The Journal of Pediatrics
Volume 155, Issue 4 , Pages 469-474 , October 2009

Pediatric Nonalcoholic Fatty Liver Disease in 2009

  • Anna Alisi, PhD

      Affiliations

    • Liver Unit, “Bambino Gesù,” Children's Hospital and Research Institute, Rome, Italy
    • ,
  • Melania Manco, MD, PhD

      Affiliations

    • Scientific Directorate of “Bambino Gesù,” Children's Hospital and Research Institute, Rome, Italy
    • ,
  • Andrea Vania, MD

      Affiliations

    • Center for Nutrition and Dietetics of the Department of Pediatrics, La Sapienza University, Rome, Italy
    • ,
  • Valerio Nobili, MD

      Affiliations

    • Liver Unit, “Bambino Gesù,” Children's Hospital and Research Institute, Rome, Italy
    • Corresponding Author InformationReprint requests: Dr. Valerio Nobili, Liver Unit, “Bambino Gesù” Children's Hospital and Research Institute, Via S. Onofrio 4, 00165 Rome, Italy.

Received 3 February 2009 ,Revised 6 May 2009 ,Accepted 9 June 2009.

References 

  1. Wang Y, Lobstein T. Worldwide trends in childhood overweight and obesity. Int J Pediatr Obes. 2006;1:11–25
  2. World Health Organisation. Physical status: the use and interpretation of anthropometry. Geneva: WHO; 1995;
  3. World Health Organisation. Obesity, preventing and managing the global epidemic: report of a WHO consultation. Geneva: WHO Technical Report Series, No. 894; 2000;
  4. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ. 2000;320:1240–1246
  5. 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
  6. 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
  7. Moran JR, Ghishan FK, Halter SA, Greene HL. Steatohepatitis in obese children: a cause of chronic liver dysfunction. Am J Gastroenterol. 1983;78:374–377
  8. Ong JP, Younossi ZM. Epidemiology and natural history of NAFLD and NASH. Clin Liver Dis. 2007;11:1–16
  9. Papandreou D, Rousso I, Mavromichalis I. Update on non-alcoholic fatty liver disease in children. Clin Nutr. 2007;26:409–415
  10. Maclaren NK, Gujral S, Ten S, Motagheti R. Childhood obesity and insulin resistance. Cell Biochem Biophys. 2007;48:73–78
  11. Dunn W, Schwimmer JB. The obesity epidemic and nonalcoholic fatty liver disease in children. Curr Gastroenterol Rep. 2008;10:67–72
  12. Manco M, Bottazzo G, DeVito R, Marcellini M, Mingrone G, Nobili V. Nonalcoholic fatty liver disease in children. J Am Coll Nutr. 2008;27:667–676
  13. Bugianesi E. Non-alcoholic steatohepatitis and cancer. Clin Liver Dis. 2007;11:191–207
  14. Wieckowska A, Feldstein AE. Diagnosis of nonalcoholic fatty liver disease: invasive versus noninvasive. Semin Liver Dis. 2008;28:386–395
  15. Patton HM, Lavine JE, Van Natta ML, Schwimmer JB, Kleiner D, Molleston J, et al. Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis. Gastroenterology. 2008;135:1961–1971
  16. Kashi MR, Torres DM, Harrison SA. Current and emerging therapies in nonalcoholic fatty liver disease. Semin Liver Dis. 2008;28:396–406
  17. Kinugasa A, Tsunamoto K, Furukawa N, Sawada T, Kusunoki T, Shimada N. Fatty liver and its fibrous changes found in simple obesity of children. J Pediatr Gastroenterol Nutr. 1984;3:408–414
  18. Franzese A, Vajro P, Argenziano A, Puzziello A, Iannucci MP, Saviano MC, et al. Liver involvement in obese children: ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population. Dig Dis Sci. 1997;42:1428–1432
  19. Strauss RS, Barlow SE, Dietz WH. Prevalence of abnormal serum aminotransferase values in overweight and obese adolescents. J Pediatr. 2000;136:727–733
  20. Schwimmer JB, McGreal N, Deutsch R, Finegold MJ, Lavine JE. Influence of gender, race, and ethnicity on suspected fatty liver in obese adolescents. Pediatrics. 2005;115:e561–e565
  21. Fishbein MH, Mogren C, Gleason T, Stevens WR. Relationship of hepatic steatosis to adipose tissue distribution in pediatric nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2006;42:83–88
  22. Nakao K, Nakata K, Ohtsubo N, Maeda M, Moriuchi T, Ichikawa T, et al. Association between nonalcoholic fatty liver, markers of obesity, and serum leptin level in young adults. Am J Gastroenterol. 2002;97:1796–1801
  23. Manco M, Bedogni G, Marcellini M, Devito R, Ciampalini P, Sartorelli MR, et al. Waist circumference correlates with liver fibrosis in children with non-alcoholic steatohepatitis. Gut. 2008;57:1283–1287
  24. Manco M, Marcellini M, Devito R, Comparcola D, Sartorelli MR, Nobili V. Metabolic syndrome and liver histology in paediatric non-alcoholic steatohepatitis. Int J Obes (Lond). 2008;32:381–387
  25. Chan DF, Li AM, Chu WC, Chan MH, Wong EM, Liu EK, et al. Hepatic steatosis in obese Chinese children. Int J Obes Relat Metab Disord. 2004;28:1257–1263
  26. Schwimmer JB, Deutsch R, Rauch JB, Behling C, Newbury R, Lavine JE. Obesity, insulin resistance, and other clinicopathological correlations of pediatric nonalcoholic fatty liver disease. J Pediatr. 2003;143:500–505
  27. Kawasaki T, Hashimoto N, Kikuchi T, Takahashi H, Uchiyama M. The relationship between fatty liver and hyperinsulinemia in obese Japanese children. J Pediatr Gastroenterol Nutr. 1997;24:317–321
  28. Weiss R, Dziura J, Burgert TS, Tamborlane WV, Taksali SE, Yeckel CW, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med. 2004;350:2362–2374
  29. Kocak N, Yuce A, Gurakan F, Ozen H. Obesity: a cause of steatohepatitis in children. Am J Gastroenterol. 2000;95:1099–1100
  30. Perseghin G, Bonfanti R, Magni S, Lattuada G, De Cobelli F, Canu T, et al. Insulin resistance and whole body energy homeostasis in obese adolescents with fatty liver disease. Am J Physiol Endocrinol Metab. 2006;291:E697–E703
  31. Louthan MV, Barve S, McClain CJ, Joshi-Barve S. Decreased serum adiponectin: an early event in pediatric nonalcoholic fatty liver disease. J Pediatr. 2005;147:835–838
  32. Nobili V, Manco M, Ciampalini P, Diciommo V, Devito R, Piemonte F, et al. Leptin, free leptin index, insulin resistance and liver fibrosis in children with non-alcoholic fatty liver disease. Eur J Endocrinol. 2006;155:735–743
  33. 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
  34. Ogden CL, Flegal KM, Carroll MD, Johnson CL. Prevalence and trends in overweight among US children and adolescents, 1999-2000. JAMA. 2002;288:1728–1732
  35. Williams DE, Cadwell BL, Cheng YJ, Cowie CC, Gregg EW, Geiss LS, et al. Prevalence of impaired fasting glucose and its relationship with cardiovascular disease risk factors in US adolescents, 1999-2000. Pediatrics. 2005;116:1122–1126
  36. Comuzzie AG, Funahashi T, Sonnenberg G, Martin LJ, Jacob HJ, Black AE, et al. The genetic basis of plasma variation in adiponectin, a global endophenotype for obesity and the metabolic syndrome. J Clin Endocrinol Metab. 2001;86:4321–4325
  37. Lee S, Bacha F, Gungor N, Arslanian SA. Racial differences in adiponectin in youth: relationship to visceral fat and insulin sensitivity. Diabetes Care. 2006;29:51–56
  38. Arslan N, Buyukgebiz B, Ozturk Y, Cakmakci H. Fatty liver in obese children: prevalence and correlation with anthropometric measurements and hyperlipidemia. Turk J Pediatr. 2005;47:23–27
  39. Guzzaloni G, Grugni G, Minocci A, Moro D, Morabito F. Liver steatosis in juvenile obesity: correlations with lipid profile, hepatic biochemical parameters and glycemic and insulinemic responses to an oral glucose tolerance test. Int J Obes Relat Metab Disord. 2000;24:772–776
  40. 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
  41. Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr. 2000;30:48–53
  42. Schwimmer JB, Behling C, Newbury R, Deutsch R, Nievergelt C, Schork NJ, et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology. 2005;42:641–649
  43. Mager DR, Roberts EA. Nonalcoholic fatty liver disease in children. Clin Liver Dis. 2006;10:109–131
  44. Lonardo A, Carani C, Carulli N, Loria P. “Endocrine NAFLD” a hormonocentric perspective of nonalcoholic fatty liver disease pathogenesis. J Hepatol. 2006;44:1196–1207
  45. Cook JS, Hoffman RP, Stene MA, Hansen JR. Effects of maturational stage on insulin sensitivity during puberty. J Clin Endocrinol Metab. 1993;77:725–730
  46. Roemmich JN, Clark PA, Lusk M, Friel A, Weltman A, Epstein LH, et al. Pubertal alterations in growth and body composition, VI: pubertal insulin resistance: relation to adiposity, body fat distribution and hormone release. Int J Obes Relat Metab Disord. 2002;26:701–709
  47. Goran MI, Gower BA. Longitudinal study on pubertal insulin resistance. Diabetes. 2001;50:2444–2450
  48. Kimata H. Increased incidence of fatty liver in non-obese Japanese children under 1 year of age with or without atopic dermatitis. Public Health. 2006;120:176–178
  49. Roberts EA. Non-alcoholic fatty liver disease (NAFLD) in children. Front Biosci. 2005;10:2306–2318
  50. Nanda K. Non-alcoholic steatohepatitis in children. Pediatr Transplant. 2004;8:613–618
  51. Siegelman ES, Rosen MA. Imaging of hepatic steatosis. Semin Liver Dis. 2001;21:71–80
  52. Manco M, Bottazzo G, DeVito R, Marcellini M, Mingrone G, Nobili V. Nonalcoholic fatty liver disease in children. J Am Coll Nutr. 2008;27:667–676
  53. Nobili V, Reale A, Alisi A, Morino G, Trenta I, Pisani M, et al. Elevated serum ALT in children presenting to the emergency unit: relationship with NAFLD. Dig Liver Dis. 2009 Apr 9;[Epub ahead of print]
  54. Ratziu V, Charlotte F, Heurtier A, Gombert S, Giral P, Bruckert E, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128:1898–1906
  55. Saadeh S, Younossi ZM, Remer EM, Gramlich T, Ong JP, Hurley M, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002;123:745–750
  56. Fishbein MH, Mogren C, Gleason T, Stevens WR. Relationship of hepatic steatosis to adipose tissue distribution in pediatric nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2006;42:83–88
  57. Pacifico L, Celestre M, Anania C, Paolantonio P, Chiesa C, Laghi A. MRI and ultrasound for hepatic fat quantification: relationships to clinical and metabolic characteristics of pediatric nonalcoholic fatty liver disease. Acta Paediatr. 2007;96:542–547
  58. Manco M, Nobili V. Utilità of MRI in the evaluation of hepatic fat content. Hepatology. 2009;50:328–329
  59. Wieckowska A, Feldstein AE. Diagnosis of nonalcoholic fatty liver disease: invasive versus noninvasive. Semin Liver Dis. 2008;28:386–395
  60. Friedrich-Rust M, Ong MF, Martens S, Sarrazin C, Bojunga J, Zeuzem S, et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology. 2008;134:960–974
  61. Nobili V, Vizzutti F, Arena U, Abraldes JG, Marra F, Pietrobattista A, et al. Accuracy and reproducibility of transient elastography for the diagnosis of fibrosis in pediatric nonalcoholic steatohepatitis. Hepatology. 2008;48:442–448
  62. Harrison SA, Oliver D, Arnold HL, Gogia S, Neuschwander-Tetri BA. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut. 2008;57:1441–1447
  63. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–854
  64. Cales P, Laine F, Boursier J, Deugnier Y, Moal V, Oberti F, et al. Comparison of blood tests for liver fibrosis specific or not to NAFLD. J Hepatol. 2009;50:165–173
  65. Ratziu V, Massard J, Charlotte F, Messous D, Imbert-Bismut F, Bonyhay L, et al. Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol. 2006;6:6
  66. Guha IN, Parkes J, Roderick P, Chattopadhyay D, Cross R, Harris S, et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology. 2008;47:455–460
  67. Nobili V, Parkes J, Bottazzo G, Marcellini M, Cross R, Newman D, et al. Performance of ELF serum markers in predicting fibrosis stage in pediatric non-alcoholic fatty liver disease. Gastroenterology. 2009;136:160–167
  68. Yilmaz Y, Ulukaya E, Dolar E. The quest for liver fibrosis biomarkers: promises from the enhanced liver fibrosis panel and beyond. Hepatology. 2009;49:1056–1057
  69. Huang M, Greenson JK, Chao C, Anderson L, Peterman D, Jacobson J, et al. One-year intense nutritional counseling results in histologic improvement in patients with non-alcoholic steatohepatitis: a pilot study. Am J Gastroenterol. 2005;100:1072–1078
  70. Nobili V, Manco M, Devito R, Di Ciommo V, Comparcola D, Sartorelli MR, et al. Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Hepatology. 2008;48:119–128
  71. Spieth LE, Harnish JD, Lenders CM, Raezer LB, Pereira MA, Hangen SJ, et al. A low-glycemic index diet in the treatment of pediatric obesity. Arch Pediatr Adolesc Med. 2000;154:947–951
  72. Roberts EA, Yap J. Nonalcoholic Fatty Liver Disease (NAFLD): approach in the adolescent patient. Curr Treat Options Gastroenterol. 2006;9:423–431
  73. Grattagliano I, Vendemiale G, Caraceni P, Domenicali M, Nardo B, Cavallari A, et al. Starvation impairs antioxidant defense in fatty livers of rats fed a choline-deficient diet. J Nutr. 2000;130:2131–2136
  74. Wu A, Sun X, Wan F, Liu Y. Modulations by dietary restriction on antioxidant enzymes and lipid peroxidation in developing mice. J Appl Physiol. 2003;94:947–952
  75. Preiss D, Sattar N. Non-alcoholic fatty liver disease: an overview of prevalence, diagnosis, pathogenesis and treatment considerations. Clin Sci (Lond). 2008;115:141–150
  76. International Pediatric Endosurgery Group Standards and Safety Committee. IPEG guidelines for surgical treatment of extremely obese adolescents. J Laparoendosc Adv Surg Tech A. 2008;18:xiv–xvi
  77. Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, Cereda JM, et al. Randomized placebo controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2006;4:1537–1543
  78. Lavine JE. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr. 2000;136:734–738
  79. Vajro P, Mandato C, Franzese A, Ciccimarra E, Lucariello S, Savoia M, et al. Vitamin E treatment in pediatric obesity-related liver disease: a randomized study. J Pediatr Gastroenterol Nutr. 2004;38:48–55
  80. 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
  81. Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, et al. Ursodeoxycholic acid for treatment of non-alcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004;39:770–778
  82. 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
  83. Jones KL, Arslanian S, Peterokova VA, Park JS, Tomlinson MJ. Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial. Diabetes Care. 2002;25:89–94
  84. Zuhri-Yafi MI, Brosnan PG, Hardin DS. Treatment of type 2 diabetes mellitus in children and adolescents. J Pediatr Endocrinol Metab. 2002;15(Suppl 1):541–546
  85. Schwimmer JB, Middleton MS, Deutsch R, Lavine JE. A phase 2 clinical trial of metformin as a treatment for nondiabetic paediatric non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2005;21:871–879
  86. Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol. 2005;100:1082–1090
  87. Nobili V, Manco M, Ciampalini P, Alisi A, Devito R, Bugianesi E, et al. Metformin use in children with nonalcoholic fatty liver disease: an open-label, 24-month, observational pilot study. Clin Ther. 2008;30:1168–1176
  88. Miyazaki Y, Mahankali A, Matsuda M, Mahankali S, Hardies J, Cusi K, et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab. 2002;87:2784–2791
  89. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology. 2003;38:1008–1017
  90. Juurinen L, Kotronen A, Graner M, Yki-Jarvinen H. Rosiglitazone reduces liver fat and insulin requirements and improves hepatic insulin sensitivity and glycemic control in patients with type 2 diabetes requiring high insulin doses. J Clin Endocrinol Metab. 2008;93:118–124
  91. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–2307
  92. Loguercio C, Federico A, Tuccillo C, Terracciano F, D'Auria MV, De Simone C, et al. Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol. 2005;39:540–543
  93. Oz HS, Im HJ, Chen TS, de Villiers WJ, McClain CJ. Glutathione-enhancing agents protect against steatohepatitis in a dietary model. J Biochem Mol Toxicol. 2006;20:39–47
  94. Ekstedt M, Franzén LE, Mathiesen UL, Holmqvist M, Bodemar G, Kechagias S. Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study. J Hepatol. 2007;47:135–141
  95. Loguercio C, Federico A, Trappoliere M, Tuccillo C, de Sio I, Di Leva A, et al. The effect of a silybin-vitamin phospholipid complex on nonalcoholic fatty liver disease: a pilot study. Dig Dis Sci. 2007;52:2387–2395
  96. Vinciguerra M, Sgroi A, Veyrat-Durebex C, Rubbia-Brandt L, Buhler LH, Foti M. Unsaturated fatty acids inhibit the expression of tumor suppressor phosphatase and tensin homolog (PTEN) via microRNA-21 up-regulation in hepatocytes. Hepatology. 2009;49:1176–1184

 The authors declare no conflicts of interest.

PII: S0022-3476(09)00568-X

doi: 10.1016/j.jpeds.2009.06.014

The Journal of Pediatrics
Volume 155, Issue 4 , Pages 469-474 , October 2009

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