A "systems medicine" approach to the study of non-alcoholic fatty liver disease

Digestive and Liver Disease

Volumn 48, Issue 3, 2016, Pages 333-342

  Petta, Salvatore ^a   Valenti, Luca ^b   Bugianesi, Elisabetta ^c   Targher, Giovanni ^d   Bellentani, Stefano ^e,f   Bonino, Ferruccio ^g   Fargion, Silvia ^b   Vanni, Ester ^c   Ferrannini, Ele ^h   Loguercio, Carmela ⁱ   Lonardo, Amedeo ^j   Marra, Fabio ^k   Mancini, Marcello ^l   Miele, Luca ^m   Nobili, Valerio ⁿ   Baroni, Gianluca Svegliati ^o   Alessandro, Federico ⁱ   Ballestri, Stefano ^p   Brunetto, Maurizia Rossana ^g   Coco, Barbara ^g   Grieco, Antonio ^m   Kondili, Loreta ^q   Nascimbeni, Fabio ^r   Prinster, Anna ^l   Romagnoli, Dante ^s   Taddei, Stefano ^g   Vella, Stefano ^q   more..

^a UNIVERSITY OF PALERMO   (Italy)

^b UNIVERSITY OF MILAN   (Italy)

^c UNIVERSITY OF TURIN   (Italy)

^d UNIVERSITY HOSPITAL OF VERONA   (Italy)

^e PRINCESS ROYAL HOSPITAL   (United Kingdom)

^f Fondazione Italiana Fegato   (Italy)

^g UNIVERSITY HOSPITAL OF PISA   (Italy)

^h INSTITUTE OF CLINICAL PHYSIOLOGY   (Italy)

ⁱ SECOND UNIVERSITY OF NAPLES   (Italy)

^j USL Modena   (Italy)

^k UNIVERSITY OF FLORENCE   (Italy)

^l CNR   (Italy)

^m CATHOLIC UNIVERSITY   (Italy)

ⁿ BAMBINO GESÙ CHILDREN S HOSPITAL   (Italy)

^o UNIVERSITÀ POLITECNICA DELLE MARCHE   (Italy)

^p Pavullo Hospital   (Italy)

^q ISTITUTO SUPERIORE DI SANITÀ   (Italy)

^r Neuroradiology Unit   (Italy)

^s Medicine NOCSAE   (Italy)

more..

Author keywords

Fatty liver; Medicine; NAFLD; NASH; Personalized; Systems medicine

Indexed keywords

FATTY ACID; INFLAMMASOME; INSULIN;

ADIPOSE TISSUE; ALCOHOL CONSUMPTION; ARTICLE; CARDIOVASCULAR RISK; CARDIOVASCULAR SYSTEM; CHILDHOOD; CHOLELITHIASIS; CLINICAL FEATURE; COHORT ANALYSIS; DIAGNOSTIC PROCEDURE; DIET; ECHOGRAPHY; ETHNICITY; FAMILY HISTORY; HEREDITY; HUMAN; IMMUNE DEFICIENCY; INSULIN RESISTANCE; INTESTINE FLORA; KUPFFER CELL; LIPOTOXICITY; METABOLIC DISORDER; METABOLIC SYNDROME X; METHODOLOGY; NONALCOHOLIC FATTY LIVER; NUTRITION; OBESITY; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTON NUCLEAR MAGNETIC RESONANCE; SEX DIFFERENCE; SYSTEMS BIOLOGY; THYROID DISEASE; VIRUS INFECTION; DISEASE COURSE; METABOLISM; NON-ALCOHOLIC FATTY LIVER DISEASE; PHENOTYPE; RISK FACTOR; SYSTEM ANALYSIS;

DISEASE PROGRESSION; HUMANS; NON-ALCOHOLIC FATTY LIVER DISEASE; PHENOTYPE; RISK FACTORS; SYSTEMS ANALYSIS; SYSTEMS BIOLOGY;

EID: 84960463900     PISSN: 15908658     EISSN: 18783562     Source Type: Journal    
DOI: 10.1016/j.dld.2015.10.027     Document Type: Article

References (198)

1. Loria P., Adinolfi L.E., Bellentani S., et al. NAFLD Expert Committee of the Associazione Italiana per lo studio del Fegato. 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 2010, 42:272-282.
2. Bellentani S., Scaglioni F., Marino M., et al. Epidemiology of non-alcoholic fatty liver disease. Digestive Diseases 2010, 28:155-161.
3. Bedogni G., Miglioli L., Masutti F., et al. Incidence and natural course of fatty liver in the general population: the Dionysos study. Hepatology 2007, 46:1387-1391.
4. Lazo M., Hernaez R., Eberhardt M.S., et al. Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994. American Journal of Epidemiology 2013, 178:38-45.
5. Li Z., Xue J., Chen P., et al. Prevalence of nonalcoholic fatty liver disease in mainland of China: a meta-analysis of published studies. Journal of Gastroenterology and Hepatology 2014, 29:42-51.
6. Baumeister S.E., Völzke H., Marschall P., et al. Impact of fatty liver disease on health care utilization and costs in a general population: a 5-year observation. Gastroenterology 2008, 134:85-94.
7. Day C.P., James O.F.W. Steatohepatitis: a tale of two hits. Gastroenterology 1998, 114:842-845.
8. Neuschwander-Tetri B.A. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 2010, 52:774-788.
9. Marra F., Lotersztajn S. Pathophysiology of NASH: perspectives for a targeted treatment. Current Pharmaceutical Design 2013, 19:5250-5269.
10. Ricchi M., Odoardi M.R., Carulli L., et al. Differential effect of oleic and palmitic acid on lipid accumulation and apoptosis in cultured hepatocytes. Journal of Gastroenterology and Hepatology 2009, 24:830-840.
11. Tilg H., Moschen A.R. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010, 52:1836-1846.
12. Donnelly K.L., Smith C.I., Schwarzenberg S.J., et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. Journal of Clinical Investigation 2005, 115:1343-1351.
13. Fabbrini E., Mohammed B.S., Magkos F., et al. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 2008, 134:424-431.
14. Yamaguchi K., Yang L., McCall S., et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 2007, 45:1366-1374.
15. Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 2012, 142:711-725.
16. Henao-Mejia J., Elinav E., Jin C., et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012, 482:179-185.
17. Csak T., Ganz M., Pespisa J., et al. Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology 2011, 54:133-144.
18. Vandanmagsar B., Youm Y.H., Ravussin A., et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nature Medicine 2011, 17:179-188.
19. Guicciardi M.E., Gores G.J. Apoptosis as a mechanism for liver disease progression. Seminars in Liver Disease 2010, 30:402-410.
20. Gambino R., Musso G., Cassader M. Redox balance in the pathogenesis of nonalcoholic fatty liver disease: mechanisms and therapeutic opportunities. Antioxidants and Redox Signalling 2011, 15:1325-1365.
21. Hernandez-Gea V., Ghiassi-Nejad Z., Rozenfeld R., et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 2012, 142:938-946.
22. Marra F., Bertolani C. Adipokines in liver diseases. Hepatology 2009, 50:957-969.
23. Wang J., Leclercq I., Brymora J.M., et al. Kupffer cells mediate leptin-induced liver fibrosis. Gastroenterology 2009, 137:713-723.
24. Tilg H., Moschen A.R. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nature Reviews Immunology 2006, 6:772-783.
25. Matthew Morris E., Fletcher J.A., Thyfault J.P., et al. The role of angiotensin II in nonalcoholic steatohepatitis. Molecular and Cellular Endocrinology 2013, 378:29-40.
26. Machado M.V., Cortez-Pinto H. Gut microbiota and nonalcoholic fatty liver disease. Annals of Hepatology 2012, 11:440-449.
27. Yilmaz Y. Review article: fructose in non-alcoholic fatty liver disease. Alimentary Pharmacology and Therapeutics 2012, 35:1135-1144.
28. Molloy J.W., Calcagno C.J., Williams C.D., et al. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. Hepatology 2012, 55:429-436.
29. Mofrad P., Contos M.J., Haque M., et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 2003, 37:1286-1292.
30. Brunt E.M., Janney C.G., Di Bisceglie A.M., et al. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. American Journal of Gastroenterology 1999, 94:2467-2474.
31. Ratziu V., Charlotte F., Heurtier A., et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005, 128:1898-1906.
32. Arun J., Jhala N., Lazenby A.J., et al. Influence of liver biopsy heterogeneity and diagnosis of nonalcoholic steatohepatitis in subjects undergoing gastric bypass. Obesity Surgery 2007, 17:155-161.
33. Charatcharoenwitthaya P., Lindor K.D. Role of radiologic modalities in the management of nonalcoholic steatohepatitis. Clinics in Liver Disease 2007, 11:37-54.
34. Mishra P., Younossi Z.M. Abdominal ultrasound for diagnosis of nonalcoholic fatty liver disease (NAFLD). American Journal of Gastroenterology 2007, 102:2716-2717.
35. Strauss S., Gavish E., Gottlieb P., et al. Interobserver and intraobserver variability in the sonographic assessment of fatty liver. American Journal of Roentgenology 2007, 189:W320-W323.
36. Dasarathy S., Dasarathy J., Khiyami A., et al. Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study. Journal of Hepatology 2009, 51:1061-1067.
37. 1H magnetic resonance spectroscopy. Obesity (Silver Spring) 2009, 17:2239-2244.
38. Mancini M., Prinster A., Annuzzi G., et al. Sonographic hepatic-renal ratio as indicator of hepatic steatosis: comparison with (1)H magnetic resonance spectroscopy. Metabolism: Clinical and Experimental 2009, 58:1724-1730.
39. 1H magnetic resonance spectroscopy in the liver: a review. Liver International 2008, 28:297-307.
40. Reeder S.B., Cruite I., Hamilton G., et al. Quantitative assessment of liver fat with magnetic resonance imaging and spectroscopy. Journal of Magnetic Resonance Imaging 2011, 34:729-749.
41. Schwenzer N.F., Springer F., Schraml C., et al. Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance. Journal of Hepatology 2009, 51:433-445.
42. Fishbein M., Castro F., Cheruku S., et al. Hepatic MRI for fat quantification. Its relationship to fat morphology, diagnosis and ultrasound. Journal of Clinical Gastroenterology 2005, 39:619-625.
43. Noworolski S.M., Lam M.M., Merriman R.B., et al. Liver steatosis: concordance of MR imaging and MR spectroscopic data with histologic grade. Radiology 2012, 264:88-96.
44. 1H-spectroscopy and chemical shift imaging at 3.0 T before hepatic surgery: reliable enough for making clinical decisions?. European Journal of Radiology 2012, 81:2990-2995.
45. Schwimmer J.B., Celedon M.A., Lavine J.E., et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology 2009, 136:1585-1592.
46. Guerrero R., Vega G.L., Grundy S.M., et al. Ethnic differences in hepatic steatosis: an insulin resistance paradox. Hepatology 2009, 49:791-801.
47. Makkonen J., Pietilainen K.H., Rissanen A., et al. 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 2009, 50:1035-1042.
48. Dongiovanni P., Anstee Q.M., Valenti L. Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment. Current Pharmaceutical Design 2013, 19:5219-5238.
49. Speliotes E.K., Yerges-Armstrong L.M., Wu J., et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genetics 2011, 7:e1001324.
50. Anstee Q.M., Darlay R., Leathart J., et al. A candidate gene approach to validation of genetic modifier associations using a large cohort with histologically characterized non-alcoholic fatty liver disease. Journal of Hepatology 2013, 58:S46.
51. Romeo S., Kozlitina J., Xing C., et al. Genetic variation in pnpla3 confers susceptibility to nonalcoholic fatty liver disease. Nature Genetics 2008, 40:1461-1465.
52. Kitamoto T., Kitamoto A., Yoneda M., et al. Genome-wide scan revealed that polymorphisms in the pnpla3, samm50, and parvb genes are associated with development and progression of nonalcoholic fatty liver disease in Japan. Human Genetics 2013, 132:783-792.
53. Kozlitina J., Smagris E., Stender S., et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nature Genetics 2014, 46:352-356.
54. Tian C., Stokowski R.P., Kershenobich D., et al. Variant in pnpla3 is associated with alcoholic liver disease. Nature Genetics 2009, 42:21-23.
55. Sookoian S., Castano G.O., Burgueno A.L., et al. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. Journal of Lipid Research 2009, 50:2111-2116.
56. Valenti L., Al-Serri A., Daly A.K., et al. Homozygosity for the pnpla3/adiponutrin i148m polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 2010, 51:1209-1217.
57. Sookoian S., Pirola C.J. Meta-analysis of the influence of i148m variant of patatin-like phospholipase domain containing 3 gene (pnpla3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 2011, 53:1883-1894.
58. Dongiovanni P., Donati B., Fares R., et al. PNPLA3 I148M polymorphism and progressive liver disease. World Journal of Gastroenterology 2013, 19:6969-6978.
59. Dongiovanni P., Petta S., Maglio C., et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 2015, 61:506-514.
60. He S., McPhaul C., Li J.Z., et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. Journal of Biological Chemistry 2010, 285:6706-6715.
61. Davis J.N., Le K.A., Walker R.W., et al. Increased hepatic fat in overweight hispanic youth influenced by interaction between genetic variation in pnpla3 and high dietary carbohydrate and sugar consumption. American Journal of Clinical Nutrition 2011, 92:1522-1527.
62. Santoro N., Savoye M., Kim G., et al. Hepatic fat accumulation is modulated by the interaction between the rs738409 variant in the pnpla3 gene and the dietary omega6/omega3 pufa intake. PLoS ONE 2012, 7:e37827.
63. Ruhanen H., Perttilä J., Hölttä-Vuori M., et al. PNPLA3 mediates hepatocyte triacylglycerol remodeling. Journal of Lipid Research 2014, 55:739-746.
64. Valenti L., Alisi A., Galmozzi E., et al. I148M patatin-like phospholipase domain containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease. Hepatology 2010, 52:1274-1280.
65. Santoro N., Zhang C.K., Zhao H., et al. Variant in the glucokinase regulatory protein (gckr) gene is associated with fatty liver in obese children and adolescents. Hepatology 2011, 55:781-789.
66. Miraglia Del Giudice E., Grandone A., Cirillo G., et al. The association of pnpla3 variants with liver enzymes in childhood obesity is driven by the interaction with abdominal fat. PLoS ONE 2011, 6:e27933.
67. Valenti L., Motta B.M., Alisi A., et al. LPIN1 rs13412852 polymorphism in pediatric non-alcoholic fatty liver disease. Journal of Pediatric Gastroenterology and Nutrition 2012, 54:588-593.
68. Nobili V., Bedogni G., Donati B., et al. The i148m variant of pnpla3 reduces the response to docosahexaenoic acid in children with non-alcoholic fatty liver disease. Journal of Medicinal Food 2013, 16:957-960.
69. Valenti L., Rumi M., Galmozzi E., et al. Patatin-like phospholipase domain-containing 3 i148m polymorphism, steatosis, and liver damage in chronic hepatitis C. Hepatology 2011, 53:791-799.
70. Vigano M., Valenti L., Lampertico P., et al. Pnpla3 i148m affects liver steatosis in patients with chronic hepatitis B. Hepatology 2013, 58:1245-1252.
71. Valenti L., Maggioni P., Piperno A., et al. Pnpla3 i148m polymorphism, steatosis, and liver damage in hereditary hemochromatosis. World Journal of Gastroenterology 2012, 18:2813-2820.
72. Trepo E., Nahon P., Bontempi G., et al. Association between the pnpla3 (rs738409 c>g) variant and hepatocellular carcinoma: evidence from a meta-analysis of individual participant data. Hepatology 2014, 59:2170-2177.
73. Valenti L., Motta B.M., Soardo G., et al. Pnpla3 i148m polymorphism, clinical presentation, and survival in patients with hepatocellular carcinoma. PLOS ONE 2013, 8:e75982.
74. Liu Y.L., Patman G., Leathart J., et al. Carriage of pnpla3 i148m is associated with increased risk of nonalcoholic fatty liver disease-associated hepatocellular carcinoma. Journal of Hepatology 2013, 58:S516.
75. Hassan M.M., Kaseb A., Etzel C.J., et al. Genetic variation in the pnpla3 gene and hepatocellular carcinoma in USA: risk and prognosis prediction. Molecular Carcinogenesis 2013, 52:E139-E147.
76. Valenti L., Dongiovanni P., Ginanni Corradini S., et al. Pnpla3 i148m variant and hepatocellular carcinoma: a common genetic variant for a rare disease. Digestive and Liver Disease 2013, 45:619-624.
77. Liu Y.L., Reeves H.L., Burt A.D., et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nature Communications 2014, 5:4309.
78. Sevastianova K., Santos A., Kotronen A., et al. Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humans. American Journal of Clinical Nutrition 2010, 96:727-734.
79. Petta S., Miele L., Bugianesi E., et al. Glucokinase regulatory protein gene polymorphism affects liver fibrosis in non-alcoholic fatty liver disease. PLOS ONE 2014, 9:e87523.
80. Fares R., Petta S., Lombardi R., et al. The UCP2-866 G>A promoter region polymorphism is associated with nonalcoholic steatohepatitis. Liver International 2014, 10.1111/liv.12707.
81. Valenti L., Canavesi E., Galmozzi E., et al. Beta-globin mutations are associated with parenchymal siderosis and fibrosis in patients with non-alcoholic fatty liver disease. Journal of Hepatology 2010, 53:927-933.
82. Cefalu A.B., Pirruccello J.P., Noto D., et al. A novel apob mutation identified by exome sequencing cosegregates with steatosis, liver cancer, and hypocholesterolemia. Arteriosclerosis, Thrombosis, and Vascular Biology 2013.
83. Nobili V., Svegliati-Baroni G., Alisi A., et al. A 360-degree overview of paediatric NAFLD: recent insights. Journal of Hepatology 2013, 58:1218-1229.
84. Fowden A.L., Giussani D.A., Forhead A.J. Intrauterine programming of physiological systems: causes and consequences. Physiology (Bethesda) 2006.
85. Nobili V., Marcellini M., Marchesini G., et al. Intrauterine growth retardation, insulin resistance, and nonalcoholic fatty liver disease in children. Diabetes Care 2007, 30:2638-2640.
86. Alisi A., Panera N., Agostoni C., et al. Intrauterine growth retardation and nonalcoholic fatty liver disease in children. International Journal of Endocrinology 2011, 2011:269853.
87. Nobili V., Bedogni G., Alisi A., et al. A protective effect of breastfeeding on the progression of nonalcoholic fatty liver disease. Archives of Disease Childhood 2009, 94:801-805.
88. Alisi A., Cianfarani S., Manco M., et al. Nonalcoholic fatty liver disease and metabolic syndrome in adolescents: pathogenetic role of genetic background and intrauterine environment. Annals of Medicine 2012, 44:29-40.
89. Papandreou D., Karabouta Z., Rousso I. Are dietary cholesterol intake and serum cholesterol levels related to nonalcoholic fatty liver disease in obese children?. Cholesterol 2012, 2012:572820.
90. Yasutake K., Nakamuta M., Shima Y., et al. Nutritional investigation of nonobese patients with nonalcoholic fatty liver disease: the significance of dietary cholesterol. Scandinavian Journal Gastroenterology 2009, 44:471-477.
91. Jin R., Le N.A., Liu S., et al. Children with NAFLD are more sensitive to the adverse metabolic effects of fructose beverages than children without NAFLD. Journal of Clinical Endocrinology and Metabolism 2012, 97:E1088-E1098.
92. Nomura K., Yamanouchi T. The role of fructose-enriched diets in mechanism of nonalcoholic fatty liver disease. Journal of Nutritional Biochemistry 2012, 23:203-208.
93. Bertolotti M., Lonardo A., Mussi C., et al. Nonalcoholic fatty liver disease and aging: epidemiology to management. World Journal of Gastroenterology 2014, 20:14185-14204.
94. Lovejoy J.C., Champagne C.M., de Jonge L., et al. Increased visceral fat and decreased energy expenditure during the menopausal transition. International Journal of Obesity 2008, 32:949-958.
95. Volzke H., Schwarz S., Baumeister S.E., et al. Menopausal status and hepatic steatosis in a general female population. Gut 2007, 56:594-595.
96. Park S.H., Jeon W.K., Kim S.H., et al. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. Journal of Gastroenterology and Hepatology 2006, 21:138-143.
97. Hamaguchi M., Kojima T., Ohbora A., et al. Aging is a risk factor of nonalcoholic fatty liver disease in premenopausal women. World Journal of Gastroenterology 2012, 18:237-243.
98. Yang J.D., Abdelmalek M.F., Pang H., et al. Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis. Hepatology 2014, 59:1406-1414.
99. Erkan G., Yilmaz G., Konca Degertekin C., et al. Presence and extent of estrogen receptor-alpha expression in patients with simple steatosis and NASH. Pathology, Research and Practice 2013, 209:429-432.
100. Itagaki T., Shimizu I., Cheng X., et al. Opposing effects of oestradiol and progesterone on intracellular pathways and activation processes in the oxidative stress induced activation of cultured rat hepatic stellate cells. Gut 2005, 54:1782-1789.
101. Yasuda M., Shimizu I., Shiba M., et al. Suppressive effects of estradiol on dimethylnitrosamine-induced fibrosis of the liver in rats. Hepatology 1999, 29:719-727.
102. Kireev R.A., Tresguerres A.C., Garcia C., et al. Hormonal regulation of pro-inflammatory and lipid peroxidation processes in liver of old ovariectomized female rats. Biogerontology 2010, 11:229-243.
103. Rogers A., Eastell R. The effect of 17beta-estradiol on production of cytokines in cultures of peripheral blood. Bone 2001, 29:30-34.
104. Rettberg J.R., Yao J., Brinton R.D. Estrogen: a master regulator of bioenergetic systems in the brain and body. Frontiers in Neuroendocrinology 2014, 35:8-30.
105. McKenzie J., Fisher B.M., Jaap A.J., et al. Effects of HRT on liver enzyme levels in women with type 2 diabetes: a randomized placebo-controlled trial. Clinical Endocrinology 2006, 65:40-44.
106. Kneeman J.M., JMisdraji J., Corey K.E. Secondary causes of nonalcoholic fatty liver disease. Therapeutic Advances in Gastroenterology 2012, 5:199-207.
107. Cohen J.C., Horton J.D., Hobbs H.H. Human fatty liver disease: old questions and new insights. Science 2011, 332:1519-1523.
108. de Wit N.J., Afman L.A., Mensink M., et al. Phenoyping the effect of diet on non-alcoholic fatty liver disease. Journal of Hepatology 2012, 57:1370-1373.
109. Sofi F., Cesari F., Abbate R., et al. Adherence to Mediterranean diet and health status: meta-analysis. BMJ 2008, 337:a1344.
110. Sofi F., Macchi C., Abbate R., et al. Mediterranean diet and health status: an updated meta-analysis and a proposal for a literature-based adherence score. Public Health Nutrition 2013, 12:1-14.
111. Musso G., Gambino R., De Michieli F., et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology 2003, 37:909-916.
112. Johnson R.K., Appel L.J., Brands M., et al. Dietary sugars intake and cardiovascular health: a scientific statement from the American Heart Association. Circulation 2009, 120:1011-1020.
113. Welsh J.A., Sharma A.J., Grellinger L., et al. Consumption of added sugars is decreasing in the United States. American Journal of Clinical Nutrition 2011, 94:726-734.
114. Vos M.B., Lavine J.E. Dietary fructose in nonalcoholic fatty liver disease. Hepatology 2013, 57:2525-2531.
115. Abdelmalek M.F., Suzuki A., Guy C., et al. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology 2010, 51:1961-1971.
116. Petta S., Marchesini G., Caracausi L., et al. Industrial, not fruit fructose intake is associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients. Journal of Hepatology 2013, 59:1169-1176.
117. Nascimbeni F., Pais R., Bellentani S., et al. From NAFLD in clinical practice to answers from guidelines. Journal of Hepatology 2013, 59:859-871.
118. Dunn W., Sanyal A.J., Brunt E.M., et al. Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD). Journal of Hepatology 2012, 57:384-391.
119. Reaven G.M. The insulin resistance syndrome: definition and dietary approaches to treatment. Annual Review of Nutrition 2005, 25:391-406.
120. Bugianesi E., Gastaldelli A., Vanni E., et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia 2005, 48:634-642.
121. Matthews D.R., Hosker J.P., Rudenski A.S., et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985, 28:412-419.
122. Wallace T.M., Levy J.C., Matthews D.R. Use and abuse of HOMA modeling. Diabetes Care 2004, 27:1487-1495.
123. Katz A., Nambi S.S., Mather K., et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. Journal of Clinical Endocrinology and Metabolism 2000, 85:2402-2410.
124. Vanni E., Bugianesi E., Kotronen A., et al. From the metabolic syndrome to NAFLD or vice versa?. Digestive and Liver Disease 2010, 42:320-330.
125. Leite N.C., Salles G.F., Araujo A.L., et al. Prevalence and associated factors of non-alcoholic fatty liver disease in patients with type-2 diabetes mellitus. Liver International 2009, 29:113-119.
126. Prashanth M., Ganesh H.K., Vima M.V., et al. Prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. Journal of the Association of Physicians of India 2009, 57:205-210.
127. Assy N., Kaita K., Mymin D., et al. Fatty infiltration of liver in hyperlipidemic patients. Digestive Diseases and Sciences 2000, 45:1929-1934.
128. Müller M.J., Lagerpusch M., Enderle J., et al. Beyond the body mass index: tracking body composition in the pathogenesis of obesity and the metabolic syndrome. Obesity Reviews 2012, SE:6-13.
129. Xu C., Yu C., Ma H., et al. 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 2013, 108:1299-1304.
130. Younossi Z.M., Stepanova M., Negro F., et al. Nonalcoholic fatty liver disease in lean individuals in the United States. Medicine 2012, 91:319-327.
131. Kwon Y.M., Oh S.W., Hwang S.S., et al. Association of nonalcoholic fatty liver disease with components of metabolic syndrome according to body mass index in Korean adults. American Journal of Gastroenterology 2012, 107:1852-1858.
132. Sung K.C., Kim B.S., Cho Y.K., et al. Predicting incident fatty liver using simple cardio-metabolic risk factors at baseline. BMC Gastroenterology 2012, 6:84.
133. Fassio E., Alvarez E., Dominguez N., et al. Natural history of non-alcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology 2004, 40:820-826.
134. Bugianesi E., Manzini P., D'Antico S., et al. Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology 2004, 39:179-187.
135. Marchesini G., Bugianesi E., Forlani G., et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003, 37:917-923.
136. Vanni E., Bugianesi E. Obesity and liver cancer. Clinics in Liver Disease 2014, 18:191-203.
137. Lonardo A., Ballestri S., Marchesini G., et al. Non-alcoholic fatty liver disease: a precursor of the metabolic syndrome. Digestive and Liver Disease 2014, 10.1016/j.dld.2014.09.020.
138. Anstee Q.M., Targher G., Day C.P. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nature Reviews Gastroenterology and Hepatology 2013, 10:330-344.
139. Carulli L., Ballestri S., Lonardo A., et al. Is nonalcoholic steatohepatitis associated with a high-though-normal thyroid stimulating hormone level and lower cholesterol levels. Internal and Emergency Medicine 2013, 8:297-305.
140. Pagadala M.R., Zein C.O., Dasarathy S., et al. Prevalence of hypothyroidism in nonalcoholic fatty liver disease. Digestive Diseases and Sciences 2012, 57:528-534.
141. Liangpunsakul S., Chalasani N. Is hypothyroidism a risk factor for non-alcoholic steatohepatitis. Journal of Clinical Gastroenterology 2003, 37:340-343.
142. Ittermann T., Haring R., Wallaschofski H., et al. Inverse association between serum free thyroxine levels and hepatic steatosis: results from the Study of Health in Pomerania. Thyroid 2012, 22:568-574.
143. Chung G.E., Kim D., Kim W., et al. Non-alcoholic fatty liver disease across the spectrum of hypothyroidism. Journal of Hepatology 2012, 57:150-156.
144. Targher G., Day C.P., Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. New England Journal of Medicine 2010, 363:1341-1350.
145. Lonardo A., Sookoian S., Chonchol M., et al. Cardiovascular and systemic risk in nonalcoholic fatty liver disease - atherosclerosis as a major player in the natural course of NAFLD. Current Pharmaceutical Design 2013, 19:5177-5192.
146. Lonardo A., Ballestri S., Targher G., et al. Diagnosis and management of cardiovascular risk in nonalcoholic fatty liver disease. Expert Review of Gastroenterology and Hepatology 2014, 1-22.
147. Ballestri S., Lonardo A., Bonapace S., et al. Risk of cardiovascular, cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease. World Journal of Gastroenterology 2014, 20:1724-1745.
148. Byrne C.D., Targher G. Ectopic fat, insulin resistance, and nonalcoholic fatty liver disease: implications for cardiovascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology 2014, 34:1155-1161.
149. Treeprasertsuk S., Leverage S., Adams L.A., et al. The Framingham risk score and heart disease in nonalcoholic fatty liver disease. Liver International 2012, 32:945-950.
150. Eichler K., Puhan M.A., Steurer J., et al. Prediction of first coronary events with the Framingham score: a systematic review. American Heart Journal 2007, 153:722-731.
151. Vuppalanchi R., Gould R.J., Wilson L.A., et al. Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). Clinical significance of serum autoantibodies in patients with NAFLD: results from the nonalcoholic steatohepatitis clinical research network. Hepatology International 2011.
152. McPherson S., Henderson E., Burt A.D., et al. Serum immunoglobulin levels predict fibrosis in patients with non-alcoholic fatty liver disease. Journal of Hepatology 2014, 10.1016/j.jhep.2014.01.010.
153. Petta S., Muratore C., Craxì A. Non-alcoholic fatty liver disease pathogenesis: the present and the future. Digestive and Liver Disease 2009, 41:615-625.
154. Wree A., Broderick L., Canbay A., et al. From NAFLD to NASH to cirrhosis - new insights into disease mechanisms. Nature Reviews Gastroenterology and Hepatology 2013, 10:627-636.
155. Gadd V.L., Skoien R., Powell E.E., et al. The portal inflammatory infiltrate and ductular reaction in human non-alcoholic fatty liver disease. Hepatology 2014, 59:1393-1405.
156. Miele L., Vallone S., Cefalo C., et al. Prevalence, characteristics and severity of non-alcoholic fatty liver disease in patients with chronic plaque psoriasis. Journal of Hepatology 2009, 51:778-786.
157. Híndi M., Levy C., Couto C.A., et al. Primary biliary cirrhosis is more severe in overweight patients. Journal of Clinical Gastroenterology 2013, 47:e28-e32.
158. Sorrentino P., Terracciano L., D'Angelo S., et al. Oxidative stress and steatosis are cofactors of liver injury in primary biliary cirrhosis. Journal of Gastroenterology 2010, 45:1053-1062.
159. Drebber U., Mueller J.J., Klein E., et al. Liver biopsy in primary biliary cirrhosis: clinicopathological data and stage. Pathology International 2009, 59:546-554.
160. Abenavoli L., Luigiano C., Larussa T., et al. Liver steatosis in celiac disease: the open door. Minerva Gastroenterologica e Dietologica 2013, 59:89-95.
161. Rojas-Feria M., Castro M., Suárez E., et al. Hepatobiliary manifestations in inflammatory bowel disease: the gut, the drugs and the liver. World Journal of Gastroenterology 2013, 19:7327-7340.
162. Kummen M., Schrumpf E., Boberg K.M. Liver abnormalities in bowel diseases. Best Practice and Research. Clinical Gastroenterology 2013, 27:531-542.
163. Wieser V., Gerner R., Moschen A.R., et al. Liver complications in inflammatory bowel diseases. Digestive Diseases 2013, 31:233-238.
164. Bugianesi E., Salamone F., Negro F. The interaction of metabolic factors with HCV infection: does it matter?. Journal of Hepatology 2012, 56(S1):S56-S65.
165. Lonardo A., Adinolfi L.E., Loria P., et al. Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology 2004, 126:586-597.
166. Rubbia-Brandt L., Quadri R., Abid K., et al. Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. Journal of Hepatology 2000, 33:106-115.
167. Abid K., Pazienza V., De Gottardi A., et al. An in vitro model of hepatitis C virus genotype 3a-associated triglycerides accumulation. Journal of Hepatology 2005, 42:744-751.
168. Piodi A., Chouteau P., Lerat H., et al. Morphological changes in intracellular lipid droplets induced by different hepatitis C virus genotype core sequences and relationship with steatosis. Hepatology 2008, 48:16-27.
169. Mihm S., Fayyazi A., Hartmann H., et al. Analysis of histopathological manifestations of chronic hepatitis C virus infection with respect to virus genotype. Hepatology 1997, 25:735-739.
170. Adinolfi L.E., Gambardella M., Andreana A., et al. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 2001, 33:1358-1364.
171. Poynard T., Ratziu V., McHutchison J., et al. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology 2003, 38:75-85.
172. Leandro G., Mangia A., Hui J., et al. HCV Meta-Analysis (on) Individual Patients' Data Study Group. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterology 2006, 130:1636-1642.
173. Shintani Y., Fujie H., Miyoshi H., et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology 2004, 126:840-848.
174. Cua I.H., Hui J.M., Kench J.G., et al. Genotype-specific interactions of insulin resistance, steatosis, and fibrosis in chronic hepatitis C. Hepatology 2008, 48:723-731.
175. Romero-Gómez M., Del Mar Viloria M., Andrade R.J., et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology 2005, 128:636-641.
176. Trepo E., Pradat P., Potthoff A., et al. Impact of pnpla3 (rs738409 c>g) polymorphism on fibrosis progression and steatosis in chronic hepatitis c. Hepatology 2011, 54:60-69.
177. Vanni E., Abate M.L., Gentilcore E., et al. Sites and mechanisms of insulin resistance in nonobese, nondiabetic patients with chronic hepatitis C. Hepatology 2009, 50:697-706.
178. Milner K.L., van der Poorten D., Trenell M., et al. Chronic hepatitis C is associated with peripheral rather than hepatic insulin resistance. Gastroenterology 2010, 138. 932-41.e1-3.
179. Petta S., Rosso C., Leung R., et al. Effects of IL28B rs12979860 CC genotype on metabolic profile and sustained virologic response in patients with genotype 1 chronic hepatitis C. Clinical Gastroenterology and Hepatology 2013, 11. 311-7.e1.
180. Petta S., Amato M., Cabibi D., et al. Visceral adiposity index is associated with histological findings and high viral load in patients with chronic hepatitis C due to genotype 1. Hepatology 2010, 52:1543-1552.
181. Patton H.M., Patel K., Behling C., et al. The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. Journal of Hepatology 2004, 40:484-490.
182. Fartoux L., Chazouilleres O., Wendum D., et al. Impact of steatosis on progression of fibrosis inpatients with mild hepatitis C. Hepatology 2005, 41:82-87.
183. Castera L., Hezode C., Roudot-Thoraval F., et al. Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies. Gut 2003, 52:288-292.
184. Pekow J.R., Bhan A.K., Zheng H., Chung R.T. Hepatic steatosis is associated with increased frequency of hepatocellular carcinoma in patients with hepatitis C-related cirrhosis. Cancer 2007, 109:2490-2496.
185. Lerat H., Honda M., Beard M.R., et al. Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus. Gastroenterology 2001, 122:352-365.
186. Rosario R., Ramakrishna B. Histopathological study of chronic hepatitis B and C: a comparison of two scoring systems. Journal of Hepatology 2003, 38:223-229.
187. Gordon A., McLean C.A., Pedersen J.S., et al. Hepatic steatosis in chronic hepatitis B and C: predictors, distribution and effect on fibrosis. Journal of Hepatology 2005, 43:38-44.
188. Peng D., Han Y., Ding H., Wei L. Hepatic steatosis in chronic hepatitis B patients is associated with metabolic factors more than viral factors. Journal of Gastroenterology and Hepatology 2008, 23:1082-1088.
189. Rastogi A., Sakhuja P., Kumar A., et al. Steatosis in chronic hepatitis B: prevalence and correlation with biochemical, histologic, viral, and metabolic parameters. Indian Journal of Pathology and Microbiology 2011, 54:454-459.
190. Kumar M., Choudhury A., Manglik N., et al. Insulin resistance in chronic hepatitis B virus infection. American Journal of Gastroenterology 2009, 104:76-82.
191. Park S.H., Kim D.J., Lee H.Y. Insulin resistance is not associated with histologic severity in nondiabetic, noncirrhotic patients with chronic hepatitis B virus infection. American Journal of Gastroenterology 2009, 104:1135-1139.
192. Petta S., Cammà C., Di Marco V., et al. Hepatic steatosis and insulin resistance are associated with severe fibrosis in patients with chronic hepatitis caused by HBV or HCV infection. Liver International 2011, 31:507-515.
193. Kim K., Kim K.H., Kim H.H., et al. Hepatitis B virus X protein induces lipogenic transcription factor SREBP1 and fatty acid synthase through the activation of nuclear receptor LXR alpha. Biochemical Journal 2008, 416:219-230.
194. Kim K., Shin H., Kim K., et al. Hepatitis B virus X protein induces hepatic steatosis via transcriptional activation of SREBP1 and PPARg. Gastroenterology 2007, 132:1955-1967.
195. Na T., Shin Y., Roh K., et al. Liver X receptor mediates hepatitis B virus X protein-induced lipogenesis in hepatitis B virus-associated hepatocellular carcinoma. Hepatology 2009.
196. Ruhl C.E., Everhart J.E. Relationship of non-alcoholic fatty liver disease with cholecystectomy in the US population. American Journal of Gastroenterology 2013, 108:952-958.
197. Fracanzani A.L., Valenti L., Russello M., et al. Gallstone disease is associated with more severe liver damage in patients with non-alcoholic fatty liver disease. PLoS ONE 2012, 7:e41183.
198. Drenos F., Grossi E., Buscema M., et al. Networks in coronary heart disease genetics as a step towards systems epidemiology. PLOS ONE 2015, 10:e0125876.