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Talari NK, Mattam U, Rahman AP, Hemmelgarn BK, Wyder MA, Sylvestre PB, Greis KD, Chella Krishnan K. Functional compartmentalization of hepatic mitochondrial subpopulations during MASH progression. Commun Biol 2025; 8:258. [PMID: 39966593 PMCID: PMC11836293 DOI: 10.1038/s42003-025-07713-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 02/11/2025] [Indexed: 02/20/2025] Open
Abstract
The role of peridroplet mitochondria (PDM) in diseased liver, such as during the progression of metabolic dysfunction-associated steatohepatitis (MASH), remains unknown. We isolated hepatic cytoplasmic mitochondria (CM) and PDM from a mouse model of diet-induced MASLD/MASH to characterize their functions from simple steatosis to advanced MASH, using chow-fed mice as controls. Our findings show an inverse relationship between hepatic CM and PDM levels from healthy to steatosis to advanced MASH. Proteomics analysis revealed these two mitochondrial populations are compositionally and functionally distinct. We found that hepatic PDM are more bioenergetically active than CM, with higher pyruvate oxidation capacity in both healthy and diseased liver. Higher respiration capacity of PDM was associated with elevated OXPHOS protein complexes and increased TCA cycle flux. In contrast, CM showed higher fatty acid oxidation capacity with MASH progression. Transmission electron microscopy revealed larger and elongated mitochondria during healthy and early steatosis, which appeared small and fragmented during MASH progression. These changes coincided with higher MFN2 protein levels in hepatic PDM and higher DRP1 protein levels in hepatic CM. These findings highlight the distinct roles of hepatic CM and PDM in MASLD progression towards MASH.
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Affiliation(s)
- Noble Kumar Talari
- Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Ushodaya Mattam
- Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Afra P Rahman
- Medical Sciences Baccalaureate Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Brook K Hemmelgarn
- Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Michael A Wyder
- Department of Cancer Biology, Proteomics Laboratory, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Pamela B Sylvestre
- Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Kenneth D Greis
- Department of Cancer Biology, Proteomics Laboratory, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Karthickeyan Chella Krishnan
- Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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Niu J, Al-Yaman W, Pinyopornpanish K, Park JS, Salazar M, Xiao H, Bena J, Lyu R, Flocco G, Junna SR, Adhami T, Sims OT, Wakim-Fleming J. The Long-Term Effect of Weight Loss on the Prevention of Progression to Cirrhosis among Patients with Obesity and MASH-Related F3 Liver Fibrosis. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2024; 21:708. [PMID: 38928954 PMCID: PMC11203621 DOI: 10.3390/ijerph21060708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 05/21/2024] [Accepted: 05/28/2024] [Indexed: 06/28/2024]
Abstract
This multi-center retrospective study examined the effect of weight loss on the prevention of progression to cirrhosis in a sample exclusively composed of patients with obesity and MASH-related F3 liver fibrosis. Adult patients with obesity and biopsy-confirmed MASH-related F3 liver fibrosis (n = 101) from two liver transplant centers in the US were included in the study. A higher proportion of patients who did not progress to cirrhosis achieved >5% weight loss at follow-up (59% vs. 30%, p = 0.045). In multivariable analysis, patients with >5% weight loss at follow-up had a lower hazard of developing cirrhosis compared to patients with no weight loss or weight gain (HR: 0.29, 95%, CI: 0.08-0.96); whereas, diabetes (HR: 3.24, 95%, CI: 1.21-8.67) and higher LDL levels (HR: 1.02, 95%, CI: 1.01-1.04) were associated with higher hazards of progression to cirrhosis. Weight loss >5% has the potential to prevent disease progression to cirrhosis in patients with obesity and MASH-related F3 liver fibrosis. The realization of this benefit requires weight loss maintenance longer than one year. Larger prospective studies are needed to determine how weight loss impacts other patient-centered outcomes such as mortality, hepatic decompensation, and hepatocellular carcinoma in patients with obesity and MASH-related F3 liver fibrosis.
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Affiliation(s)
- Jiafei Niu
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Foundation, Cleveland, OH 44106, USA; (J.N.); (W.A.-Y.); (K.P.); (J.S.P.); (M.S.); (G.F.); (S.R.J.); (T.A.); (J.W.-F.)
| | - Wael Al-Yaman
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Foundation, Cleveland, OH 44106, USA; (J.N.); (W.A.-Y.); (K.P.); (J.S.P.); (M.S.); (G.F.); (S.R.J.); (T.A.); (J.W.-F.)
- Department of Gastroenterology, St. Joseph Mercy Ann Arbor Hospital, Ypsiilanti, MI 48197, USA
| | - Kanokwan Pinyopornpanish
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Foundation, Cleveland, OH 44106, USA; (J.N.); (W.A.-Y.); (K.P.); (J.S.P.); (M.S.); (G.F.); (S.R.J.); (T.A.); (J.W.-F.)
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Ji Seok Park
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Foundation, Cleveland, OH 44106, USA; (J.N.); (W.A.-Y.); (K.P.); (J.S.P.); (M.S.); (G.F.); (S.R.J.); (T.A.); (J.W.-F.)
| | - Miguel Salazar
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Foundation, Cleveland, OH 44106, USA; (J.N.); (W.A.-Y.); (K.P.); (J.S.P.); (M.S.); (G.F.); (S.R.J.); (T.A.); (J.W.-F.)
| | - Huijun Xiao
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44106, USA; (H.X.); (J.B.); (R.L.)
| | - James Bena
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44106, USA; (H.X.); (J.B.); (R.L.)
| | - Ruishen Lyu
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44106, USA; (H.X.); (J.B.); (R.L.)
| | - Gianina Flocco
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Foundation, Cleveland, OH 44106, USA; (J.N.); (W.A.-Y.); (K.P.); (J.S.P.); (M.S.); (G.F.); (S.R.J.); (T.A.); (J.W.-F.)
| | - Shilpa R. Junna
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Foundation, Cleveland, OH 44106, USA; (J.N.); (W.A.-Y.); (K.P.); (J.S.P.); (M.S.); (G.F.); (S.R.J.); (T.A.); (J.W.-F.)
| | - Talal Adhami
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Foundation, Cleveland, OH 44106, USA; (J.N.); (W.A.-Y.); (K.P.); (J.S.P.); (M.S.); (G.F.); (S.R.J.); (T.A.); (J.W.-F.)
| | - Omar T. Sims
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Foundation, Cleveland, OH 44106, USA; (J.N.); (W.A.-Y.); (K.P.); (J.S.P.); (M.S.); (G.F.); (S.R.J.); (T.A.); (J.W.-F.)
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44106, USA; (H.X.); (J.B.); (R.L.)
| | - Jamile Wakim-Fleming
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Foundation, Cleveland, OH 44106, USA; (J.N.); (W.A.-Y.); (K.P.); (J.S.P.); (M.S.); (G.F.); (S.R.J.); (T.A.); (J.W.-F.)
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3
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Sun C, Lan F, Zhou Q, Guo X, Jin J, Wen C, Guo Y, Hou Z, Zheng J, Wu G, Li G, Yan Y, Li J, Ma Q, Yang N. Mechanisms of hepatic steatosis in chickens: integrated analysis of the host genome, molecular phenomics and gut microbiome. Gigascience 2024; 13:giae023. [PMID: 38837944 PMCID: PMC11152177 DOI: 10.1093/gigascience/giae023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 01/14/2024] [Accepted: 04/22/2024] [Indexed: 06/07/2024] Open
Abstract
Hepatic steatosis is the initial manifestation of abnormal liver functions and often leads to liver diseases such as nonalcoholic fatty liver disease in humans and fatty liver syndrome in animals. In this study, we conducted a comprehensive analysis of a large chicken population consisting of 705 adult hens by combining host genome resequencing; liver transcriptome, proteome, and metabolome analysis; and microbial 16S ribosomal RNA gene sequencing of each gut segment. The results showed the heritability (h2 = 0.25) and duodenal microbiability (m2 = 0.26) of hepatic steatosis were relatively high, indicating a large effect of host genetics and duodenal microbiota on chicken hepatic steatosis. Individuals with hepatic steatosis had low microbiota diversity and a decreased genetic potential to process triglyceride output from hepatocytes, fatty acid β-oxidation activity, and resistance to fatty acid peroxidation. Furthermore, we revealed a molecular network linking host genomic variants (GGA6: 5.59-5.69 Mb), hepatic gene/protein expression (PEMT, phosphatidyl-ethanolamine N-methyltransferase), metabolite abundances (folate, S-adenosylmethionine, homocysteine, phosphatidyl-ethanolamine, and phosphatidylcholine), and duodenal microbes (genus Lactobacillus) to hepatic steatosis, which could provide new insights into the regulatory mechanism of fatty liver development.
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Affiliation(s)
- Congjiao Sun
- State Key Laboratory of Animal Biotech Breeding, Department of Animal
Genetics and Breeding, College of Animal Science and Technology, China Agricultural
University, Beijing 100193, China
| | - Fangren Lan
- State Key Laboratory of Animal Biotech Breeding, Department of Animal
Genetics and Breeding, College of Animal Science and Technology, China Agricultural
University, Beijing 100193, China
| | - Qianqian Zhou
- State Key Laboratory of Animal Biotech Breeding, Department of Animal
Genetics and Breeding, College of Animal Science and Technology, China Agricultural
University, Beijing 100193, China
| | - Xiaoli Guo
- State Key Laboratory of Animal Biotech Breeding, Department of Animal
Genetics and Breeding, College of Animal Science and Technology, China Agricultural
University, Beijing 100193, China
| | - Jiaming Jin
- State Key Laboratory of Animal Biotech Breeding, Department of Animal
Genetics and Breeding, College of Animal Science and Technology, China Agricultural
University, Beijing 100193, China
| | - Chaoliang Wen
- State Key Laboratory of Animal Biotech Breeding, Department of Animal
Genetics and Breeding, College of Animal Science and Technology, China Agricultural
University, Beijing 100193, China
| | - Yanxin Guo
- State Key Laboratory of Animal Biotech Breeding, Department of Animal
Genetics and Breeding, College of Animal Science and Technology, China Agricultural
University, Beijing 100193, China
| | - Zhuocheng Hou
- State Key Laboratory of Animal Biotech Breeding, Department of Animal
Genetics and Breeding, College of Animal Science and Technology, China Agricultural
University, Beijing 100193, China
| | - Jiangxia Zheng
- State Key Laboratory of Animal Biotech Breeding, Department of Animal
Genetics and Breeding, College of Animal Science and Technology, China Agricultural
University, Beijing 100193, China
| | - Guiqin Wu
- Beijing Engineering Research Centre of Layer,
Beijing 101206, China
| | - Guangqi Li
- Beijing Engineering Research Centre of Layer,
Beijing 101206, China
| | - Yiyuan Yan
- Beijing Engineering Research Centre of Layer,
Beijing 101206, China
| | - Junying Li
- State Key Laboratory of Animal Biotech Breeding, Department of Animal
Genetics and Breeding, College of Animal Science and Technology, China Agricultural
University, Beijing 100193, China
| | - Qiugang Ma
- State Key Laboratory of Animal Biotech Breeding, Department of Animal
Genetics and Breeding, College of Animal Science and Technology, China Agricultural
University, Beijing 100193, China
| | - Ning Yang
- State Key Laboratory of Animal Biotech Breeding, Department of Animal
Genetics and Breeding, College of Animal Science and Technology, China Agricultural
University, Beijing 100193, China
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Beiriger J, Chauhan K, Khan A, Shahzad T, Parra NS, Zhang P, Chen S, Nguyen A, Yan B, Bruckbauer J, Halegoua-DeMarzio D. Advancements in Understanding and Treating NAFLD: A Comprehensive Review of Metabolic-Associated Fatty Liver Disease and Emerging Therapies. LIVERS 2023; 3:637-656. [DOI: 10.3390/livers3040042] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
This paper provides a comprehensive review of the current understanding of non-alcoholic fatty liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH), focusing on key factors influencing its pathogenesis and emerging therapeutic strategies. This review highlights the growing prevalence of NAFLD and NASH, emphasizing their multifactorial nature. The manuscript identifies various contributors to NAFLD development, including genetic, dietary, and environmental factors, while examining the intricate interplay between these factors and their impact on hepatic lipid metabolism, inflammation, and insulin resistance. Genetic predisposition, dietary fat intake, and excessive fructose consumption are discussed as significant contributors to NAFLD progression. The article emphasizes the lack of a single therapeutic approach and underscores the need for combination strategies. Lifestyle interventions, particularly weight loss through diet and exercise, remain crucial, while pharmacological options like GLP-1 receptor agonists, obeticholic acid, lanifibranor, and resmetirom show promise but require further validation. Bariatric surgery and emerging endoscopic procedures offer potential in eligible patients. In sum, this article underscores the complexity of NAFLD and NASH, addresses key factors influencing pathogenesis, and discusses emerging therapies advocating for a multifaceted approach to this increasingly prevalent and clinically relevant condition.
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Affiliation(s)
- Jacob Beiriger
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Kashyap Chauhan
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Adnan Khan
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Taha Shahzad
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Natalia Salinas Parra
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Peter Zhang
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Sarah Chen
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Anh Nguyen
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Brian Yan
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - John Bruckbauer
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Dina Halegoua-DeMarzio
- Department of Internal Medicine, Division of Gastroenterology & Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
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Razmpour F, Daryabeygi-Khotbehsara R, Soleimani D, Asgharnezhad H, Shamsi A, Bajestani GS, Nematy M, Pour MR, Maddison R, Islam SMS. Application of machine learning in predicting non-alcoholic fatty liver disease using anthropometric and body composition indices. Sci Rep 2023; 13:4942. [PMID: 36973382 PMCID: PMC10043285 DOI: 10.1038/s41598-023-32129-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 03/22/2023] [Indexed: 03/29/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, which can progress from simple steatosis to advanced cirrhosis and hepatocellular carcinoma. Clinical diagnosis of NAFLD is crucial in the early stages of the disease. The main aim of this study was to apply machine learning (ML) methods to identify significant classifiers of NAFLD using body composition and anthropometric variables. A cross-sectional study was carried out among 513 individuals aged 13 years old or above in Iran. Anthropometric and body composition measurements were performed manually using body composition analyzer InBody 270. Hepatic steatosis and fibrosis were determined using a Fibroscan. ML methods including k-Nearest Neighbor (kNN), Support Vector Machine (SVM), Radial Basis Function (RBF) SVM, Gaussian Process (GP), Random Forest (RF), Neural Network (NN), Adaboost and Naïve Bayes were examined for model performance and to identify anthropometric and body composition predictors of fatty liver disease. RF generated the most accurate model for fatty liver (presence of any stage), steatosis stages and fibrosis stages with 82%, 52% and 57% accuracy, respectively. Abdomen circumference, waist circumference, chest circumference, trunk fat and body mass index were among the most important variables contributing to fatty liver disease. ML-based prediction of NAFLD using anthropometric and body composition data can assist clinicians in decision making. ML-based systems provide opportunities for NAFLD screening and early diagnosis, especially in population-level and remote areas.
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Affiliation(s)
- Farkhondeh Razmpour
- Department of Nutrition, Faculty of Medicine, Hormozgan University of Medical Sciences, Shahid Chamran Boulevard, Bandar Abbas, Iran.
| | | | - Davood Soleimani
- Department of Nutrition, School of Nutrition Sciences and Food Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hamzeh Asgharnezhad
- Institute for Intelligent Systems Research and Innovation (IISRI), Geelong Waurn Ponds Victoria, Australia
| | - Afshar Shamsi
- Biomedical Machine Learning Lab, University of New South Whales, Sydney, Australia
- Concordia Institute for Information Systems Engineering, Concordia University, Montreal, Canada
| | - Ghasem Sadeghi Bajestani
- Department of Biomedical Engineering, Faculty of Engineering, Imam Reza International University, Mashhad, Iran
| | - Mohsen Nematy
- Metabolic Syndrome Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Ralph Maddison
- Institute for Physical Activity and Nutrition (IPAN), Deakin University, Geelong Victoria, Australia
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Ismaiel A, Portincasa P, Dumitrascu DL. Natural History of Nonalcoholic Fatty Liver Disease. ESSENTIALS OF NON-ALCOHOLIC FATTY LIVER DISEASE 2023:19-43. [DOI: 10.1007/978-3-031-33548-8_3] [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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Park Y, Sinn DH, Kim K, Gwak GY. The association of non-alcoholic fatty liver disease between parents and adolescent children. Aliment Pharmacol Ther 2023; 57:245-252. [PMID: 36271616 DOI: 10.1111/apt.17257] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/17/2022] [Accepted: 10/07/2022] [Indexed: 12/27/2022]
Abstract
BACKGROUND Data reporting the heritability of non-alcoholic fatty liver disease (NAFLD) are highly variable. AIMS To investigate the association of NAFLD between parents and their adolescent children using a nationwide, population-based cohort. METHODS We analysed 1737 families with both parents and adolescent children aged 12-18 who participated in Korean National Health and Nutrition Examination Surveys (KNHANES) between 2010 and 2019. NAFLD was defined by body mass index and elevated alanine aminotransferase levels in children and by the hepatic steatosis index in parents. RESULTS The prevalence of NAFLD in adolescent children with either parent with NAFLD was higher than that in those without a parent with NAFLD (10.2% vs. 3.1%, p < 0.001). In a model fully adjusted for demographic, nutritional, behavioural and metabolic risk factors, children with either parent with NAFLD had a higher odds ratio (OR) for NAFLD (OR = 1.75, 95% CI: 1.02-3.00) than those without a parent with NAFLD. Compared to those without a parent with NAFLD, the fully adjusted ORs of NAFLD in children with paternal NAFLD, maternal NAFLD and NAFLD in both parents were 1.80 (95% CI: 1.01-3.20), 2.21 (95% CI: 1.11-4.42) and 2.60 (95% CI: 1.03-6.54), respectively. CONCLUSION Adolescent children with a parent with NAFLD were at increased risk of NAFLD; risk was higher when both parents had NAFLD. Further studies are needed to explore the benefit of NAFLD screening in children who have a parent with NAFLD.
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Affiliation(s)
- Yewan Park
- Department of Internal Medicine, Kyung Hee University Medical Center, Seoul, South Korea.,Department of Digital Health, SAIHST, Sungkyunkwan University, Seoul, South Korea
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Kyunga Kim
- Department of Digital Health, SAIHST, Sungkyunkwan University, Seoul, South Korea.,Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, South Korea
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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Josloff K, Beiriger J, Khan A, Gawel RJ, Kirby RS, Kendrick AD, Rao AK, Wang RX, Schafer MM, Pearce ME, Chauhan K, Shah YB, Marhefka GD, Halegoua-DeMarzio D. Comprehensive Review of Cardiovascular Disease Risk in Nonalcoholic Fatty Liver Disease. J Cardiovasc Dev Dis 2022; 9:419. [PMID: 36547416 PMCID: PMC9786069 DOI: 10.3390/jcdd9120419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 11/16/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
Nonalcoholic Fatty Liver Disease (NAFLD) is a growing global phenomenon, and its damaging effects in terms of cardiovascular disease (CVD) risk are becoming more apparent. NAFLD is estimated to affect around one quarter of the world population and is often comorbid with other metabolic disorders including diabetes mellitus, hypertension, coronary artery disease, and metabolic syndrome. In this review, we examine the current evidence describing the many ways that NAFLD itself increases CVD risk. We also discuss the emerging and complex biochemical relationship between NAFLD and its common comorbid conditions, and how they coalesce to increase CVD risk. With NAFLD's rising prevalence and deleterious effects on the cardiovascular system, a complete understanding of the disease must be undertaken, as well as effective strategies to prevent and treat its common comorbid conditions.
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Affiliation(s)
- Kevan Josloff
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Jacob Beiriger
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Adnan Khan
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Richard J. Gawel
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Richard S. Kirby
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Aaron D. Kendrick
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Abhinav K. Rao
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Roy X. Wang
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Michelle M. Schafer
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Margaret E. Pearce
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Kashyap Chauhan
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Yash B. Shah
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Gregary D. Marhefka
- Department of Internal Medicine, Division of Cardiology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Dina Halegoua-DeMarzio
- Department of Internal Medicine, Division of Gastroenterology & Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
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Wajsbrot NB, Leite NC, Salles GF, Villela-Nogueira CA. Non-alcoholic fatty liver disease and the impact of genetic, epigenetic and environmental factors in the offspring. World J Gastroenterol 2022; 28:2890-2899. [PMID: 35978876 PMCID: PMC9280730 DOI: 10.3748/wjg.v28.i25.2890] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/20/2022] [Accepted: 05/14/2022] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and is strongly associated with metabolic deregulation. More recently, a significant impact of parental NAFLD in the offspring was demonstrated and has been widely discussed. However, pathogenetic pathways implicated in the inheritance by the offspring and relatives are still under debate. Probably, multiple mechanisms are involved as well as in NAFLD pathogenesis itself. Among the multifactorial involved mechanisms, genetic, epigenetic and environmental backgrounds are strongly related to NAFLD development in the offspring. Thus, based on recent evidence from the available literature concerning genetic, epigenetic and environmental disease modifiers, this review aimed to discuss the relationship between parental NAFLD and its impact on the offspring.
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Affiliation(s)
- Natalia Balassiano Wajsbrot
- Division of Hepatology, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro 20941-913, Brazil
| | - Nathalie Carvalho Leite
- Division of Hepatology, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro 20941-913, Brazil
| | - Gil F Salles
- Department of Internal Medicine, Medical School, Federal University of Rio de Janeiro, Rio de Janeiro 22750-240, Brazil
| | - Cristiane A Villela-Nogueira
- Department of Internal Medicine, Medical School, Federal University of Rio de Janeiro, Rio de Janeiro 22750-240, Brazil
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10
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Yang S, Cheng J, Zhang R, Sun H, Zhang H, Lyu S, Duan W. Metabolic dysfunction-associated fatty liver disease and liver fibrosis: Prevalence and associated factors in the middle-aged and older US population. Hepatol Res 2022; 52:176-186. [PMID: 34751487 DOI: 10.1111/hepr.13728] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 10/17/2021] [Accepted: 10/20/2021] [Indexed: 12/13/2022]
Abstract
AIM The global burden of chronic liver disease is substantial. Limited studies have reported the prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and liver fibrosis among middle-aged and older people. Therefore, we aimed to determine the nationwide prevalence of and associated factors for MAFLD and fibrosis in adults aged 45-79 years from the United States. METHODS This cross-sectional study utilized data from the 2017-2018 cycle of the National Health and Nutrition Examination Survey conducted with a nationally representative sample of the civilian, noninstitutionalized US population. Hepatic steatosis and fibrosis were assessed by transient elastography with controlled attenuation parameter and liver stiffness measurement, respectively. RESULTS A total of 1186 eligible participants aged 45-79 years were finally included in the analyses. The estimated prevalence of MAFLD, significant fibrosis (F ≥ F2), and advanced fibrosis (F ≥ F3) was 48.6% (95% confidence interval [CI], 43.1%-54.0%), 9.5% (95% CI, 6.8%-12.7%), and 6.7% (95% CI, 4.1%-10.1%), respectively. Multivariable logistic regression revealed an increased MAFLD predisposition in subjects with metabolic disorders including overweight/obesity, abdominal obesity, hypertension, and diabetes mellitus. Moreover, the presence of depression was an independent and strong predictor of MAFLD risk (odds ratio = 3.23; 95% CI, 1.37-7.11). Elevated liver enzymes, hypertension, diabetes mellitus, hepatitis virus infection, and steatosis were associated with a high risk of significant fibrosis. CONCLUSIONS Newly defined MAFLD is highly prevalent in the US middle-aged and older population. Approximately 1 in 10 people has significant liver fibrosis. In addition to metabolic disorders, the presence of depression potentially increases the risk of MAFLD.
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Affiliation(s)
- Sheng Yang
- Department of Epidemiology and Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jiawen Cheng
- Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China
| | - Rui Zhang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University and Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Huiwen Sun
- Department of Geriatrics, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China
| | - Hui Zhang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University and Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Sali Lyu
- Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Weiwei Duan
- Department of Epidemiology and Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
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11
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Meroni M, Longo M, Tria G, Dongiovanni P. Genetics Is of the Essence to Face NAFLD. Biomedicines 2021; 9:1359. [PMID: 34680476 PMCID: PMC8533437 DOI: 10.3390/biomedicines9101359] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 09/27/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. It is closely related to obesity, insulin resistance (IR) and dyslipidemia so much so it is considered the hepatic manifestation of the Metabolic Syndrome. The NAFLD spectrum extends from simple steatosis to nonalcoholic steatohepatitis (NASH), a clinical condition which may progress up to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). NAFLD is a complex disease whose pathogenesis is shaped by both environmental and genetic factors. In the last two decades, several heritable modifications in genes influencing hepatic lipid remodeling, and mitochondrial oxidative status have been emerged as predictors of progressive hepatic damage. Among them, the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, the Transmembrane 6 superfamily member 2 (TM6SF2) p.E167K and the rs641738 membrane bound-o-acyltransferase domain-containing 7 (MBOAT7) polymorphisms are considered the most robust modifiers of NAFLD. However, a forefront frontier in the study of NAFLD heritability is to postulate score-based strategy, building polygenic risk scores (PRS), which aggregate the most relevant genetic determinants of NAFLD and biochemical parameters, with the purpose to foresee patients with greater risk of severe NAFLD, guaranteeing the most highly predictive value, the best diagnostic accuracy and the more precise individualized therapy.
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Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
- Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, 20122 Milano, Italy
| | - Giada Tria
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
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12
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Bonacini M, Kassamali F, Kari S, Lopez Barrera N, Kohla M. Racial differences in prevalence and severity of non-alcoholic fatty liver disease. World J Hepatol 2021; 13:763-773. [PMID: 34367497 PMCID: PMC8326166 DOI: 10.4254/wjh.v13.i7.763] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 04/08/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
The aim of this review is to assess the evidence regarding racial differences in the prevalence and severity of nonalcoholic fatty liver disease (NAFLD). We reviewed the published literature that reported prevalence, severity, and genetic associations of NAFLD in different ethnic groups. The metabolic syndrome (MetS) has been associated with NAFLD, but each component of the MetS is present in various races in different percentages and their effect on NAFLD appears to be dissimilar. An elevated triglyceride (TG) level seems to have the strongest association with NAFLD. The latter is more prevalent in Hispanic patients; Blacks have lower TG levels and a lower NAFLD prevalence, compared to Caucasians or Hispanics. The severity of liver fibrosis is lower in some, but not all biopsy-based studies of Black patients. No study has evaluated the severity of liver disease controlling for the individual components of MetS, especially TG. Important racial differences in the prevalence of selected genetic polymorphisms, particularly PNPLA-3 and MBOAT7 have been documented, together with their effects on the prevalence of liver steatosis and fibrosis. Data on overall and liver mortality have found no significant differences according to race/ethnicity, with the possible exception of one paper reporting lower cirrhosis mortality in Black patients. We conclude that NAFLD is more prevalent in Hispanics and less in Blacks. This is supported by differences in key genetic polymorphisms associated with hepatic fat storage. However, there is presently insufficient evidence to firmly conclude that race, per se, plays a role in the development of liver fibrosis and its complications. Further studies, appropriately controlled for diet, exercise, and individual MetS parameters are needed.
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Affiliation(s)
- Maurizio Bonacini
- Department of Gastroenterology and Hepatology, California Pacific Medical Center, California Pacific Medical Center, San Francisco, CA 94115, United States
| | - Farah Kassamali
- Department of Gastroenterology and Hepatology, California Pacific Medical Center, San Francisco, CA 94115, United States
| | - Swathi Kari
- Department of Internal Medicine, St. Mary's medical Center, San Francisco, CA 94117, United States
| | | | - Mohamed Kohla
- Department of Hepatology, National Liver Institute, Menoufiya University, Shibin Al Kom 32511, Menoufiya, Egypt
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13
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Mongraw-Chaffin M, Hairston KG, Hanley AJG, Tooze JA, Norris JM, Palmer ND, Bowden DW, Lorenzo C, Chen YDI, Wagenknecht LE. Association of Visceral Adipose Tissue and Insulin Resistance with Incident Metabolic Syndrome Independent of Obesity Status: The IRAS Family Study. Obesity (Silver Spring) 2021; 29:1195-1202. [PMID: 33998167 PMCID: PMC9022784 DOI: 10.1002/oby.23177] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/12/2021] [Accepted: 03/08/2021] [Indexed: 01/23/2023]
Abstract
OBJECTIVE Although increasing evidence suggests that visceral adipose tissue (VAT) is a major underlying cause of metabolic syndrome (MetS), few studies have measured VAT at multiple time points in diverse populations. VAT and insulin resistance were hypothesized to differ by MetS status within BMI category in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study and, further, that baseline VAT and insulin resistance and increases over time are associated with incident MetS. METHODS Generalized estimating equations were used for differences in body fat distribution and insulin resistance by MetS status. Mixed effects logistic regression was used for the association of baseline and change in adiposity and insulin resistance with incident MetS across 5 years, adjusted for age, sex, race/ethnicity, and family correlation. RESULTS VAT and insulin sensitivity differed significantly by MetS status and BMI category at baseline. VAT and homeostatic model assessment of insulin resistance (HOMA-IR) at baseline (VAT odds ratio [OR] = 1.16 [95% CI: 1.12-2.31]; HOMA-IR OR = 1.85 [95% CI: 1.32-2.58]) and increases over time (VAT OR = 1.55 [95% CI: 1.22-1.98]; HOMA-IR OR = 3.23 [95% CI: 2.20-4.73]) were associated with incident MetS independent of BMI category. CONCLUSIONS Differing levels of VAT may be driving metabolic heterogeneity within BMI categories. Both overall and abdominal obesity (VAT) may play a role in the development of MetS. Increased VAT over time contributed additional risk.
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Affiliation(s)
| | - Kristen G Hairston
- Department of Endocrinology and Metabolism, Wake Forest School of Medicine, Winston-Salem, NC
| | - Anthony JG Hanley
- Department of Nutritional Sciences, University of Toronto, Toronto, Canada
| | - Janet A Tooze
- Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC
| | - Jill M Norris
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Nicolette D Palmer
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC
| | - Donald W Bowden
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC
| | - Carlos Lorenzo
- Department of Medicine, University of Texas at San Antonio Health Sciences Center, San Antonio TX
| | - Yii-Der Ida Chen
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Lynne E Wagenknecht
- Department of Epidemiology & Prevention, Wake Forest School of Medicine, Winston-Salem, NC
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14
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Bouchard C. Genetics of Obesity: What We Have Learned Over Decades of Research. Obesity (Silver Spring) 2021; 29:802-820. [PMID: 33899337 DOI: 10.1002/oby.23116] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 12/14/2022]
Abstract
There is a genetic component to human obesity that accounts for 40% to 50% of the variability in body weight status but that is lower among normal weight individuals (about 30%) and substantially higher in the subpopulation of individuals with obesity and severe obesity (about 60%-80%). The appreciation that heritability varies across classes of BMI represents an important advance. After controlling for BMI, ectopic fat and fat distribution traits are characterized by heritability levels ranging from 30% to 55%. Defects in at least 15 genes are the cause of monogenic obesity cases, resulting mostly from deficiencies in the leptin-melanocortin signaling pathway. Approximately two-thirds of the BMI heritability can be imputed to common DNA variants, whereas low-frequency and rare variants explain the remaining fraction. Diminishing allele effect size is observed as the number of obesity-associated variants expands, with most BMI-increasing or -decreasing alleles contributing only a few grams or less to body weight. Obesity-promoting alleles exert minimal effects in normal weight individuals but have larger effects in individuals with a proneness to obesity, suggesting a higher penetrance; however, it is not known whether these larger effect sizes precede obesity or are caused by an obese state. The obesity genetic risk is conditioned by thousands of DNA variants that make genetically based obesity prevention and treatment a major challenge.
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Affiliation(s)
- Claude Bouchard
- Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
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15
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Satapathy SK, Marella HK, Heda RP, Ganguli S, Kirthi Reddy Y, Podila PSB, Clark I, Maliakkal B. African Americans have a distinct clinical and histologic profile with lower prevalence of NASH and advanced fibrosis relative to Caucasians. Eur J Gastroenterol Hepatol 2021; 33:388-398. [PMID: 32317586 DOI: 10.1097/meg.0000000000001735] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Racial/ethnic disparities have been reported in the prevalence of nonalcoholic fatty liver disease (NAFLD). Thus, we aimed to understand the inter-ethnic clinical, biochemical, and histological differences in a large cohort of Caucasians and African-Americans (AA). METHODS Laboratory and liver biopsy data of 942 NAFLD patients were retrospectively analyzed. Nine hundred seven patients were included in the analysis: 677 (74.6%) Caucasians and 230 (25.3%) AA. RESULTS AA had higher mean BMI compared to Caucasians (42.6 ± 9.5 vs. 39 ± 8.6 kg/m2). The prevalence of nonalcoholic steatohepatitis (NASH), defined by NAFLD activity score (NAS . 5), was higher in the Caucasians (n = 67) compared to AA (n = 7) (9.8% vs. 3%, P = 0.0007). One hundred fifteen patients (12.8%) had advanced fibrosis: 109 (16.2%) Caucasians and six (2.6%) AA. No AA patients had stage 4 fibrosis or cirrhosis. Multivariate logistic regression analysis revealed advanced fibrosis was significantly associated with age at liver biopsy (OR 1.03, 95% CI 1.0.1.1, P = 0.017, lower platelet count (OR 0.99, 95% CI 0.98.0.99, P = <0.0001), AST/ALT ratio (OR 5.19, 95% CI 2.9.9.2, P <0.0001) and Caucasian race (OR 7.49, 95% CI 2.53.22.2, P = 0.0003). Advanced fibrosis in AA was predicted by lower platelet count and AST/ALT ratio. Whereas Advanced fibrosis in Caucasians was predicted by age at biopsy, lower platelet count and AST/ALT ratio. CONCLUSION The AA have a distinct clinical and histologic phenotype. Caucasians have a significantly greater proportion of NASH and are eight times more likely to develop advanced fibrosis than AA.
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Affiliation(s)
- Sanjaya K Satapathy
- Division of Transplant Surgery, Department of Surgery, Methodist University Hospital Transplant Institute, University of Tennessee Health Science Center, Memphis, Tennessee
- Division of Hepatology and Liver Transplantation, Sandra Atlas Bass Center for Liver Diseases, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, New York
| | | | - Rajiv P Heda
- University of Tennessee Health Science Center, College of Medicine, Methodist University Hospital, Memphis, Tennessee
| | - Surosree Ganguli
- Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Yala Kirthi Reddy
- Department of Medicine, University of Tennessee Health Science Center
| | - Pradeep S B Podila
- Division of Transplant Surgery, Department of Surgery, Methodist University Hospital Transplant Institute, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Ian Clark
- Department of Pathology, Methodist University Hospital, Memphis, Tennessee, USA
| | - Benedict Maliakkal
- Division of Transplant Surgery, Department of Surgery, Methodist University Hospital Transplant Institute, University of Tennessee Health Science Center, Memphis, Tennessee
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16
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Choudhary NS, Duseja A. Genetic and epigenetic disease modifiers: non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Transl Gastroenterol Hepatol 2021; 6:2. [PMID: 33409397 DOI: 10.21037/tgh.2019.09.06] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 09/04/2019] [Indexed: 12/12/2022] Open
Abstract
Inter-individual and inter-ethnic differences and difference in the severity and progression of liver disease among patients with non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) suggests the involvement of genetic and epigenetic factors in their pathogenesis. This article reviews the genetic and epigenetic modifiers in patients with NAFLD and ALD. Evidence regarding the genetic and epigenetic disease modifiers of NAFLD and ALD was reviewed by searching the available literature. Both genome wide association studies (GWAS) and candidate gene studies pertaining to the pathogenesis in both diseases were included. Clinical implications of the available information are also discussed. Several studies have shown association of both NAFLD and ALD with I148M PNPLA3 variant. In addition to the higher prevalence of hepatic steatosis, the I148M PNPLA3 variant is also associated with severity of liver disease and risk of hepatocellular carcinoma (HCC). TM6SF2 is the other genetic variant shown to be significantly associated with hepatic steatosis and cirrhosis in patients with NAFLD and ALD. The Membrane bound O-acyltransferase domain-containing 7 (MBOAT7) genetic variant is also associated with both NAFLD and ALD. In addition to these mutations, several variants related to the genes involved in glucose metabolism, insulin resistance, lipid metabolism, oxidative stress, inflammatory pathways, fibrosis have also been shown to be the disease modifiers in patients with NAFLD and ALD. Epigenetics involving several micro RNAs and DNA methylation could also modify the disease course in NAFLD and ALD. In conclusion the available literature suggests that genetics and epigenetics are involved in the pathogenesis of NAFLD and ALD which may affect the disease prevalence, severity and response to treatment in these patients.
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Affiliation(s)
- Narendra Singh Choudhary
- Institute of Liver Transplantation and Regenerative Medicine, Medanta, The Medicity, Gurgaon, Delhi (NCR), India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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17
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Samji NS, Snell PD, Singal AK, Satapathy SK. Racial Disparities in Diagnosis and Prognosis of Nonalcoholic Fatty Liver Disease. Clin Liver Dis (Hoboken) 2020; 16:66-72. [PMID: 32922753 PMCID: PMC7474141 DOI: 10.1002/cld.948] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 01/29/2020] [Accepted: 02/11/2020] [Indexed: 02/04/2023] Open
Affiliation(s)
- Naga Swetha Samji
- Department of Internal MedicineTennova Cleveland HospitalClevelandTN
| | - Peter D. Snell
- Department of Internal MedicineUniversity of Tennessee Health Science CenterMemphisTN
| | - Ashwani K. Singal
- Department of Internal MedicineUniversity of South Dakota Sanford School of Medicine and Avera Transplant InstituteSioux FallsSD
| | - Sanjaya K. Satapathy
- Division of Hepatology, Sandra Atlas Bass Center for Liver DiseasesNorthwell HealthManhassetNY
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18
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DiStefano JK. Fructose-mediated effects on gene expression and epigenetic mechanisms associated with NAFLD pathogenesis. Cell Mol Life Sci 2020; 77:2079-2090. [PMID: 31760464 PMCID: PMC7440926 DOI: 10.1007/s00018-019-03390-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a chronic, frequently progressive condition that develops in response to excessive hepatocyte fat accumulation (i.e., steatosis) in the absence of significant alcohol consumption. Liver steatosis develops as a result of imbalanced lipid metabolism, driven largely by increased rates of de novo lipogenesis and hepatic fatty acid uptake and reduced fatty acid oxidation and/or disposal to the circulation. Fructose is a naturally occurring simple sugar, which is most commonly consumed in modern diets in the form of sucrose, a disaccharide comprised of one molecule of fructose covalently bonded with one molecule of glucose. A number of observational and experimental studies have demonstrated detrimental effects of dietary fructose consumption not only on diverse metabolic outcomes such as insulin resistance and obesity, but also on hepatic steatosis and NAFLD-related fibrosis. Despite the compelling evidence that excessive fructose consumption is associated with the presence of NAFLD and may even promote the development and progression of NAFLD to more clinically severe phenotypes, the molecular mechanisms by which fructose elicits effects on dysregulated liver metabolism remain unclear. Emerging data suggest that dietary fructose may directly alter the expression of genes involved in lipid metabolism, including those that increase hepatic fat accumulation or reduce hepatic fat removal. The aim of this review is to summarize the current research supporting a role for dietary fructose intake in the modulation of transcriptomic and epigenetic mechanisms underlying the pathogenesis of NAFLD.
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Affiliation(s)
- Johanna K DiStefano
- Diabetes and Fibrotic Disease Unit, Translational Genomics Research Institute, 445 N 5th Street, Phoenix, AZ, 85004, USA.
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19
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Kallwitz E, Tayo BO, Kuniholm MH, Daviglus M, Zeng D, Isasi CR, Cotler SJ. Association of HSD17B13 rs72613567:TA with non-alcoholic fatty liver disease in Hispanics/Latinos. Liver Int 2020; 40:889-893. [PMID: 31965669 DOI: 10.1111/liv.14387] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 01/15/2020] [Accepted: 01/16/2020] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) disproportionately affects Hispanic/Latinos and rates of NAFLD vary among Hispanics from different background groups. Genetic variants and continental ancestry contribute to NAFLD disparities among Hispanics. We evaluated two newly identified NAFLD-associated single nucleotide polymorphisms of HSD17B13, rs72613567:TA and rs62305723:A in Hispanics/Latinos. METHODS Clinical data, genotypes of variants of interest and estimates of continental ancestry were extracted from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) database, which includes a cohort of 16 415 US Hispanic/Latinos. Surrogate endpoints for NAFLD were suspected NAFLD based on unexplained aminotransferase elevation, continuous ALT levels and FIB-4 scores to estimate hepatic fibrosis. RESULTS In all, 9342 participants were included for analysis. The rs72613567:TA allele was found in 15.3% and the rs62305723:A allele was identified in 4.5% of HCHS/SOL participants. rs72613567:TA was less frequent in persons with vs without suspected NAFLD (12.4% vs 15.7%, P < .001) and rs72613567:TA was associated with lower FIB-4 scores (P = .01). For persons with the NAFLD-associated PNPLA3 rs738409:G allele, the presence of rs72613567:TA was associated with a lower rate of suspected NAFD (odds ratio = 0.76, P < .001). rs72613567:TA was less frequent in Hispanic/Latino background groups with higher rates of suspected NAFLD. The rs62305723:A allele was not associated with suspected NAFLD or FIB-4 score. CONCLUSION The rs72613567:TA allele is associated with lower rates of suspected NAFLD and lower FIB-4 scores among Hispanic/Latinos and with lower rates of suspected NAFLD in persons with the PNPLA3 rs738409:G allele. The rs72613567:TA allele contributes to NAFLD disparities among Hispanic/Latino background groups.
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Affiliation(s)
- Eric Kallwitz
- Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
| | - Bamidele O Tayo
- Parkinson School of Health Sciences and Public Health, Loyola University Chicago, Maywood, IL, USA
| | - Mark H Kuniholm
- School of Public Health, State University of New York, Albany, NY, USA
| | - Martha Daviglus
- Institute of Minority Health Research, University of Illinois, Chicago, IL, USA
| | - Donglin Zeng
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA
| | - Carmen R Isasi
- Department of Epidemiology and Population Health, Einstein College of Medicine, New York, NY, USA
| | - Scott J Cotler
- Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
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Abstract
Nonalcoholic fatty liver disease is strongly associated with obesity and the metabolic syndrome, but genetic factors also contribute to disease susceptibility. Human genetic studies have identified several common genetic variants contributing to nonalcoholic fatty liver disease initiation and progression. These findings have provided new insights into the pathogenesis of nonalcoholic fatty liver disease and opened up new avenues for the development of therapeutic interventions. In this review, we summarize the current state of knowledge about the genetic determinants of nonalcoholic fatty liver disease, focusing on the most robustly validated genetic risk factors and on recently discovered modifiers of disease progression.
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Affiliation(s)
- Julia Kozlitina
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8591, USA.
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21
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Caprio S, Santoro N, Weiss R. Childhood obesity and the associated rise in cardiometabolic complications. Nat Metab 2020; 2:223-232. [PMID: 32694781 PMCID: PMC9425367 DOI: 10.1038/s42255-020-0183-z] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 02/17/2020] [Indexed: 02/06/2023]
Abstract
Childhood obesity is one of the most serious global public-health challenges of the twenty-first century. Over the past four decades, the number of children and adolescents with obesity has risen more than tenfold. Worldwide, an increasing number of youth are facing greater exposure to obesity throughout their lives, and this increase will contribute to the early development of type 2 diabetes, fatty liver and cardiovascular complications. Herein, we provide a brief overview of trends in the global shifts in, and environmental and genetic determinants of, childhood obesity. We then discuss recent progress in the elucidation of the central role of insulin resistance, the key element linking obesity and cardiovascular-risk-factor clustering, and the potential mechanisms through which ectopic lipid accumulation leads to insulin resistance and its associated cardiometabolic complications in obese adolescents. In the absence of effective prevention and intervention programs, childhood obesity will have severe public-health consequences for decades to come.
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Affiliation(s)
- Sonia Caprio
- Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA.
| | - Nicola Santoro
- Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA.
| | - Ram Weiss
- Department of Pediatrics, Ruth Rappaport Children's Hospital, Rambam Medical Center, Technion School of Medicine, Haifa, Israel.
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Genetic contributions to NAFLD: leveraging shared genetics to uncover systems biology. Nat Rev Gastroenterol Hepatol 2020; 17:40-52. [PMID: 31641249 DOI: 10.1038/s41575-019-0212-0] [Citation(s) in RCA: 204] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/05/2019] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects around a quarter of the global population, paralleling worldwide increases in obesity and metabolic syndrome. NAFLD arises in the context of systemic metabolic dysfunction that concomitantly amplifies the risk of cardiovascular disease and diabetes. These interrelated conditions have long been recognized to have a heritable component, and advances using unbiased association studies followed by functional characterization have created a paradigm for unravelling the genetic architecture of these conditions. A novel perspective is to characterize the shared genetic basis of NAFLD and other related disorders. This information on shared genetic risks and their biological overlap should in future enable the development of precision medicine approaches through better patient stratification, and enable the identification of preventive and therapeutic strategies. In this Review, we discuss current knowledge of the genetic basis of NAFLD and of possible pleiotropy between NAFLD and other liver diseases as well as other related metabolic disorders. We also discuss evidence of causality in NAFLD and other related diseases and the translational significance of such evidence, and future challenges from the study of genetic pleiotropy.
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Cardiovascular Risk in Non-Alcoholic Fatty Liver Disease: Mechanisms and Therapeutic Implications. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16173104. [PMID: 31455011 PMCID: PMC6747357 DOI: 10.3390/ijerph16173104] [Citation(s) in RCA: 126] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 08/18/2019] [Accepted: 08/21/2019] [Indexed: 02/06/2023]
Abstract
New evidence suggests that non-alcoholic fatty liver disease (NAFLD) has a strong multifaceted relationship with diabetes and metabolic syndrome, and is associated with increased risk of cardiovascular events, regardless of traditional risk factors, such as hypertension, diabetes, dyslipidemia, and obesity. Given the pandemic-level rise of NAFLD—in parallel with the increasing prevalence of obesity and other components of the metabolic syndrome—and its association with poor cardiovascular outcomes, the question of how to manage NAFLD properly, in order to reduce the burden of associated incident cardiovascular events, is both timely and highly relevant. This review aims to summarize the current knowledge of the association between NAFLD and cardiovascular disease, and also to discuss possible clinical strategies for cardiovascular risk assessment, as well as the spectrum of available therapeutic strategies for the prevention and treatment of NAFLD and its downstream events.
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Kumar A, Shalimar, Walia GK, Gupta V, Sachdeva MP. Genetics of nonalcoholic fatty liver disease in Asian populations. J Genet 2019. [DOI: 10.1007/s12041-019-1071-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Zhang ZT, Qi WX, Liu CX, Yin SW, Zhao Y, Li-Ling J, Lv Y. A small supernumerary marker chromosome resulting in mosaic partial tetrasomy 4q26-q31.21 in a foetus with multiple congenital malformations. J Genet 2019; 98:22. [PMID: 30945692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
A parental diagnosis was performed for an unborn foetus of a healthy couple, who was due for ultrasound detection of multiple malformations and abnormal amniotic fluid karyotypes. For an accurate diagnosis, routine G-banding analysis and next generation sequencing (NGS) were carried out. Finally, conventional cytogenetic analysis suggested that the foetus had a karyotype of47,XX,+mar[52]/46,XN, meanwhile NGS also revealed a partial tetrasomy of 27.84Mb from 4q26-q31.21 (117,385,735-145,225,759), and G-banding analysis excluded the couple to have carried the 4q26-q31.21 duplication. We have identified a de novo mosaic small supernumerary marker chromosomes (sSMC) derived from 4q26-q31.21 in a foetus with hemivertebra, polydactyly, abnormal ears, and heart and ventricular septal defect.
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Affiliation(s)
- Zhi-Tao Zhang
- Liaoning Centre for Prenatal Diagnosis, Department of Gynecology and Obstetrics, Shengjing Hospital Affiliated to China Medical University, Shenyang 110004, People's Republic of China.
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Lim U, Monroe KR, Buchthal S, Fan B, Cheng I, Kristal BS, Lampe JW, Hullar MA, Franke AA, Stram DO, Wilkens LR, Shepherd J, Ernst T, Marchand LL. Propensity for Intra-abdominal and Hepatic Adiposity Varies Among Ethnic Groups. Gastroenterology 2019; 156:966-975.e10. [PMID: 30445012 PMCID: PMC6409195 DOI: 10.1053/j.gastro.2018.11.021] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 10/17/2018] [Accepted: 11/01/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS We compared fat storage in the abdominal region among individuals from 5 different ethnic-racial groups to determine whether fat storage is associated with disparities observed in metabolic syndrome and other obesity-associated diseases. METHODS We collected data from 1794 participants in the Multiethnic Cohort Study (60-77 years old; of African, European [white], Japanese, Latino, or Native Hawaiian ancestry) with body mass index values of 17.1-46.2 kg/m2. From May 2013 through April 2016, participants visited the study clinic to undergo body measurements, an interview, and a blood collection. Participants were evaluated by dual-energy x-ray absorptiometry and abdominal magnetic resonance imaging. Among ethnic groups, we compared adiposity of the trunk, intra-abdominal visceral cavity, and liver, adjusting for total fat mass; we evaluated the association of adult weight change with abdominal adiposity; and we examined the prevalence of metabolic syndrome mediated by abdominal adiposity. RESULTS Relative amounts of trunk, visceral, and liver fat varied significantly with ethnicity-they were highest in Japanese Americans, lowest in African Americans, and intermediate in the other groups. Compared with African Americans, the mean visceral fat area was 45% and 73% greater in Japanese American men and women, respectively, and the mean measurements of liver fat were 61% and 122% greater in Japanese American men and women. The visceral and hepatic adiposity associated with weight gain since participants were 21 years old varied in a similar pattern among ethnic-racial groups. In the mediation analysis, visceral and liver fat jointly accounted for a statistically significant fraction of the difference in metabolic syndrome prevalence, compared with white persons, for African Americans, Japanese Americans, and Native Hawaiian women, independently of total fat mass. CONCLUSIONS In an analysis of data from the participants in the Multiethnic Cohort Study, we found extensive differences among ethnic-racial groups in the propensity to store fat intra-abdominally. This observation should be considered by clinicians in the prevention and early detection of metabolic disorders.
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Affiliation(s)
- Unhee Lim
- University of Hawaii Cancer Center, University of Hawaii at Mānoa, Honolulu, Hawaii.
| | - Kristine R. Monroe
- Keck School of Medicine, University of Southern California, Los Angeles, California, U.S.A
| | - Steve Buchthal
- John A. Burns School of Medicine, University of Hawaii at Mānoa, Honolulu, Hawaii, U.S.A
| | - Bo Fan
- School of Medicine, University of California San Francisco, San Francisco, California, U.S.A
| | - Iona Cheng
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, U.S.A
| | - Bruce S. Kristal
- Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A
| | - Johanna W. Lampe
- Fred Hutchinson Cancer Research Center, Seattle, Washington, U.S.A
| | | | - Adrian A. Franke
- University of Hawaii Cancer Center, University of Hawaii at Mānoa, Honolulu, Hawaii, U.S.A
| | - Daniel O. Stram
- Keck School of Medicine, University of Southern California, Los Angeles, California, U.S.A
| | - Lynne R. Wilkens
- University of Hawaii Cancer Center, University of Hawaii at Mānoa, Honolulu, Hawaii, U.S.A
| | - John Shepherd
- University of Hawaii Cancer Center, University of Hawaii at Mānoa, Honolulu, Hawaii, U.S.A
| | - Thomas Ernst
- University of Maryland School of Medicine, Baltimore, Maryland, U.S.A
| | - Loïc Le Marchand
- University of Hawaii Cancer Center, University of Hawaii at Mānoa, Honolulu, Hawaii, U.S.A
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Bessone F, Razori MV, Roma MG. Molecular pathways of nonalcoholic fatty liver disease development and progression. Cell Mol Life Sci 2019; 76:99-128. [PMID: 30343320 PMCID: PMC11105781 DOI: 10.1007/s00018-018-2947-0] [Citation(s) in RCA: 373] [Impact Index Per Article: 62.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/10/2018] [Accepted: 10/15/2018] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a main hepatic manifestation of metabolic syndrome. It represents a wide spectrum of histopathological abnormalities ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis and, eventually, cirrhosis and hepatocellular carcinoma. While hepatic simple steatosis seems to be a rather benign manifestation of hepatic triglyceride accumulation, the buildup of highly toxic free fatty acids associated with insulin resistance-induced massive free fatty acid mobilization from adipose tissue and the increased de novo hepatic fatty acid synthesis from glucose acts as the "first hit" for NAFLD development. NAFLD progression seems to involve the occurrence of "parallel, multiple-hit" injuries, such as oxidative stress-induced mitochondrial dysfunction, endoplasmic reticulum stress, endotoxin-induced, TLR4-dependent release of inflammatory cytokines, and iron overload, among many others. These deleterious factors are responsible for the triggering of a number of signaling cascades leading to inflammation, cell death, and fibrosis, the hallmarks of NASH. This review is aimed at integrating the overwhelming progress made in the characterization of the physiopathological mechanisms of NAFLD at a molecular level, to better understand the factor influencing the initiation and progression of the disease.
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Affiliation(s)
- Fernando Bessone
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - María Valeria Razori
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570, 2000, Rosario, Argentina
| | - Marcelo G Roma
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570, 2000, Rosario, Argentina.
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NASH Leading Cause of Liver Transplant in Women: Updated Analysis of Indications For Liver Transplant and Ethnic and Gender Variances. Am J Gastroenterol 2018; 113:1649-1659. [PMID: 29880964 PMCID: PMC9083888 DOI: 10.1038/s41395-018-0088-6] [Citation(s) in RCA: 423] [Impact Index Per Article: 60.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 04/01/2018] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Chronic infection with hepatitis C virus (HCV) was previously the leading indication for liver transplant (LT) in the United States. However, since 2014 the use of direct-acting antivirals (DAAs) has decreased the chronic HCV burden, while the prevalence of nonalcoholic steatohepatitis (NASH) has risen substantially through the last decade. Both gender and ethnic disparities in indications for LT have been shown in the past but no data on this have been reported since the implementation of DAAs. METHODS We assessed changes in etiologies for LT listing and in gender and ethnic differences in those listed for LT. Adult patients registered for LT in the United Network for Organ Sharing/Organ Procurement and Transplantation Network database between January 1, 2004 and December 31, 2016 were included. Multinomial logistic regression modeling was used to test for changes in waitlist or liver transplant rates. RESULTS The study included 127,164 adult patients registered for LT. By 2016, alcoholic liver disease (ALD) was the leading etiology for waitlisting and LT; NASH was second; hepatocellular carcinoma (HCC) due to chronic HCV and chronic HCV alone were 3rd and 4th. NASH was the leading cause for LT for women and the 2nd leading cause for men (following ALD). NASH increased as the cause in all ethnic subgroups and was the leading cause in 2016 among Asian, Hispanic, and non-Hispanic white females. We also found that although the indication for liver transplant for hepatocellular carcinoma (HCC) due to HCV has increased over the years, this indication decreased for the first time between 2015 and 2016 in both males and females. CONCLUSIONS NASH is currently the second leading cause for LT waitlist registration/liver transplantation overall, and in females, the leading cause. Given the rate of increase, NASH will likely rise to become the leading indication for LT in males as well.
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The Role of Long Non-Coding RNAs (lncRNAs) in the Development and Progression of Fibrosis Associated with Nonalcoholic Fatty Liver Disease (NAFLD). Noncoding RNA 2018; 4:ncrna4030018. [PMID: 30134610 PMCID: PMC6162709 DOI: 10.3390/ncrna4030018] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 08/14/2018] [Accepted: 08/17/2018] [Indexed: 12/11/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of conditions ranging from hepatic steatosis to inflammation (nonalcoholic steatohepatitis or NASH) with or without fibrosis, in the absence of significant alcohol consumption. The presence of fibrosis in NASH patients is associated with greater liver-related morbidity and mortality; however, the molecular mechanisms underlying the development of fibrosis and cirrhosis in NAFLD patients remain poorly understood. Long non-coding RNAs (lncRNAs) are emerging as key contributors to biological processes that are underpinning the initiation and progression of NAFLD fibrosis. This review summarizes the experimental findings that have been obtained to date in animal models of liver fibrosis and NAFLD patients with fibrosis. We also discuss the potential applicability of circulating lncRNAs to serve as biomarkers for the diagnosis and prognosis of NAFLD fibrosis. A better understanding of the role played by lncRNAs in NAFLD fibrosis is critical for the identification of novel therapeutic targets for drug development and improved, noninvasive methods for disease diagnosis.
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Chronic liver diseases and the potential use of S-adenosyl-L-methionine as a hepatoprotector. Eur J Gastroenterol Hepatol 2018; 30:893-900. [PMID: 29683981 DOI: 10.1097/meg.0000000000001141] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chronic liver diseases result in overall deterioration of health status and changes in metabolism. The search for strategies to control and combat these hepatic diseases has witnessed a great boom in the last decades. Nutritional therapy for controlling and managing liver diseases may be a positive influence as it improves the function of the liver. In this review, we focus mainly on describing liver conditions such as nonalcoholic fatty liver disease, and intrahepatic cholestasis as well as using S-adenosyl-L-methionine as a dietary supplement and its potential alternative therapeutic effect to correct the hepatic dysfunction associated with these conditions.
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Lamri A, Pigeyre M, Garver WS, Meyre D. The Extending Spectrum of NPC1-Related Human Disorders: From Niemann-Pick C1 Disease to Obesity. Endocr Rev 2018; 39:192-220. [PMID: 29325023 PMCID: PMC5888214 DOI: 10.1210/er.2017-00176] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 01/02/2018] [Indexed: 12/22/2022]
Abstract
The Niemann-Pick type C1 (NPC1) protein regulates the transport of cholesterol and fatty acids from late endosomes/lysosomes and has a central role in maintaining lipid homeostasis. NPC1 loss-of-function mutations in humans cause NPC1 disease, a rare autosomal-recessive lipid-storage disorder characterized by progressive and lethal neurodegeneration, as well as liver and lung failure, due to cholesterol infiltration. In humans, genome-wide association studies and post-genome-wide association studies highlight the implication of common variants in NPC1 in adult-onset obesity, body fat mass, and type 2 diabetes. Heterozygous human carriers of rare loss-of-function coding variants in NPC1 display an increased risk of morbid adult obesity. These associations have been confirmed in mice models, showing an important interaction with high-fat diet. In this review, we describe the current state of knowledge for NPC1 variants in relationship to pleiotropic effects on metabolism. We provide evidence that NPC1 gene variations may predispose to common metabolic diseases by modulating steroid hormone synthesis and/or lipid homeostasis. We also propose several important directions of research to further define the complex roles of NPC1 in metabolism. This review emphasizes the contribution of NPC1 to obesity and its metabolic complications.
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Affiliation(s)
- Amel Lamri
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Marie Pigeyre
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.,INSERM 1190, European Genomics Institute for Diabetes, University of Lille, CHRU Lille, Lille, France
| | - William S Garver
- Department of Biochemistry and Molecular Biology, School of Medicine, University of New Mexico, Albuquerque, New Mexico
| | - David Meyre
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
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Younossi ZM, Henry L, Bush H, Mishra A. Clinical and Economic Burden of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Clin Liver Dis 2018; 22:1-10. [PMID: 29128049 DOI: 10.1016/j.cld.2017.08.001] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease with an increasing global prevalence associated with tremendous clinical, economic, and health-related quality-of-life burden. Clinically, NAFLD is considered the liver manifestation of metabolic syndrome. However, diagnosing NAFLD presents significant challenges due to the limited noninvasive and accurate diagnostic tools available to not only accurately diagnose nonalcoholic steatohepatitis but also to stage hepatic fibrosis, the major predictor of long-term outcomes, including mortality.
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Affiliation(s)
- Zobair M Younossi
- Department of Medicine, Center for Liver Diseases, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA 22042, USA; Betty and Guy Beatty Center for Integrated Research, Inova Health System, 3300 Gallows Road, Falls Church, VA 22042, USA.
| | - Linda Henry
- Center for Outcomes Research in Liver Disease, 2411 I Street NW, Washington, DC 20037, USA
| | - Haley Bush
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, 3300 Gallows Road, Falls Church, VA 22042, USA
| | - Alita Mishra
- Department of Medicine, Center for Liver Diseases, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA 22042, USA
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Lim HW, Bernstein DE. Risk Factors for the Development of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis, Including Genetics. Clin Liver Dis 2018; 22:39-57. [PMID: 29128060 DOI: 10.1016/j.cld.2017.08.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease is emerging as the most common cause of chronic liver disease worldwide. This trend is, in part, secondary, to the growing incidence of obesity, type 2 diabetes, and metabolic syndrome. Other risk factors include age, gender, race/ethnicity, genetic predisposition, and polycystic ovarian disease. With the introduction of genome-wide association studies, genetic mutations contributing to inherited susceptibility to steatosis have been identified, which hold keys to future improvement in diagnosis and management. This article expands on the aforementioned risk factors and summarizes the current available data on genetic and environmental factors associated with this common entity.
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Affiliation(s)
- Huei-Wen Lim
- Department of Internal Medicine, Northwell Health, 400 Community Drive, Manhasset, NY 11030, USA
| | - David E Bernstein
- Department of Gastroenterology and Hepatology, Northwell Health, Center for Liver Diseases, 400 Community Drive, Manhasset, NY 11030, USA.
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Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018; 67:328-357. [PMID: 28714183 DOI: 10.1002/hep.29367] [Citation(s) in RCA: 4760] [Impact Index Per Article: 680.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 06/29/2017] [Indexed: 02/06/2023]
Affiliation(s)
| | - Zobair Younossi
- Center for Liver Disease and Department of Medicine, Inova Fairfax Hospital, Falls Church, VA
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Prysyazhnyuk VP, Rossokha ZI, Gorovenko NG. Variation in particular biochemical indicators, cytokine and adipokine profiles of the blood, and the structural and functional parameters of the liver in patients with nonalcoholic fatty liver disease and different genotypes by the polymorphic locus A313G of the GSTP1 gene. CYTOL GENET+ 2017. [DOI: 10.3103/s0095452717060111] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Peters HPF, Schrauwen P, Verhoef P, Byrne CD, Mela DJ, Pfeiffer AFH, Risérus U, Rosendaal FR, Schrauwen-Hinderling V. Liver fat: a relevant target for dietary intervention? Summary of a Unilever workshop. J Nutr Sci 2017; 6:e15. [PMID: 28630692 PMCID: PMC5468740 DOI: 10.1017/jns.2017.13] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 03/09/2017] [Indexed: 12/20/2022] Open
Abstract
Currently it is estimated that about 1 billion people globally have non-alcoholic fatty liver disease (NAFLD), a condition in which liver fat exceeds 5 % of liver weight in the absence of significant alcohol intake. Due to the central role of the liver in metabolism, the prevalence of NAFLD is increasing in parallel with the prevalence of obesity, insulin resistance and other risk factors of metabolic diseases. However, the contribution of liver fat to the risk of type 2 diabetes mellitus and CVD, relative to other ectopic fat depots and to other risk markers, is unclear. Various studies have suggested that the accumulation of liver fat can be reduced or prevented via dietary changes. However, the amount of liver fat reduction that would be physiologically relevant, and the timeframes and dose-effect relationships for achieving this through different diet-based approaches, are unclear. Also, it is still uncertain whether the changes in liver fat per se or the associated metabolic changes are relevant. Furthermore, the methods available to measure liver fat, or even individual fatty acids, differ in sensitivity and reliability. The present report summarises key messages of presentations from different experts and related discussions from a workshop intended to capture current views and research gaps relating to the points above.
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Affiliation(s)
- Harry P. F. Peters
- Unilever R&D Vlaardingen, Olivier van Noortlaan 120, Vlaardingen, The Netherlands
| | - Patrick Schrauwen
- Department of Human Biology, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Petra Verhoef
- Unilever R&D Vlaardingen, Olivier van Noortlaan 120, Vlaardingen, The Netherlands
| | - Christopher D. Byrne
- Nutrition and Metabolism, Faculty of Medicine, University of Southampton & Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton, UK
| | - David J. Mela
- Unilever R&D Vlaardingen, Olivier van Noortlaan 120, Vlaardingen, The Netherlands
| | - Andreas F. H. Pfeiffer
- Department of Endocrinology, Diabetes and Nutrition, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin
- Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam and German Center for Diabetes Research, DZD, Neuherberg, Germany
| | - Ulf Risérus
- Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism Unit, Uppsala University, Sweden
| | - Frits R. Rosendaal
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Vera Schrauwen-Hinderling
- Department of Human Biology, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
- Department of Radiology, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
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Sookoian S, Pirola CJ. Genetic predisposition in nonalcoholic fatty liver disease. Clin Mol Hepatol 2017; 23:1-12. [PMID: 28268262 PMCID: PMC5381829 DOI: 10.3350/cmh.2016.0109] [Citation(s) in RCA: 164] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 11/04/2016] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease whose prevalence has reached global epidemic proportions. Although the disease is relatively benign in the early stages, when severe clinical forms, including nonalcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma, occur, they result in worsening the long-term prognosis. A growing body of evidence indicates that NAFLD develops from a complex process in which many factors, including genetic susceptibility and environmental insults, are involved. In this review, we focused on the genetic component of NAFLD, with special emphasis on the role of genetics in the disease pathogenesis and natural history. Insights into the topic of the genetic susceptibility in lean individuals with NAFLD and the potential use of genetic tests in identifying individuals at risk are also discussed.
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Affiliation(s)
- Silvia Sookoian
- Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires - National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
| | - Carlos J Pirola
- Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires - National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
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Setiawan VW, Stram DO, Porcel J, Lu SC, Le Marchand L, Noureddin M. Prevalence of chronic liver disease and cirrhosis by underlying cause in understudied ethnic groups: The multiethnic cohort. Hepatology 2016; 64:1969-1977. [PMID: 27301913 PMCID: PMC5115980 DOI: 10.1002/hep.28677] [Citation(s) in RCA: 224] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 05/21/2016] [Indexed: 12/14/2022]
Abstract
UNLABELLED Chronic liver disease (CLD) and cirrhosis are major sources of morbidity and mortality in the United States. Little is known about the epidemiology of these two diseases in ethnic minority populations in the United States. We examined the prevalence of CLD and cirrhosis by underlying etiologies among African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites in the Multiethnic Cohort. CLD and cirrhosis cases were identified using Medicare claims between 1999 and 2012 among the fee-for-service participants (n = 106,458). We used International Classification of Diseases Ninth Revision codes, body mass index, history of diabetes mellitus, and alcohol consumption from questionnaires to identify underlying etiologies. A total of 5,783 CLD (3,575 CLD without cirrhosis and 2,208 cirrhosis) cases were identified. The prevalence of CLD ranged from 3.9% in African Americans and Native Hawaiians to 4.1% in whites, 6.7% in Latinos, and 6.9% in Japanese. Nonalcoholic fatty liver disease (NAFLD) was the most common cause of CLD in all ethnic groups combined (52%), followed by alcoholic liver disease (21%). NAFLD was the most common cause of cirrhosis in the entire cohort. By ethnicity, NAFLD was the most common cause of cirrhosis in Japanese Americans, Native Hawaiians, and Latinos, accounting for 32% of cases. Alcoholic liver disease was the most common cause of cirrhosis in whites (38.2%), while hepatitis C virus was the most common cause in African Americans (29.8%). CONCLUSIONS We showed racial/ethnic variations in the prevalence of CLD and cirrhosis by underlying etiology; NAFLD was the most common cause of CLD and cirrhosis in the entire cohort, and the high prevalence of NAFLD among Japanese Americans and Native Hawaiians is a novel finding, warranting further studies to elucidate the causes. (Hepatology 2016;64:1969-1977).
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Affiliation(s)
- Veronica Wendy Setiawan
- Department of Preventive Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA,Norris Comprehensive Cancer Center, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA
| | - Daniel O. Stram
- Department of Preventive Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA
| | - Jacqueline Porcel
- Norris Comprehensive Cancer Center, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA
| | - Shelly C. Lu
- Fatty Liver Program, Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Loїc Le Marchand
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Mazen Noureddin
- Fatty Liver Program, Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA,Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Sherif ZA, Saeed A, Ghavimi S, Nouraie SM, Laiyemo AO, Brim H, Ashktorab H. Global Epidemiology of Nonalcoholic Fatty Liver Disease and Perspectives on US Minority Populations. Dig Dis Sci 2016; 61:1214-1225. [PMID: 27038448 PMCID: PMC4838529 DOI: 10.1007/s10620-016-4143-0;] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 03/21/2016] [Indexed: 08/28/2024]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome predicted to be the next global epidemic affecting millions of people worldwide. The natural course of this disease including its subtype, non-alcoholic steatohepatitis (NASH), is not clearly defined especially in the African-American segment of the US population. AIMS To conduct a review of the global epidemiology of NAFLD with emphasis on US minority populations. METHODS A thorough search of evidence-based literature was conducted using the Pubmed database and commercial web sources such as Medscape and Google Scholar. RESULTS NAFLD and its subtype NASH are becoming the principal cause of chronic liver disease across the world. In the US, Hispanics are the most disproportionately affected ethnic group with hepatic steatosis, and elevated aminotransferase levels, whereas African-Americans are the least affected. Genetic disparities involved in lipid metabolism seem to be the leading explanation for the lowest incidence and prevalence of both NAFLD and NASH in African-Americans. CONCLUSIONS The unprecedented rise in the prevalence of NAFLD globally requires an initiation of population cohort studies with long-term follow-up to determine the incidence and natural history of NAFLD and its underrepresentation in African-Americans. Future studies should also focus on the delineation of the interplay between genetic and environmental factors that trigger the development of NAFLD and NASH.
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Affiliation(s)
- Zaki A Sherif
- Department of Biochemistry and Molecular Biology, Howard University, 520 W Street NW, Washington, DC, 20059, USA.
- College of Medicine, Howard University, Washington, DC, USA.
| | - Armana Saeed
- Cancer Center, Howard University, Washington, DC, USA
| | - Shima Ghavimi
- Department of Medicine, Howard University, Washington, DC, USA
- Howard University Hospital, Howard University, Washington, DC, USA
| | - Seyed-Mehdi Nouraie
- Department of Medicine, Howard University, Washington, DC, USA
- Howard University Hospital, Howard University, Washington, DC, USA
| | - Adeyinka O Laiyemo
- Department of Medicine, Howard University, Washington, DC, USA
- Division of Gastroenterology, Howard University, Washington, DC, USA
- Howard University Hospital, Howard University, Washington, DC, USA
| | - Hassan Brim
- Department of Pathology, Howard University, Washington, DC, USA
- Cancer Center, Howard University, Washington, DC, USA
- College of Medicine, Howard University, Washington, DC, USA
| | - Hassan Ashktorab
- Department of Medicine, Howard University, Washington, DC, USA
- Cancer Center, Howard University, Washington, DC, USA
- Howard University Hospital, Howard University, Washington, DC, USA
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40
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Kalia HS, Gaglio PJ. The Prevalence and Pathobiology of Nonalcoholic Fatty Liver Disease in Patients of Different Races or Ethnicities. Clin Liver Dis 2016; 20:215-24. [PMID: 27063265 DOI: 10.1016/j.cld.2015.10.005] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is emerging as the most common cause of liver disease in the United States. The prevalence varies dramatically when comparing individuals of different races and ethnicities. Rates are highest in Hispanic patient populations compared with non-Hispanic whites and African Americans, despite similar rates of the metabolic syndrome and risk factors. This observation remains poorly characterized; variations in genes that effect lipid metabolism may play a role. This article describes the prevalence of NAFLD in patients of different races or ethnicities, and discusses pathophysiologic mechanisms that may explain why these differences exist.
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Affiliation(s)
- Harmit S Kalia
- Department of Medicine, Montefiore Einstein Liver Center, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th Street, Rosenthal 2 Red Zone, Bronx, NY 10467, USA
| | - Paul J Gaglio
- Center for Liver Disease and Transplantation, Columbia University Medical Center, PH-14, 622 West 168th Street, New York, NY 10032, USA.
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Sherif ZA, Saeed A, Ghavimi S, Nouraie SM, Laiyemo AO, Brim H, Ashktorab H. Global Epidemiology of Nonalcoholic Fatty Liver Disease and Perspectives on US Minority Populations. Dig Dis Sci 2016; 61:1214-25. [PMID: 27038448 PMCID: PMC4838529 DOI: 10.1007/s10620-016-4143-0] [Citation(s) in RCA: 126] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 03/21/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome predicted to be the next global epidemic affecting millions of people worldwide. The natural course of this disease including its subtype, non-alcoholic steatohepatitis (NASH), is not clearly defined especially in the African-American segment of the US population. AIMS To conduct a review of the global epidemiology of NAFLD with emphasis on US minority populations. METHODS A thorough search of evidence-based literature was conducted using the Pubmed database and commercial web sources such as Medscape and Google Scholar. RESULTS NAFLD and its subtype NASH are becoming the principal cause of chronic liver disease across the world. In the US, Hispanics are the most disproportionately affected ethnic group with hepatic steatosis, and elevated aminotransferase levels, whereas African-Americans are the least affected. Genetic disparities involved in lipid metabolism seem to be the leading explanation for the lowest incidence and prevalence of both NAFLD and NASH in African-Americans. CONCLUSIONS The unprecedented rise in the prevalence of NAFLD globally requires an initiation of population cohort studies with long-term follow-up to determine the incidence and natural history of NAFLD and its underrepresentation in African-Americans. Future studies should also focus on the delineation of the interplay between genetic and environmental factors that trigger the development of NAFLD and NASH.
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Affiliation(s)
- Zaki A Sherif
- Department of Biochemistry and Molecular Biology, Howard University, 520 W Street NW, Washington, DC, 20059, USA.
- College of Medicine, Howard University, Washington, DC, USA.
| | - Armana Saeed
- Cancer Center, Howard University, Washington, DC, USA
| | - Shima Ghavimi
- Department of Medicine, Howard University, Washington, DC, USA
- Howard University Hospital, Howard University, Washington, DC, USA
| | - Seyed-Mehdi Nouraie
- Department of Medicine, Howard University, Washington, DC, USA
- Howard University Hospital, Howard University, Washington, DC, USA
| | - Adeyinka O Laiyemo
- Department of Medicine, Howard University, Washington, DC, USA
- Division of Gastroenterology, Howard University, Washington, DC, USA
- Howard University Hospital, Howard University, Washington, DC, USA
| | - Hassan Brim
- Department of Pathology, Howard University, Washington, DC, USA
- Cancer Center, Howard University, Washington, DC, USA
- College of Medicine, Howard University, Washington, DC, USA
| | - Hassan Ashktorab
- Department of Medicine, Howard University, Washington, DC, USA
- Cancer Center, Howard University, Washington, DC, USA
- Howard University Hospital, Howard University, Washington, DC, USA
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Setiawan VW, Lim U, Lipworth L, Lu SC, Shepherd J, Ernst T, Wilkens LR, Henderson BE, Le Marchand L. Sex and Ethnic Differences in the Association of Obesity With Risk of Hepatocellular Carcinoma. Clin Gastroenterol Hepatol 2016; 14:309-16. [PMID: 26404865 PMCID: PMC4718778 DOI: 10.1016/j.cgh.2015.09.015] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 09/04/2015] [Accepted: 09/08/2015] [Indexed: 01/09/2023]
Abstract
BACKGROUND & AIMS Obesity is associated with increased risk for hepatocellular carcinoma (HCC), but the risk associated with obesity may vary by sex or ethnicity. We examined whether the association of body mass index (BMI) with HCC incidence, as well as correlations of BMI with total, visceral, and hepatic adiposity, differs among ethnic groups. METHODS We collected data from the Multiethnic Cohort Study, a population-based prospective cohort study of more than 215,000 men and women from Hawaii and California that was assembled from 1993 through 1996. After a median follow-up of 16.6 years, 482 incident HCC cases were identified among 168,476 participants. BMI and risk factor data were obtained from a baseline questionnaire. Cox regression analyses were used to calculate hazard ratios (HRs) and confidence intervals (CIs) for HCC associated with BMI. The black subjects in the Southern Community Cohort Study were included as a replication cohort. RESULTS BMI was associated with HCC in men (HR per 5 kg/m(2) increase, 1.26; 95% CI, 1.12-1.42) but not in women (HR, 1.06; 95% CI, 0.90-1.25) (P(interaction) = .009). Although BMI was strongly associated with HCC in Japanese, white, and Latino men, there was no association in black men (P(interaction) = .002). Similarly, no association was found in the blacks who participated in the Southern Community Cohort Study. BMI correlated with total fat mass, measured by dual-energy x-ray absorptiometry, in men and women and in all ethnic groups (R ≥ 0.9). However, there was a lower correlation value for BMI and visceral or liver fat measured by abdominal magnetic resonance imaging in black men (R < 0.5) and in women (R < 0.8). CONCLUSIONS On the basis of an analysis of data from the Multiethnic Cohort Study, the association between BMI and HCC differs between sexes and among ethnicities. The lack of association in black men warrants further investigation. Rather than studying markers of total adiposity, studies of obesity and HCC should move beyond BMI and use a better measure for fat-specific depots.
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Affiliation(s)
- Veronica Wendy Setiawan
- Department of Preventive Medicine, University of Southern California, Los Angeles, California; Norris Comprehensive Cancer Center, Los Angeles, California.
| | - Unhee Lim
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii
| | - Loren Lipworth
- Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Shelly C Lu
- Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - John Shepherd
- Department of Radiology, University of California San Francisco, San Francisco, California
| | - Thomas Ernst
- Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii
| | - Lynne R Wilkens
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii
| | - Brian E Henderson
- Department of Preventive Medicine, University of Southern California, Los Angeles, California; Norris Comprehensive Cancer Center, Los Angeles, California
| | - Loïc Le Marchand
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii
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Liu X, Henkel AS, LeCuyer BE, Schipma MJ, Anderson KA, Green RM. Hepatocyte X-box binding protein 1 deficiency increases liver injury in mice fed a high-fat/sugar diet. Am J Physiol Gastrointest Liver Physiol 2015; 309:G965-74. [PMID: 26472223 PMCID: PMC4683298 DOI: 10.1152/ajpgi.00132.2015] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 10/08/2015] [Indexed: 01/31/2023]
Abstract
Fatty liver is associated with endoplasmic reticulum stress and activation of the hepatic unfolded protein response (UPR). Reduced hepatic expression of the UPR regulator X-box binding protein 1 spliced (XBP1s) is associated with human nonalcoholic steatohepatitis (NASH), and feeding mice a high-fat diet with fructose/sucrose causes progressive, fibrosing steatohepatitis. This study examines the role of XBP1 in nonalcoholic fatty liver injury and fatty acid-induced cell injury. Hepatocyte-specific Xbp1-deficient (Xbp1(-/-)) mice were fed a high-fat/sugar (HFS) diet for up to 16 wk. HFS-fed Xbp1(-/-) mice exhibited higher serum alanine aminotransferase levels compared with Xbp1(fl/fl) controls. RNA sequencing and Gene Ontogeny pathway analysis of hepatic mRNA revealed that apoptotic process, inflammatory response, and extracellular matrix structural constituent pathways had enhanced activation in HFS-fed Xbp1(-/-) mice. Liver histology demonstrated enhanced injury and fibrosis but less steatosis in the HFS-fed Xbp1(-/-) mice. Hepatic Col1a1 and Tgfβ1 gene expression, as well as Chop and phosphorylated JNK (p-JNK), were increased in Xbp1(-/-) compared with Xbp1(fl/fl) mice after HFS feeding. In vitro, stable XBP1-knockdown Huh7 cells (Huh7-KD) and scramble control cells (Huh7-SCR) were generated and treated with palmitic acid (PA) for 24 h. PA-treated Huh7-KD cells had increased cytotoxicity measured by lactate dehydrogenase release, apoptotic nuclei, and caspase3/7 activity assays compared with Huh7-SCR cells. CHOP and p-JNK expression was also increased in Huh7-KD cells following PA treatment. In conclusion, loss of XBP1 enhances injury in both in vivo and in vitro models of fatty liver injury. We speculate that hepatic XBP1 plays an important protective role in pathogenesis of NASH.
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Affiliation(s)
- Xiaoying Liu
- Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and
| | - Anne S. Henkel
- 1Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and
| | - Brian E. LeCuyer
- 1Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and
| | - Matthew J. Schipma
- 2Next Generation Sequencing Core: Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Kristy A. Anderson
- 1Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and
| | - Richard M. Green
- 1Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and
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Loomba R, Schork N, Chen CH, Bettencourt R, Bhatt A, Ang B, Nguyen P, Hernandez C, Richards L, Salotti J, Lin S, Seki E, Nelson KE, Sirlin CB, Brenner D. Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin Study. Gastroenterology 2015; 149:1784-93. [PMID: 26299412 PMCID: PMC4663110 DOI: 10.1053/j.gastro.2015.08.011] [Citation(s) in RCA: 293] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 08/05/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Little is known about the heritability of hepatic fibrosis, and the heritability of hepatic steatosis has not been assessed systematically in adults. We investigated the heritability of hepatic fibrosis and steatosis in a community-dwelling twin cohort. METHODS We performed a cross-sectional analysis of a cohort of well-characterized twins residing in Southern California including 60 pairs of twins (42 monozygotic and 18 dizygotic; average age, 45.7 ± 22.1 y; average body mass index, 26.4 ± 5.7 kg/m(2)). We collected data on medical history, physical examinations, fasting laboratory test results, and liver health; all participants underwent an advanced magnetic resonance imaging (MRI) examination of the liver from January 2012 through January 2015. Hepatic steatosis was quantified noninvasively by MRI and determined based on the proton-density fat fraction (MRI-PDFF); liver fibrosis was measured based on stiffness measured by magnetic resonance elastography. RESULTS Twenty-six of the 120 subjects (21.7%) had nonalcoholic fatty liver disease (defined as MRI-PDFF ≥ 5% after exclusion of other causes of hepatic steatosis). The presence of hepatic steatosis correlated between monozygotic twins (r(2) = 0.70; P < .0001) but not between dizygotic twins (r(2) = 0.36; P = .2). The level of liver fibrosis also correlated between monozygotic twins (r(2) = 0.48; P < .002) but not between dizygotic twins (r(2) = 0.12; P = .7). In multivariable models adjusted for age, sex, and ethnicity, the heritability of hepatic steatosis (based on MRI-PDFF) was 0.52 (95% confidence interval, 0.31-0.73; P < 1.1 × 10(-11)) and the heritability of hepatic fibrosis (based on liver stiffness) was 0.5 (95% confidence interval, 0.28-0.72; P <6.1 × 10(-11)). CONCLUSIONS A study of twins provides evidence that hepatic steatosis and hepatic fibrosis are heritable traits.
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Affiliation(s)
- Rohit Loomba
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, California; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California; Division of Epidemiology, Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, California.
| | - Nicholas Schork
- Human Biology, J. Craig Venter Institute, La Jolla, CA 92037
| | - Chi-Hua Chen
- Department of Radiology, University of California, San Diego, La Jolla, CA 92093
| | - Ricki Bettencourt
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA 92093
| | - Ana Bhatt
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA 92093
| | - Brandon Ang
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA 92093
| | - Phirum Nguyen
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA 92093
| | - Carolyn Hernandez
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA 92093
| | - Lisa Richards
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA 92093
| | - Joanie Salotti
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA 92093
| | - Steven Lin
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA 92093
| | - Ekihiro Seki
- Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093
| | - Karen E Nelson
- Human Biology, J. Craig Venter Institute, La Jolla, CA 92037
| | - Claude B Sirlin
- Liver Imaging Group, University of California, San Diego, La Jolla, CA 92093
| | - David Brenner
- Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093
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Kahali B, Halligan B, Speliotes EK. Insights from Genome-Wide Association Analyses of Nonalcoholic Fatty Liver Disease. Semin Liver Dis 2015; 35:375-91. [PMID: 26676813 PMCID: PMC4941959 DOI: 10.1055/s-0035-1567870] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis, which can progress to nonalcoholic steatohepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma in the absence of excessive alcohol consumption. Nonalcoholic fatty liver disease will become the number one cause of liver disease worldwide by 2020. Nonalcoholic fatty liver disease is correlated albeit imperfectly with obesity and other metabolic diseases such as diabetes, hyperlipidemia, and cardiovascular disease, but exactly how having one of these diseases contributes to the development of other metabolic diseases is only now being elucidated. Development of NAFLD and related metabolic diseases is genetically influenced in the population, and recent genome-wide association studies (GWASs) have discovered genetic variants that associate with these diseases. These GWAS-associated variants cannot only help us to identify individuals at high risk of developing NAFLD, but also to better understand its pathophysiology so that we can develop more effective treatments for this disease and related metabolic diseases in the future.
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Affiliation(s)
- Bratati Kahali
- Division of Gastroenterology, Department of Internal Medicine, Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | - Brian Halligan
- Division of Gastroenterology, Department of Internal Medicine, Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | - Elizabeth K. Speliotes
- Division of Gastroenterology, Department of Internal Medicine, Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
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Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a growing health issue around the world. AIM This study is to investigate whether adult prevalence of NAFLD correlates with national economic status. METHODS Literature search on PubMed database was conducted to identify eligible records fully published before September 2014. Gross national income (GNI) per capita was chosen to evaluate national economic status. Pearson coefficient, linear regression, and unpaired t test were performed in the statistical analyses. RESULTS Twenty-one population-based surveys (seven in East Asia, five in South Asia, three in Middle East, and six in Europe) were included. The pooled prevalence of NAFLD was 24.24%, and the global prevalence was positively correlated with GNI per capita (r = 0.4782, P = 0.0283). Europe witnessed a higher prevalence (28.04%) than Middle East (12.95%, P = 0.0092) and East Asia (19.24%, P = 0.0083). Male presented a higher prevalence than female (P = 0.019), especially in Europe (P = 0.0132) and in Caucasians (P = 0.0383). Furthermore, male prevalence and rural prevalence individually were correlated with economic status (r = 0.5725, P = 0.0257 and r = 0.7389, P = 0.0060). Lastly, the urban (23.93%) witnessed a higher prevalence than the rural or the urban + rural (12.65%, P = 0.0141) in the countries of GNI per capita <$10,000. CONCLUSIONS This study suggested that countries with higher economic status tend to present a higher prevalence of NAFLD. It is believed to provide a distinctive epidemiologic perspective to global situation of NAFLD.
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Edelman D, Kalia H, Delio M, Alani M, Krishnamurthy K, Abd M, Auton A, Wang T, Wolkoff AW, Morrow BE. Genetic analysis of nonalcoholic fatty liver disease within a Caribbean-Hispanic population. Mol Genet Genomic Med 2015; 3:558-69. [PMID: 26740948 PMCID: PMC4694126 DOI: 10.1002/mgg3.168] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 07/07/2015] [Accepted: 07/09/2015] [Indexed: 12/18/2022] Open
Abstract
We explored potential genetic risk factors implicated in nonalcoholic fatty liver disease (NAFLD) within a Caribbean–Hispanic population in New York City. A total of 316 individuals including 40 subjects with biopsy‐proven NAFLD, 24 ethnically matched non‐NAFLD controls, and a 252 ethnically mixed random sampling of Bronx County, New York were analyzed. Genotype analysis was performed to determine allelic frequencies of 74 known single‐nucleotide polymorphisms (SNPs) associated with NAFLD risk based on previous genome‐wide association study (GWAS) and candidate gene studies. Additionally, the entire coding region of PNPLA3, a gene showing the strongest association to NAFLD was subjected to Sanger sequencing. Results suggest that both rare and common DNA variations in PNPLA3 and SAMM50 may be correlated with NAFLD in this small population study, while common DNA variations in CHUK and ERLIN1, may have a protective interaction. Common SNPs in ENPP1 and ABCC2 have suggestive association with fatty liver, but with less compelling significance. In conclusion, Hispanic patients of Caribbean ancestry may have different interactions with NAFLD genetic modifiers; therefore, further investigation with a larger sample size, into this Caribbean–Hispanic population is warranted.
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Affiliation(s)
- Deborah Edelman
- Department of GeneticsAlbert Einstein College of Medicine1301 Morris Park Ave.BronxNew York10461
| | - Harmit Kalia
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
| | - Maria Delio
- Department of GeneticsAlbert Einstein College of Medicine1301 Morris Park Ave.BronxNew York10461
- Marion Bessin Liver Research CenterAlbert Einstein College of MedicineBronxNew York10461
| | - Mustafa Alani
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
| | - Karthik Krishnamurthy
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
| | - Mortadha Abd
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
| | - Adam Auton
- Department of GeneticsAlbert Einstein College of Medicine1301 Morris Park Ave.BronxNew York10461
| | - Tao Wang
- Department of Epidemiology & Population HealthAlbert Einstein College of MedicineBronxNew York10461
| | - Allan W. Wolkoff
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
- Marion Bessin Liver Research CenterAlbert Einstein College of MedicineBronxNew York10461
- Department of Anatomy and Structural BiologyAlbert Einstein College of MedicineBronxNew York10461
| | - Bernice E. Morrow
- Department of GeneticsAlbert Einstein College of Medicine1301 Morris Park Ave.BronxNew York10461
- Department of Anatomy and Structural BiologyAlbert Einstein College of MedicineBronxNew York10461
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Abstract
Nonalcoholic fatty liver disease is a common cause of chronic liver disease and has been an increasingly studied topic of research as the obesity epidemic has been growing. There is a significant morbidity and mortality with uncontrolled steatohepatitis, which can progress to fibrosis, cirrhosis and hepatocellular carcinoma. The prevalence of this disease has been estimated to be roughly one-third of the western population, thought to be largely due to diet and sedentary lifestyle. Several treatments have been studied including vitamin E, insulin-sensitizing agents and ursodeoxycholic acid; however, the only treatment shown to improve the histologic changes of nonalcoholic fatty liver disease is weight loss. Given the proven benefit of weight loss, there may be reason to screen at-risk populations; however, limited availability of other disease-modifying treatments may limit the cost-benefit ratios. A better understanding of the diagnosis and management of this condition is required to alter the course of this modifiable disease.
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Affiliation(s)
- Amanda Tamar Schneier
- Department of Liver Diseases, Icahn School of Medicine at Mount Sinai,1 Gustave Levy Place, New York, NY 10029, USA
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Abstract
This article discusses common liver diseases in the adolescent. Briefly reviewed is the evaluation of the adolescent with new-onset liver enzyme elevation. Then the article discusses common liver diseases, such as nonalcoholic fatty liver disease, hepatitis, metabolic disease, biliary atresia, cystic fibrosis, and inherited disorders of cholestasis. Finally, a management approach to the adolescent with liver disease is outlined, noting the challenges that must be addressed to effectively care for not only liver disease in the adolescent but also the patient as a whole.
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Affiliation(s)
- Alisha M Mavis
- Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Siragusa Transplantation Center, Ann & Robert H. Lurie Children's Hospital, 225 East Chicago Avenue, Chicago, IL 60611, USA
| | - Estella M Alonso
- Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Siragusa Transplantation Center, Ann & Robert H. Lurie Children's Hospital, 225 East Chicago Avenue, Chicago, IL 60611, USA.
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Vodkin I, Valasek MA, Bettencourt R, Cachay E, Loomba R. Clinical, biochemical and histological differences between HIV-associated NAFLD and primary NAFLD: a case-control study. Aliment Pharmacol Ther 2015; 41:368-78. [PMID: 25496369 DOI: 10.1111/apt.13052] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Revised: 11/18/2014] [Accepted: 11/24/2014] [Indexed: 01/14/2023]
Abstract
BACKGROUND There are limited data regarding the clinical, biochemical and liver histological characteristics of patients with HIV-associated nonalcoholic fatty liver disease (NAFLD), and whether this entity differs in presentation and severity from primary NAFLD AIM: To examine the clinical and histological differences between HIV-associated NAFLD and primary NAFLD. METHODS This is a cross-sectional, case-control study comparing patients with HIV-associated NAFLD vs. patients with primary NAFLD. HIV-infected patients were identified from a database of consecutive liver biopsies performed at the University of California at San Diego, over a 13-year period. HIV-infected patients with biopsy-proven NAFLD were selected as cases, after exclusion of other causes of liver disease and hepatic steatosis. Age-sex-matched controls with biopsy-proven primary NAFLD were randomly identified from the same pathology database. All biopsies underwent a standardised, detailed, histological research evaluation by a liver pathologist who was blinded to clinical and case-control status. RESULTS Compared to age-sex-matched patients with primary NAFLD (n = 33), patients with HIV-associated NAFLD (n = 33) had significantly higher mean aspartate aminotransferase (P < 0.001), alanine aminotransferase (P < 0.001), alkaline phosphatase (P = 0.003) and serum triglycerides (P = 0.024). Similarly, compared to age-sex-matched primary NAFLD, patients with HIV-associated NAFLD had significantly higher rates of definite steatohepatitis (37% vs. 63%, P = 0.04), and more features of liver injury, including lobular inflammation (<0.001) and acidophil bodies (<0.001). CONCLUSION Compared to age-sex-matched primary NAFLD, HIV-associated NAFLD has increased severity of liver disease and a higher prevalence of NASH.
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Affiliation(s)
- I Vodkin
- Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA
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