Epidemiological modifiers of non-alcoholic fatty liver disease: Focus on high-risk groups

Digestive and Liver Disease - Tập 47 Số 12 - Trang 997-1006 - 2015
Amedeo Lonardo1, Stefano Bellentani2,1, Curtis K. Argo3, Stefano Ballestri4, Christopher D. Byrne5, Stephen H. Caldwell3, Helena Cortez‐Pinto6, Antonio Grieco7, Mariana Verdelho Machado6, Luca Miele7, Giovanni Targher8
1Internal Medicine and Outpatient Liver Clinic, NOCSAE Baggiovara, Azienda USL di Modena, Modena, Italy
2Department of Gastroenterology and Endoscopy, NOCSE Baggiovara, Azienda USL di Modena Modena, Italy
3UNIVERSITY OF VIRGINIA, Charlottesville, VA USA
4Internal Medicine Pavullo Hospital, Azienda USL di Modena, Modena, Italy
5Nutrition and Metabolism, University of Southampton, Southampton National Institute for Health Research Biomedical Research Centre, Southampton, UK
6Department of Gastroenterology, University Hospital of Santa Maria, Faculty of Medicine, Lisbon, Portugal
7Institute of Internal Medicine, Catholic University of Rome, Rome, Italy
8Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy

Tóm tắt

Từ khóa


Tài liệu tham khảo

Scaglioni, 2011, ASH and NASH, Digestive Diseases, 29, 202, 10.1159/000323886

Chalasani, 2012, The diagnosis and management of nonalcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association, Hepatology, 55, 2005, 10.1002/hep.25762

Targher, 2009, Nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome, Seminars in Thrombosis and Hemostasis, 35, 277, 10.1055/s-0029-1222606

Anstee, 2013, Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis, Nature Reviews Gastroenterology & Hepatology, 10, 330, 10.1038/nrgastro.2013.41

Machado, 2014, Management of fatty liver disease with the metabolic syndrome, Expert Review of Gastroenterology & Hepatology, 8, 487, 10.1586/17474124.2014.903798

Lonardo, 2015, Nonalcoholic fatty liver disease: a precursor of the metabolic syndrome, Digestive and Liver Disease, 47, 181, 10.1016/j.dld.2014.09.020

Lonardo, 2013, Cardiovascular and systemic risk in nonalcoholic fatty liver disease – atherosclerosis as a major player in the natural course of NAFLD, Current Pharmaceutical Design, 19, 5177, 10.2174/1381612811319290003

Byrne, 2014, Ectopic fat, insulin resistance, and nonalcoholic fatty liver disease: implications for cardiovascular disease, Arteriosclerosis, Thrombosis, and Vascular Biology, 34, 1155, 10.1161/ATVBAHA.114.303034

Baumeister, 2008, Impact of fatty liver disease on health care utilization and costs in a general population: a 5-year observation, Gastroenterology, 134, 85, 10.1053/j.gastro.2007.10.024

Argo, 2009, Epidemiology and natural history of non-alcoholic steatohepatitis, Clinics in Liver Disease, 13, 511, 10.1016/j.cld.2009.07.005

Musso, 2011, Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity, Annals of Medicine, 43, 617, 10.3109/07853890.2010.518623

Nascimbeni, 2013, From NAFLD in clinical practice to answers from guidelines, Journal of Hepatology, 59, 859, 10.1016/j.jhep.2013.05.044

Lonardo, 1999, Fatty liver and nonalcoholic steatohepatitis. Where do we stand and where are we going?, Digestive Diseases, 17, 80, 10.1159/000016909

Machado, 2014, Non-alcoholic fatty liver disease: what the clinician needs to know, World Journal of Gastroenterology, 20, 12956, 10.3748/wjg.v20.i36.12956

Loria, 2010, Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee, Digestive and Liver Disease, 42, 272, 10.1016/j.dld.2010.01.021

Fan, 2005, Prevalence of and risk factors for fatty liver in a general population of Shanghai, China, Journal of Hepatology, 43, 508, 10.1016/j.jhep.2005.02.042

Lonardo, 2006, Fatty liver, carotid disease and gallstones: a study of age-related associations, World Journal of Gastroenterology, 12, 5826, 10.3748/wjg.v12.i36.5826

Hu, 2012, Prevalence and factors associated with nonalcoholic fatty liver disease in Shanghai work-units, BMC Gastroenterology, 12, 123, 10.1186/1471-230X-12-123

Eguchi, 2012, Prevalence and associated metabolic factors of nonalcoholic fatty liver disease in the general population from 2009 to 2010 in Japan: a multicenter large retrospective study, Journal of Gastroenterology, 47, 586, 10.1007/s00535-012-0533-z

Wang, 2014, Sex-specific prevalence of fatty liver disease and associated metabolic factors in Wuhan, south central China, European Journal of Gastroenterology and Hepatology, 26, 1015, 10.1097/MEG.0000000000000151

Lee, 2007, Prevalence and risk factors of non-alcoholic fatty liver disease in potential living liver donors in Korea: a review of 589 consecutive liver biopsies in a single center, Journal of Hepatology, 47, 239, 10.1016/j.jhep.2007.02.007

Zhou, 2007, Prevalence of fatty liver disease and its risk factors in the population of South China, World Journal of Gastroenterology, 13, 6419, 10.3748/wjg.v13.i47.6419

Caballeria, 2010, Prevalence and factors associated with the presence of nonalcoholic fatty liver disease in an adult population in Spain, European Journal of Gastroenterology and Hepatology, 22, 24, 10.1097/MEG.0b013e32832fcdf0

Shen, 2003, Prevalence of nonalcoholic fatty liver among administrative officers in Shanghai: an epidemiological survey, World Journal of Gastroenterology, 9, 1106, 10.3748/wjg.v9.i5.1106

Zelber-Sagi, 2006, Prevalence of primary non-alcoholic fatty liver disease in a population-based study and its association with biochemical and anthropometric measures, Liver International, 26, 856, 10.1111/j.1478-3231.2006.01311.x

Wong, 2012, Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in Hong Kong Chinese: a population study using proton-magnetic resonance spectroscopy and transient elastography, Gut, 61, 409, 10.1136/gutjnl-2011-300342

Chen, 2006, Prevalence and risk factors of nonalcoholic fatty liver disease in an adult population of Taiwan: metabolic significance of nonalcoholic fatty liver disease in nonobese adults, Journal of Clinical Gastroenterology, 40, 745, 10.1097/00004836-200609000-00016

Foster, 2013, The prevalence and clinical correlates of nonalcoholic fatty liver disease (NAFLD) in African Americans: the multiethnic study of atherosclerosis (MESA), Digestive Diseases and Sciences, 58, 2392, 10.1007/s10620-013-2652-7

Xu, 2013, Prevalence and risk factors for the development of nonalcoholic fatty liver disease in a nonobese Chinese population: the Zhejiang Zhenhai Study, American Journal of Gastroenterology, 108, 1299, 10.1038/ajg.2013.104

Yang, 2014, High red blood cell distribution width is closely associated with nonalcoholic fatty liver disease, European Journal of Gastroenterology and Hepatology, 26, 174, 10.1097/MEG.0b013e328365c403

Park, 2006, Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults, Journal of Gastroenterology and Hepatology, 21, 138, 10.1111/j.1440-1746.2005.04086.x

Wang, 2013, Prevalence and associated metabolic factors of fatty liver disease in the elderly, Experimental Gerontology, 48, 705, 10.1016/j.exger.2013.05.059

Koehler, 2012, Prevalence and risk factors of non-alcoholic fatty liver disease in the elderly: results from the Rotterdam study, Journal of Hepatology, 57, 1305, 10.1016/j.jhep.2012.07.028

Younossi, 2012, Nonalcoholic fatty liver disease in lean individuals in the United States, Medicine, 91, 319, 10.1097/MD.0b013e3182779d49

Frith, 2009, Non-alcoholic fatty liver disease in older people, Gerontology, 55, 607, 10.1159/000235677

Noureddin, 2013, Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients, Hepatology, 58, 1644, 10.1002/hep.26465

Singh, 2008, Independent predictors of steatohepatitis and fibrosis in Asian Indian patients with non-alcoholic steatohepatitis, Digestive Diseases and Sciences, 53, 1967, 10.1007/s10620-007-0074-0

Bambha, 2012, Ethnicity and nonalcoholic fatty liver disease, Hepatology, 55, 769, 10.1002/hep.24726

Tapper, 2014, Simple non-invasive biomarkers of advanced fibrosis in the evaluation of non-alcoholic fatty liver disease, Gastroenterology Reports, 2, 276, 10.1093/gastro/gou034

Hossain, 2009, Independent predictors of fibrosis in patients with nonalcoholic fatty liver disease, Clinical Gastroenterology and Hepatology, 7, 1224, 10.1016/j.cgh.2009.06.007

Argo, 2009, Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis, Journal of Hepatology, 51, 371, 10.1016/j.jhep.2009.03.019

Yang, 2014, Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis, Hepatology, 59, 1406, 10.1002/hep.26761

Bertolotti, 2014, Nonalcoholic fatty liver disease and aging: epidemiology to management, World Journal of Gastroenterology, 20, 14185, 10.3748/wjg.v20.i39.14185

Adams, 2005, The natural history of nonalcoholic fatty liver disease: a population-based cohort study, Gastroenterology, 129, 113, 10.1053/j.gastro.2005.04.014

Ong, 2008, Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease, Journal of Hepatology, 49, 608, 10.1016/j.jhep.2008.06.018

Rafiq, 2009, Long-term follow-up of patients with nonalcoholic fatty liver, Clinical Gastroenterology and Hepatology, 7, 234, 10.1016/j.cgh.2008.11.005

Stepanova, 2013, Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD), Digestive Diseases and Sciences, 58, 3017, 10.1007/s10620-013-2743-5

Bedogni, 2007, Incidence and natural course of fatty liver in the general population: the Dionysos study, Hepatology, 46, 1387, 10.1002/hep.21827

Haring, 2009, Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl transpeptidase levels, Hepatology, 50, 1403, 10.1002/hep.23135

Browning, 2004, Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity, Hepatology, 40, 1387, 10.1002/hep.20466

Weston, 2005, Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease, Hepatology, 41, 372, 10.1002/hep.20554

Lazo, 2013, Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988–1994, American Journal of Epidemiology, 178, 38, 10.1093/aje/kws448

Tota-Maharaj, 2014, Ethnic and sex differences in fatty liver on cardiac computed tomography: the multi-ethnic study of atherosclerosis, Mayo Clinic Proceedings, 89, 493, 10.1016/j.mayocp.2013.12.015

Kallwitz, 2009, The histologic spectrum of liver disease in African-American, non-Hispanic white, and Hispanic obesity surgery patients, American Journal of Gastroenterology, 104, 64, 10.1038/ajg.2008.12

Dongiovanni, 2013, Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment, Current Pharmaceutical Design, 19, 5219, 10.2174/13816128113199990381

Struben, 2000, Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds, American Journal of Medicine, 108, 9, 10.1016/S0002-9343(99)00315-0

Willner, 2001, Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease, American Journal of Gastroenterology, 96, 2957, 10.1111/j.1572-0241.2001.04667.x

Tokushige, 2008, Familial aggregation in patients with non-alcoholic steatohepatitis, Internal Medicine, 47, 405, 10.2169/internalmedicine.47.0476

Brouwers, 2006, Heritability and genetic loci of fatty liver in familial combined hyperlipidemia, Journal of Lipid Research, 47, 2799, 10.1194/jlr.M600312-JLR200

Abdelmalek, 2006, Familial aggregation of insulin resistance in first-degree relatives of patients with nonalcoholic fatty liver disease, Clinical Gastroenterology and Hepatology, 4, 1162, 10.1016/j.cgh.2006.06.001

Schwimmer, 2009, Heritability of nonalcoholic fatty liver disease, Gastroenterology, 136, 1585, 10.1053/j.gastro.2009.01.050

Bathum, 2001, Evidence for a substantial genetic influence on biochemical liver function tests: results from a population-based Danish twin study, Clinical Chemistry, 47, 81, 10.1093/clinchem/47.1.81

Makkonen, 2009, Genetic factors contribute to variation in serum alanine aminotransferase activity independent of obesity and alcohol: a study in monozygotic and dizygotic twins, Journal of Hepatology, 50, 1035, 10.1016/j.jhep.2008.12.025

Loomba, 2010, Genetic covariance between gamma-glutamyl transpeptidase and fatty liver risk factors: role of beta2-adrenergic receptor genetic variation in twins, Gastroenterology, 139, 836, 10.1053/j.gastro.2010.06.009

Jermendy, 2011, Effect of genetic and environmental influences on cardiometabolic risk factors: a twin study, Cardiovascular Diabetology, 10, 96, 10.1186/1475-2840-10-96

Tarnoki, 2012, Heritability of non-alcoholic fatty liver disease and association with abnormal vascular parameters: a twin study, Liver International, 32, 1287, 10.1111/j.1478-3231.2012.02823.x

Zarrinpar, 2015, Serum microRNAs explain discordance of non-alcoholic fatty liver disease in monozygotic and dizygotic twins: a prospective study, Gut

Singal, 2014, The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis, American Journal of Gastroenterology, 109, 325, 10.1038/ajg.2013.476

Sookoian, 2009, A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity, Journal of Lipid Research, 50, 2111, 10.1194/jlr.P900013-JLR200

Speliotes, 2010, PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease, Hepatology, 52, 904, 10.1002/hep.23768

Valenti, 2010, Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease, Hepatology, 51, 1209, 10.1002/hep.23622

Rotman, 2010, The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease, Hepatology, 52, 894, 10.1002/hep.23759

Valenti, 2010, I148M patatin-like phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease, Hepatology, 52, 1274, 10.1002/hep.23823

Beer, 2009, The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver, Human Molecular Genetics, 18, 4081, 10.1093/hmg/ddp357

Petta, 2014, Glucokinase regulatory protein gene polymorphism affects liver fibrosis in non-alcoholic fatty liver disease, PLOS ONE, 9, e87523, 10.1371/journal.pone.0087523

Speliotes, 2011, Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits, PLOS Genetics, 7, e1001324, 10.1371/journal.pgen.1001324

Gorden, 2013, Genetic variation at NCAN locus is associated with inflammation and fibrosis in non-alcoholic fatty liver disease in morbid obesity, Human Heredity, 75, 34, 10.1159/000346195

Nobili, 2014, A 4-polymorphism risk score predicts steatohepatitis in children with nonalcoholic fatty liver disease, Journal of Pediatric Gastroenterology and Nutrition, 58, 632, 10.1097/MPG.0000000000000279

Petta, 2012, IL28B and PNPLA3 polymorphisms affect histological liver damage in patients with non-alcoholic fatty liver disease, Journal of Hepatology, 56, 1356, 10.1016/j.jhep.2012.01.007

Miele, 2008, The Kruppel-like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease, Gastroenterology, 135, 10.1053/j.gastro.2008.04.004

Sookoian, 2015, Genetic variation in TM6SF2 and the risk of nonalcoholic fatty liver disease and histological disease severity, Hepatology, 61, 515, 10.1002/hep.27556

Fawcett, 2008, Evaluating the role of LPIN1 variation in insulin resistance, body weight, and human lipodystrophy in UK populations, Diabetes, 57, 2527, 10.2337/db08-0422

Valenti, 2012, LPIN1 rs13412852 polymorphism in pediatric nonalcoholic fatty liver disease, Journal of Pediatric Gastroenterology and Nutrition, 54, 588, 10.1097/MPG.0b013e3182442a55

Alberti, 2009, Circulation, 120, 1640, 10.1161/CIRCULATIONAHA.109.192644

Reaven, 1988, Role of insulin resistance in human disease, Diabetes, 37, 1595, 10.2337/diab.37.12.1595

National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), 2002, Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report, Circulation, 106, 3143, 10.1161/circ.106.25.3143

Byrne, 2009, Metabolic disturbances in non-alcoholic fatty liver disease, Clinical Science (London), 116, 539, 10.1042/CS20080253

Byrne, 2012, Dorothy Hodgkin Lecture 2012: non-alcoholic fatty liver disease, insulin resistance and ectopic fat: a new problem in diabetes management, Diabetic Medicine, 29, 1098, 10.1111/j.1464-5491.2012.03732.x

Targher, 2013, Clinical review: nonalcoholic fatty liver disease: a novel cardiometabolic risk factor for type 2 diabetes and its complications, Journal of Clinical Endocrinology and Metabolism, 98, 483, 10.1210/jc.2012-3093

Armstrong, 2014, Extrahepatic complications of nonalcoholic fatty liver disease, Hepatology, 59, 1174, 10.1002/hep.26717

Singh, 2015, Fibrosis progression in nonalcoholic fatty liver vs. non-alcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies, Clinical Gastroenterology and Hepatology, 13, 643, 10.1016/j.cgh.2014.04.014

Sung, 2014, Development of new fatty liver, or resolution of existing fatty liver, over five years of follow-up, and risk of incident hypertension, Journal of Hepatology, 60, 1040, 10.1016/j.jhep.2014.01.009

Ryoo, 2014, Clinical association between non-alcoholic fatty liver disease and the development of hypertension, Journal of Gastroenterology and Hepatology, 29, 1926, 10.1111/jgh.12643

Loria, 2005, Gallstone disease in non-alcoholic fatty liver: prevalence and associated factors, Journal of Gastroenterology and Hepatology, 20, 1176, 10.1111/j.1440-1746.2005.03924.x

Perlstein, 2006, Uric acid and the development of hypertension: the normative aging study, Hypertension, 48, 1031, 10.1161/01.HYP.0000248752.08807.4c

Afzali, 2010, Association between serum uric acid level and chronic liver disease in the United States, Hepatology, 52, 578, 10.1002/hep.23717

Keenan, 2012, Relation of uric acid to serum levels of high-sensitivity C-reactive protein, triglycerides, and high-density lipoprotein cholesterol and to hepatic steatosis, American Journal of Cardiology, 110, 1787, 10.1016/j.amjcard.2012.08.012

Xu, 2014, Associations of non-high density lipoprotein cholesterol and traditional blood lipid profiles with hyperuricemia among middle-aged and elderly Chinese people: a community-based cross-sectional study, Lipids in Health and Disease, 13, 117, 10.1186/1476-511X-13-117

Lonardo, 2002, Fasting insulin and uric acid levels but not indices of iron metabolism are independent predictors of non-alcoholic fatty liver disease. A case–control study, Digestive and Liver Disease, 34, 204, 10.1016/S1590-8658(02)80194-3

Kuo, 2010, Gout and risk of non-alcoholic fatty liver disease, Scandinavian Journal of Rheumatology, 39, 466, 10.3109/03009741003742797

Hwang, 2011, The relationship between normal serum uric acid and nonalcoholic fatty liver disease, Journal of Korean Medical Science, 26, 386, 10.3346/jkms.2011.26.3.386

Petta, 2011, Hyperuricemia is associated with histological liver damage in patients with non-alcoholic fatty liver disease, Alimentary Pharmacology and Therapeutics, 34, 757, 10.1111/j.1365-2036.2011.04788.x

Ryu, 2011, Serum uric acid levels predict incident nonalcoholic fatty liver disease in healthy Korean men, Metabolism: Clinical and Experimental, 60, 860, 10.1016/j.metabol.2010.08.005

Vos, 2012, Correlation of vitamin E, uric acid, and diet composition with histologic features of pediatric NAFLD, Journal of Pediatric Gastroenterology and Nutrition, 54, 90, 10.1097/MPG.0b013e318229da1a

Sirota, 2013, Elevated serum uric acid levels are associated with non-alcoholic fatty liver disease independently of metabolic syndrome features in the United States: liver ultrasound data from the National Health and Nutrition Examination Survey, Metabolism: Clinical and Experimental, 62, 392, 10.1016/j.metabol.2012.08.013

Xu, 2010, High serum uric acid increases the risk for nonalcoholic Fatty liver disease: a prospective observational study, PLoS ONE, 5, e11578, 10.1371/journal.pone.0011578

Xie, 2013, Serum uric acid and non-alcoholic fatty liver disease in non-diabetic Chinese men, PLoS ONE, 8, e67152, 10.1371/journal.pone.0067152

Kotronen, 2007, Liver fat in the metabolic syndrome, Journal of Clinical Endocrinology and Metabolism, 92, 3490, 10.1210/jc.2007-0482

Kotronen, 2008, Liver fat is increased in type 2 diabetic patients and underestimated by serum alanine aminotransferase compared with equally obese nondiabetic subjects, Diabetes Care, 31, 165, 10.2337/dc07-1463

Ryysy, 2000, Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients, Diabetes, 49, 749, 10.2337/diabetes.49.5.749

Maximos, 2015, The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease, Hepatology, 61, 153, 10.1002/hep.27395

Portillo-Sanchez, 2015, High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels, Journal of Clinical Endocrinology and Metabolism, 100, 2231, 10.1210/jc.2015-1966

Michelotti, 2013, NAFLD, NASH and liver cancer, Nature Reviews Gastroenterology & Hepatology, 10, 656, 10.1038/nrgastro.2013.183

de Marco, 1999, Cause-specific mortality in type 2 diabetes. The Verona Diabetes Study, Diabetes Care, 22, 756, 10.2337/diacare.22.5.756

Porepa, 2010, Newly diagnosed diabetes mellitus as a risk factor for serious liver disease, Canadian Medical Association Journal, 182, E526, 10.1503/cmaj.092144

Campbell, 2012, Diabetes and cause-specific mortality in a prospective cohort of one million U.S. adults, Diabetes Care, 35, 1835, 10.2337/dc12-0002

Zoppini, 2014, Mortality from chronic liver diseases in diabetes, American Journal of Gastroenterology, 109, 1020, 10.1038/ajg.2014.132

Adams, 2010, Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study, American Journal of Gastroenterology, 105, 1567, 10.1038/ajg.2010.18

Targher, 2007, Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients, Diabetes Care, 30, 2119, 10.2337/dc07-0349

Targher, 2010, Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease, New England Journal of Medicine, 363, 1341, 10.1056/NEJMra0912063

Targher, 2014, CKD and nonalcoholic fatty liver disease, American Journal of Kidney Diseases, 64, 638, 10.1053/j.ajkd.2014.05.019

Targher, 2008, Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients, Diabetologia, 51, 444, 10.1007/s00125-007-0897-4

Targher, 2008, Increased risk of CKD among type 2 diabetics with nonalcoholic fatty liver disease, Journal of the American Society of Nephrology, 19, 1564, 10.1681/ASN.2007101155

Centre WHOM, 2013

Nguyen, 2010, The epidemiology of obesity, Gastroenterology Clinics of North America, 39, 1, 10.1016/j.gtc.2009.12.014

Tsigos, 2008, Management of obesity in adults: European clinical practice guidelines, Obesity Facts, 1, 106, 10.1159/000126822

Sturm, 2003, Increases in clinically severe obesity in the United States, 1986–2000, Archives of Internal Medicine, 163, 2146, 10.1001/archinte.163.18.2146

Marchesini, 2003, Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome, Hepatology, 37, 917, 10.1053/jhep.2003.50161

Bellentani, 2001, The spectrum of liver disease in the general population: lesson from the Dionysos study, Journal of Hepatology, 35, 531, 10.1016/S0168-8278(01)00151-9

Fabbrini, 2010, Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications, Hepatology, 51, 679, 10.1002/hep.23280

Vernon, 2011, Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults, Alimentary Pharmacology and Therapeutics, 34, 274, 10.1111/j.1365-2036.2011.04724.x

Machado, 2006, Hepatic histology in obese patients undergoing bariatric surgery, Journal of Hepatology, 45, 600, 10.1016/j.jhep.2006.06.013

Zelber-Sagi, 2012, Predictors for incidence and remission of NAFLD in the general population during a seven-year prospective follow-up, Journal of Hepatology, 56, 1145, 10.1016/j.jhep.2011.12.011

Junior, 2012, Clinical predictors of different grades of nonalcoholic fatty liver disease, Obesity Surgery, 22, 248, 10.1007/s11695-011-0438-6

Angulo, 1999, Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis, Hepatology, 30, 1356, 10.1002/hep.510300604

Calle, 2003, Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults, New England Journal of Medicine, 348, 1625, 10.1056/NEJMoa021423

Kabir, 2005, Molecular evidence supporting the portal theory: a causative link between visceral adiposity and hepatic insulin resistance, American Journal of Physiology. Endocrinology and Metabolism, 288, E454, 10.1152/ajpendo.00203.2004

Wajchenberg, 2002, Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome, Hormone and Metabolic Research, 34, 616, 10.1055/s-2002-38256

Rocha, 2011, Visceral abdominal and subfascial femoral adipose tissue have opposite associations with liver fat in overweight and obese premenopausal Caucasian women, Journal of Lipids, 2011, 154672, 10.1155/2011/154672

van der Poorten, 2013, Hepatic fat loss in advanced nonalcoholic steatohepatitis: are alterations in serum adiponectin the cause, Hepatology, 57, 2180, 10.1002/hep.26072

Wong, 2014, Obesity and non-alcoholic fatty liver disease: disparate associations among Asian populations, World Journal of Hepatology, 6, 263, 10.4254/wjh.v6.i5.263

Colak, 2012, Relation of epicardial adipose tissue and carotid intima-media thickness in patients with nonalcoholic fatty liver disease, European Journal of Gastroenterology and Hepatology, 24, 613, 10.1097/MEG.0b013e3283513f19

Iacobellis, 2014, Epicardial fat thickness and nonalcoholic fatty liver disease in obese subjects, Obesity (Silver Spring), 22, 332, 10.1002/oby.20624

Granér, 2014, Ectopic fat depots and left ventricular function in nondiabetic men with nonalcoholic fatty liver disease, Circulation: Cardiovascular Imaging, 8, e001979

Petta, 2015, Epicardial fat, cardiac geometry and cardiac function in patients with non-alcoholic fatty liver disease: association with the severity of liver disease, Journal of Hepatology, 62, 928, 10.1016/j.jhep.2014.11.030

Cheung, 2007, The impact of fat distribution on the severity of nonalcoholic fatty liver disease and metabolic syndrome, Hepatology, 46, 1091, 10.1002/hep.21803

Ulucan, 2015, Epicardial fat and liver disease; the contribution of cardio autonomic nervous system function, Journal of Hepatology, 62, 1214, 10.1016/j.jhep.2015.01.008

Pagadala, 2012, Non-alcoholic fatty liver disease and obesity: not all about body mass index, American Journal of Gastroenterology, 107, 1859, 10.1038/ajg.2012.320

Bluher, 2010, The distinction of metabolically ‘healthy’ from ‘unhealthy’ obese individuals, Current Opinion in Lipidology, 21, 38, 10.1097/MOL.0b013e3283346ccc

Hinnouho, 2013, Metabolically healthy obesity and risk of mortality: does the definition of metabolic health matter, Diabetes Care, 36, 2294, 10.2337/dc12-1654

Park, 2003, The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988–1994, Archives of Internal Medicine, 163, 427, 10.1001/archinte.163.4.427

Consultation, 2004, Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies, Lancet, 363, 157, 10.1016/S0140-6736(03)15268-3

Ruderman, 1998, The metabolically obese, normal-weight individual revisited, Diabetes, 47, 699, 10.2337/diabetes.47.5.699

Messier, 2010, Metabolically healthy but obese individuals: relationship with hepatic enzymes, Metabolism: Clinical and Experimental, 59, 20, 10.1016/j.metabol.2009.06.020

Thelwall, 2013, Hepatic cholesteryl ester accumulation in lysosomal acid lipase deficiency: non-invasive identification and treatment monitoring by magnetic resonance, Journal of Hepatology, 59, 543, 10.1016/j.jhep.2013.04.016

Reiner, 2014, Lysosomal acid lipase deficiency – an under-recognized cause of dyslipidaemia and liver dysfunction, Atherosclerosis, 235, 21, 10.1016/j.atherosclerosis.2014.04.003

Balwani, 2013, Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease, Hepatology, 58, 950, 10.1002/hep.26289

Valayannopoulos, 2014, Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency, Journal of Hepatology, 61, 1135, 10.1016/j.jhep.2014.06.022

Fallo, 2009, Non-alcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in essential hypertension, Nutrition, Metabolism and Cardiovascular Diseases, 19, 646, 10.1016/j.numecd.2008.12.007

Zhang, 2011, Prevalence and etiology of abnormal liver tests in an adult population in Jilin, China, International Journal of Medical Sciences, 8, 254, 10.7150/ijms.8.254

Hou, 2011, Non-alcoholic fatty liver disease's prevalence and impact on alanine aminotransferase associated with metabolic syndrome in the Chinese, Journal of Gastroenterology and Hepatology, 26, 722, 10.1111/j.1440-1746.2010.06509.x

Liao, 2013, Prevalence and features of fatty liver detected by physical examination in Guangzhou, World Journal of Gastroenterology, 19, 5334, 10.3748/wjg.v19.i32.5334

Lonardo, 1997, The ‘bright liver’ syndrome. Prevalence and determinants of a bright liver echo pattern, Italian Journal of Gastroenterology and Hepatology, 29, 351

Rudwill, 2015, Effect of enforced physical inactivity induced by 60-d of bed rest on hepatic markers of NAFLD in healthy normal-weight women, Liver International, 35, 1700, 10.1111/liv.12743

Schult, 2011, Overweight and hypertriglyceridemia are risk factors for liver cirrhosis in middle-aged Swedish men, Scandinavian Journal of Gastroenterology, 46, 738, 10.3109/00365521.2011.560679

Männistö, 2014, Lipoprotein subclass metabolism in nonalcoholic steatohepatitis, Journal of Lipid Research, 55, 2676, 10.1194/jlr.P054387

Corey, 2012, Non-high-density lipoprotein cholesterol as a biomarker for nonalcoholic steatohepatitis, Clinical Gastroenterology and Hepatology, 10, 651, 10.1016/j.cgh.2012.01.017

Siddiqui, 2014, Severity of nonalcoholic fatty liver disease and progression to cirrhosis associate with atherogenic lipoprotein profile, Clinical Gastroenterology and Hepatology, 13

Bhala, 2011, The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study, Hepatology, 54, 1208, 10.1002/hep.24491

Loria, 2014, Cardiovascular risk, lipidemic phenotype and steatosis. A comparative analysis of cirrhotic and non-cirrhotic liver disease due to varying etiology, Atherosclerosis, 232, 99, 10.1016/j.atherosclerosis.2013.10.030

Graham, 2012, Dyslipidemias in the prevention of cardiovascular disease: risks and causality, Current Cardiology Reports, 14, 709, 10.1007/s11886-012-0313-7

Lonardo, 2015, Diagnosis and management of cardiovascular risk in nonalcoholic fatty liver disease, Expert Review of Gastroenterology & Hepatology, 9, 629, 10.1586/17474124.2015.965143

Tarugi, 1996, Fatty liver in heterozygous hypobetalipoproteinemia caused by a novel truncated form of apolipoprotein B, Gastroenterology, 111, 1125, 10.1016/S0016-5085(96)70082-3

Lonardo, 2006, Hepatic steatosis and insulin resistance: does etiology make a difference, Journal of Hepatology, 44, 190, 10.1016/j.jhep.2005.06.018

Di Filippo, 2014, Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia, Journal of Hepatology, 61, 891, 10.1016/j.jhep.2014.05.023

Promrat, 2010, Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis, Hepatology, 51, 121, 10.1002/hep.23276

Harrison, 2009, Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial, Hepatology, 49, 80, 10.1002/hep.22575

Glass, 2015, Total body weight loss of ≥10% is associated with improved hepatic fibrosis in patients with nonalcoholic steatohepatitis, Digestive Diseases and Sciences, 60, 1024, 10.1007/s10620-014-3380-3

Keating, 2012, Exercise and non-alcoholic fatty liver disease: a systematic review and meta-analysis, Journal of Hepatology, 57, 157, 10.1016/j.jhep.2012.02.023

Scaglioni, 2013, Short-term multidisciplinary non-pharmacological intervention is effective in reducing liver fat content assessed non-invasively in patients with nonalcoholic fatty liver disease (NAFLD), Clinics and Research in Hepatology and Gastroenterology, 37, 353, 10.1016/j.clinre.2012.10.009

Haufe, 2013, Long-lasting improvements in liver fat and metabolism despite body weight regain after dietary weight loss, Diabetes Care, 36, 3786, 10.2337/dc13-0102

Mummadi, 2008, Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis, Clinical Gastroenterology and Hepatology, 6, 1396, 10.1016/j.cgh.2008.08.012

Lonardo, 2011, Insulin resistance in nonalcoholic steatohepatitis: necessary but not sufficient - death of a dogma from analysis of therapeutic studies, Expert Review of Gastroenterology & Hepatology, 5, 279, 10.1586/egh.11.19

Lazo, 2010, Effect of a 12-month intensive lifestyle intervention on hepatic steatosis in adults with type 2 diabetes, Diabetes Care, 33, 2156, 10.2337/dc10-0856

Bacchi, 2013, Both resistance training and aerobic training reduce hepatic fat content in type 2 diabetic subjects with nonalcoholic fatty liver disease (the RAED2 Randomized Trial), Hepatology, 58, 1287, 10.1002/hep.26393

Belfort, 2006, A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis, New England Journal of Medicine, 355, 2297, 10.1056/NEJMoa060326

Klonoff, 2008, Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years, Current Medical Research and Opinion, 24, 275, 10.1185/030079908X253870

Goh, 2015, Renin–angiotensin system and fibrosis in non-alcoholic fatty liver disease, Liver International, 35, 979, 10.1111/liv.12611

Yokohama, 2004, Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis, Hepatology, 40, 1222, 10.1002/hep.20420

Georgescu, 2007, Therapeutic options in non-alcoholic steatohepatitis (NASH). Are all agents alike? Results of a preliminary study, Journal of Gastrointestinal and Liver Diseases, 16, 39

Georgescu, 2009, Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis, World Journal of Gastroenterology, 15, 942, 10.3748/wjg.15.942

Scorletti, 2014, Effects of purified eicosapentaenoic and docosahexaenoic acids in non-alcoholic fatty liver disease: results from the *WELCOME study, Hepatology, 60, 1211, 10.1002/hep.27289

Argo, 2015, Effects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial, Journal of Hepatology, 62, 190, 10.1016/j.jhep.2014.08.036

Sanyal, 2014, No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial, Gastroenterology, 147, 377, 10.1053/j.gastro.2014.04.046

Taylor, 2013, Statins for the primary prevention of cardiovascular disease, Cochrane Database of Systematic Reviews, 1, CD004816

Eslami, 2013, Statins for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, Cochrane Database of Systematic Reviews, 12, CD008623

Park, 2011, Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease, Journal of Gastroenterology, 46, 101, 10.1007/s00535-010-0291-8

Takeshita, 2014, The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial, Diabetologia, 57, 878, 10.1007/s00125-013-3149-9

Neuschwander-Tetri, 2015, Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial, Lancet, 385, 956, 10.1016/S0140-6736(14)61933-4

Ratziu, 2010, A position statement on NAFLD/NASH based on the EASL 2009 special conference, Journal of Hepatology, 53, 372, 10.1016/j.jhep.2010.04.008