essential trace element that plays an important role in maintaining health, and affecting gene expression, signal transduction and regulation of apoptosis. It is uncertain whether serum zinc levels are altered in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). We aimed to investigate the association between serum zinc levels and the severity of hepatic necro-inflammation (HN) in patients with MAFLD. METHODS AND RESULTS Liver disease severity was graded histologically using the NAFLD activity score. HN was defined as the sum of ballooning and lobular inflammation. We used a smooth function regression model to analyze the relationship between serum zinc levels and HN. A total of 561 (76.5% men) patients with biopsy-confirmed MAFLD were enrolled. They had a mean age of 41.3 years, and a mean serum zinc level of 17.0 ± 4.1 μmol/L. Compared to those with mild hepatic necro-inflammation (MHN, grades 0-2; n = 286), patients with severe hepatic necro-inflammation (SHN, grades 3-5; n = 275) had lower serum zinc concentrations (16.3 ± 4.2 vs. 17.6 ± 4.0 μmol/L; p < 0.001). However, a threshold saturation effect analysis showed that there was an inflection in serum zinc levels at 24 μmol/L. After adjustment for potential confounders, serum zinc levels <24 μmol/L were inversely associated with SHN (adjusted-odds ratio 0.88, 95%CI 0.83-0.93; p < 0.001), whereas serum zinc levels >24 μmol/L were positively associated with SHN (adjusted-odds ratio 1.42, 95%CI: 1.03-1.97; p = 0.035). CONCLUSIONS There is a J-shaped relationship between serum zinc levels and the severity of hepatic necro-inflammation in patients with biopsy-proven MAFLD.
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Affiliation(s)
- Sui-Dan Chen
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Huai Zhang
- Department of Biostatistics and Medical Record, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Rafael S Rios
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yang-Yang Li
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Pei-Wu Zhu
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yi Jin
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hong-Lei Ma
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liang-Jie Tang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Gang Li
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ou-Yang Huang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Kenneth I Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Christopher D Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Giovanni Targher
- Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China.
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Xu K, Zheng KI, Zhu PW, Liu WY, Ma HL, Li G, Tang LJ, Rios RS, Targher G, Byrne CD, Wang XD, Chen YP, Zheng MH. Interaction of SAMM50-rs738491, PARVB-rs5764455 and PNPLA3-rs738409 Increases Susceptibility to Nonalcoholic Steatohepatitis. J Clin Transl Hepatol 2022; 10:219-229. [PMID: 35528982 PMCID: PMC9039704 DOI: 10.14218/jcth.2021.00067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/26/2021] [Accepted: 07/01/2021] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND AND AIMS Previous studies have reported that the single nucleotide polymorphisms (SNPs) of SAMM50-rs738491, PARVB-rs5764455 and PNPLA3-rs738409 are associated with nonalcoholic fatty liver disease (NAFLD). However, no studies have examined the effect of interactions between these three genotypes to affect liver disease severity. We assessed the effect of these three SNPs on nonalcoholic steatohepatitis (NASH) and also examined the gene-gene interactions in a Chinese population with biopsy-confirmed NAFLD. METHODS We enrolled 415 consecutive adult individuals with biopsy-proven NAFLD. Multivariable logistic regression analysis was undertaken to test associations between NASH and SNPs in SAMM50-rs738491, PARVB-rs5764455 and PNPLA3-rs738409. Gene-gene interactions were analyzed by performing a generalized multifactor dimensionality reduction (GMDR) analysis. RESULTS The mean ± standard deviation age of these 415 patients was 41.3±12.5 years, and 75.9% were men. Patients with SAMM50-rs738491 TT, PARVB-rs5764455 AA or PNPLA3-rs738409 GG genotypes had a higher risk of NASH, even after adjustment for age, sex and body mass index. GMDR analysis showed that the combination of all three SNPs was the best model for predicting NASH. Additionally, the odds ratio of the haplotype T-A-G for predicting the risk of NASH was nearly three times higher than that of the haplotype G-C-C. CONCLUSIONS NAFLD patients carrying the SAMM50-rs738491 TT, PARVB-rs5764455 AA or PNPLA3-rs738409 GG genotypes are at greater risk of NASH. These three SNPs may synergistically interact to increase susceptibility to NASH.
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Affiliation(s)
- Ke Xu
- NAFLD Research Center, Department of Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Kenneth I. Zheng
- NAFLD Research Center, Department of Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Pei-Wu Zhu
- Department of Laboratory Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wen-Yue Liu
- Department of Endocrinology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hong-Lei Ma
- NAFLD Research Center, Department of Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Gang Li
- NAFLD Research Center, Department of Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Liang-Jie Tang
- NAFLD Research Center, Department of Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Rafael S. Rios
- NAFLD Research Center, Department of Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Christopher D. Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Xiao-Dong Wang
- NAFLD Research Center, Department of Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang, China
| | - Yong-Ping Chen
- NAFLD Research Center, Department of Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang, China
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang, China
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Wang TY, Wang RF, Bu ZY, Targher G, Byrne CD, Sun DQ, Zheng MH. Association of metabolic dysfunction-associated fatty liver disease with kidney disease. Nat Rev Nephrol 2022; 18:259-268. [PMID: 35013596 DOI: 10.1038/s41581-021-00519-y] [Citation(s) in RCA: 120] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/24/2021] [Indexed: 02/08/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of fat in more than 5% of hepatocytes in the absence of excessive alcohol consumption and other secondary causes of hepatic steatosis. In 2020, the more inclusive term metabolic (dysfunction)-associated fatty liver disease (MAFLD) - defined by broader diagnostic criteria - was proposed to replace the term NAFLD. The new terminology and revised definition better emphasize the pathogenic role of metabolic dysfunction and uses a set of definitive, inclusive criteria for diagnosis. Diagnosis of MAFLD is based on evidence of hepatic steatosis (as assessed by liver biopsy, imaging techniques or blood biomarkers and scores) in persons who are overweight or obese and have type 2 diabetes mellitus or metabolic dysregulation, regardless of the coexistence of other liver diseases or excessive alcohol consumption. The known association between NAFLD and chronic kidney disease (CKD) and our understanding that CKD can occur as a consequence of metabolic dysfunction suggests that individuals with MAFLD - who by definition have fatty liver and metabolic comorbidities - are at increased risk of CKD. In this Perspective article, we discuss the clinical associations between MAFLD and CKD, the pathophysiological mechanisms by which MAFLD may increase the risk of CKD and the potential drug treatments that may benefit both conditions.
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Affiliation(s)
- Ting-Yao Wang
- Department of Nephrology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Rui-Fang Wang
- Department of Nephrology, the Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, China
| | - Zhi-Ying Bu
- Department of Nephrology, the Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, China
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Christopher D Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Dan-Qin Sun
- Department of Nephrology, the Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, China.
- Affiliated Wuxi Clinical College of Nantong University, Wuxi, China.
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, China.
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China.
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Labenz C, Toenges G, Zheng MH, Ding D, Myers RP, Galle PR, Armandi A, Ampuero J, Gómez MR, Bugianesi E, Anstee QM, Schattenberg JM. Derivation and validation of the nonalcoholic fatty liver disease cirrhosis score (NCS) to distinguish bridging fibrosis from cirrhosis. Eur J Intern Med 2022; 98:53-60. [PMID: 35058147 DOI: 10.1016/j.ejim.2021.12.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/04/2021] [Accepted: 12/08/2021] [Indexed: 12/20/2022]
Abstract
Separation of bridging fibrosis from cirrhosis in non-alcoholic fatty liver disease (NAFLD) is critical to guide management. Therefore, it was the aim of this study to develop an easy-to-perform score distinguishing F3 and F4 fibrosis in NAFLD. A derivation cohort comprising 251 NAFLD patients with F3 or F4 was used to develop the NAFLD Cirrhosis Score (NCS). The NCS was validated in three independent cohorts with liver histology comprising 1666 participants from the STELLAR trials, 47 patients from China and 2058 patients from the European NAFLD Registry. A model including INR, gGT, ALT, platelets and age discriminated best between patients with bridging fibrosis and cirrhosis with an area under the curve (AUC) of 0.733 (95%CI 0.671-0.795). The diagnostic performance of the NCS was similar in the STELLAR studies (AUC 0.700; 95%CI 0.680-0.730) and a smaller cohort from China (AUC 0.727; 95%CI 0.533-0.921). In the European NAFLD Registry, spanning all histological fibrosis stages, the NCS exhibited an AUC of 0.798 (95%CI 0.766-0.830) to detect cirrhosis. We derived two NCS cut-off values (<64.5 and >79.17) to classify patients at low, intermediate, or high risk for the presence of cirrhosis. Using these cut-offs, further diagnostic workup could be avoided by ruling in or ruling out cirrhosis in approximately half of the patients. Furthermore, NCS identified patients at risk for progression to cirrhosis in the F3 cohort and liver-related outcomes in the F4 cohort. CONCLUSION: The NCS is a simple tool to improve the identification of compensated cirrhosis within the large group of advanced disease stage and provides prognostic information. Overall, the differentiation of F3 from F4 disease using standard laboratory remains difficult and does not exceed moderate accuracy.
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Affiliation(s)
- Christian Labenz
- Department of Internal Medicine I, University Medical Centre of the Johannes Gutenberg-University, Mainz, Germany; Metabolic Liver Research Program, University Medical Centre of the Johannes Gutenberg-University, Mainz, Germany; Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
| | - Gerrit Toenges
- Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, China.
| | - Dora Ding
- Gilead Sciences, Inc., Foster City, CA, USA.
| | | | - Peter R Galle
- Department of Internal Medicine I, University Medical Centre of the Johannes Gutenberg-University, Mainz, Germany; Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
| | - Angelo Armandi
- Department of Medical Sciences, Division of Gastroenterology, AOU Citta della Salute e della Scienza, University of Torino, Italy.
| | - Javier Ampuero
- Digestive Disease Department, Virgen del Rocio University Hospital, Sevilla, Spain.
| | - Manuel Romero Gómez
- Digestive Disease Department, Virgen del Rocio University Hospital, Sevilla, Spain.
| | - Elisabetta Bugianesi
- Department of Medical Sciences, Division of Gastroenterology, AOU Citta della Salute e della Scienza, University of Torino, Italy.
| | - Quentin M Anstee
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom.
| | - Jörn M Schattenberg
- Department of Internal Medicine I, University Medical Centre of the Johannes Gutenberg-University, Mainz, Germany; Metabolic Liver Research Program, University Medical Centre of the Johannes Gutenberg-University, Mainz, Germany; Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
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28
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Sun QF, Tang LJ, Wang MJ, Zhu PW, Li YY, Ma HL, Huang OY, Hong L, Li G, Byrne CD, Targher G, Liu WY, Lu Y, Ding JG, Zheng MH. Potential Blood DNA Methylation Biomarker Genes for Diagnosis of Liver Fibrosis in Patients With Biopsy-Proven Non-alcoholic Fatty Liver Disease. Front Med (Lausanne) 2022; 9:864570. [PMID: 35433752 PMCID: PMC9008751 DOI: 10.3389/fmed.2022.864570] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 02/22/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND AND OBJECTIVE This pilot study aimed to identify potential blood DNA methylation (BDM) biomarker genes for the diagnosis of liver fibrosis in non-alcoholic fatty liver disease (NAFLD). METHODS We included a total of 16 NAFLD patients with significant (SLF, liver fibrosis stage ≥ 2) and 16 patients with non-significant liver fibrosis (NSLF, fibrosis stages 0-1). The association between BDM and liver fibrosis was analyzed. Genes were selected based on a stepwise-filtering with CpG islands containing significant differentially methylated probes. RESULTS The two groups of patients were distinguishable through both t-distributed stochastic neighbor embedding (t-SNE) analysis and unsupervised hierarchical clustering analysis based on their BDM status. BDM levels were significantly higher in the NSLF group than in the SLF group. The methylation levels in the island and shelf regions were also significantly higher in the NSLF group, as well as the methylation levels in the first exon, 3'-untranslated region, body, ExonBnd, non-intergenic region, transcription start site (TSS)1500, and TSS200 regions (all p < 0.05). BDM status was associated with greater histological liver fibrosis, but not with age, sex, or other histological features of NAFLD (p < 0.05). The methylation levels of the hypomethylated CpG island region of CISTR, IFT140, and RGS14 genes were increased in the NSLF group compared to the SLF group (all p < 0.05). CONCLUSION BDM may stratify NAFLD patients with significant and non-significant liver fibrosis. The CISTR, IFT140, and RGS14 genes are potential novel candidate BDM biomarkers for liver fibrosis and these pilot data suggest further work on BDM biomarkers is warranted.
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Affiliation(s)
- Qing-Feng Sun
- Department of Infectious Diseases, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liang-Jie Tang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ming-Jie Wang
- Department of Gastroenterology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Pei-Wu Zhu
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yang-Yang Li
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hong-Lei Ma
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of General Practice, Affiliated People’s Hospital, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - Ou-Yang Huang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liang Hong
- Department of Infectious Diseases, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Gang Li
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Christopher D. Byrne
- National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, United Kingdom
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, Azienda Ospedaliera Universitaria Integrata Verona, University of Verona, Verona, Italy
| | - Wen-Yue Liu
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yan Lu
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ji-Guang Ding
- Department of Infectious Diseases, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
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Baratta F, D’Erasmo L, Di Costanzo A, Umbro I, Pastori D, Angelico F, Del Ben M. Metabolic Syndrome but Not Fatty Liver-Associated Genetic Variants Correlates with Glomerular Renal Function Decline in Patients with Non-Alcoholic Fatty Liver Disease. Biomedicines 2022; 10:720. [PMID: 35327522 PMCID: PMC8944982 DOI: 10.3390/biomedicines10030720] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/15/2022] [Accepted: 03/17/2022] [Indexed: 12/25/2022] Open
Abstract
The association between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) has been extensively demonstrated. Recent studies have focused attention on the role of patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism in the association between NAFLD and CKD in non-metabolic adults and children, but the genetic impact on NAFLD-CKD association is still a matter of debate. The aim of the study was to investigate the impact of PNPLA3, transmembrane 6 superfamily member 2 (TM6SF2), membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and glucokinase regulatory protein (GCKR) gene variants rather than metabolic syndrome features on renal function in a large population of NAFLD patients. The present study is a post hoc analysis of the Plinio Study (ClinicalTrials.gov: NCT04036357). PNPLA3, TM6SF2, MBOAT7 and GCKR genes were analyzed by using real-time PCR with TaqMan probes. Glomerular filtration rate (GFR) was estimated with CKD-EPI. We analyzed 538 NAFLD; 47.2% had GFR < 90 mL/min/1.73 m2 while 5.9% had GFR < 60 mL/min/1.73 m2. The distribution of genotypes was superimposable according to GFR cut-offs. Results from the multivariable regression model did not show any correlation between genotypes and renal function. Conversely, metabolic syndrome was highly associated with GFR < 90 mL/min/1.73 m2 (odds ratio (OR): 1.58 [1.10−2.28]) and arterial hypertension with GFR < 60 mL/min/1.73 m2 (OR: 1.50 [1.05−2.14]). In conclusion, the association between NAFLD and CKD might be related to the shared metabolic risk factors rather than the genetic NAFLD background.
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Affiliation(s)
- Francesco Baratta
- Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (F.B.); (D.P.); (M.D.B.)
| | - Laura D’Erasmo
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00161 Rome, Italy;
| | - Alessia Di Costanzo
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00161 Rome, Italy;
| | - Ilaria Umbro
- Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (F.B.); (D.P.); (M.D.B.)
| | - Daniele Pastori
- Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (F.B.); (D.P.); (M.D.B.)
| | - Francesco Angelico
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00161 Rome, Italy;
| | - Maria Del Ben
- Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (F.B.); (D.P.); (M.D.B.)
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Mantovani A, Dalbeni A, Beatrice G, Cappelli D, Gomez-Peralta F. Non-Alcoholic Fatty Liver Disease and Risk of Macro- and Microvascular Complications in Patients with Type 2 Diabetes. J Clin Med 2022; 11:jcm11040968. [PMID: 35207239 PMCID: PMC8878156 DOI: 10.3390/jcm11040968] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 02/01/2022] [Accepted: 02/10/2022] [Indexed: 02/01/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome. To date, NAFLD is the most frequent chronic liver disease seen day by day in clinical practice across most high-income countries, affecting nearly 25–30% of adults in the general population and up to 70% of patients with T2DM. Over the last few decades, it clearly emerged that NAFLD is a “multisystemic disease” and that the leading cause of death among patients with NAFLD is cardiovascular disease (CVD). Indeed, several observational studies and some meta-analyses have documented that NAFLD, especially its advanced forms, is strongly associated with fatal and non-fatal cardiovascular events, as well as with specific cardiac complications, including sub-clinical myocardial alteration and dysfunction, heart valve diseases and cardiac arrhythmias. Importantly, across various studies, these associations remained significant after adjustment for established cardiovascular risk factors and other confounders. Additionally, several observational studies and some meta-analyses have also reported that NAFLD is independently associated with specific microvascular conditions, such as chronic kidney disease and distal or autonomic neuropathy. Conversely, data regarding a potential association between NAFLD and retinopathy are scarce and often conflicting. This narrative review will describe the current evidence about the association between NAFLD and the risk of macro- and microvascular manifestations of CVD, especially in patients with T2DM. We will also briefly discuss the biological mechanisms underpinning the association between NAFLD and its advanced forms and macro- and microvascular CVD.
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Affiliation(s)
- Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, 37126 Verona, Italy; (G.B.); (D.C.)
- Correspondence: (A.M.); (F.G.-P.)
| | - Andrea Dalbeni
- Section of General Medicine C and Liver Unit, University and Azienda Ospedaliera Universitaria Integrata of Verona, 37126 Verona, Italy;
| | - Giorgia Beatrice
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, 37126 Verona, Italy; (G.B.); (D.C.)
| | - Davide Cappelli
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, 37126 Verona, Italy; (G.B.); (D.C.)
| | - Fernando Gomez-Peralta
- Endocrinology and Nutrition Unit, Segovia General Hospital, 40002 Segovia, Spain
- Correspondence: (A.M.); (F.G.-P.)
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Park S, Lee S, Kim Y, Cho S, Kim K, Chul Kim Y, Han SS, Lee H, Lee JP, Joo KW, Lim CS, Kim YS, Kim DK. Causal effects from non-alcoholic fatty liver disease on kidney function: A Mendelian randomization study. Liver Int 2022; 42:412-418. [PMID: 34843158 DOI: 10.1111/liv.15118] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 11/25/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS An observational association between nonalcoholic fatty liver disease (NAFLD) and kidney function impairment has been reported. We aimed to investigate the causal effects from NAFLD on estimated glomerular filtration rate (eGFR) by a Mendelian randomization (MR) study. METHODS We first performed single-variant MR with rs738409 as a genetic instrument for NAFLD. Another genetic instrument was developed from a genome-wide association study for biopsy-confirmed NAFLD among individuals of European ancestry (1483 cases and 17 781 controls). The eGFR outcome was assessed in individuals of white British ancestry from the UK Biobank (N = 321 405). The associations were reassessed in the negative control subgroup (body mass index < 30 kg/m2 , absence of central obesity, and serum alanine aminotransferase level ≤ 20 IU/mL) with a low probability of developing NAFLD. As a replication analysis, a summary-level MR was performed with the European ancestry CKDGen dataset (N = 567 460). RESULTS In the UK Biobank, a genetic predisposition for NAFLD, determined either by the single SNP rs738409 or by the group of variants, was significantly associated with a reduced eGFR even with adjustment for metabolic disorders. Although the associations were not significant in the negative control subgroup with a low probability of developing NAFLD, they were significant in the subgroup with a remaining risk of NAFLD, suggesting the absence of a horizontal pleiotropic pathway. The summary-level MR from the CKDGen dataset supported the causal effects of NAFLD on reduced eGFR. CONCLUSIONS This MR analysis supports the causal reduction in kidney function by NAFLD.
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Affiliation(s)
- Sehoon Park
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.,Department of Internal Medicine, Armed Forces Capital Hospital, Gyeonggi-do, Korea
| | - Soojin Lee
- Division of Nephrology, Department of Internal Medicine, Uijeongbu Eulji University Medical Center, Gyeonggi-do, Korea
| | - Yaerim Kim
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Semin Cho
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Kwangsoo Kim
- Transdisciplinary Department of Medicine & Advanced Technology, Seoul National University Hospital, Seoul, Korea
| | - Yong Chul Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Seung Seok Han
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Kidney Research Institute, Seoul National University, Seoul, Korea
| | - Hajeong Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Kidney Research Institute, Seoul National University, Seoul, Korea
| | - Jung Pyo Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.,Kidney Research Institute, Seoul National University, Seoul, Korea.,Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Kwon Wook Joo
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.,Kidney Research Institute, Seoul National University, Seoul, Korea
| | - Chun Soo Lim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.,Kidney Research Institute, Seoul National University, Seoul, Korea.,Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Yon Su Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.,Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.,Kidney Research Institute, Seoul National University, Seoul, Korea
| | - Dong Ki Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.,Kidney Research Institute, Seoul National University, Seoul, Korea
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32
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Tan EXX, Lee JWJ, Jumat NH, Chan WK, Treeprasertsuk S, Goh GBB, Fan JG, Song MJ, Charatcharoenwitthaya P, Duseja A, Imajo K, Nakajima A, Seki Y, Kasama K, Kakizaki S, Lesmana LA, Zheng KI, Zheng MH, Koh CJ, Ho KY, Goh KL, Wong VWS, Dan YY. Non-obese non-alcoholic fatty liver disease (NAFLD) in Asia: an international registry study. Metabolism 2022; 126:154911. [PMID: 34648769 DOI: 10.1016/j.metabol.2021.154911] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 10/06/2021] [Accepted: 10/07/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND A significant proportion of the non-alcoholic fatty liver disease (NAFLD) population is non-obese. Prior studies reporting the severity of NAFLD amongst non-obese patients were heterogenous. Our study, using data from the largest biopsy-proven NAFLD international registry within Asia, aims to characterize the demographic, metabolic and histological differences between non-obese and obese NAFLD patients. METHODS 1812 biopsy-proven NAFLD patients across nine countries in Asia assessed between 2006 and 2019 were pooled into a curated clinical registry. Demographic, metabolic and histological differences between non-obese and obese NAFLD patients were evaluated. The performance of Fibrosis-4 index for liver fibrosis (FIB-4) and NAFLD fibrosis score (NFS) to identify advanced liver disease across the varying obesity subgroups was compared. A random forest analysis was performed to identify novel predictors of fibrosis and steatohepatitis in non-obese patients. FINDINGS One-fifth (21.6%) of NAFLD patients were non-obese. Non-obese NAFLD patients had lower proportions of NASH (50.5% vs 56.5%, p = 0.033) and advanced fibrosis (14.0% vs 18.7%, p = 0.033). Metabolic syndrome in non-obese individuals was associated with NASH (OR 1.59, 95% CI 1.01-2.54, p = 0.047) and advanced fibrosis (OR 1.88, 95% CI 0.99-3.54, p = 0.051). FIB-4 performed better than the NFS score (AUROC 81.5% vs 73.7%, p < 0.001) when classifying patients with F2-4 fibrosis amongst non-obese NAFLD patients. Haemoglobin, GGT, waist circumference and cholesterol are additional variables found on random forest analysis useful for identifying non-obese NAFLD patients with advanced liver disease. CONCLUSION A substantial proportion of non-obese NAFLD patients has NASH or advanced fibrosis. FIB-4, compared to NFS better identifies non-obese NAFLD patients with advanced liver disease. Serum GGT, cholesterol, haemoglobin and waist circumference, which are neither components of NFS nor FIB-4, are important biomarkers for advanced liver disease in non-obese patients.
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Affiliation(s)
- Eunice Xiang-Xuan Tan
- Division of Gastroenterology and Hepatology, National University Health System, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jonathan Wei-Jie Lee
- Division of Gastroenterology and Hepatology, National University Health System, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Nur Halisah Jumat
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | | | | | - Jian-Gao Fan
- Shanghai Jiaotong University School of Medicine, Shanghai, China
| | | | | | - Ajay Duseja
- Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Kento Imajo
- Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Atsushi Nakajima
- Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | | | | | - Satoru Kakizaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan
| | | | - Kenneth I Zheng
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Calvin J Koh
- Division of Gastroenterology and Hepatology, National University Health System, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Khek-Yu Ho
- Division of Gastroenterology and Hepatology, National University Health System, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | | | - Yock-Young Dan
- Division of Gastroenterology and Hepatology, National University Health System, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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Gao F, He Q, Li G, Huang OY, Tang LJ, Wang XD, Targher G, Byrne CD, Luo JW, Zheng MH. A novel quantitative ultrasound technique for identifying non-alcoholic steatohepatitis. Liver Int 2022; 42:80-91. [PMID: 34564946 DOI: 10.1111/liv.15064] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 08/09/2021] [Accepted: 09/19/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS There remains a need to develop a non-invasive, accurate and easy-to-use tool to identify patients with non-alcoholic steatohepatitis (NASH). Successful clinical and preclinical applications demonstrate the ability of quantitative ultrasound (QUS) techniques to improve medical diagnostics. We aimed to develop and validate a diagnostic tool, based on QUS analysis, for identifying NASH. METHODS A total of 259 Chinese individuals with biopsy-proven non-alcoholic fatty liver disease (NAFLD) were enrolled in the study. The histological spectrum of NAFLD was classified according to the NASH clinical research network scoring system. Radiofrequency (RF) data, raw data of iLivTouch, was acquired for further QUS analysis. The least absolute shrinkage and selection operator (LASSO) method was used to select the most useful predictive features. RESULTS Eighteen candidate RF parameters were reduced to two significant parameters by shrinking the regression coefficients with the LASSO method. We built a novel QUS score based on these two parameters, and this QUS score showed good discriminatory capacity and calibration for identifying NASH both in the training set (area under the ROC curve [AUROC]: 0.798, 95% confidence interval [CI] 0.731-0.865; Hosmer-Lemeshow test, P = .755) and in the validation set (AUROC: 0.816, 95% CI 0.725-0.906; Hosmer-Lemeshow test, P = .397). Subgroup analysis showed that the QUS score performed well in different subgroups. CONCLUSIONS The QUS score, which was developed from QUS, provides a novel, non-invasive and practical way for identifying NASH.
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Affiliation(s)
- Feng Gao
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qiong He
- Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, China
- Tsinghua-Peking Joint Center for Life Sciences Department, Tsinghua University, Beijing, China
| | - Gang Li
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ou-Yang Huang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liang-Jie Tang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiao-Dong Wang
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Christopher D Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Jian-Wen Luo
- Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, China
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, China
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Association between rs738408, rs738409 and rs139051polymorphisms in PNPLA3 gene and non-alcoholic fatty liver disease. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2021.101472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Villani R, Magnati GP, De Girolamo G, Sangineto M, Romano AD, Cassano T, Serviddio G. Genetic Polymorphisms and Clinical Features in Diabetic Patients With Fatty Liver: Results From a Single-Center Experience in Southern Italy. Front Med (Lausanne) 2021; 8:737759. [PMID: 34746177 PMCID: PMC8566437 DOI: 10.3389/fmed.2021.737759] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 09/10/2021] [Indexed: 12/12/2022] Open
Abstract
Genetic background may be involved in the promotion and progression of non-alcoholic fatty liver disease (NAFLD). Previous studies have suggested that the single nucleotide polymorphisms (SNPs) may be associated with the specific clinical features in the patients with hepatic steatosis; however, data on the patients with diabetes from Southern Italy are lacking. We enrolled 454 patients and 260 of them had type 2 diabetes. We studied the PNPLA3 rs738409, LPIN1 rs13412852, KLF6 rs3750861, SOD2 rs4880, TM6SF2 rs58542926, and ZNF624 rs12603226 SNPs and their distribution in the study population. Lipid profile, liver stiffness, and kidney function were also studied to understand the potential role of the SNPs in the development of clinical phenotypes. No differences were observed in the distribution of polymorphisms between the diabetic and non-diabetic subjects. Carriers of risk allele G for PNPLA3 rs738409 SNP showed a lower mean value of serum triglycerides and a higher liver stiffness. Risk allele for KLF6 rs3750861 and SOD2 rs4880 polymorphism had a lower estimated glomerular filtration rate (eGFR) value, whereas no differences in the glucose and glycated hemoglobin level were observed in the subgroups by the different genotypes. Genetic polymorphisms are useful to identify the patients at higher risk of development of liver fibrosis and lower eGFR values in the patients with diabetes and NAFLD. Their use in clinical practice may help the clinicians to identify the patients who require a more strict follow-up program.
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Affiliation(s)
- Rosanna Villani
- C.U.R.E. (University Centre for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Grazia Pia Magnati
- C.U.R.E. (University Centre for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Giuseppe De Girolamo
- C.U.R.E. (University Centre for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Moris Sangineto
- C.U.R.E. (University Centre for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Antonino Davide Romano
- C.U.R.E. (University Centre for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Tommaso Cassano
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gaetano Serviddio
- C.U.R.E. (University Centre for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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36
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Wu XX, Zheng KI, Boursier J, Chan WK, Yilmaz Y, Romero-Gómez M, El Kassas M, Targher G, Byrne CD, Huang ZM, Zheng MH. acNASH index to diagnose nonalcoholic steatohepatitis: a prospective derivation and global validation study. EClinicalMedicine 2021; 41:101145. [PMID: 34646997 PMCID: PMC8495106 DOI: 10.1016/j.eclinm.2021.101145] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 09/04/2021] [Accepted: 09/14/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND There is an unmet need for non-invasive biomarkers for the diagnosis of nonalcoholic steatohepatitis (NASH) in non-specialized settings. We aimed to develop and validate a non-invasive test for diagnosing NASH in individuals with biopsy-proven nonalcoholic fatty liver disease (NAFLD). METHODS We developed a non-invasive test named the acNASH index that combines serum creatinine and aspartate aminotransferase levels in a derivation cohort of 390 Chinese NAFLD patients admitted to the hepatology center of the First Affiliated Hospital of Wenzhou Medical University (China) between December 2016 and September 2019 and subsequently validated in five external cohorts of different ethnicities of patients with biopsy-confirmed NAFLD (pooled n=1,089). FINDINGS The performance of the acNASH index for identifying NASH (defined as NAFLD activity score ≥5 with score of ≥1 for each steatosis, lobular inflammation and ballooning) was good in the derivation cohort with an area under receiver operating characteristics (AUROC) of 0·818 (95%CI 0·777-0·860). A cutoff of acNASH index <4·15 gave a sensitivity (Se) of 91%, a specificity (Sp) of 48% and a negative predictive value (NPV) of 83% for ruling-out NASH, conversely, a cutoff of acNASH >7·73 gave a Sp of 91%, Se of 53% and a positive predictive value (PPV) of 85% for ruling-in NASH. In the pooled validation cohort (n=1,089), the diagnostic performance of the index was also good with AUROC=0·805 (95%CI 0·780-0·830), NPV of 93% for ruling-out NASH and PPV of 73% for ruling-in NASH. Subgroup analyses showed similar performance in patients with diabetes or subjects with normal serum transaminase levels. INTERPRETATION The acNASH index shows promising utility as a simple non-invasive biomarker for diagnosing NASH among adults with biopsy-proven NAFLD of different ethnicities from different countries. FUNDING The National Natural Science Foundation of China (82070588), High Level Creative Talents from Department of Public Health in Zhejiang Province (S2032102600032) and Project of New Century 551 Talent Nurturing in Wenzhou.
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Key Words
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- AUROC, area under receiver operating characteristics
- BMI, body mass index
- CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration
- CRN, Clinical Research Network
- GAA, guanidine-acetic acid
- HBV, chronic viral hepatitis B
- HCV, chronic viral hepatitis C
- NAFLD, nonalcoholic fatty liver disease
- NAS, NAFLD Activity Score
- NASH, nonalcoholic steatohepatitis
- NPV, negative predictive value
- Nonalcoholic steatohepatitis
- PERSONS, Prospective Epidemic Research Specifically Of NASH
- PPV, positive predictive value
- SCr, serum creatinine
- Se, sensitivity
- Sp, specificity
- T2DM, type 2 diabetes mellitus
- e-GFR, estimated glomerular filtration rate
- metabolic dysfunction-associated fatty liver disease
- nonalcoholic fatty liver disease
- primary care
- scoring system
- screening
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Affiliation(s)
- Xi-Xi Wu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Kenneth I. Zheng
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jérôme Boursier
- Department of Hepato-Gastroenterology, Angers University Hospital, Angers, France
| | - Wah-Kheong Chan
- Gastroenterology and Hepatology Unit, Gastrointestinal Endoscopy Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Yusuf Yilmaz
- Liver Research Unit, Institute of Gastroenterology, Marmara University, Istanbul, Turkey
- Department of Gastroenterology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Manuel Romero-Gómez
- Hospital Universitario Virgen del Rocío de Sevilla, Instituto de Biomedicina de Sevilla, Biomedical Research Networking Center in Hepatic and Digestive Diseases, Sevilla, Spain
| | - Mohamed El Kassas
- Department of Endemic Medicine, Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Verona, Italy
| | - Christopher D. Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Zhi-Ming Huang
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, China
- The Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
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Wang ZH, Zheng KI, Wang XD, Qiao J, Li YY, Zhang L, Zheng MH, Wu J. LC-MS-based lipidomic analysis in distinguishing patients with nonalcoholic steatohepatitis from nonalcoholic fatty liver. Hepatobiliary Pancreat Dis Int 2021; 20:452-459. [PMID: 34256994 DOI: 10.1016/j.hbpd.2021.05.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 05/19/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is one of the main liver diseases, and its pathologic profile includes nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). However, there is no reliable non-invasive parameter in distinguishing NASH from NAFL in clinical practice. The present study was to find a non-invasive way to differentiate these two categories of NAFLD via lipidomic analysis. METHODS Lipidomic analysis was used to determine the changes of lipid moieties in blood from 20 NAFL and 10 NASH patients with liver biopsy. Liver histology was evaluated after hematoxylin and eosin staining and Masson's trichrome staining. The profile of lipid metabolites in correlation with steatosis, inflammation, hepatocellular necroptosis, fibrosis, and NAFLD activity score (NAS) was analyzed. RESULTS Compared with NAFL patients, NASH patients had higher degree of steatosis, ballooning degeneration, lobular inflammation. A total of 434 different lipid molecules were identified, which were mainly composed of various phospholipids and triacylglycerols. Many lipids, such as phosphatidylcholine (PC) (P-22:0/18:1), sphingomyelin (SM) (d14:0/18:0), SM (d14:0/24:0), SM (d14:0/22:0), phosphatidylethanolamine (PE) (18:0/22:5), PC (O-22:2/12:0), and PC (26:1/11:0) were elevated in the NASH group compared to those in the NAFL group. Specific analysis revealed an overall lipidomic profile shift from NAFL to NASH, and identified valuable lipid moieties, such as PCs [PC (14:0/18:2), PE (18:0/22:5) and PC (26:1/11:0)] or plasmalogens [PC (O-22:0/0:0), PC (O-18:0/0:0), PC (O-16:0/0:0)], which were significantly altered in NASH patients. In addition, PC (14:0/18:2), phosphatidic acid (18:2/24:4) were positively correlated with NAS; whereas PC (18:0/0:0) was correlated positively with fibrosis score. CONCLUSIONS The present study revealed overall lipidomic profile shift from NAFL to NASH, identified valuable lipid moieties which may be non-invasive biomarkers in the categorization of NAFLD. The correlations between lipid moieties and NAS and fibrosis scores indicate that these lipid biomarkers may be used to predict the severity of the disease.
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Affiliation(s)
- Zhong-Hua Wang
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Kenneth I Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Xiao-Dong Wang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou 325000, China; The Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou 325000, China
| | - Jin Qiao
- Department of General Practice, Huaihai Middle Road Community Health Service Center of Huangpu District, Shanghai 200025, China
| | - Yang-Yang Li
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Li Zhang
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou 325000, China; The Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou 325000, China
| | - Jian Wu
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China; Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China; Laboratory of Fatty Liver and Metabolic Diseases, Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai 200032, China.
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Ma HL, Chen SD, Zheng KI, Yu Y, Wang XX, Tang LJ, Li G, Rios RS, Huang OY, Zheng XY, Xu RA, Targher G, Byrne CD, Wang XD, Chen YP, Zheng MH. TA allele of rs2070673 in the CYP2E1 gene is associated with lobular inflammation and nonalcoholic steatohepatitis in patients with biopsy-proven nonalcoholic fatty liver disease. J Gastroenterol Hepatol 2021; 36:2925-2934. [PMID: 34031913 DOI: 10.1111/jgh.15554] [Citation(s) in RCA: 2] [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: 12/18/2020] [Revised: 05/10/2021] [Accepted: 05/21/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Cytochrome P450 2E1 (CYP2E1) plays a role in lipid metabolism, and by increasing hepatic oxidative stress and inflammation, the upregulation of CYP2E1 is involved in development of nonalcoholic steatohepatitis (NASH). We aimed to explore the relationship between CYP2E1-333A>T (rs2070673) and the histological severity of nonalcoholic fatty liver disease (NAFLD). METHODS We studied 438 patients with biopsy-proven NAFLD. NASH was defined as NAFLD Activity Score ≥ 5 with existence of steatosis, ballooning, and lobular inflammation. CYP2E1-333A>T (rs2070673) was genotyped by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Serum cytokines related to inflammation were measured by the Bio-plex 200 system to investigate possible mediating factors involved in the process. RESULTS The TA genotype of rs2070673 had a higher prevalence of moderate/severe lobular inflammation (27.6% vs 20.3% vs 13.3%, P < 0.01) and NASH (55.7% vs 42.4% vs 40.5%, P < 0.01) compared with the AA and TT genotypes, respectively. In multivariable regression modeling, the heterozygote state TA was associated with moderate/severe lobular inflammation (adjusted odds ratio: 2.31, 95% confidence interval 1.41-3.78, P < 0.01) or NASH (adjusted odds ratio: 1.82, 95% confidence interval 1.22-2.69, P < 0.01), independently of age, sex, common metabolic risk factors, and presence of liver fibrosis. Compared with no-NASH, NASH patients had significantly higher levels of serum interleukin-1 receptor antagonist, interleukin-18, and interferon-inducible protein-10 (IP-10), whereas only IP-10 was increased with the rs2070673 TA variant (P = 0.01). Mediation analysis showed that IP-10 was responsible for ~60% of the association between the rs2070672 and NASH. CONCLUSIONS The TA allele of rs2070673 is strongly associated with lobular inflammation and NASH, and this effect appears to be largely mediated by serum IP-10 levels.
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Affiliation(s)
- Hong-Lei Ma
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Sui-Dan Chen
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Kenneth I Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yue Yu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xin-Xin Wang
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liang-Jie Tang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Gang Li
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Rafael S Rios
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ou-Yang Huang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiao-Yong Zheng
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ren-Ai Xu
- Department of Pharmacy, Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Christopher D Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Xiao-Dong Wang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Yong-Ping Chen
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
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Umbro I, Baratta F, Angelico F, Del Ben M. Nonalcoholic Fatty Liver Disease and the Kidney: A Review. Biomedicines 2021; 9:1370. [PMID: 34680486 PMCID: PMC8533178 DOI: 10.3390/biomedicines9101370] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 09/23/2021] [Accepted: 09/28/2021] [Indexed: 12/23/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is associated with several extrahepatic manifestations such as cardiovascular disease and sleep apnea. Furthermore, NAFLD is reported to be associated with an increased risk of incident chronic kidney disease (CKD). Inflammation and oxidative stress are suggested to be the key factors involved in the inflammatory mechanisms and pathways linking NAFLD to CKD and are responsible for both the pathogenesis and the progression of CKD in NAFLD patients. This review aims to provide a more comprehensive overview of the association between CKD and NAFLD, also considering the effect of increasing severity of NAFLD. A PubMed search was conducted using the terms "non-alcoholic fatty liver disease AND kidney". In total, 537 articles were retrieved in the last five years and 12 articles were included in the qualitative analysis. Our results showed that CKD developed more frequently in NAFLD patients compared to those without NAFLD. This association persisted after adjustment for traditional risk factors and according to the severity of NAFLD. Therefore, patients with NAFLD should be considered at high risk of CKD. Intensive multidisciplinary surveillance over time is needed, where hepatologists and nephrologists must act together for better and earlier treatment of NAFLD patients.
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Affiliation(s)
- Ilaria Umbro
- Geramed Dialysis Center, Fiano Romano, 00065 Rome, Italy
| | - Francesco Baratta
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (F.B.); (M.D.B.)
| | - Francesco Angelico
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00161 Rome, Italy;
| | - Maria Del Ben
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (F.B.); (M.D.B.)
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Xiang H, Wu Z, Wang J, Wu T. Research progress, challenges and perspectives on PNPLA3 and its variants in Liver Diseases. J Cancer 2021; 12:5929-5937. [PMID: 34476007 PMCID: PMC8408107 DOI: 10.7150/jca.57951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 07/26/2021] [Indexed: 12/02/2022] Open
Abstract
The human patatin-like phospholipase domain-containing 3 gene (PNPLA3) is highly expressed in liver and adipose tissue and encodes a transmembrane polypeptide chain containing 481 amino acids. The I148M variant of PNPLA3 is a single nucleotide polymorphism, which is related to a variety of liver and cardiovascular diseases and their complications (such as non-alcoholic fatty liver disease, liver fibrosis, coronary artery disease). This review mainly describes the pathophysiological effects of PNPLA3 and its variants, and their roles in the progression of liver disease and its complications.
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Affiliation(s)
- Hongjiao Xiang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zecheng Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Junmin Wang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tao Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Han E, Kim MK, Jang BK, Kim HS. Albuminuria Is Associated with Steatosis Burden in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease. Diabetes Metab J 2021; 45:698-707. [PMID: 33517613 PMCID: PMC8497925 DOI: 10.4093/dmj.2020.0118] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 07/31/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND This study aimed to investigate the association between hepatic steatosis burden and albuminuria in Korean patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). METHODS We recruited 100 patients with both T2DM and NAFLD, but without chronic kidney disease. Albuminuria was defined as a spot urinary albumin-to-creatinine ratio (ACR) ≥30 mg/g. Transient elastography was performed, and the steatosis burden was quantified by controlled attenuation parameter (CAP) with significant steatosis defined as CAP >302 dB/m. RESULTS The prevalence of significant steatosis and albuminuria was 56.0% and 21.0%, respectively. Subjects with significant steatosis were significantly younger and had a significantly shorter duration of T2DM, greater waist circumference, and higher body mass index, total cholesterol, triglyceride, and low density lipoprotein cholesterol levels, than subjects without severe NAFLD (all P<0.05). Albuminuria was higher in patients with significant steatosis than in patients without significant steatosis (32.1% vs. 6.8%, P=0.002). Urinary ACR showed a correlation with CAP (r=0.331, P=0.001), and multiple linear regression analysis revealed a significant association between a high degree of albuminuria and high CAP value (r=0.321, P=0.001). Additionally, multivariate logistic regression analysis demonstrated the independent association between urinary ACR and significant steatosis after adjustment for confounding factors including age, body mass index, duration of T2DM, low density lipoprotein level, and renin-angiotensin system blocker use (odds ratio, 1.88; 95% confidence interval, 1.31 to 2.71; P=0.001). CONCLUSION T2DM patients with NAFLD had a higher prevalence of albuminuria, which correlated with their steatosis burden.
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Affiliation(s)
- Eugene Han
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Mi Kyung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Byoung Kuk Jang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Hye Soon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
- Corresponding author: Hye Soon Kim https://orcid.org/0000-0001-6298-3506 Department of Internal Medicine, Keimyung University School of Medicine, 1095 Dalgubeol-daero, Dalseo-gu, Daegu 42601, Korea E-mail:
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Tan LJ, Jung H, Kim SA, Shin S. The Association Between Coffee Consumption and Nonalcoholic Fatty Liver Disease in the South Korean General Population. Mol Nutr Food Res 2021; 65:e2100356. [PMID: 34319647 DOI: 10.1002/mnfr.202100356] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 07/12/2021] [Indexed: 12/30/2022]
Abstract
SCOPE To identify the cross-sectional and prospective association between coffee consumption and nonalcoholic fatty liver disease (NAFLD) among South Korean adults. METHODS AND RESULTS Participants are selected from the Health Examinees study. NAFLD is defined using three non-invasive indexes: fatty liver index (FLI), hepatic steatosis index, and fibrosis-4 calculator (FIB-4). In the cross-sectional analysis, higher habitual coffee consumption is associated with a lower risk for NAFLD, define using the FLI, (men, odds ratio [OR] 0.702; women, OR 0.810) compared with non-consumers. Participants who consumed coffee with sugar and creamer also have a lower risk for NAFLD, defined using the FIB-4, compared with non-coffee-consumers (men, OR 0.739; women, OR 0.807). A prospective analysis indicated that higher coffee consumption is associated with a lower incidence of NAFLD, defined using the FLI, in men (hazard ratio, 0.706). In both men and women, a lower FIB-4 index score is associated with higher coffee consumption regardless of coffee type (all p-value <0.05). CONCLUSIONS Coffee consumption of >3 cups per day has a protective effect against the development of NAFLD to a certain extent, and a negative association is found between coffee consumed with sugar and creamer and the FIB-4 index score in South Korean adults.
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Affiliation(s)
- Li-Juan Tan
- Department of Food and Nutrition, Chung-Ang University, Gyeonggi-do, 17546, South Korea
| | - Hyein Jung
- Department of Food and Nutrition, Chung-Ang University, Gyeonggi-do, 17546, South Korea
| | - Seong-Ah Kim
- Department of Urban Society, The Seoul Institute, Seoul, 06756, South Korea
| | - Sangah Shin
- Department of Food and Nutrition, Chung-Ang University, Gyeonggi-do, 17546, South Korea
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Li X, Xia M, Ma H, Hu Y, Yan H, He W, Lin H, Zhao NQ, Gao J, Gao X. Liver fat content is independently associated with microalbuminuria in a normotensive, euglycaemic Chinese population: a community-based, cross-sectional study. BMJ Open 2021; 11:e044237. [PMID: 34187816 PMCID: PMC8245469 DOI: 10.1136/bmjopen-2020-044237] [Citation(s) in RCA: 0] [Impact Index Per Article: 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: 09/04/2020] [Accepted: 06/02/2021] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVE Non-alcoholic fatty liver disease (NAFLD) is associated with microalbuminuria (MA) in patients with diabetes/pre-diabetes. Whether this association is mediated by blood glucose and blood pressure (BP) remains unclear. This study investigated whether liver fat content (LFC) was associated with MA in a normotensive and non-diabetic population. DESIGN A cross-sectional substudy. SETTINGS LFC was determined from the hepatic/renal echogenicity ratio at ultrasound. MA was defined as an albumin-to-creatinine ratio (ACR) of 30-300 µg/mg (early- morning urine sample). Multivariable logistic regression and receiver operating characteristic (ROC) curve analyses were used to evaluate LFC as a predictor of MA. PARTICIPANTS Between May 2010 and June 2011, this cross-sectional, community-based study enrolled residents from Shanghai (China), aged ≥40 years and with normal glucose tolerance and BP. RESULTS A total of 550 residents (median age, 57 years; 174 men) were enrolled and stratified according to LFC quartiles. ACR (p<0.001) and MA prevalence (p=0.012) increased across the LFC quartiles. Multivariable logistic regression showed that the OR for MA (per SD increase in LFC) was 1.840 (95% CI 1.173 to 2.887, p=0.008) after adjustment for potential confounders including age, gender, waist-hip ratio, blood urea nitrogen, systolic and diastolic BP, fasting blood glucose, postprandial glucose, low-density lipoprotein-cholesterol, triglycerides, high-density lipoprotein-cholesterol, total cholesterol, estimated glomerular filtration rate and lipid-lowering drugs. The ROC analysis revealed that the optimal LFC cut-off value for predicting MA was 6.82%. CONCLUSION LFC is independently associated with MA in normotensive, euglycaemic middle-aged and elderly Chinese individuals. Screening for MA in people with NAFLD might facilitate early intervention to minimise kidney disease risk.
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Affiliation(s)
- Xiaoming Li
- Department of Endocrinology and Metabolism, Zhongshan Hospital Fudan University, Shanghai, China
- Department of Geriatric Medicine, Fujian Provincial Hospital, Fujian Provincial Institute of Clinical Geriatrics, Fujian Provincial Key Laboratory of Geriatric Diseases, Fujian Medical University, Fuzhou, China
| | - Mingfeng Xia
- Department of Endocrinology and Metabolism, Zhongshan Hospital Fudan University, Shanghai, China
| | - Hui Ma
- Department of Endocrinology and Metabolism, Zhongshan Hospital Fudan University, Shanghai, China
| | - Yu Hu
- Department of Endocrinology and Metabolism, Zhongshan Hospital Fudan University, Shanghai, China
| | - Hongmei Yan
- Department of Endocrinology and Metabolism, Zhongshan Hospital Fudan University, Shanghai, China
| | - Wanyuan He
- Department of Ultrasonography, Zhongshan Hospital Fudan University, Shanghai, China
| | - Huandong Lin
- Department of Endocrinology and Metabolism, Zhongshan Hospital Fudan University, Shanghai, China
| | - Nai Qing Zhao
- Statistics, School of Public Health, Fudan University, Shanghai, China
| | - Jian Gao
- Department of Evidence Base Medicine Center, Zhongshan Hospital Fudan University, Shanghai, China
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital Fudan University, Shanghai, China
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Cai X, Sun L, Liu X, Zhu H, Zhang Y, Zheng S, Huang Y. Non-alcoholic fatty liver disease is associated with increased risk of chronic kidney disease. Ther Adv Chronic Dis 2021; 12:20406223211024361. [PMID: 34249302 PMCID: PMC8237225 DOI: 10.1177/20406223211024361] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 04/26/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND AND AIMS Whether non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of incident chronic kidney disease (CKD) independent of established cardio-renal risk factors remains controversial. We aimed to provide a quantitative estimate of the association and strength between NAFLD and risk of CKD after adjustment for multiple cardio-renal risk factors. METHODS We searched electronic databases (PubMed, Embase, and Google Scholar) for studies published from database inception until 30 November 2020. Analysis included cohort studies that reported multivariable-adjusted risk ratios [including odds ratios, relative risks (RRs), or hazard ratios] and 95% confidence intervals (CIs) for CKD of NAFLD compared with individuals without NAFLD. RESULTS A total of 11 cohort studies were included comprising 1,198,242 participants (46.3% women) for analysis. The median follow-up duration was 3.7 years, with 31,922 cases of incident CKD. Compared with individuals without NAFLD, unadjusted models showed that NAFLD was associated with a higher risk of CKD (RR 1.54, 95% CI 1.38-1.71). After adjusting for multiple cardio-renal risk factors, the CKD risk was still significantly increased in patients with NAFLD (RR 1.39, 95% CI 1.27-1.52). Compared with individuals without NAFLD, the adjusted absolute risk increase in NAFLD for CKD was 5.1 (95% CI 3.5-6.8) per 1000 person-years. CONCLUSION NAFLD is associated with an increased risk of incident CKD independent of established cardio-renal risk factors.
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Affiliation(s)
- Xiaoyan Cai
- Department of Scientific Research and
Education, Shunde Hospital, Southern Medical University, Foshan, China
| | - Lichang Sun
- Department of Cardiology, Shunde Hospital,
Southern Medical University, Foshan, China
| | - Xiong Liu
- Department of Cardiology, Shunde Hospital,
Southern Medical University, Foshan, China
| | - Hailan Zhu
- Department of Cardiology, Shunde Hospital,
Southern Medical University, Foshan, China
| | - Yang Zhang
- Department of Cardiology, Shunde Hospital,
Southern Medical University, Foshan, China
| | - Sulin Zheng
- Department of Cardiology, Shunde Hospital,
Southern Medical University, Foshan, China
| | - Yuli Huang
- Department of Cardiology, Shunde Hospital,
Southern Medical University, Jiazhi Road, Lunjiao Town, Shunde District,
Foshan, 528300, PR China
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Sun DQ, Wang TY, Zheng KI, Zhang HY, Wang XD, Targher G, Byrne CD, Chen YP, Yuan WJ, Jin Y, Zheng MH. The HSD17B13 rs72613567 variant is associated with lower levels of albuminuria in patients with biopsy-proven nonalcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 2021; 31:1822-1831. [PMID: 33853719 DOI: 10.1016/j.numecd.2021.02.018] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 01/13/2021] [Accepted: 02/16/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Several susceptibility gene variants predisposing to nonalcoholic fatty liver disease (NAFLD) have been identified in chronic kidney disease (CKD). Evidence supports that 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) rs72613567 plays a role in NAFLD development by affecting lipid homeostasis. Since lipid droplets may accumulate in the kidneys and contribute to renal injury, we investigated the association between the HSD17B13 rs72613567 variant and markers of renal function/injury in NAFLD. METHODS AND RESULTS We measured estimated glomerular filtration rate (eGFR), urinary/serum neutrophil gelatinase-associated lipocalin (NGAL), and urinary albumin-to-creatinine ratio (u-ACR) in individuals with biopsy-proven NAFLD. Multivariable regression analyses were undertaken to examine the associations between the HSD17B13 rs72613567 variant and markers of renal function/injury. Individuals were stratified by HSD17B13 rs72613567 genotypes into -/-, A/- and A/A groups. HSD17B13 rs72613567 genotypes were not significantly associated with eGFR and urinary/serum NGAL levels. Conversely, the prevalence of abnormal albuminuria in the A/- + A/A group was lower than in the -/- group (4.92% vs. 19.35%, p = 0.001). Additionally, the mean u-ACR levels were lower among carriers of the A/- or A/A genotypes with coexisting hypertension or diabetes, than among those with the -/- genotype. The risk of abnormal albuminuria (adjusted-odds ratio 0.16, p = 0.001) remained significantly lower in the A/- + A/A group after adjustment for established renal risk factors and histologic severity of NAFLD. CONCLUSION HSD17B13 rs72613567: A allele is associated with a lower risk of having abnormal albuminuria, but not with lower eGFR or urinary/serum NGAL levels, in patients with biopsy-proven NAFLD.
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Affiliation(s)
- Dan-Qin Sun
- Affiliated Wuxi Clinical College of Nantong University, Wuxi, China; Department of Nephrology, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, China; Department of Nephrology, Shanghai General Hospital of Nanjing Medical University, Shanghai, China
| | - Ting-Yao Wang
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Kenneth I Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hao-Yang Zhang
- School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, China
| | - Xiao-Dong Wang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou, China
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Christopher D Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Yong-Ping Chen
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou, China
| | - Wei-Jie Yuan
- Department of Nephrology, Shanghai General Hospital of Nanjing Medical University, Shanghai, China
| | - Yan Jin
- Affiliated Wuxi Clinical College of Nantong University, Wuxi, China; Department of Gastroenterology, the Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, China.
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China.
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Diabetic Kidney Disease, Cardiovascular Disease and Non-Alcoholic Fatty Liver Disease: A New Triumvirate? J Clin Med 2021; 10:jcm10092040. [PMID: 34068699 PMCID: PMC8126096 DOI: 10.3390/jcm10092040] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/03/2021] [Accepted: 05/06/2021] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease is a highly prevalent disease worldwide with a renowned relation to cardiovascular disease and chronic kidney disease. These diseases share a common pathophysiology including insulin resistance, oxidative stress, chronic inflammation, dysbiosis and genetic susceptibilities. Non-alcoholic fatty liver disease is especially prevalent and more severe in type 2 diabetes. Patients with non-alcoholic fatty liver disease should have liver fibrosis assessment in order to identify those at the highest risk of adverse outcomes so that appropriate management strategies can be implemented. Early diagnosis and treatment of non-alcoholic fatty liver disease could ameliorate the burden of cardiovascular disease and chronic kidney disease.
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Heda R, Yazawa M, Shi M, Bhaskaran M, Aloor FZ, Thuluvath PJ, Satapathy SK. Non-alcoholic fatty liver and chronic kidney disease: Retrospect, introspect, and prospect. World J Gastroenterol 2021; 27:1864-1882. [PMID: 34007127 PMCID: PMC8108029 DOI: 10.3748/wjg.v27.i17.1864] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 03/07/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
With the growing prevalence of obesity and diabetes in the United States and across the world, a rise in the overall incidence and prevalence of non-alcoholic fatty liver disease (NAFLD) is expected. The risk factors for NAFLD are also associated with the development of chronic kidney disease (CKD). We review the epidemiology, risk factors, genetics, implications of gut dysbiosis, and specific pathogenic mechanisms linking NAFLD to CKD. Mechanisms such as ectopic lipid accumulation, cellular signaling abnormalities, and the interplay between fructose consumption and uric acid accumulation have led to the emergence of potential therapeutic implications for this patient population. Transplant evaluation in the setting of both NAFLD and CKD is also reviewed. Potential strategies for surveillance and management include the monitoring of comorbidities, the use of non-invasive fibrosis scoring systems, and the measurement of laboratory markers. Lastly, we discuss the management of patients with NAFLD and CKD, from preventative measures to experimental interventions.
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Affiliation(s)
- Rajiv Heda
- Department of Internal Medicine, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Masahiko Yazawa
- Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
| | - Michelle Shi
- Department of Internal Medicine, Donald and Barbara Zucker School of Medicine, Northwell Health, Manhasset, NY 11030, United States
| | - Madhu Bhaskaran
- Department of Nephrology, Northwell Health/Zucker School of Medicine at Hosftra, Manhasset, NY 11030, United States
| | - Fuad Zain Aloor
- Department of Internal Medicine, Baylor College of Medicine, Houston, TX 77030, United States
| | - Paul J Thuluvath
- Institute of Digestive Health & Liver Diseases, Mercy Medical Center, Baltimore, MD 21202, United States
| | - Sanjaya K Satapathy
- Department of Internal Medicine, Donald and Barbara Zucker School of Medicine, Northwell Health, Manhasset, NY 11030, United States
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48
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Chen S, Guo H, Xie M, Zhou C, Zheng M. Neutrophil: An emerging player in the occurrence and progression of metabolic associated fatty liver disease. Int Immunopharmacol 2021; 97:107609. [PMID: 33887577 DOI: 10.1016/j.intimp.2021.107609] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/01/2021] [Accepted: 03/20/2021] [Indexed: 12/12/2022]
Abstract
Metabolic-associated fatty liver disease (MAFLD) is a common type of chronic liver disease characterized by excessive lipid accumulation in hepatocytes, but the pathogenesis is still unclear. Neutrophils, the most abundant immune cells in the human body, defend against pathogens and regulate the inflammatory response. Recent studies have indicated that excessive liver infiltration of neutrophils is a significant histological hallmark of MAFLD, and neutrophils and their derived granule proteins participate in different stages of MAFLD, including hepatic steatosis, inflammation, fibrosis, cirrhosis and hepatocellular carcinoma. Hence, in this review, we summarize the role of neutrophils in the occurrence and progression of MAFLD and provide a perspective for the clinical application of neutrophils in MAFLD diagnosis and treatment.
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Affiliation(s)
- Shiwei Chen
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou 310000, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310000, China; National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, China
| | - Huiting Guo
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou 310000, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310000, China; National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, China
| | - Mingjie Xie
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou 310000, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310000, China; National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, China
| | - Cheng Zhou
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou 310000, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310000, China; National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, China.
| | - Min Zheng
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou 310000, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310000, China; National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, China.
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49
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Xu G, Wang YM, Ying MM, Chen SD, Li ZR, Ma HL, Zheng MH, Wu J, Ding C. Serum lipocalin-2 is a potential biomarker for the clinical diagnosis of nonalcoholic steatohepatitis. Clin Mol Hepatol 2021; 27:329-345. [PMID: 33465844 PMCID: PMC8046622 DOI: 10.3350/cmh.2020.0261] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 12/30/2020] [Accepted: 01/18/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND/AIMS Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) characterized by hepatic steatosis, inflammation, hepatocellular injury, and fibrosis. We aimed to investigate the usefulness of a key biomarker, lipocalin-2 (LCN2), for the detection of NASH progression. METHODS A mouse NASH model was established using a high-fat diet and a high-sugar drinking water. Gene expression profile of the NASH model was analyzed using RNA sequencing. Moreover, 360 NAFLD patients (steatosis, 83; NASH, 277), 40 healthy individuals, and 87 patients with alcoholic fatty liver disease were recruited. RESULTS Inflammatory infiltration, focal necrosis in the leaflets, steatosis, and fibrosis were documented in the mouse liver. In total, 504 genes were differentially expressed in the livers of NASH mice, and showed significant functional enrichment in the inflammation-related category. Upregulated liver LCN2 was found to be significantly interactive with various interleukins and toll-like receptors. Serum LCN2 levels were significantly increased in NAFLD patients. Serum LCN2 levels were correlated with steatosis, intralobular inflammation, semiquantitative fibrosis score, and nonalcoholic fatty liver disease activity score. The area under the curve of serum LCN2 was 0.987 with a specificity of 100% and a sensitivity of 93.5% for NASH diagnosis, and 0.977 with almost the same specificity and sensitivity for steatosis. CONCLUSION LCN2 might be involved in the transition from NAFL to NASH by mediating inflammation. Serum LCN2 levels might be a novel biomarker for the diagnosis of NASH.
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Affiliation(s)
- Gang Xu
- Department of Laboratory Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yu-Min Wang
- Department of Laboratory Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Miao-Miao Ying
- Department of Pathology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Sui-Dan Chen
- Department of Pathology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zong-Rui Li
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hong-Lei Ma
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Jian Wu
- Department of Medical Microbiology and Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China
- Shanghai Institute of Liver Diseases, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chunming Ding
- Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China
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50
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Zheng KI, Sun DQ, Jin Y, Zhu PW, Zheng MH. Clinical utility of the MAFLD definition. J Hepatol 2021; 74:989-991. [PMID: 33347953 DOI: 10.1016/j.jhep.2020.12.016] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 12/10/2020] [Accepted: 12/13/2020] [Indexed: 01/01/2023]
Affiliation(s)
- Kenneth I Zheng
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Dan-Qin Sun
- Affiliated Wuxi Clinical College of Nantong University, Wuxi, China; Department of Nephrology, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, China
| | - Yi Jin
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Pei-Wu Zhu
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China.
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