Pediatric Non-alcoholic Fatty Liver Disease

Current Gastroenterology Reports

Volumn 18, Issue 5, 2016, Pages

  Uppal, Vikas ^a,b   Mansoor, Sana ^a,b   Furuya, Katryn N ^a,b  

^a NEMOURS ALFRED I DUPONT HOSPITAL FOR CHILDREN   (United States)

^b THOMAS JEFFERSON UNIVERSITY   (United States)

Author keywords

Childhood obesity; Cirrhosis; Hepatic fibrosis; Non alcoholic fatty liver disease; Non alcoholic steatohepatitis; Pediatric

Indexed keywords

ALANINE AMINOTRANSFERASE; ASPARTATE AMINOTRANSFERASE; BIOLOGICAL MARKER; CYTOKERATIN 18; PROBIOTIC AGENT;

ALANINE AMINOTRANSFERASE BLOOD LEVEL; AMINO ACID SUBSTITUTION; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; BARIATRIC SURGERY; CLINICAL EFFECTIVENESS; CLINICAL FEATURE; ELASTOGRAPHY; EXERCISE; FATTY ACID METABOLISM; FATTY ACID TRANSPORT; GASTRIC BANDING; GENETIC MARKER; HIGH RISK PATIENT; HUMAN; INTESTINE FLORA; LIFESTYLE MODIFICATION; LIPID PEROXIDATION; LIVER BIOPSY; LONG TERM SURVIVAL; LOW CALORY DIET; MAGNETIC RESONANCE ELASTOGRAPHY; NONALCOHOLIC FATTY LIVER; NUCLEAR MAGNETIC RESONANCE IMAGING; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; OXIDATIVE STRESS; PATHOGENESIS; PREVALENCE; REVIEW; ROUX Y ANASTOMOSIS; SAFETY; SINGLE NUCLEOTIDE POLYMORPHISM; SLEEVE GASTRECTOMY; CHILD; COMPLICATION; LIVER; NON-ALCOHOLIC FATTY LIVER DISEASE; OBESITY; PATHOLOGY;

CHILD; HUMANS; LIVER; NON-ALCOHOLIC FATTY LIVER DISEASE; OBESITY;

EID: 84964237549     PISSN: 15228037     EISSN: 1534312X     Source Type: Journal    
DOI: 10.1007/s11894-016-0498-9     Document Type: Review

References (102)

1. Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, et al. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut. 2009;58(11):1538–44.
2. Marzuillo P, Grandone A, Perrone L, et al. Understanding the pathophysiological mechanisms in the pediatric nonalcoholic fatty liver disease: the role of genetics. World J Gastroenterol. 2015;7(11):1439–43.
3. Marzuillo P, Del Giudice EM, Santoro N. Pediatric non-alcoholic fatty liver disease: new insights and future directions. World J Gastroenterol. 2014;6(4):217–25.
4. Marzuillo P, Del Giudice EM, Santoro N. Pediatric fatty liver disease: role of ethnicity and genetics. World J Gastroenterol. 2014;20(23):7347–55.
5. McPherson S, Hardy T, Henderson E, et al. Evidence of NAFLD progression from steatosis to fibrosing steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol. 2015;62(5):1148–55.
6. Preiss D, Sattar N. Non-alcoholic fatty liver disease: an overview of prevalence, diagnosis, pathogenesis and treatment considerations. Clin Sci. 2008;115(5):141–50.
7. Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology. 2011;53(6):1874–82.
8. Schwimmer JB, Behling C, Newbury R, et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology. 2005;42(3):641–9.
9. Molleston JP, White F, Teckman J, et al. Obese children with steatohepatitis can develop cirrhosis in childhood. Am J Gastroenterol. 2002;97(9):2460–2.
10. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149(2):389–97. Retrospective study demonstrating that hepatic fibrosis is the single most important prognostic marker in NAFLD.
11. Xanthakos S, Miles L, Bucuvalas J, et al. Histologic spectrum of nonalcoholic fatty liver disease in morbidly obese adolescents. Clin Gastroenterol Hepatol. 2006;4(2):226–32.
12. Loomba R, Sirlin CB, Schwimmer JB, et al. Advances in pediatric nonalcoholic fatty liver disease. Hepatology. 2009;50(4):1282–93.
13. Schwimmer JB, McGreal N, Deutsch R, et al. Influence of gender, race, and ethnicity of suspected fatty liver in obese adolescents. Pediatrics. 2005;115(5):e561–656.
14. Schwimmer JB, Deutsch R, Kahen T, et al. Prevalence of fatty liver in children and adolescents. Pediatrics. 2006;118(4):1388–93.
15. Nomura H, Kashiwagi S, Hayashi J, et al. Prevalence of fatty liver in a general population of Okinawa. Jpn Jpn J Med. 1988;27(2):142–9.
16. Park HS, Han JS, Choi KM, et al. Relation between elevated serum alanine aminotransferase and metabolic syndrome in Korean adolescents. Am J Clin Nutr. 2005;82(5):1046–51.
17. Kahali B, Halligan B, Spelitoes E. Insights from genome-wide association analyses of nonalcoholic fatty liver disease. Semin Liver Dis. 2015;35(4):375–91.
18. Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114(4):842–5.
19. D’Adamo E, Cali AM, Weiss R, et al. Central role of fatty liver in the pathogenesis of insulin resistance in obese adolescents. Diabetes Care. 2010;33(8):1817–22.
20. Cali AM, De Oliveira AM, Kim H, et al. Glucose dysregulation and hepatic steatosis in obese adolescents: is there a link? Hepatology. 2009;49(6):1896–903.
21. Giorgio V, Prono F, Graziano F, et al. Pediatric non alcoholic fatty liver disease: old and new concepts on development, progression, metabolic insight and potential treatment targets. BMC Pediatr. 2013;13(40):1–10.
22. Zhu L, Baker RD, Baker SS. From multiple hits to multiple therapeutic targets of non-alcoholic fatty liver disease. Curr Drug Targets. 2015;16(12):1272–3.
23. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52(5):1836–46.
24. Schwimmer JB, Celedone MA, Lavine JE, et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology. 2009;136(5):1585–92.
25. Loomba R, Schork N, Chen CH, et al. Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterology. 2015;149(7):1784–93.
26. Marchesini G, Petta S, Dalle Grave R. Diet, weight loss, and liver health in nonalcoholic fatty liver disease: pathophysiology, evidence, and practice. Hepatology. 2015. doi:10.1002/hep28392. Important review article highlighting the importance of dietary and life style modifications which lead to weight loss and improvement in NAFLD.
27. Huang Y, He S, Li JZ, et al. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc Natl Acad Sci U S A. 2010;107(17):7892–7.
28. He S, McPhaul C, Li JZ, et al. A sequence variation (l148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem. 2010;285(9):6706–15.
29. Pirazzi C, Adiels M, Burza MA, et al. Patatin-like phospholipase domain-containing 3 (PNPLA3) l148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J Hepatol. 2012;57(6):1276–82.
30. Kozlitina J, Smargris E, Stender S, et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2014;46(4):352–6.
31. Goffredo M, Caprio S, Feldstein AE, et al. Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: a multiethnic study. Hepatology. 2016;63(1):117–25. The role of the single nucleotide polymorphism, rs58542926 in the TM6SF2 gene in pediatric NAFLD.
32. Arslan N. Obesity, fatty liver disease and intestinal microbiota. World J Gastroenterol. 2014;20(44):16452–63.
33. Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut microbiome in obese and lean twins. Nature. 2009;457(7228):480–4.
34. Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012;143(4):913–6.
35. Qin J, Li Y, Cai Z, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490(7418):55–60.
36. Boursier J, Mueller O, Barret M, et al. The severity of NAFLD is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology. 2015. doi:10.1002/hep28356. This study examines the role of intestinal dysbiosis in NAFLD.
37. Schwimmer JB, Deutsch R, Rauch JB, et al. Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. J Pediatr. 2003;143(4):500–5.
38. Lavine JE, Schwimmer JB. Nonalcoholic fatty liver disease in the pediatric population. Clin Liver Dis. 2004;8(3):549–58.
39. Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr. 2000;30(1):48–53.
40. Alkhouri N, De Vito R, Alisi A, et al. Development and validation of a new histological score for pediatric non-alcoholic fatty liver disease. J Hepatol. 2012;57(6):1312–8.
41. Barlow SE, Expert Committee. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics. 2007;120(S4):S164–S92.
42. Schwimmer JB, Dunn W, Norman GJ, et al. SAFETY study: alanine aminotransferase cutoff values are set too high for reliable detection of pediatric chronic liver disease. Gastroenterology. 2010;138(4):1357–64.
43. Molleston JP, Schwimmer JB, Yates KP, et al. Histologic abnormalities in children with nonalcoholic fatty liver disease and normal or mildly elevated alanine aminotransferase levels. J Pediatr. 2014;164(4):707–13.
44. Kim H, Taksali SE, Dufour S, et al. Comparative MR study of hepatic fat quantification using single-voxel proton spectroscopy, two-point dixon and three-point IDEAL. Magn Reson Med. 2008;59(3):521–7.
45. Shannon A, Alkhouri N, Carter-Kent C, et al. Ultrasonographic quantitative estimation of hepatic steatosis in children with nonalcoholic fatty liver disease (NAFLD). J Pediatr Gastroenterol Nutr. 2011;53(2):190–5.
46. Tiniakos DG, Vos MB, Brunt EM. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol. 2010;5:145–71.
47. Brunt EM. Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2010;7(4):195–203.
48. Caldwell S, Ikura Y, Dias D, et al. Hepatocellular ballooning in NASH. J Hepatol. 2010;53(4):719–23.
49. Lavine JE, Schwimmer JB, Van Natta ML, et al. 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(16):1659–68.
50. Sanyal AJ, Chalasani N, Kowdley KV, et al. Piogrlitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675–85.
51. Carter-Kent C, Yerian LM, Brunt EM, et al. Nonalcoholic steatohepatitis in children: a mutlicenter clinicopathological study. Hepatology. 2009;50(4):1113–20.
52. Brunt EM, Janney CG, Di Bisceglie AM, et al. Nonalcoholic steatohepatitis:a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94(9):2467–74.
53. Kleiner DE, Brunt EM, Van Natta ML, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–21.
54. Dezsofi A, Baumann U, Dhawan A, et al. Liver biopsy in children: position paper of the ESPGHAN Hepatology Committee. J Pediatr Gastroenterol Nutr. 2015;60:408–20.
55. Vajro P, Lenta S, Socha P, et al. Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee. J Pediatr Gastroenterol Nutr. 2012;54(5):700–13. Most updated position statement on the screening and diagnosis of pediatric NAFLD.
56. Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–54.
57. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317–25.
58. Yang HR, Kim HR, Kim MJ, et al. Noninvasive parameters and hepatic fibrosis scores in children with nonalcoholic fatty liver disease. World J Gastroenterol. 2012;18(13):1525–30.
59. Mansoor S, Yerian L, Kohli R, et al. The evaluation of hepatic fibrosis scores in children with nonalcoholic fatty liver disease. Dig Dis Sci. 2015;60(5):1440–7.
60. Nobili V, Alisi A, Vania A, et al. The pediatric NAFLD fibrosis index: a predictor of liver fibrosis in children with non-alcoholic fatty liver disease. BMC Med. 2009;7:21.
61. Feldstein AE, Alkhouri N, De Vito R, et al. Serum cytokeratin-18 fragment levels are useful biomarkers for nonalcoholic steatohepatitis in children. Am J Gastroenterol. 2013;108:1526–31.
62. Feldstein AE, Wieckowska A, Lopez R, et al. Cytokeratin-18 fragment levels as noninvasive biomarker for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology. 2009;50(4):1072–8.
63. Mandelia C, Collyer E, Mansoor S, et al. Plasma Cytokeratin-18 level as a novel biomarker for liver fibrosis in children with nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2016.
64. Nobili V, Alisi A, Torre G, et al. Hyaluronic acid predicts hepatic fibrosis in children with nonalcoholic fatty liver disease. Transl Res. 2010;156(4):229–34.
65. Guha IN, Parkes J, Roderick P, et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology. 2008;47(2):455–60.
66. Nobili V, Parkes J, Bottazzo G, et al. Performance of ELF serum markers in predicting fibrosis stage in pediatric non-alcoholic fatty liver disease. Gastroenterology. 2009;136(1):160–7.
67. Alkhouri N, Carter-Kent C, Lopez R, et al. A combination of the pediatric NAFLD fibrosis index and enhanced liver fibrosis test identifies children with fibrosis. Clin Gastroenterol Hepatol. 2011;9(2):150–5.
68. Stibbe KJ, Verveer C, Francke J, et al. Comparison of non-invasive assessment to diagnose liver fibrosis in chronic hepatitis B and C patients. Scan J Gastroenterol. 2011;46(7–8):962–72.
69. deLedinghen V, Le Bail B, Rebouissoux L, et al. Liver stiffness measurement in children using FibroScan: feasibility study and comparison with Fibrotest, aspartate transaminase to platelets ratio index, and liver biopsy. J Pediatr Gastroenterol Nutr. 2007;45(4):443–50.
70. Goldschmidt I, Streckenbach C, Dingemann C, et al. Application and limitations of transient liver elastography in children. J Pediatr Gastroenterol Nutr. 2013;57(1):109–13.
71. Petta S, Di Marco V, Camma C, et al. Reliability of liver stiffness measurement in non-alcoholic fatty liver disease: the effects of body mass index. Aliment Pharmacol Ther. 2011;33(12):1350–60.
72. Koh H, Kim S, Kim MJ, et al. Hepatic fat quantification magnetic resonance for monitoring treatment response in pediatric nonalcoholic steatohepatitis. World J Gastroenterol. 2015;21(33):3741–8.
73. Idilman IS, Keskin O, Celik A, et al. A comparison of liver fat content as determined by magnetic resonance imaging-proton density fat fraction and MRS versus liver histology in non-alcoholic fatty liver disease. Acta Radiol. 2015.
74. Permutt Z, Le TA, Peterson MR, et al. Correlation between liver histology and novel magnetic resonance imaging in adult patients with non-alcoholic fatty liver disease - MRI accurately quantifies hepatic steatosis in NAFLD. Aliment Pharmacol Ther. 2012;36(1):22–9.
75. Schwimmer JB, Middleton MS, Behling C, et al. Magnetic resonance imaging and liver histology as biomarkers of hepatic steatosis in children with nonalcoholic fatty liver disease. Hepatology. 2015;61(6):1887–95.
76. Achmad E, Yokoo T, Hamilton G, et al. Feasibility of and agreement between MR imaging and spectroscopic estimation of hepatic proton density fat fraction in children with known or suspected nonalcoholic fatty liver disease. Abdom Imaging. 2015;40(8):3084–90.
77. Yin M, Talwalkar JA, Glaser KJ, et al. Assessment of hepatic fibrosis with magnetic resonance elastography. Clin Gastroenterol Hepatol. 2007;5(10):1207–13.
78. Imajo K, Kessoku T, Honda Y, et al. Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography. Gastroenterology 2015.
79. Cui J, Ang B, Haufe W, et al. Comparative diagnostic accuracy of magnetic resonance elastography vs. eight clinical prediction rules for non-invasive diagnosis of advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease: a prospective study. Aliment Pharmacol Ther. 2015;41(12):1271–80.
80. Venkatesh SK, Yin M, Ehman RL. Magnetic resonance elastography of liver: technique, analysis, and clinical applications. J Magn Reson Imaging. 2013;37(3):544–55.
81. Xanthakos SA, Podberesky DJ, Serai SD, et al. Use of magnetic resonance elastography to assess hepatic fibrosis in children with chronic liver disease. J Pediatr. 2014;164(1):186–8.
82. Maurantonio M, Ballestri S, Odoardi MR, et al. Treatment of atherogenic liver based on the pathogenesis of nonalcoholic fatty liver disease: a novel approach to reduce cardiovascular risk? Arch Med Res. 2011;42(5):337–53.
83. Nobili V, Manco M, De Vito R, et al. Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Hepatology. 2008;48(1):119–28.
84. Gidding SS, Dennison BA, Birch LL, et al. Dietary recommendations for children and adolescents: a guide for practitioners: consensus statement from the American Heart Association. Circulation. 2005;112(13):2061–75.
85. Vajro P, Mandato C, Licenziati MR, et al. Effects of Lactobacillus rhamnosus strain GG in pediatric obesity-related liver disease. J Pediatr Gastroenterol Nutr. 2011;52(6):740–3.
86. Alisi A, Bedogni G, Baviera G, et al. Randomised clinical trial: the beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2014;39(11):1276–85.
87. Loguercio C, Federico A, Tuccillo C, et al. Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol. 2005;39(6):540–3.
88. Parker HM, Johnson NA, Burdon CA, et al. Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol. 2012;56(4):944–51.
89. Masteron GS, Plevris JN, Hayes PC. Review article: omega-3 fatty acids - a promising novel therapy for non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2010;31(7):679–392.
90. Nobili V, Bedogni G, Alisi A, et al. 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(4):350–3.
91. Nobili V, Alisi A, Della Corte C, et al. Docosahexaenoic acid for the treatment of fatty liver: randomised controlled trial in children. Nutr Metab Cardiovasc Dis. 2013;23(11):1066–70.
92. Janczyk W, Lebensztein D, Wierzbicka-Rucinska A, et al. Omega-3 Fatty acids therapy in children with nonalcoholic Fatty liver disease: a randomized controlled trial. J Pediatr. 2015;166(6):1358–63.
93. Janczyk W, Socha P, Lebensztein D, et al. Omega-3 fatty acids for treatment of non-alcoholic fatty liver disease: design and rationale of randomized controlled trial. BMC Pediatr. 2013.
94. Sanyal AJ, Abdelmalek MF, Suzuki A, et al. No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology. 2014;147(2):374–87.
95. Scorletti E, Bhatia L, McCormick KG, et al. Effects of purified eicosapentaenoic and docosahexaenoic acids in nonalcoholic fatty liver disease: results from the Welcome* study. Hepatology. 2014;60(4):1211–21.
96. Lavine JE. Vitamin E, treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr. 2000;136(6):734–8.
97. Vajro P, Franzese A, Valerio G, et al. Lack of efficacy of ursodeoxycholic acid for the treatment of liver abnormalities in obese children. J Pediatr. 2000;136(6):739–43.
98. Ratziu V, Giral P, Jacqueminet S, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology. 2008;135(1):100–10.
99. Du J, Ma Y, Yu C, et al. Effects of pentoxifylline on nonalcoholic fatty liver disease: a meta-analysis. World J Gastroenterol. 2014;20(2):569–77.
100. Zein CO, Yerian LM, Gogate P, et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology. 2011;54(5):1610–9.
101. Adorini L, Purzanski M, Shapiro D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today. 2012;17–18:988–97.
102. Nobili V, Vajro P, Dezsofi A, et al. Indications and limitations of bariatric intervention in severely obese children and adolescents with and without nonalcoholic steatohepatitis: ESPGHAN Hepatology Committee Position Statement. J Pediatr Gastroenterol Nutr. 2015;60(4):550–61. Consensus statement on the role of bariatric surgery in pediatric NASH.