Paediatric non-alcoholic fatty liver disease: An overview

Obesity Reviews

Volumn 16, Issue 5, 2015, Pages 393-405

  Alkhater, S A ^a  

^a IMAM ABDULRAHMAN BIN FAISAL UNIVERSITY   (Saudi Arabia)

Author keywords

Non alcoholic fatty liver disease; Non alcoholic steatohepatitis; Obesity; Paediatric

Indexed keywords

ANTIOXIDANT; CYTOPROTECTIVE AGENT; INSULIN SENSITIZING AGENT;

ACANTHOSIS NIGRICANS; ARTICLE; BARIATRIC SURGERY; CHILDHOOD OBESITY; CYTOKINE PRODUCTION; DECOMPENSATED LIVER CIRRHOSIS; DIET; DIET SUPPLEMENTATION; EXERCISE; HUMAN; HYPERTRANSAMINASEMIA; LIFESTYLE MODIFICATION; LIVER BIOPSY; LIVER CELL CARCINOMA; LIVER FIBROSIS; LIVER TRANSPLANTATION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; OUTCOME ASSESSMENT; PATHOGENESIS; PREVALENCE; RANDOMIZED CONTROLLED TRIAL (TOPIC); UPPER ABDOMINAL PAIN; WAIST CIRCUMFERENCE; WEIGHT REDUCTION; CARDIOVASCULAR DISEASES; CHILD; COMPLICATION; DISEASE COURSE; MASS SCREENING; NON-ALCOHOLIC FATTY LIVER DISEASE; PATHOPHYSIOLOGY; PEDIATRIC OBESITY; PRACTICE GUIDELINE; PUBLIC HEALTH; RISK FACTOR;

CARDIOVASCULAR DISEASES; CHILD; DISEASE PROGRESSION; HUMANS; MASS SCREENING; NON-ALCOHOLIC FATTY LIVER DISEASE; PEDIATRIC OBESITY; PRACTICE GUIDELINES AS TOPIC; PUBLIC HEALTH; RISK FACTORS;

EID: 84927974995     PISSN: 14677881     EISSN: 1467789X     Source Type: Journal    
DOI: 10.1111/obr.12271     Document Type: Article

References (140)

1. Tiniakos DG, Vos MB, Brunt EM. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol 2010; 5: 145-171.
2. Chalasani N, Younossi Z, Lavine JE etal. The diagnosis and management of non-alcoholic 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 2012; 55: 2005-2023.
3. Day CP. Natural history of NAFLD: remarkably benign in the absence of cirrhosis. Gastroenterology 2005; 129: 375-378.
4. Marchesini G, Brizi M, Bianchi G etal. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001; 50: 1844-1850.
5. Lipshultz SE, Messiah SE, Miller TL. Pediatric Metabolic Syndrome: Comprehensive Clinical Review and Related Health Issues. Springer Verlag: London, 2012.
6. Eckel RH, Alberti KG, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2010; 375: 181-183.
7. Miranda PJ, DeFronzo RA, Califf RM, Guyton JR. Metabolic syndrome: definition, pathophysiology, and mechanisms. Am Heart J 2005; 149: 33-45.
8. Janssen I, Katzmarzyk PT, Boyce WF etal. Comparison of overweight and obesity prevalence in school-aged youth from 34 countries and their relationships with physical activity and dietary patterns. Obes Rev 2005; 6: 123-132.
9. Ji CY, Cooperative Study on Childhood Obesity: Working Group on Obesity in China (WGOC). The prevalence of childhood overweight/obesity and the epidemic changes in 1985-2000 for Chinese school-age children and adolescents. Obes Rev 2008; 9(Suppl. 1): 78-81.
10. Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, Benson JT, Enders FB, Angulo P. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut 2009; 58: 1538-1544.
11. Giorgio V, Prono F, Graziano F, Nobili V. Pediatric non alcoholic fatty liver disease: old and new concepts on development, progression, metabolic insight and potential treatment targets. BMC Pediatr 2013; 13: 40.
12. Strauss RS, Barlow SE, Dietz WH. Prevalence of abnormal serum aminotransferase values in overweight and obese adolescents. J Pediatr 2000; 136: 727-733.
13. Fraser A, Longnecker MP, Lawlor DA. Prevalence of elevated alanine aminotransferase among US adolescents and associated factors: NHANES 1999-2004. Gastroenterology 2007; 133: 1814-1820.
14. Barshop NJ, Sirlin CB, Schwimmer JB, Lavine JE. Review article: epidemiology, pathogenesis and potential treatments of paediatric non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2008; 28: 13-24.
15. Tominaga K, Kurata JH, Chen YK etal. Prevalence of fatty liver in Japanese children and relationship to obesity. An epidemiological ultrasonographic survey. Dig Dis Sci 1995; 40: 2002-2009.
16. Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr 2000; 30: 48-53.
17. Fishbein MH, Miner M, Mogren C, Chalekson J. The spectrum of fatty liver in obese children and the relationship of serum aminotransferases to severity of steatosis. J Pediatr Gastroenterol Nutr 2003; 36: 54-61.
18. Tazawa Y, Noguchi H, Nishinomiya F, Takada G. Serum alanine aminotransferase activity in obese children. Acta Paediatr 1997; 86: 238-241.
19. Manton ND, Lipsett J, Moore DJ, Davidson GP, Bourne AJ, Couper RT. Non-alcoholic steatohepatitis in children and adolescents. Med J Aust 2000; 173: 476-479.
20. Dasarathy S, Dasarathy J, Khiyami A, Joseph R, Lopez R, McCullough AJ. Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study. J Hepatol 2009; 51: 1061-1067.
21. Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics 2006; 118: 1388-1393.
22. Loomba R, Sirlin CB, Schwimmer JB, Lavine JE. Advances in pediatric nonalcoholic fatty liver disease. Hepatology 2009; 50: 1282-1293.
23. Maurantonio M, Ballestri S, Odoardi MR, Lonardo A, Loria P. Treatment of atherogenic liver based on the pathogenesis of nonalcoholic fatty liver disease: a novel approach to reduce cardiovascular risk? Arch Med Res 2011; 42: 337-353.
24. Alisi A, Manco M, Devito R, Nobili V. Fatty liver disease. In: Freemark M (ed.). Pediatric Obesity: Etiology, Pathogenesis and Treatment. Humana Press: Totowa, 2010, pp. 201-222.
25. El-Karaksy HM, el-Koofy NM, Anwar GM, el-Mougy FM, el-Hennawy A, Fahmy ME. Predictors of non-alcoholic fatty liver disease in obese and overweight Egyptian children: single center study. Saudi J Gastroenterol 2011; 17: 40-46.
26. Schwimmer JB, Deutsch R, Rauch JB, Behling C, Newbury R, Lavine JE. Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. J Pediatr 2003; 143: 500-505.
27. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 2004; 114: 147-152.
28. Day CP, James OF. Steatohepatitis: a tale of two 'hits'? Gastroenterology 1998; 114: 842-845.
29. Neels JG, Olefsky JM. Inflamed fat: what starts the fire? J Clin Invest 2006; 116: 33-35.
30. Feldstein AE, Canbay A, Guicciardi ME, Higuchi H, Bronk SF, Gores GJ. Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice. J Hepatol 2003; 39: 978-983.
31. Feldstein AE, Canbay A, Angulo P etal. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 2003; 125: 437-443.
32. Schwabe RF, Uchinami H, Qian T, Bennett BL, Lemasters JJ, Brenner DA. Differential requirement for c-Jun NH2-terminal kinase in TNFalpha- and Fas-mediated apoptosis in hepatocytes. FASEB J 2004; 18: 720-722.
33. Wieckowska A, Zein NN, Yerian LM, Lopez AR, McCullough AJ, Feldstein AE. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology 2006; 44: 27-33.
34. Feldstein AE, Wieckowska A, Lopez AR, Liu YC, Zein NN, McCullough AJ. Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 2009; 50: 1072-1078.
35. Day CP. Genetic and environmental susceptibility to non-alcoholic fatty liver disease. Dig Dis 2010; 28: 255-260.
36. Carvalhana S, Machado MV, Cortez-Pinto H. Improving dietary patterns in patients with nonalcoholic fatty liver disease. Curr Opin Clin Nutr Metab Care 2012; 15: 468-473.
37. Papandreou D, Rousso I, Malindretos P etal. Are saturated fatty acids and insulin resistance associated with fatty liver in obese children? Clin Nutr 2008; 27: 233-240.
38. McKeown NM, Meigs JB, Liu S, Saltzman E, Wilson PW, Jacques PF. Carbohydrate nutrition, insulin resistance, and the prevalence of the metabolic syndrome in the Framingham offspring cohort. Diabetes Care 2004; 27: 538-546.
39. Barrera F, George J. The role of diet and nutritional intervention for the management of patients with NAFLD. Clin Liver Dis 2014; 18: 91-112.
40. Lau C, Faerch K, Glümer C etal. Dietary glycemic index, glycemic load, fiber, simple sugars, and insulin resistance: the Inter99 study. Diabetes Care 2005; 28: 1397-1403.
41. Lim JS, Mietus-Snyder M, Valente A, Schwarz JM, Lustig RH. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol 2010; 7: 251-264.
42. Thuy S, Ladurner R, Volynets V etal. Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake. J Nutr 2008; 138: 1452-1455.
43. Abdelmalek MF, Suzuki A, Guy C etal. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology 2010; 51: 1961-1971.
44. Musso G, Gambino R, De Michieli F etal. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology 2003; 37: 909-916.
45. Hashemi Kani A, Alavian SM, Esmaillzadeh A, Adibi P, Azadbakht L. Dietary quality indices and biochemical parameters among patients with non alcoholic fatty liver disease (NAFLD). Hepat Mon 2013; 13: e10943.
46. Kennedy ET, Ohls J, Carlson S, Fleming K. The healthy eating index: design and applications. J Am Diet Assoc 1995; 95: 1103-1108.
47. Valenti L, Alisi A, Galmozzi E etal. I148M patatin-like phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease. Hepatology 2010; 52: 1274-1280.
48. Willner IR, Waters B, Patil SR, Reuben A, Morelli J, Riely CA. Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol 2001; 96: 2957-2961.
49. Nobili V, Svegliati-Baroni G, Alisi A, Miele L, Valenti L, Vajro P. A 360-degree overview of paediatric NAFLD: recent insights. J Hepatol 2013; 58: 1218-1229.
50. Di Rosa M, Malaguarnera L. Genetic variants in candidate genes influencing NAFLD progression. J Mol Med (Berl) 2012; 90: 105-118.
51. Naik A, Košir R, Rozman D. Genomic aspects of NAFLD pathogenesis. Genomics 2013; 102: 84-95.
52. Schwimmer JB, Behling C, Newbury R etal. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology 2005; 42: 641-649.
53. Manco M, Bedogni G, Marcellini M etal. Waist circumference correlates with liver fibrosis in children with non-alcoholic steatohepatitis. Gut 2008; 57: 1283-1287.
54. Moucari R, Asselah T, Cazals-Hatem D etal. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology 2008; 134: 416-423.
55. Powell EE, Jonsson JR, Clouston AD. Steatosis: co-factor in other liver diseases. Hepatology 2005; 42: 5-13.
56. Naveau S, Giraud V, Borotto E, Aubert A, Capron F, Chaput JC. Excess weight risk factor for alcoholic liver disease. Hepatology 1997; 25: 108-111.
57. Powell EE, Ali A, Clouston AD etal. Steatosis is a cofactor in liver injury in hemochromatosis. Gastroenterology 2005; 129: 1937-1943.
58. Bugianesi E. Non-alcoholic steatohepatitis and cancer. Clin Liver Dis 2007; 11: 191-207.
59. Adams LA, Waters OR, Knuiman MW, Elliott RR, Olynyk JK. NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: an eleven-year follow-up study. Am J Gastroenterol 2009; 104: 861-867.
60. Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011; 43: 617-649.
61. D'Adamo E, Cali AM, Weiss R etal. Central role of fatty liver in the pathogenesis of insulin resistance in obese adolescents. Diabetes Care 2010; 33: 1817-1822.
62. Cai D, Yuan M, Frantz DF etal. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 2005; 11: 183-190.
63. Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013; 10: 330-344.
64. Alkhouri N, Carter-Kent C, Elias M, Feldstein AE. Atherogenic dyslipidemia and cardiovascular risk in children with nonalcoholic fatty liver disease. Clin Lipidol 2011; 6: 305-314.
65. Pacifico L, Anania C, Martino F etal. Functional and morphological vascular changes in pediatric nonalcoholic fatty liver disease. Hepatology 2010; 52: 1643-1651.
66. Schwimmer JB, Pardee PE, Lavine JE, Blumkin AK, Cook S. Cardiovascular risk factors and the metabolic syndrome in pediatric nonalcoholic fatty liver disease. Circulation 2008; 118: 277-283.
67. Pacifico L, Nobili V, Anania C, Verdecchia P, Chiesa C. Pediatric nonalcoholic fatty liver disease, metabolic syndrome and cardiovascular risk. World J Gastroenterol 2011; 17: 3082-3091.
68. Schwimmer JB, Deutsch R, Behling C, Lavine JE. Fatty liver as a determinant of atherosclerosis. Hepatology 2005; 42: 610A.
69. Patton HM, Sirlin C, Behling C, Middleton M, Schwimmer JB, Lavine JE. Pediatric nonalcoholic fatty liver disease: a critical appraisal of current data and implications for future research. J Pediatr Gastroenterol Nutr 2006; 43: 413-427.
70. Fishbein M, Mogren J, Mogren C, Cox S, Jennings R. Undetected hepatomegaly in obese children by primary care physicians: a pitfall in the diagnosis of pediatric nonalcoholic fatty liver disease. Clin Pediatr (Phila) 2005; 44: 135-141.
71. Loguercio C, De Simone T, D'Auria MV etal. Non-alcoholic fatty liver disease: a multicentre clinical study by the Italian Association for the study of the liver. Dig Liver Dis 2004; 36: 398-405.
72. Molleston JP, Schwimmer JB, Yates KP etal. Histological abnormalities in children with nonalcoholic fatty liver disease and normal or mildly elevated alanine aminotransferase levels. J Pediatr 2014; 164: 707-713.
73. Shannon A, Alkhouri N, Carter-Kent C etal. Ultrasonographic quantitative estimation of hepatic steatosis in children with NAFLD. J Pediatr Gastroenterol Nutr 2011; 53: 190-195.
74. Strauss S, Gavish E, Gottlieb P, Katsnelson L. Interobserver and intraobserver variability in the sonographic assessment of fatty liver. Am J Roentgenol 2007; 189: W320-W323.
75. Saadeh S, Younossi ZM, Remer EM etal. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002; 123: 745-750.
76. Schwenzer NF, Springer F, Schraml C, Stefan N, Machann J, Schick F. Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance. J Hepatol 2009; 51: 433-445.
77. Alisi A, de Vito R, Monti L, Nobili V. Liver fibrosis in paediatric liver diseases. Best Pract Res Clin Gastroenterol 2011; 25: 259-268.
78. Hsu E, Murray K. Is nonalcoholic fatty liver disease in children the same disease as in adults? Clin Liver Dis 2012; 16: 587-598.
79. Irwan R, Edens MA, Sijens PE. Assessment of the variations in fat content in normal liver using a fast MR imaging method in comparison with results obtained by spectroscopic imaging. Eur Radiol 2008; 18: 806-813.
80. Guiu B, Loffroy R, Petit JM etal. Mapping of liver fat with triple-echo gradient echo imaging: validation against 3.0-T proton MR spectroscopy. Eur Radiol 2009; 19: 1786-1793.
81. Yin M, Talwalkar JA, Glaser KJ etal. Assessment of hepatic fibrosis with magnetic resonance elastography. Clin Gastroenterol Hepatol 2007; 5: 1207-1213.
82. Nobili V, Vizzutti F, Arena U etal. Accuracy and reproducibility of transient elastography for the diagnosis of fibrosis in pediatric nonalcoholic steatohepatitis. Hepatology 2008; 48: 442-448.
83. Bohte AE, Nederveen AJ, Stoker J. Hepatic fat-content assessment using magnetic resonance-based methods. Imaging Med 2011; 3: 193-206.
84. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 2006; 43(Suppl. 1): S99-S112.
85. Bedossa P. Current histological classification of NAFLD: strength and limitations. Hepatol Int 2013; 7: 765-770.
86. Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander-Tetri BA, NASH Clinical Research Network (CRN). Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology 2011; 53: 810-820.
87. Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD, American Association for the Study of Liver Diseases. Liver biopsy. Hepatology 2009; 49: 1017-1044.
88. Feldstein AE, Alkhouri N, De Vito R, Alisi A, Lopez R, Nobili V. Serum cytokeratin-18 fragment levels are useful biomarkers for nonalcoholic steatohepatitis in children. Am J Gastroenterol 2013; 108: 1526-1531.
89. Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 2010; 53: 372-384.
90. Daniels SR. Prevention of atherosclerotic cardiovascular disease: what is the best approach and how early should we start? J Am Coll Cardiol 2014; 63: 2786-2788.
91. Alisi A, Nobili V. Non-alcoholic fatty liver disease in children now: lifestyle changes and pharmacologic treatments. Nutrition 2012; 28: 722-726.
92. Hickman IJ, Clouston AD, Macdonald GA etal. Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis C. Gut 2002; 51: 89-94.
93. Torres DM, Harrison SA. Diagnosis and therapy of nonalcoholic steatohepatitis. Gastroenterology 2008; 134: 1682-1698.
94. Nobili V, Manco M, Devito R etal. Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Hepatology 2008; 48: 119-128.
95. U.S. Department of Agriculture, U.S. Department of Health and Human Services. Dietary Guidelines for Americans, 7th edn. U.S. Government Printing Office Publishing House: Washington, DC, 2010.
96. Berg F, Buechner J, Parham E, Weight Realities Division of the Society for Nutrition Education. Guidelines for childhood obesity prevention programs: promoting healthy weight in children. J Nutr Educ Behav 2003; 35: 1-4.
97. Gidding SS, Dennison BA, Birch LL etal. Dietary recommendations for children and adolescents: a guide for practitioners. Pediatrics 2006; 117: 544-559.
98. Vos MB, Weber MB, Welsh J etal. Fructose and oxidized low-density lipoprotein in pediatric nonalcoholic fatty liver disease: a pilot study. Arch Pediatr Adolesc Med 2009; 163: 674-675.
99. Lê KA, Tappy L. Metabolic effects of fructose. Curr Opin Clin Nutr Metab Care 2006; 9: 469-475.
100. Mikines KJ, Sonne B, Farrell PA, Tronier B, Galbo H. Effect of physical exercise on sensitivity and responsiveness to insulin in humans. Am J Physiol 1988; 254: E248-E259.
101. Dela F, Mikines KJ, von Linstow M, Secher NH, Galbo H. Effect of training on insulin-mediated glucose uptake in human muscle. Am J Physiol 1992; 263: E1134-E1143.
102. Van der Heijden GJ, Wang ZJ, Chu ZD etal. A 12-week aerobic exercise program reduces hepatic fat accumulation and insulin resistance in obese, Hispanic adolescents. Obesity (Silver Spring) 2010; 18: 384-390.
103. Yap JYK, O'Connor C, Mager DR, Taylor G, Roberts EA. Diagnostic challenges of nonalcoholic fatty liver disease (NAFLD) in children of normal weight. Clin Res Hepatol Gastroenterol 2011; 35: 500-505.
104. Vajro P, Lenta S, Pignata C etal. Therapeutic options in pediatric non alcoholic fatty liver disease: current status and future directions. Ital J Pediatr 2012; 38: 55.
105. Chitturi S, Abeygunasekera S, Farrell GC etal. Nash and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002; 35: 373-379.
106. Schwimmer JB, Middleton MS, Deutsch R, Lavine JE. A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2005; 21: 871-879.
107. Nobili V, Manco M, Ciampalini P etal. Metformin use in children with nonalcoholic fatty liver disease: an open-label, 24-month, observational pilot study. Clin Ther 2008; 30: 1168-1176.
108. Lavine JE, Schwimmer JB, Van Natta ML etal. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011; 305: 1659-1668.
109. Belfort R, Harrison SA, Brown K etal. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355: 2297-2307.
110. Trauner M, Claudel T, Fickert P, Moustafa T, Wagner M. Bile acids as regulators of hepatic lipid and glucose metabolism. Dig Dis 2010; 28: 220-224.
111. Vajro P, Franzese A, Valerio G, Iannucci MP, Aragione N. Lack of efficacy of ursodeoxycholic acid for the treatment of liver abnormalities in obese children. J Pediatr 2000; 136: 739-743.
112. Leuschner UFH, Lindenthal B, Herrmann G etal. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology 2010; 52: 472-479.
113. Dufour JF, Oneta CM, Gonvers JJ etal. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin E in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2006; 4: 1537-1543.
114. Lavine JE. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr 2000; 136: 734-738.
115. Vajro P, Mandato C, Franzese A etal. Vitamin E treatment in pediatric obesity-related liver disease: a randomized study. J Pediatr Gastroenterol Nutr 2004; 38: 48-55.
116. Nobili V, Manco M, Devito R, Ciampalini P, Piemonte F, Marcellini M. Effect of vitamin E on aminotransferase levels and insulin resistance in children with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2006; 24: 1553-1561.
117. Wang CL, Liang L, Fu JF etal. Effect of lifestyle intervention on non-alcoholic fatty liver disease in Chinese obese children. World J Gastroenterol 2008; 14: 1598-1602.
118. Vos MB, Colvin R, Belt P etal. Correlation of vitamin E, uric acid, and diet composition with histologic features of pediatric NAFLD. J Pediatr Gastroenterol Nutr 2012; 54: 90-96.
119. Nobili V, Bedogni G, Alisi A etal. Docosahexaenoic acid supplementation decreases liver fat content in children with non-alcoholic fatty liver disease: double-blind randomised controlled clinical trial. Arch Dis Child 2011; 96: 350-353.
120. Nobili V, Alisi A, Della Corte C etal. Docosahexaenoic acid for the treatment of fatty liver: randomised controlled trial in children. Nutr Metab Cardiovasc Dis 2013; 23: 1066-1070.
121. Masterton GS, Plevris JN, Hayes PC. Review article: omega-3 fatty acids - a promising novel therapy for non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2010; 31: 679-692.
122. Nobili V, Carpino G, Alisi A etal. Role of docosahexaenoic acid treatment in improving liver histology in pediatric nonalcoholic fatty liver disease. PLoS ONE 2014; 9: e88005.
123. Musso G, Gambino R, Cassader M. Gut microbiota as a regulator of energy homeostasis and ectopic fat deposition: mechanisms and implications for metabolic disorders. Curr Opin Lipidol 2010; 21: 76-83.
124. Payne AN, Chassard C, Lacroix C. Gut microbial adaptation to dietary consumption of fructose, artificial sweeteners and sugar alcohols: implications for host-microbe interactions contributing to obesity. Obes Rev 2012; 13: 799-809.
125. Spruss A, Kanuri G, Wagnerberger S, Haub S, Bischoff SC, Bergheim I. Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice. Hepatology 2009; 50: 1094-1104.
126. Loguercio C, Federico A, Tuccillo C etal. Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol 2005; 39: 540-543.
127. Vajro P, Mandato C, Licenziati MR etal. Effects of Lactobacillus rhamnosus strain GG in pediatric obesity-related liver disease. J Pediatr Gastroenterol Nutr 2011; 52: 740-743.
128. Iacono A, Raso GM, Canani RB, Calignano A, Meli R. Probiotics as an emerging therapeutic strategy to treat NAFLD: focus on molecular and biochemical mechanisms. J Nutr Biochem 2011; 22: 699-711.
129. Pan MH, Lai CS, Tsai ML, Ho CT. Chemoprevention of nonalcoholic fatty liver disease by dietary natural compounds. Mol Nutr Food Res 2014; 58: 147-171.
130. Klein S, Mittendorfer B, Eagon JC etal. Gastric bypass surgery improves metabolic and hepatic abnormalities associated with nonalcoholic fatty liver disease. Gastroenterology 2006; 130: 1564-1572.
131. Mathurin P, Hollebecque A, Arnalsteen L etal. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology 2009; 137: 532-540.
132. Nadler EP, Youn HA, Ren CJ, Fielding GA. An update on 73 US obese pediatric patients treated with laparoscopic adjustable gastric banding: comorbidity resolution and compliance data. J Pediatr Surg 2008; 43: 141-146.
133. Nadler EP, Reddy S, Isenalumhe A etal. Laparoscopic adjustable gastric banding for morbidly obese adolescents affects android fat loss, resolution of comorbidities, and improved metabolic status. J Am Coll Surg 2009; 209: 638-644.
134. Pardee PE, Lavine JE, Schwimmer JB. Diagnosis and treatment of pediatric nonalcoholic steatohepatitis and the implications for bariatric surgery. Semin Pediatr Surg 2009; 18: 144-151.
135. Della Corte C, Vajro P, Socha P, Nobili V. Pediatric non-alcoholic fatty liver disease: recent advances. Clin Res Hepatol Gastroenterol 2014; 38: 419-422.
136. Lindbäck SM, Gabbert C, Johnson BL etal. Pediatric nonalcoholic fatty liver disease: a comprehensive review. Adv Pediatr 2010; 57: 85-140.
137. Dohil R, Meyer L, Schmeltzer S, Cabrera BL, Lavine JE, Phillips SA. The effect of cysteamine bitartrate on adiponectin multimerization in non-alcoholic fatty liver disease and healthy subjects. J Pediatr 2012; 161: 639-645.
138. Zein CO, Yerian LM, Gogate P etal. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 2011; 54: 1610-1619.
139. Li W, Zheng L, Sheng C, Cheng X, Qing L, Qu S. Systematic review on the treatment of pentoxifylline in patients with non-alcoholic fatty liver disease. Lipids Health Dis 2011; 10: 49.
140. Miura K, Seki E, Ohnishi H, Brenner DA. Role of toll-like receptors and their downstream molecule in the development of nonalcoholic fatty liver disease. Gastroenterol Res Pract 2010; 2010: 362847.