Advertisement

Nonalcoholic Fatty Liver Disease in Children

  • Hannah I. Awai
  • Kimberly P. Newton
  • Jeffrey B. SchwimmerEmail author

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the pediatric population, present in 3–12 % of children from industrialized nations. In children, NAFLD is more common in boys than girls. The prevalence of NAFLD increases with age and with obesity. The pathogenesis is influenced by maternal factors such as preconception weight and gestational diabetes. Guidelines exist that recommend screening obese children for NAFLD; however, there is controversy in the implementation of these guidelines. In children, the available evidence does not support the use of ultrasound for diagnosis or grading of fatty liver. MRI is promising, but at this time does not have sufficient accuracy to be considered diagnostic for an individual child. Diagnosis of NAFLD in children ultimately requires liver biopsy. The histology of NAFLD in children differs from that of adults and is characterized by more severe steatosis, greater portal inflammation and fibrosis, and less hepatocyte ballooning and perisinusoidal fibrosis. Advanced fibrosis has been reported in 5–15 % of children with NAFLD. Cardiovascular outcomes are also important as children with NAFLD have high rates of dyslipidemia, hypertension, and left ventricular structural and functional abnormalities. Adolescence is a vulnerable developmental period, and anxiety, depression, and impaired quality of life are all common in pediatric NAFLD. Clinical management is focused on the assessment of and improvement in global health with an emphasis on lifestyle optimization. Because of the prevalence and severity of NAFLD in children, targeted therapies are a pressing need.

Keywords

Pediatric Obesity Liver biopsy NASH Diabetes Epidemiology Imaging Cardiovascular Maternal Biomarker 

Notes

Funding

This work was supported in part by the following grants from NIDDK—DK088925-02S1, DK090350, and DK088831—and by UL1RR031980 from the NCRR for the Clinical and Translational Research Institute at UCSD. The funders did not participate in the preparation, review, or approval of the manuscript. The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

References

  1. 1.
    Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics. 2006;118:1388–93.PubMedCrossRefGoogle Scholar
  2. 2.
    Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003;37:1202–19.PubMedCrossRefGoogle Scholar
  3. 3.
    Brunt EM. Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis. 2001;21:3–16.PubMedCrossRefGoogle Scholar
  4. 4.
    Brunt EM. Nonalcoholic steatohepatitis. Semin Liver Dis. 2004;24:3–20.PubMedGoogle Scholar
  5. 5.
    Schwimmer JB, Behling C, Newbury R, Deutsch R, Nievergelt C, Schork NJ, Lavine JE. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology. 2005;42:641–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Ko JS, Yoon JM, Yang HR, Myung JK, Kim H, Kang GH, Cheon JE, Seo JK. Clinical and histological features of nonalcoholic fatty liver disease in children. Dig Dis Sci. 2009;54:2225–30.PubMedCrossRefGoogle Scholar
  7. 7.
    Nobili V, Marcellini M, Devito R, Ciampalini P, Piemonte F, Comparcola D, Sartorelli MR, Angulo P. NAFLD in children: a prospective clinical-pathological study and effect of lifestyle advice. Hepatology. 2006;44:458–65.PubMedCrossRefGoogle Scholar
  8. 8.
    Carter-Kent C, Yerian LM, Brunt EM, Angulo P, Kohli R, Ling SC, Xanthakos SA, Whitington PF, Charatcharoenwitthaya P, Yap J, Lopez R, Mccullough AJ, Feldstein AE. Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study. Hepatology. 2009;50:1113–20.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, Mccullough AJ, Sanyal AJ, Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.PubMedCrossRefGoogle Scholar
  10. 10.
    Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander-Tetri BA, Network NCR. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology. 2011;53:810–20.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Rorat M, Jurek T, Kuchar E, Szenborn L, Golema W, Halon A. Liver steatosis in Polish children assessed by medicolegal autopsies. World J Pediatr. 2013;9:68–72.PubMedCrossRefGoogle Scholar
  12. 12.
    Fraser A, Longnecker MP, Lawlor DA. Prevalence of elevated alanine aminotransferase among US adolescents and associated factors: NHANES 1999-2004. Gastroenterology. 2007;133:1814–20.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Schwimmer JB, Dunn W, Norman GJ, Pardee PE, Middleton MS, Kerkar N, Sirlin CB. SAFETY study: alanine aminotransferase cutoff values are set too high for reliable detection of pediatric chronic liver disease. Gastroenterology. 2010;138:1357–64, 1364 e1–2.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Welsh JA, Karpen S, Vos MB. Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988-1994 to 2007-2010. J Pediatr. 2013;162:496–500 e1.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Wiegand S, Keller KM, Robl M, L’Allemand D, Reinehr T, Widhalm K, Holl RW. Obese boys at increased risk for nonalcoholic liver disease: evaluation of 16,390 overweight or obese children and adolescents. Int J Obes (Lond). 2010;34:1468–74.CrossRefGoogle Scholar
  16. 16.
    Park HS, Han JH, Choi KM, Kim SM. Relation between elevated serum alanine aminotransferase and metabolic syndrome in Korean adolescents. Am J Clin Nutr. 2005;82:1046–51.PubMedGoogle Scholar
  17. 17.
    Kistler KD, Molleston J, Unalp A, Abrams SH, Behling C, Schwimmer JB, Nonalcoholic Steatohepatitis Clinical Research Network. Symptoms and quality of life in obese children and adolescents with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2010;31:396–406.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Schwimmer JB, Newton KP, Awai HI, Choi LJ, Garcia MA, Ellis LL, Vanderwall K, Fontanesi J. Paediatric gastroenterology evaluation of overweight and obese children referred from primary care for suspected non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2013;38:1267–77.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    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:e561–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Ayonrinde OT, Olynyk JK, Beilin LJ, Mori TA, Pennell CE, De Klerk N, Oddy WH, Shipman P, Adams LA. Gender-specific differences in adipose distribution and adipocytokines influence adolescent nonalcoholic fatty liver disease. Hepatology. 2011;53:800–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Quiros-Tejeira RE, Rivera CA, Ziba TT, Mehta N, Smith CW, Butte NF. Risk for nonalcoholic fatty liver disease in Hispanic youth with BMI > or =95th percentile. J Pediatr Gastroenterol Nutr. 2007;44:228–36.PubMedCrossRefGoogle Scholar
  22. 22.
    Xanthakos S, Miles L, Bucuvalas J, Daniels S, Garcia V, Inge T. Histologic spectrum of nonalcoholic fatty liver disease in morbidly obese adolescents. Clin Gastroenterol Hepatol. 2006;4:226–32.PubMedCrossRefGoogle Scholar
  23. 23.
    Patton HM, Lavine JE, Van Natta ML, Schwimmer JB, Kleiner D, Molleston J, Nonalcoholic Steatohepatitis Clinical Research Network. Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis. Gastroenterology. 2008;135:1961–71 e2.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Davis JN, Le KA, Walker RW, Vikman S, Spruijt-Metz D, Weigensberg MJ, Allayee H, Goran MI. Increased hepatic fat in overweight Hispanic youth influenced by interaction between genetic variation in PNPLA3 and high dietary carbohydrate and sugar consumption. Am J Clin Nutr. 2010;92:1522–7.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Goran MI, Walker R, Le KA, Mahurkar S, Vikman S, Davis JN, Spruijt-Metz D, Weigensberg MJ, Allayee H. Effects of PNPLA3 on liver fat and metabolic profile in Hispanic children and adolescents. Diabetes. 2010;59:3127–30.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Rotman Y, Koh C, Zmuda JM, Kleiner DE, Liang TJ. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology. 2010;52:894–903.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Swiderska-Syn M, Suzuki A, Guy CD, Schwimmer JB, Abdelmalek MF, Lavine JE, Diehl AM. Hedgehog pathway and pediatric nonalcoholic fatty liver disease. Hepatology. 2013;57:1814–25.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Clore JN. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120:1183–92.PubMedCrossRefGoogle Scholar
  29. 29.
    Lomonaco R, Ortiz-Lopez C, Orsak B, Webb A, Hardies J, Darland C, Finch J, Gastaldelli A, Harrison S, Tio F, Cusi K. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology. 2012;55:1389–97.PubMedCrossRefGoogle Scholar
  30. 30.
    Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115:1343–51.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Barrows BR, Parks EJ. Contributions of different fatty acid sources to very low-density lipoprotein-triacylglycerol in the fasted and fed states. J Clin Endocrinol Metab. 2006;91:1446–52.PubMedCrossRefGoogle Scholar
  32. 32.
    Fabbrini E, Dehaseth D, Deivanayagam S, Mohammed BS, Vitola BE, Klein S. Alterations in fatty acid kinetics in obese adolescents with increased intrahepatic triglyceride content. Obesity (Silver Spring). 2009;17:25–9.CrossRefGoogle Scholar
  33. 33.
    Heptulla RA, Stewart A, Enocksson S, Rife F, Ma TY, Sherwin RS, Tamborlane WV, Caprio S. In situ evidence that peripheral insulin resistance in adolescents with poorly controlled type 1 diabetes is associated with impaired suppression of lipolysis: a microdialysis study. Pediatr Res. 2003;53:830–5.PubMedCrossRefGoogle Scholar
  34. 34.
    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;143:500–5.PubMedCrossRefGoogle Scholar
  35. 35.
    Do Nascimento JH, Epifanio M, Soder RB, Baldisserotto M. MRI-diagnosed nonalcoholic fatty liver disease is correlated to insulin resistance in adolescents. Acad Radiol. 2013;20:1436–42.PubMedCrossRefGoogle Scholar
  36. 36.
    Kim JS, Le KA, Mahurkar S, Davis JN, Goran MI. Influence of elevated liver fat on circulating adipocytokines and insulin resistance in obese Hispanic adolescents. Pediatr Obes. 2012;7:158–64.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Deboer MD, Wiener RC, Barnes BH, Gurka MJ. Ethnic differences in the link between insulin resistance and elevated ALT. Pediatrics. 2013;132:e718–26.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Louthan MV, Theriot JA, Zimmerman E, Stutts JT, Mcclain CJ. Decreased prevalence of nonalcoholic fatty liver disease in black obese children. J Pediatr Gastroenterol Nutr. 2005;41:426–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005;11:183–90.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Musso G, Gambino R, Cassader M. Non-alcoholic fatty liver disease from pathogenesis to management: an update. Obes Rev. 2010;11:430–45.PubMedCrossRefGoogle Scholar
  41. 41.
    Nobili V, Carpino G, Alisi A, Franchitto A, Alpini G, De Vito R, Onori P, Alvaro D, Gaudio E. Hepatic progenitor cells activation, fibrosis, and adipokines production in pediatric nonalcoholic fatty liver disease. Hepatology. 2012;56:2142–53.PubMedCrossRefGoogle Scholar
  42. 42.
    Fitzpatrick E, Dew TK, Quaglia A, Sherwood RA, Mitry RR, Dhawan A. Analysis of adipokine concentrations in paediatric non-alcoholic fatty liver disease. Pediatr Obes. 2012;7:471–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology. 2012;142:711–25 e6.PubMedCrossRefGoogle Scholar
  44. 44.
    Lin YC, Chang PF, Chang MH, Ni YH. A common variant in the peroxisome proliferator-activated receptor-gamma coactivator-1alpha gene is associated with nonalcoholic fatty liver disease in obese children. Am J Clin Nutr. 2013;97:326–31.PubMedCrossRefGoogle Scholar
  45. 45.
    Connolly MK, Bedrosian AS, Mallen-ST Clair J, Mitchell AP, Ibrahim J, Stroud A, Pachter HL, Bar-Sagi D, Frey AB, Miller G. In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-alpha. J Clin Invest. 2009;119:3213–25.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Nieto N. Oxidative-stress and IL-6 mediate the fibrogenic effects of [corrected] Kupffer cells on stellate cells. Hepatology. 2006;44:1487–501.PubMedCrossRefGoogle Scholar
  47. 47.
    Wang J, Leclercq I, Brymora JM, Xu N, Ramezani-Moghadam M, London RM, Brigstock D, George J. Kupffer cells mediate leptin-induced liver fibrosis. Gastroenterology. 2009;137:713–23.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Boyraz M, Cekmez F, Karaoglu A, Cinaz P, Durak M, Bideci A. Serum adiponectin, leptin, resistin and RBP4 levels in obese and metabolic syndrome children with nonalcoholic fatty liver disease. Biomark Med. 2013;7:737–45.PubMedCrossRefGoogle Scholar
  49. 49.
    Diez JJ, Iglesias P. The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol. 2003;148:293–300.PubMedCrossRefGoogle Scholar
  50. 50.
    Louthan MV, Barve S, Mcclain CJ, Joshi-Barve S. Decreased serum adiponectin: an early event in pediatric nonalcoholic fatty liver disease. J Pediatr. 2005;147:835–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Burgert TS, Taksali SE, Dziura J, Goodman TR, Yeckel CW, Papademetris X, Constable RT, Weiss R, Tamborlane WV, Savoye M, Seyal AA, Caprio S. Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat. J Clin Endocrinol Metab. 2006;91:4287–94.PubMedCrossRefGoogle Scholar
  52. 52.
    Zhu L, Baker SS, Gill C, Liu W, Alkhouri R, Baker RD, Gill SR. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology. 2013;57:601–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Schwimmer JB, Celedon MA, Lavine JE, Salem R, Campbell N, Schork NJ, Shiehmorteza M, Yokoo T, Chavez A, Middleton MS, Sirlin CB. Heritability of nonalcoholic fatty liver disease. Gastroenterology. 2009;136:1585–92.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40:1461–5.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Romeo S, Sentinelli F, Cambuli VM, Incani M, Congiu T, Matta V, Pilia S, Huang-Doran I, Cossu E, Loche S, Baroni MG. The 148M allele of the PNPLA3 gene is associated with indices of liver damage early in life. J Hepatol. 2010;53:335–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Lin YC, Chang PF, Hu FC, Yang WS, Chang MH, Ni YH. A common variant in the PNPLA3 gene is a risk factor for non-alcoholic fatty liver disease in obese Taiwanese children. J Pediatr. 2011;158:740–4.PubMedCrossRefGoogle Scholar
  57. 57.
    Giudice EM, Grandone A, Cirillo G, Santoro N, Amato A, Brienza C, Savarese P, Marzuillo P, Perrone L. The association of PNPLA3 variants with liver enzymes in childhood obesity is driven by the interaction with abdominal fat. PLoS One. 2011;6:e27933.PubMedCrossRefGoogle Scholar
  58. 58.
    Larrieta-Carrasco E, Leon-Mimila P, Villarreal-Molina T, Villamil-Ramirez H, Romero-Hidalgo S, Jacobo-Albavera L, Gutierrez-Vidal R, Lopez-Contreras BE, Guillen-Pineda LE, Sanchez-Munoz F, Bojalil R, Mejia-Dominguez AM, Mendez-Sanchez N, Dominguez-Lopez A, Aguilar-Salinas CA, Canizales-Quinteros S. Association of the I148M/PNPLA3 variant with elevated alanine transaminase levels in normal-weight and overweight/obese Mexican children. Gene. 2013;520:185–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Santoro N, Kursawe R, D’Adamo E, Dykas DJ, Zhang CK, Bale AE, Cali AM, Narayan D, Shaw MM, Pierpont B, Savoye M, Lartaud D, Eldrich S, Cushman SW, Zhao H, Shulman GI, Caprio S. A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents. Hepatology. 2010;52:1281–90.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Valenti L, Alisi A, Galmozzi E, Bartuli A, Del Menico B, Alterio A, Dongiovanni P, Fargion S, Nobili V. I148M patatin-like phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease. Hepatology. 2010;52:1274–80.PubMedCrossRefGoogle Scholar
  61. 61.
    Vos MB, Colvin R, Belt P, Molleston JP, Murray KF, Rosenthal P, Schwimmer JB, Tonascia J, Unalp A, Lavine JE. Correlation of vitamin E, uric acid, and diet composition with histologic features of pediatric NAFLD. J Pediatr Gastroenterol Nutr. 2012;54:90–6.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Santoro N, Savoye M, Kim G, Marotto K, Shaw MM, Pierpont B, Caprio S. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Brumbaugh DE, Tearse P, Cree-Green M, Fenton LZ, Brown M, Scherzinger A, Reynolds R, Alston M, Hoffman C, Pan Z, Friedman JE, Barbour LA. Intrahepatic fat is increased in the neonatal offspring of obese women with gestational diabetes. J Pediatr. 2013;162:930–6 e1.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Modi N, Murgasova D, Ruager-Martin R, Thomas EL, Hyde MJ, Gale C, Santhakumaran S, Dore CJ, Alavi A, Bell JD. The influence of maternal body mass index on infant adiposity and hepatic lipid content. Pediatr Res. 2011;70:287–91.PubMedCrossRefGoogle Scholar
  65. 65.
    Ugalde-Nicalo PA, Schwimmer JB. On the origin of pediatric nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2015;60(2):147–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Nobili V, Bedogni G, Alisi A, Pietrobattista A, Alterio A, Tiribelli C, Agostoni C. A protective effect of breastfeeding on the progression of non-alcoholic fatty liver disease. Arch Dis Child. 2009;94:801–5.PubMedCrossRefGoogle Scholar
  67. 67.
    Alisi A, Manco M, Vania A, Nobili V. Pediatric nonalcoholic fatty liver disease in 2009. J Pediatr. 2009;155:469–74.PubMedCrossRefGoogle Scholar
  68. 68.
    Manco M, Bedogni G, Marcellini M, Devito R, Ciampalini P, Sartorelli MR, Comparcola D, Piemonte F, Nobili V. Waist circumference correlates with liver fibrosis in children with non-alcoholic steatohepatitis. Gut. 2008;57:1283–7.PubMedCrossRefGoogle Scholar
  69. 69.
    Inge TH, Zeller MH, Jenkins TM, Helmrath M, Brandt ML, Michalsky MP, Harmon CM, Courcoulas A, Horlick M, Xanthakos SA, Dolan L, Mitsnefes M, Barnett SJ, Buncher R. Perioperative outcomes of adolescents undergoing bariatric surgery: the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. JAMA Pediatr. 2014;168:47–53.PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Holterman AX, Guzman G, Fantuzzi G, Wang H, Aigner K, Browne A, Holterman M. Nonalcoholic fatty liver disease in severely obese adolescent and adult patients. Obesity (Silver Spring). 2013;21:591–7.CrossRefGoogle Scholar
  71. 71.
    Yap JY, 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;35:500–5.PubMedCrossRefGoogle Scholar
  72. 72.
    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;32:381–7.CrossRefGoogle Scholar
  73. 73.
    Mager DR, Ling S, Roberts EA. Anthropometric and metabolic characteristics in children with clinically diagnosed nonalcoholic fatty liver disease. Paediatr Child Health. 2008;13:111–7.PubMedCentralPubMedGoogle Scholar
  74. 74.
    Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr. 2000;30:48–53.PubMedCrossRefGoogle Scholar
  75. 75.
    Barlow SE, Expert C. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics. 2007;120 Suppl 4:S164–92.PubMedCrossRefGoogle Scholar
  76. 76.
    Vuppalanchi R, Jain AK, Deppe R, Yates K, Comerford M, Masuoka HC, Neuschwander-Tetri BA, Loomba R, Brunt EM, Kleiner DE, Molleston JP, Schwimmer JB, Lavine JE, Tonascia J, Chalasani N. Relationship between changes in serum levels of keratin 18 and changes in liver histology in children and adults with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2014;12(12):2121–30.e1–2.PubMedCrossRefGoogle Scholar
  77. 77.
    Lee CK, Perez-Atayde AR, Mitchell PD, Raza R, Afdhal NH, Jonas MM. Serum biomarkers and transient elastography as predictors of advanced liver fibrosis in a United States cohort: the Boston children’s hospital experience. J Pediatr. 2013;163:1058–64 e2.PubMedCrossRefGoogle Scholar
  78. 78.
    Lebensztejn DM, Wierzbicka A, Socha P, Pronicki M, Skiba E, Werpachowska I, Kaczmarski M. Cytokeratin-18 and hyaluronic acid levels predict liver fibrosis in children with non-alcoholic fatty liver disease. Acta Biochim Pol. 2011;58:563–6.PubMedGoogle Scholar
  79. 79.
    Giannini C, Feldstein AE, Santoro N, Kim G, Kursawe R, Pierpont B, Caprio S. Circulating levels of FGF-21 in obese youth: associations with liver fat content and markers of liver damage. J Clin Endocrinol Metab. 2013;98:2993–3000.PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Awai HI, Newton KP, Sirlin CB, Behling C, Schwimmer JB. Evidence and recommendations for imaging liver fat in children, based on systematic review. Clin Gastroenterol Hepatol. 2014;12:765–73.PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    El-Koofy N, El-Karaksy H, El-Akel W, Helmy H, Anwar G, El-Sayed R, El-Hennawy A. Ultrasonography as a non-invasive tool for detection of nonalcoholic fatty liver disease in overweight/obese Egyptian children. Eur J Radiol. 2012;81:3120–3.PubMedCrossRefGoogle Scholar
  82. 82.
    Shannon A, Alkhouri N, Carter-Kent C, Monti L, Devito R, Lopez R, Feldstein AE, Nobili V. Ultrasonographic quantitative estimation of hepatic steatosis in children With NAFLD. J Pediatr Gastroenterol Nutr. 2011;53:190–5.PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Pacifico L, Martino MD, Catalano C, Panebianco V, Bezzi M, Anania C, Chiesa C. T1-weighted dual-echo MRI for fat quantification in pediatric nonalcoholic fatty liver disease. World J Gastroenterol. 2011;17:3012–9.PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Fishbein MH, Gardner KG, Potter CJ, Schmalbrock P, Smith MA. Introduction of fast MR imaging in the assessment of hepatic steatosis. Magn Reson Imaging. 1997;15:287–93.PubMedCrossRefGoogle Scholar
  85. 85.
    Meisamy S, Hines CD, Hamilton G, Sirlin CB, Mckenzie CA, Yu H, Brittain JH, Reeder SB. Quantification of hepatic steatosis with T1-independent, T2-corrected MR imaging with spectral modeling of fat: blinded comparison with MR spectroscopy. Radiology. 2011;258:767–75.PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Yokoo T, Bydder M, Hamilton G, Middleton MS, Gamst AC, Wolfson T, Hassanein T, Patton HM, Lavine JE, Schwimmer JB, Sirlin CB. Nonalcoholic fatty liver disease: diagnostic and fat-grading accuracy of low-flip-angle multiecho gradient-recalled-echo MR imaging at 1.5 T. Radiology. 2009;251:67–76.PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Yokoo T, Shiehmorteza M, Hamilton G, Wolfson T, Schroeder ME, Middleton MS, Bydder M, Gamst AC, Kono Y, Kuo A, Patton HM, Horgan S, Lavine JE, Schwimmer JB, Sirlin CB. Estimation of hepatic proton-density fat fraction by using MR imaging at 3.0 T. Radiology. 2011;258:749–59.PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Bydder M, Yokoo T, Hamilton G, Middleton MS, Chavez AD, Schwimmer JB, Lavine JE, Sirlin CB. Relaxation effects in the quantification of fat using gradient echo imaging. Magn Reson Imaging. 2008;26:347–59.PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Yu H, Shimakawa A, Mckenzie CA, Brodsky E, Brittain JH, Reeder SB. Multiecho water-fat separation and simultaneous R2* estimation with multifrequency fat spectrum modeling. Magn Reson Med. 2008;60:1122–34.PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Yu H, Shimakawa A, Hines CD, Mckenzie CA, Hamilton G, Sirlin CB, Brittain JH, Reeder SB. Combination of complex-based and magnitude-based multiecho water-fat separation for accurate quantification of fat-fraction. Magn Reson Med. 2011;66:199–206.PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Schwimmer JB, Middleton MS, Behling C, Newton KP, Awai HI, Paiz MN, Lam J, Hooker JC, Hamilton G, Fontanesi J, Sirlin CB. Magnetic resonance imaging and liver histology as biomarkers of hepatic steatosis in children with nonalcoholic fatty liver disease. Hepatology. 2014. doi: 10.1002/hep.27666 [Epub ahead of print].Google Scholar
  92. 92.
    Wang CL, Liang L, Fu JF, Zou CC, Hong F, Xue JZ, Lu JR, Wu XM. Effect of lifestyle intervention on non-alcoholic fatty liver disease in Chinese obese children. World J Gastroenterol. 2008;14:1598–602.PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Reinehr T, Schmidt C, Toschke AM, Andler W. Lifestyle intervention in obese children with non-alcoholic fatty liver disease: 2-year follow-up study. Arch Dis Child. 2009;94:437–42.PubMedCrossRefGoogle Scholar
  94. 94.
    Vos MB, Weber MB, Welsh J, Khatoon F, Jones DP, Whitington PF, Mcclain CJ. Fructose and oxidized low-density lipoprotein in pediatric nonalcoholic fatty liver disease: a pilot study. Arch Pediatr Adolesc Med. 2009;163:674–5.PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    De Piano A, Prado WL, Caranti DA, Siqueira KO, Stella SG, Lofrano M, Tock L, Cristofalo DM, Lederman H, Tufik S, De Mello MT, Damaso AR. Metabolic and nutritional profile of obese adolescents with nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2007;44:446–52.PubMedCrossRefGoogle Scholar
  96. 96.
    Pozzato C, Verduci E, Scaglioni S, Radaelli G, Salvioni M, Rovere A, Cornalba G, Riva E, Giovannini M. Liver fat change in obese children after a 1-year nutrition-behavior intervention. J Pediatr Gastroenterol Nutr. 2010;51:331–5.PubMedGoogle Scholar
  97. 97.
    Gronbaek H, Lange A, Birkebaek NH, Holland-Fischer P, Solvig J, Horlyck A, Kristensen K, Rittig S, Vilstrup H. Effect of a 10-week weight loss camp on fatty liver disease and insulin sensitivity in obese Danish children. J Pediatr Gastroenterol Nutr. 2012;54:223–8.PubMedCrossRefGoogle Scholar
  98. 98.
    Campos RM, De Mello MT, Tock L, Silva PL, Masquio DC, De Piano A, Sanches PL, Carnier J, Corgosinho FC, Foschini D, Tufik S, Damaso AR. Aerobic plus resistance training improves bone metabolism and inflammation in adolescents who are obese. J Strength Cond Res. 2014;28:758–66.PubMedCrossRefGoogle Scholar
  99. 99.
    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;7:251–64.PubMedCrossRefGoogle Scholar
  100. 100.
    Ouyang X, Cirillo P, Sautin Y, Mccall S, Bruchette JL, Diehl AM, Johnson RJ, Abdelmalek MF. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. 2008;48:993–9.PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Jin R, Welsh JA, Le NA, Holzberg J, Sharma P, Martin DR, Vos MB. Dietary fructose reduction improves markers of cardiovascular disease risk in Hispanic-American adolescents with NAFLD. Nutrients. 2014;6:3187–201.PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Lavine JE. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr. 2000;136:734–8.PubMedCrossRefGoogle Scholar
  103. 103.
    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;24:1553–61.PubMedCrossRefGoogle Scholar
  104. 104.
    Nobili V, Manco M, Devito R, Di Ciommo V, Comparcola D, Sartorelli MR, Piemonte F, Marcellini M, Angulo P. Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Hepatology. 2008;48:119–28.PubMedCrossRefGoogle Scholar
  105. 105.
    Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, Abrams SH, Scheimann AO, Sanyal AJ, Chalasani N, Tonascia J, Unalp A, Clark JM, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR, Nonalcoholic Steatohepatitis Clinical Research Network. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011;305:1659–68.PubMedCentralPubMedCrossRefGoogle Scholar
  106. 106.
    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;136:739–43.PubMedCrossRefGoogle Scholar
  107. 107.
    Dohil R, Schmeltzer S, Cabrera BL, Wang T, Durelle J, Duke KB, Schwimmer JB, Lavine JE. Enteric-coated cysteamine for the treatment of paediatric non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2011;33:1036–44.PubMedCrossRefGoogle Scholar
  108. 108.
    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;161:639–45 e1.PubMedCrossRefGoogle Scholar
  109. 109.
  110. 110.
    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;21:871–9.PubMedCrossRefGoogle Scholar
  111. 111.
    Nobili V, Manco M, Ciampalini P, Alisi A, Devito R, Bugianesi E, Marcellini M, Marchesini G. Metformin use in children with nonalcoholic fatty liver disease: an open-label, 24-month, observational pilot study. Clin Ther. 2008;30:1168–76.PubMedCrossRefGoogle Scholar
  112. 112.
    Nobili V, Bedogni G, Alisi A, Pietrobattista A, Rise P, Galli C, Agostoni C. 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;96:350–3.PubMedCrossRefGoogle Scholar
  113. 113.
    Vajro P, Mandato C, Licenziati MR, Franzese A, Vitale DF, Lenta S, Caropreso M, Vallone G, Meli R. Effects of Lactobacillus rhamnosus strain GG in pediatric obesity-related liver disease. J Pediatr Gastroenterol Nutr. 2011;52:740–3.PubMedCrossRefGoogle Scholar
  114. 114.
    Alisi A, Bedogni G, Baviera G, Giorgio V, Porro E, Paris C, Giammaria P, Reali L, Anania F, Nobili V. Randomised clinical trial: the beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2014;39:1276–85.PubMedCentralPubMedCrossRefGoogle Scholar
  115. 115.
    Nadler EP, Reddy S, Isenalumhe A, Youn HA, Peck V, Ren CJ, Fielding GA. Laparoscopic adjustable gastric banding for morbidly obese adolescents affects android fat loss, resolution of comorbidities, and improved metabolic status. J Am Coll Surg. 2009;209:638–44.PubMedCrossRefGoogle Scholar
  116. 116.
    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;43:141–6.PubMedCrossRefGoogle Scholar
  117. 117.
    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;58:1538–44.PubMedCentralPubMedCrossRefGoogle Scholar
  118. 118.
    Brunt EM, Kleiner DE, Belt PH, Molleston JP, Schwimmer JB, Lavine JE, Neus-Chwander-Tetri BA. Pediatric nonalcoholic fatty liver disease (NAFLD): histological feature changes over time in paired biopsies from the NASH CRN. Hepatology. 2014;60:290A.Google Scholar
  119. 119.
    Molleston JP, Schwimmer JB, Yates KP, Murray KF, Cummings OW, Lavine JE, Brunt EM, Scheimann AO, Unalp-Arida A. Histological abnormalities in children with nonalcoholic fatty liver disease and normal or mildly elevated alanine aminotransferase levels. J Pediatr. 2014;164:707–713 e3.PubMedCentralPubMedCrossRefGoogle Scholar
  120. 120.
    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;118:277–83.PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    Cali AM, Zern TL, Taksali SE, De Oliveira AM, Dufour S, Otvos JD, Caprio S. Intrahepatic fat accumulation and alterations in lipoprotein composition in obese adolescents: a perfect proatherogenic state. Diabetes Care. 2007;30:3093–8.PubMedCrossRefGoogle Scholar
  122. 122.
    Sartorio A, Del Col A, Agosti F, Mazzilli G, Bellentani S, Tiribelli C, Bedogni G. Predictors of non-alcoholic fatty liver disease in obese children. Eur J Clin Nutr. 2007;61:877–83.PubMedCrossRefGoogle Scholar
  123. 123.
    Schwimmer JB, Zepeda A, Newton KP, Xanthakos SA, Behling C, Hallinan EK, Donithan M, Tonascia J. Longitudinal assessment of high blood pressure in children with nonalcoholic fatty liver disease. PLoS One. 2014;9:e112569.PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Sert A, Pirgon O, Aypar E, Yilmaz H, Odabas D. Relationship between left ventricular mass and carotid intima media thickness in obese adolescents with non-alcoholic fatty liver disease. J Pediatr Endocrinol Metab. 2012;25:927–34.PubMedCrossRefGoogle Scholar
  125. 125.
    Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, Hobbs HH, Dobbins RL. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab. 2005;288:E462–8.PubMedCrossRefGoogle Scholar
  126. 126.
    Singh GK, Vitola BE, Holland MR, Sekarski T, Patterson BW, Magkos F, Klein S. Alterations in ventricular structure and function in obese adolescents with nonalcoholic fatty liver disease. J Pediatr. 2013;162:1160–8 1168 e1.PubMedCentralPubMedCrossRefGoogle Scholar
  127. 127.
    Pacifico L, Bezzi M, Lombardo CV, Romaggioli S, Ferraro F, Bascetta S, Chiesa C. Adipokines and C-reactive protein in relation to bone mineralization in pediatric nonalcoholic fatty liver disease. World J Gastroenterol. 2013;19:4007–14.PubMedCentralPubMedCrossRefGoogle Scholar
  128. 128.
    Mathurin P, Durand F, Ganne N, Mollo JL, Lebrec D, Degott C, Erlinger S, Benhamou JP, Bernuau J. Ischemic hepatitis due to obstructive sleep apnea. Gastroenterology. 1995;109:1682–4.PubMedCrossRefGoogle Scholar
  129. 129.
    Henrion J, Colin L, Schapira M, Heller FR. Hypoxic hepatitis caused by severe hypoxemia from obstructive sleep apnea. J Clin Gastroenterol. 1997;24:245–9.PubMedCrossRefGoogle Scholar
  130. 130.
    Sundaram SS, Sokol RJ, Capocelli KE, Pan Z, Sullivan JS, Robbins K, Halbower AC. Obstructive sleep apnea and hypoxemia are associated with advanced liver histology in pediatric nonalcoholic fatty liver disease. J Pediatr. 2014;164:699–706 e1.PubMedCentralPubMedCrossRefGoogle Scholar
  131. 131.
    Nobili V, Cutrera R, Liccardo D, Pavone M, Devito R, Giorgio V, Verrillo E, Baviera G, Musso G. Obstructive sleep apnea syndrome affects liver histology and inflammatory cell activation in pediatric nonalcoholic fatty liver disease, regardless of obesity/insulin resistance. Am J Respir Crit Care Med. 2014;189:66–76.PubMedCrossRefGoogle Scholar
  132. 132.
    Nadeau KJ, Klingensmith G, Zeitler P. Type 2 diabetes in children is frequently associated with elevated alanine aminotransferase. J Pediatr Gastroenterol Nutr. 2005;41:94–8.PubMedCrossRefGoogle Scholar
  133. 133.
    Bedogni G, Gastaldelli A, Manco M, De Col A, Agosti F, Tiribelli C, Sartorio A. Relationship between fatty liver and glucose metabolism: a cross-sectional study in 571 obese children. Nutr Metab Cardiovasc Dis. 2012;22:120–6.PubMedCrossRefGoogle Scholar
  134. 134.
    Aygun C, Kocaman O, Sahin T, Uraz S, Eminler AT, Celebi A, Senturk O, Hulagu S. Evaluation of metabolic syndrome frequency and carotid artery intima-media thickness as risk factors for atherosclerosis in patients with nonalcoholic fatty liver disease. Dig Dis Sci. 2008;53:1352–7.PubMedCrossRefGoogle Scholar
  135. 135.
    Pardee PE, Dunn W, Schwimmer JB. Non-alcoholic fatty liver disease is associated with low bone mineral density in obese children. Aliment Pharmacol Ther. 2012;35:248–54.PubMedCentralPubMedCrossRefGoogle Scholar
  136. 136.
    Pacifico L, Di Martino M, De Merulis A, Bezzi M, Osborn JF, Catalano C, Chiesa C. Left ventricular dysfunction in obese children and adolescents with nonalcoholic fatty liver disease. Hepatology. 2014;59:461–70.PubMedCrossRefGoogle Scholar
  137. 137.
    Manco M, Ciampalini P, Nobili V. Low levels of 25-hydroxyvitamin D(3) in children with biopsy-proven nonalcoholic fatty liver disease. Hepatology. 2010;51:2229. Author reply 2230.PubMedCrossRefGoogle Scholar
  138. 138.
    Nobili V, Giorgio V, Liccardo D, Bedogni G, Morino G, Alisi A, Cianfarani S. Vitamin D levels and liver histological alterations in children with nonalcoholic fatty liver disease. Eur J Endocrinol. 2014;170:547–53.PubMedCrossRefGoogle Scholar
  139. 139.
    Hourigan SK, Abrams S, Yates K, Pfeifer K, Torbenson M, Murray K, Roth C, Kowdley K, Scheimann AO, The NASH CRN. The relationship between vitamin D status and non-alcoholic fatty liver disease in children. J Pediatr Gastroenterol Nutr. 2015;60(3):396–404.PubMedCrossRefGoogle Scholar
  140. 140.
    Kerkar N, D’Urso C, Van Nostrand K, Kochin I, Gault A, Suchy F, Miloh T, Arnon R, Chu J, Annunziato R. Psychosocial outcomes for children with nonalcoholic fatty liver disease over time and compared to obese controls. J Pediatr Gastroenterol Nutr. 2013;56(1):77–82.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Hannah I. Awai
    • 1
    • 2
    • 3
  • Kimberly P. Newton
    • 2
    • 3
  • Jeffrey B. Schwimmer
    • 1
    • 2
    • 3
    Email author
  1. 1.Liver Imaging Group, Department of RadiologyUniversity of California, San Diego School of MedicineSan DiegoUSA
  2. 2.Division of Gastroenterology, Hepatology, and Nutrition, Department of PediatricsUniversity of California, San Diego School of MedicineSan DiegoUSA
  3. 3.Department of GastroenterologyRady Children’s Hospital San DiegoSan DiegoUSA

Personalised recommendations