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Non-alcoholic fatty liver infiltration in children: an underdiagnosed evolving disease

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Abstract

Non-alcoholic fatty liver disease (NAFLD) constitutes the most common liver disease, one that is still underdiagnosed in pediatric populations (as well as in the general population), this due to the progressive increase in childhood obesity observed both in developed and developing countries during the last few decades. The pathophysiology of the disease has not been thoroughly clarified yet. The condition displays common pathways in adults and children; however, there are age-related differences. Unlike adults, children with NAFLD require extensive laboratory analysis, because underlying pathologies other than obesity may contribute to the evolution of the disease. Despite the presence of several serum markers and imaging techniques that contribute to NAFLD diagnosis, liver biopsy remains the gold standard diagnostic procedure. Early intervention and obesity prevention are mandatory, as NAFLD is reversible at an early stage. If left undiagnosed and untreated, NAFLD can progress to steatohepatitis (NASH) and subsequent liver failure, a potentially lethal complication. Of note, there are no treatment options when advanced liver fibrosis occurs. This review summarizes literature data on NAFLD in childhood indicating that this is an evolving disease and a significant component of the metabolic syndrome. Pediatricians should be aware of this entity, screening children at high risk and providing appropriate early management, in collaboration with pediatric subspecialists.

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References

  1. Ogden CL, Carroll MD, Curtin LR, Lamb MM, Flegal KM (2010) Prevalence of high body mass index in US children and adolescents, 2007-2008. JAMA 3:242–249

    Google Scholar 

  2. Pan L, Freedman DS, Gillespie C, Park S, Sherry B (2011) Incidences of obesity and extreme obesity among US adults: findings from the 2009 Behavioral Risk Factor Surveillance System. Popul Health Metrics 9(1):56

    Google Scholar 

  3. Brunt EM (2010) Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 7:195–203

    PubMed  Google Scholar 

  4. Mencin AA, Lavine JE (2011) Nonalcoholic fatty liver disease in children. Curr Opin Clin Nutr Metab Care 14(2):151–157

    CAS  PubMed  Google Scholar 

  5. Schwimmer JB, Pardee PE, Lavine JE, Blumkin AK, Cook S (2008) Cardiovascular risk factors and the metabolic syndrome in pediatric nonalcoholic fatty liver disease. Circulation 3:277–283

    Google Scholar 

  6. Della Corte C, Alisi A, Saccari A, De Vito R, Vania A, Nobili V (2012) Nonalcoholic fatty liver in children and adolescents: an overview. J Adolesc Health 51:305–312

    PubMed  Google Scholar 

  7. Barshop NJ, Sirlin CB, Schwimmer JB, Lavine JE (2008) Review article: epidemiology, pathogenesis and potential treatments of paediatric non-alcoholic fatty liver disease. Aliment Pharmacol Ther 28:13–24

    CAS  PubMed  Google Scholar 

  8. Moya M (2008) An update in prevention and treatment of pediatric obesity. World J Pediatr 4:173–185

    PubMed  Google Scholar 

  9. Bellentani S, Scaglioni F, Marino M, Bedogni G (2010) Epidemiology of non-alcoholic fatty liver disease. Dig Dis 28:155–161

    PubMed  Google Scholar 

  10. Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C (2006) Prevalence of fatty liver in children and adolescents. Pediatrics 118:1388–1393

    PubMed  Google Scholar 

  11. Rorat M, Jurek T, Kuchar E, Szenborn L, Golema W, Halon A (2013) Liver steatosis in polish children assessed by medicolegal autopsies. World J Pediatr 9:68–72

    PubMed  Google Scholar 

  12. Oddy WH, Herbison CE, Jacoby P, Ambrosini GL, O'Sullivan TA, Ayonrinde OT et al (2013) The Western dietary pattern is prospectively associated with nonalcoholic fatty liver disease in adolescence. Am J Gastroenterol 108:778–785

    CAS  PubMed  Google Scholar 

  13. Wiegand S, Keller KM, Röbl M, L’Allemand D, Reinehr T, Widhalm K, APV-Study Group and the German Competence Network Adipositas et al (2010) Obese boys at increased risk for nonalcoholic liver disease: evaluation of 16,390 overweight or obese children and adolescents. Int J Obes 34:1468–1474

    CAS  Google Scholar 

  14. Tominaga K, Fujimoto E, Suzuki K, Hayashi M, Ichikawa M, Inaba Y (2009) Prevalence of non-alcoholic fatty liver disease in children and relationship to metabolic syndrome, insulin resistance, and waist circumference. Environ Health Prev Med 14:142–149

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Alavian SM, Mohammad-Alizadeh AH, Esna-Ashari F, Ardalan G, Hajarizadeh B (2009) Non-alcoholic fatty liver disease prevalence among school-aged children and adolescents in Iran and its association with biochemical and anthropometric measures. Liver Int 29:159–163

    CAS  PubMed  Google Scholar 

  16. Chaturvedi K, Vohra P (2012) Non-alcoholic fatty liver disease in children. Indian Pediatr 49:757–758

    PubMed  Google Scholar 

  17. Alisi A, Feldstein AE, Villani A, Raponi M, Nobili V (2012) Pediatric nonalcoholic fatty liver disease: a multidisciplinary approach. Nat Rev Gastroenterol Hepatol 9:152–161

    CAS  PubMed  Google Scholar 

  18. Day CP (2010) Genetic and environmental susceptibility to non-alcoholic fatty liver disease. Dig Dis 28:255–260

    PubMed  Google Scholar 

  19. Janczyk W, Socha P (2012) Non-alcoholic fatty liver disease in children. Clin Res Hepatol Gastroenterol 36:297–300

    PubMed  Google Scholar 

  20. Giorgio V, Prono F, Graziano F, Nobili V (2013) Pediatric non-alcoholic fatty liver disease: old and new concepts on development, progression, metabolic insight and potential treatment targets. BMC Pediatr 25:13–40

    Google Scholar 

  21. Cambuli VM, Musiu MC, Incani M, Paderi M, Serpe R, Marras V et al (2008) Assessment of adiponectin and leptin as biomarkers of positive metabolic outcomes after lifestyle intervention in overweight and obese children. J Clin Endocrinol Metab 93:3051–3057

    CAS  PubMed  Google Scholar 

  22. Burgert TS, Taksali SE, Dziura J, Goodman TR, Yeckel CW, Papademetris X et al (2006) Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat. J Clin Endocrinol Metab 91:4287–4294

    CAS  PubMed  Google Scholar 

  23. Giby VG, Ajith TA (2014) Role of adipokines and peroxisome proliferator-activated receptors in nonalcoholic fatty liver disease. World J Hepatol 6:570–579

    PubMed  PubMed Central  Google Scholar 

  24. Monteiro PA, Antunes Bde M, Silveira LS, Christofaro DG, Fernandes RA, Freitas Junior IF (2014) Body composition variables as predictors of NAFLD by ultrasound in obese children and adolescents. BMC Pediatr 14:25

    PubMed  PubMed Central  Google Scholar 

  25. Paniagua JA, Escandell-Morales JM, Gil-Contreras D, Berral de la Rosa FJ, Romero-Jimenez M, Gómez-Urbano A et al (2014) Central obesity and altered peripheral adipose tissue gene expression characterize the NAFLD patient with insulin resistance: role of nutrition and insulin challenge. Nutrition 30:177–185

    CAS  PubMed  Google Scholar 

  26. do S Alve de Carvalho M, Coelho Cabral P, Kruze Grande de Arruda I, Goretti Pessoa Araújo de Burgos M, da Silva Diniz A, Barros Pernambuco JR et al (2012) Risk factors associated with hepatic steatosis: a study in patients in the Northeast Brazil. Nutr Hosp 27:1344–1350

    Google Scholar 

  27. Martins C, Freitas I Jr, Pizarro A, Aires L, Silva G, Santos MP et al (2013) Cardiorespiratory fitness, but not central obesity or C-reactive protein, is related to liver function in obese children. Pediatr Exerc Sci 25:3–11

    PubMed  Google Scholar 

  28. Kelishadi R, Abtahi SH, Qorbani M, Heshmat R, Esmaeil Motlagh M, Taslimi M et al (2012) First National Report on aminotransaminases' percentiles in children of the Middle East and North Africa (MENA): the CASPIAN-III study. Hepat Mon 12:e7711

    PubMed  PubMed Central  Google Scholar 

  29. Schwimmer JB, Celedon MA, Lavine JE, Salem R, Campbell N, Schork NJ et al (2009) Heritability of nonalcoholic fatty liver disease. Gastroenterology 136:1585–1592

    PubMed  Google Scholar 

  30. Willner IR, Waters B, Patil SR, Reuben A, Morelli J, Riely CA (2001) Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol 96:2957–2961

    CAS  PubMed  Google Scholar 

  31. Lin YC, Chang PF, Chang MH, Ni YH (2014) Genetic variants in GCKR and PNPLA3 confer susceptibility to nonalcoholic fatty liver disease in obese individuals. Am J Clin Nutr 99:869–874

    CAS  PubMed  Google Scholar 

  32. Rotman Y, Koh C, Zmuda JM, Kleiner DE, Liang TJ, NASH CRN (2010) The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology 52:894–903

    CAS  PubMed  Google Scholar 

  33. Walker RW, Sinatra F, Hartiala J, Weigensberg M, Spruijt-Metz D, Alderete TL et al (2013) Genetic and clinical markers of elevated liver fat content in overweight and obese Hispanic children. Obesity (Silver Spring) 21:E790–E797

    CAS  Google Scholar 

  34. Santoro N, Kursawe R, D'Adamo E, Dykas DJ, Zhang CK, Bale AE et al (2010) A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents. Hepatology 52:1281–1290

    CAS  PubMed  Google Scholar 

  35. Nobili V, Liccardo D, Bedogni G, Salvatori G, Gnani D, Bersani I et al (2014) Influence of dietary pattern, physical activity, and I148M PNPLA3 on steatosis severity in at-risk adolescents. Genes Nutr 9:392

    PubMed  PubMed Central  Google Scholar 

  36. Csaki LS, Dwyer JR, Fong LG, Tontonoz P, Young SG, Reue K (2013) Lipins, lipinopathies, and the modulation of cellular lipid storage and signaling. Prog Lipid Res 52:305–316

    CAS  PubMed  Google Scholar 

  37. Valenti L, Motta BM, Alisi A, Sartorelli R, Buonaiuto G, Dongiovanni P et al (2012) LPIN1 rs13412852 polymorphism in pediatric nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr 54:588–593

    CAS  PubMed  Google Scholar 

  38. Mahdessian H, Taxiarchis A, Popov S, Silveira A, Franco-Cereceda A, Hamsten A et al (2014) TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content. Proc Natl Acad Sci U S A 111:8913–8918

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Dongiovanni P, Petta S, Maglio C, Fracanzani AL, Pipitone R, Mozzi E et al (2014) TM6SF2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 61:506–514

    Google Scholar 

  40. Vajro P, Lenta S, Socha P, Dhawan A, McKiernan P, Baumann U et al (2012) Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN hepatology committee. J Pediatr Gastroenterol Nutr 54:700–713

    PubMed  Google Scholar 

  41. Lin YC, Chang PF, Hu FC, Chang MH, Ni YH (2009) Variants in the UGT1A1 gene and the risk of pediatric nonalcoholic fatty liver disease. Pediatrics 124(6):e1221–e1227

    PubMed  Google Scholar 

  42. Welsh JA, Karpen S, Vos MB (2013) Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988-1994 to 2007-2010. J Pediatr 162:496–500

    PubMed  Google Scholar 

  43. Gupta R, Bhangoo A, Matthews NA, Anhalt H, Matta Y, Lamichhane B et al (2011) The prevalence of non-alcoholic fatty liver disease and metabolic syndrome in obese children. J Pediatr Endocrinol Metab 24:907–911

    CAS  PubMed  Google Scholar 

  44. Imhof A, Kratzer W, Boehm B, Meitinger K, Trischler G, Steinbach G et al (2007) Prevalence of non-alcoholic fatty liver and characteristics in overweight adolescents in the general population. Eur J Epidemiol 22:889–897

    PubMed  Google Scholar 

  45. Fernandes MT, Ferraro AA, de Azevedo RA, Fagundes Neto U (2010) Metabolic differences between male and female adolescents with non-alcoholic fatty liver disease, as detected by ultrasound. Acta Paediatr 99:1218–1223

    CAS  PubMed  Google Scholar 

  46. Suzuki A, Abdelmalek MF, Schwimmer JB, Lavine JE, Scheimann AO, Unalp-Arida A et al (2012) Nonalcoholic steatohepatitis clinical research network. Association between puberty and features of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 10:786–794

    PubMed  PubMed Central  Google Scholar 

  47. Wolfgram PM, Connor EL, Rehm JL, Eickhoff JC, Reeder SB, Allen DB (2014) Ethnic differences in the effects of hepatic fat deposition on insulin resistance in nonobese middle school girls. Obesity (Silver Spring) 22:243–248

    CAS  Google Scholar 

  48. Deboer MD, Wiener RC, Barnes BH, Gurka MJ (2013) Ethnic differences in the link between insulin resistance and elevated ALT. Pediatrics 132:e718–e726

    PubMed  PubMed Central  Google Scholar 

  49. Hudson OD, Nunez M, Shaibi GQ (2012) Ethnicity and elevated liver transaminases among newly diagnosed children with type 2 diabetes. BMC Pediatr 12:174

    PubMed  PubMed Central  Google Scholar 

  50. Papandreou D, Karabouta Z, Rousso I (2012) Are dietary cholesterol intake and serum cholesterol levels related to nonalcoholic Fatty liver disease in obese children? Cholesterol 2012:572820

    PubMed  PubMed Central  Google Scholar 

  51. Nakamuta M, Fujino T, Yada R, Yada M, Yasutake K, Yoshimoto T et al (2009) Impact of cholesterol metabolism and the LXRalpha-SREBP-1c pathway on nonalcoholic fatty liver disease. Int J Mol Med 23:603–608

    CAS  PubMed  Google Scholar 

  52. Sundaram SS, Zeitler P, Nadeau K (2009) The metabolic syndrome and nonalcoholic fatty liver disease in children. Curr Opin Pediatr 21:529–535

    PubMed  PubMed Central  Google Scholar 

  53. Ludvigsson JF, Elfström P, Broomé U, Ekbom A, Montgomery SM (2007) Celiac disease and risk of liver disease: a general population-based study. Clin Gastroenterol Hepatol 5:63–69

    PubMed  Google Scholar 

  54. Bray GA, Popkin BM (2014) Dietary sugar and body weight: have we reached a crisis in the epidemic of obesity and diabetes?: health be damned! Pour on the sugar. Diabetes Care 37:950–956

    CAS  PubMed  Google Scholar 

  55. Chung M, Ma J, Patel K, Berger S, Lau J, Lichtenstein AH (2014) Fructose, high-fructose corn syrup, sucrose, and nonalcoholic fatty liver disease or indexes of liver health: a systematic review and meta-analysis. Am J Clin Nutr 100:833–849

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Chiu S, Sievenpiper JL, de Souza RJ, Cozma AI, Mirrahimi A, Carleton AJ et al (2014) Effect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials. Eur J Clin Nutr 68:416–423

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Abdelmalek MF, Suzuki A, Guy C, Unalp-Arida A, Colvin R, Johnson RJ et al (2010) Nonalcoholic steatohepatitis clinical research network. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology 51:1961–1971

    CAS  PubMed  Google Scholar 

  58. O’Sullivan TA, Oddy WH, Bremner AP, Sherriff JL, Ayonrinde OT, Olynyk JK et al (2014) Lower fructose intake may help protect against development of nonalcoholic fatty liver in adolescents with obesity. Pediatr Gastroenterol Nutr 58:624–631

    Google Scholar 

  59. Jin R, Le NA, Liu S, Farkas Epperson M, Ziegler TR, Welsh JA et al (2012) Children with NAFLD are more sensitive to the adverse metabolic effects of fructose beverages than children without NAFLD. J Clin Endocrinol Metab 97:E1088–E1098

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Jin R, Willment A, Patel SS, Sun X, Song M, Mannery YO et al (2014) Fructose induced endotoxemia in pediatric nonalcoholic fatty liver disease. Int J Hepatol 2014:560620

    PubMed  PubMed Central  Google Scholar 

  61. Lebda MA, Tohamy HG, El-Sayed YS (2017) Long-term soft drink and aspartame intake induces hepatic damage via dysregulation of adipocytokines and alteration of the lipid profile and antioxidant status. Nutr Res 41:47–55

    CAS  PubMed  Google Scholar 

  62. Holvoet P, Rull A, García-Heredia A, López-Sanromà S, Geeraert B, Joven J et al (2015) Stevia-derived compounds attenuate the toxic effects of ectopic lipid accumulation in the liver of obese mice: a transcriptomic and metabolomic study. Food Chem Toxicol 77:22–33

    CAS  PubMed  Google Scholar 

  63. Ritze Y, Bárdos G, Hubert A, Böhle M, Bischoff SC (2014) Effect of tryptophan supplementation on diet-induced non-alcoholic fatty liver disease in mice. Br J Nutr 112:1–7

    CAS  PubMed  Google Scholar 

  64. Nobili V, Bedogni G, Alisi A, Pietrobattista A, Alterio A, Tiribelli C et al (2009) A protective effect of breastfeeding on the progression of non-alcoholic fatty liver disease. Arch Dis Child 94:801–805

    CAS  PubMed  Google Scholar 

  65. Nobili V, Alisi A, Panera N, Agostoni C (2008) Low birth weight and catch-up-growth associated with metabolic syndrome: a ten year systematic review. Pediatr Endocrinol Rev 6:241–247

    PubMed  Google Scholar 

  66. Breij LM, Kerkhof GF, Hokken-Koelega AC (2014) Accelerated infant weight gain and risk for nonalcoholic fatty liver disease in early adulthood. J Clin Endocrinol Metab 99:1189–1195

    CAS  PubMed  Google Scholar 

  67. Nobili V, Cutrera R, Liccardo D, Pavone M, Devito R, Giorgio V et al (2014) 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 189:66–76

    CAS  PubMed  Google Scholar 

  68. Eng K, Lopez R, Liccardo D, Nobili V, Alkhouri N (2014) A non-invasive prediction model for non-alcoholic steatohepatitis in paediatric patients with non-alcoholic fatty liver disease. Dig Liver Dis 46:1008–1013

    PubMed  Google Scholar 

  69. Bacopoulou F, Efthymiou V, Landis G, Rentoumis A, Chrousos GP (2015) Waist circumference, waist-to-hip ratio and waist-to-height ratio reference percentiles for abdominal obesity among Greek adolescents. BMC Pediatr 4:15–50

    Google Scholar 

  70. Schwimmer JB, Dunn W, Norman GJ, Pardee PE, Middleton MS, Kerkar N et al (2010) SAFETY study: alanine aminotransferase cutoff values are set too high for reliable detection of pediatric chronic liver disease. Gastroenterology 138:1357–1364

    CAS  PubMed  Google Scholar 

  71. Elizondo-Montemayor L, Ugalde-Casas PA, Lam-Franco L, Bustamante-Careaga H, Serrano-González M, Gutiérrez NG et al (2014) Association of ALT and the metabolic syndrome among Mexican children. Obes Res Clin Pract 8:e79–e87

    PubMed  Google Scholar 

  72. Wei C, Ford A, Hunt L, Crowne EC, Shield JP (2011) Abnormal liver function in children with metabolic syndrome from a UK-based obesity clinic. Arch Dis Child 96:1003–1007

    PubMed  Google Scholar 

  73. Poustchi H, George J, Esmaili S, Esna-Ashari F, Ardalan G, Sepanlou SG et al (2011) Gender differences in healthy ranges for serum alanine aminotransferase levels in adolescence. PLoS One 6:e21178

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Molleston JP, Schwimmer JB, Yates KP, Murray KF, Cummings OW, Lavine JE et al (2014) NASH clinical research network. Histological abnormalities in children with nonalcoholic fatty liver disease and normal or mildly elevated alanine aminotransferase levels. J Pediatr 164:707–713

    CAS  PubMed  Google Scholar 

  75. Patton HM, Lavine JE, Van Natta ML, Schwimmer JB, Kleiner D, Molleston J (2008) Nonalcoholic steatohepatitis clinical research network. Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis. Gastroenterology 135:1961–1971

    PubMed  Google Scholar 

  76. Wieckowska A, Feldstein AE (2008) Diagnosis of nonalcoholic fatty liver disease: invasive versus noninvasive. Semin Liver Dis 28:386–395

    CAS  PubMed  Google Scholar 

  77. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR (1999) Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 94:2467–2474

    CAS  PubMed  Google Scholar 

  78. Carter-Kent C, Yerian LM, Brunt EM, Angulo P, Kohli R, Ling SC et al (2009) Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study. Hepatology 50:1113–1120

    PubMed  Google Scholar 

  79. Schwimmer JB, Behling C, Newbury R, Deutsch R, Nievergelt C, Schork NJ et al (2005) Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology 42:641–649

    PubMed  Google Scholar 

  80. Nobili V, Marcellini M, Devito R, Ciampalini P, Piemonte F, Comparcola D et al (2006) NAFLD in children: a prospective clinical-pathological study and effect of lifestyle advice. Hepatology 44:458–465

    PubMed  Google Scholar 

  81. Takahashi Y, Fukusato T (2010) Pediatric nonalcoholic fatty liver disease: overview with emphasis on histology. World J Gastroenterol 16:5280–5285

    PubMed  PubMed Central  Google Scholar 

  82. Juluri R, Vuppalanchi R, Olson J, Unalp A, Van Natta ML, Cummings OW et al (2011) Generalizability of the nonalcoholic steatohepatitis clinical research network histologic scoring system for nonalcoholic fatty liver disease. J Clin Gastroenterol 45:55–58

    PubMed  PubMed Central  Google Scholar 

  83. Alkhouri N, De Vito R, Alisi A, Yerian L, Lopez R, Feldstein AE et al (2012) Development and validation of a new histological score for pediatric non-alcoholic fatty liver disease. J Hepatol 57:1312–1318

    PubMed  Google Scholar 

  84. Roberts EA (2007) Pediatric nonalcoholic fatty liver disease (NAFLD): a "growing" problem? J Hepatol 46:1133–1142

    CAS  PubMed  Google Scholar 

  85. Feldstein AE, Wieckowska A, Lopez AR, Liu YC, Zein NN, McCullough AJ (2009) Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 50:1072–1078

    CAS  PubMed  Google Scholar 

  86. Chan WK, Sthaneshwar P, Nik Mustapha NR, Mahadeva S (2014) Limited utility of plasma M30 in discriminating non-alcoholic steatohepatitis from steatosis--a comparison with routine biochemical markers. PLoS One 9:e105903

    PubMed  PubMed Central  Google Scholar 

  87. Vuppalanchi R, Jain AK, Deppe R, Yates K, Comerford M, Masuoka HC et al (2014) 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 12:2121–2130

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Feldstein AE, Alkhouri N, De Vito R, Alisi A, Lopez R, Nobili V (2013) Serum cytokeratin-18 fragment levels are useful biomarkers for nonalcoholic steatohepatitis in children. Am J Gastroenterol 108:1526–1531

    CAS  PubMed  Google Scholar 

  89. Fitzpatrick E, Mitry RR, Quaglia A, Hussain MJ, DeBruyne R, Dhawan A (2010) Serum levels of CK18 M30 and leptin are useful predictors of steatohepatitis and fibrosis in paediatric NAFLD. J Pediatr Gastroenterol Nutr 51:500–506

    CAS  PubMed  Google Scholar 

  90. Nobili V, Parola M, Alisi A, Marra F, Piemonte F, Mombello C et al (2010) Oxidative stress parameters in paediatric non-alcoholic fatty liver disease. Int J Mol Med 26:471–476

    CAS  PubMed  Google Scholar 

  91. Torun E, Gökçe S, Ozgen İT, Aydın S, Cesur Y (2014) Serum paraoxonase activity and oxidative stress and their relationship with obesity-related metabolic syndrome and non-alcoholic fatty liver disease in obese children and adolescents. J Pediatr Endocrinol Metab 27:667–675

    CAS  PubMed  Google Scholar 

  92. Puri K, Nobili V, Melville K, Corte CD, Sartorelli MR, Lopez R et al (2013) Serum bilirubin level is inversely associated with nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr 57:114–118

    CAS  PubMed  Google Scholar 

  93. Lebensztejn DM, Wojtkowska M, Skiba E, Werpachowska I, Tobolczyk J, Kaczmarski M (2009) Serum concentration of adiponectin, leptin and resistin in obese children with non-alcoholic fatty liver disease. Adv Med Sci 54:177–182

    CAS  PubMed  Google Scholar 

  94. Lebensztejn DM, Kowalczuk D, Tarasów E, Skiba E, Kaczmarski M (2010) Tumor necrosis factor alpha and its soluble receptors in obese children with NAFLD. Adv Med Sci 55:74–79

    CAS  PubMed  Google Scholar 

  95. Koot BG, van der Baan-Slootweg OH, Bohte AE, Nederveen AJ, van Werven JR, Tamminga-Smeulders CL et al (2013) Accuracy of prediction scores and novel biomarkers for predicting nonalcoholic fatty liver disease in obese children. Obesity (Silver Spring) 21:583–590

    CAS  Google Scholar 

  96. Ratziu V, Massard J, Charlotte F, Messous D, Imbert-Bismut F, Bonyhay L et al (2006) LIDO study group; CYTOL study group. Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol 6:6

    PubMed  PubMed Central  Google Scholar 

  97. Shah AG, Lydecker A, Murray K, Tetri BN, Contos MJ, Sanyal AJ (2009) Nash clinical research network. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 7:1104–1112

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Nobili V, Parkes J, Bottazzo G, Marcellini M, Cross R, Newman D et al (2009) Performance of ELF serum markers in predicting fibrosis stage in pediatric non-alcoholic fatty liver disease. Gastroenterology 136:160–167

    CAS  PubMed  Google Scholar 

  99. Mazhar SM, Shiehmorteza M, Sirlin CB (2009) Noninvasive assessment of hepatic steatosis. Clin Gastroenterol Hepatol 7:135–140

    PubMed  Google Scholar 

  100. Hamer OW, Aguirre DA, Casola G, Lavine JE, Woenckhaus M, Sirlin CB (2006) Fatty liver: imaging patterns and pitfalls. Radiographics 26:1637–1653

    PubMed  Google Scholar 

  101. Shannon A, Alkhouri N, Carter-Kent C, Monti L, Devito R, Lopez R et al (2011) Ultrasonographic quantitative estimation of hepatic steatosis in children with NAFLD. J Pediatr Gastroenterol Nutr 53:190–195

    PubMed  PubMed Central  Google Scholar 

  102. Kim SH, Lee JM, Han JK, Lee JY, Lee KH, Han CJ et al (2006) Hepatic macrosteatosis: predicting appropriateness of liver donation by using MR imaging--correlation with histopathologic findings. Radiology 240:116–129

    PubMed  Google Scholar 

  103. Limanond P, Raman SS, Lassman C, Sayre J, Ghobrial RM, Busuttil RW et al (2004) Macrovesicular hepatic steatosis in living related liver donors: correlation between CT and histologic findings. Radiology 230:276–280

    PubMed  Google Scholar 

  104. Bohte AE, van Werven JR, Bipat S, Stoker J (2011) The diagnostic accuracy of US, CT, MRI and 1H-MRS for the evaluation of hepatic steatosis compared with liver biopsy: a meta-analysis. Eur Radiol 21:87–97

    PubMed  Google Scholar 

  105. Boursier J, Isselin G, Fouchard-Hubert I, Oberti F, Dib N, Lebigot J et al (2010) Acoustic radiation force impulse: a new ultrasonographic technology for the widespread noninvasive diagnosis of liver fibrosis. Eur J Gastroenterol Hepatol 22:1074–1084

    PubMed  Google Scholar 

  106. Marginean CO, Marginean C (2012) Elastographic assessment of liver fibrosis in children: a prospective single center experience. Eur J Radiol 81:e870–e874

    PubMed  Google Scholar 

  107. Loomba R, Wolfson T, Ang B, Booker J, Behling C, Peterson M et al (2014) Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study. Hepatology 60:1920–1928

    CAS  PubMed  Google Scholar 

  108. Vajro P, Lenta S, Pignata C, Salerno M, D'Aniello R, De Micco I et al (2012) Therapeutic options in pediatric non-alcoholic fatty liver disease: current status and future directions. Ital J Pediatr 38:55

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Alisi A, Nobili V (2012) Non-alcoholic fatty liver disease in children now: lifestyle changes and pharmacologic treatments. Nutrition 28:722–726

    CAS  PubMed  Google Scholar 

  110. Ryan MC, Itsiopoulos C, Thodis T, Ward G, Trost N, Hofferberth S et al (2013) The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol 59:138–143

    CAS  PubMed  Google Scholar 

  111. Reinehr T, Schmidt C, Toschke AM, Andler W (2009) Lifestyle intervention in obese children with non-alcoholic fatty liver disease: 2-year follow-up study. Arch Dis Child 94:437–442

    CAS  PubMed  Google Scholar 

  112. Verduci E, Pozzato C, Banderali G, Radaelli G, Arrizza C, Rovere A et al (2013) Changes of liver fat content and transaminases in obese children after 12-mo nutritional intervention. World J Hepatol 5:505–512

    PubMed  PubMed Central  Google Scholar 

  113. Shah K, Stufflebam A, Hilton TN, Sinacore DR, Klein S, Villareal DT (2009) Diet and exercise interventions reduce intrahepatic fat content and improve insulin sensitivity in obese older adults. Obesity (Silver Spring) 17:2162–2168

    Google Scholar 

  114. Nobili V, Manco M, Devito R, Di Ciommo V, Comparcola D, Sartorelli MR et al (2008) Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Hepatology 48:119–128

    CAS  PubMed  Google Scholar 

  115. Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P et al (2011) Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 305:1659–1668

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Dohil R, Schmeltzer S, Cabrera BL, Wang T, Durelle J, Duke KB et al (2011) Enteric-coated cysteamine for the treatment of paediatric non-alcoholic fatty liver disease. Aliment Pharmacol Ther 33:1036–1044

    CAS  PubMed  Google Scholar 

  117. Vajro P, Franzese A, Valerio G, Iannucci MP, Aragione N (2000) Lack of efficacy of ursodeoxycholic acid for the treatment of liver abnormalities in obese children. J Pediatr 136:739–743

    CAS  PubMed  Google Scholar 

  118. Murer SB, Aeberli I, Braegger CP, Gittermann M, Hersberger M, Leonard SW et al (2014) Antioxidant supplements reduced oxidative stress and stabilized liver function tests but did not reduce inflammation in a randomized controlled trial in obese children and adolescents. J Nutr 144:193–201

    CAS  PubMed  Google Scholar 

  119. Nobili V, Bedogni G, Alisi A, Pietrobattista A, Risé P, Galli C et al (2011) Docosahexaenoic acid supplementation decreases liver fat content in children with non-alcoholic fatty liver disease: double-blind randomised controlled clinical trial. Arch Dis Child 96:350–353

    PubMed  Google Scholar 

  120. Nobili V, Carpino G, Alisi A, De Vito R, Franchitto A, Alpini G et al (2014) Role of docosahexaenoic acid treatment in improving liver histology in pediatric nonalcoholic fatty liver disease. PLoS One 9(2):e88005

    PubMed  PubMed Central  Google Scholar 

  121. Zöhrer E, Alisi A, Jahnel J, Mosca A, Della Corte C, Crudele A et al (2017) Efficacy of docosahexaenoic acid-choline-vitamin E in paediatric NASH: a randomized controlled clinical trial. Appl Physiol Nutr Metab 42:948–954

    PubMed  Google Scholar 

  122. Pardee PE, Lavine JE, Schwimmer JB (2009) Diagnosis and treatment of pediatric nonalcoholic steatohepatitis and the implications for bariatric surgery. Semin Pediatr Surg 18:144–151

    PubMed  PubMed Central  Google Scholar 

  123. Weiner RA (2010) Surgical treatment of non-alcoholic steatohepatitis and non-alcoholic fatty liver disease. Dig Dis 28:2742–2279

    Google Scholar 

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Authors and Affiliations

  1. First Department of Pediatrics, Division of Endocrinology, Diabetes and Metabolism, Medical School, National and Kapodistrian University of Athens, “Aghia Sophia” Children’s Hospital, Athens, Greece

    Flora Tzifi, George Chrousos & Christina Kanaka-Gantenbein

  2. Athens Medical Group, Marousi, Greece

    Flora Tzifi & Andreas Fretzayas

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  1. Flora Tzifi
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Tzifi, F., Fretzayas, A., Chrousos, G. et al. Non-alcoholic fatty liver infiltration in children: an underdiagnosed evolving disease. Hormones 18, 255–265 (2019). https://doi.org/10.1007/s42000-019-00107-7

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