DOI QR코드

DOI QR Code

Noninvasive diagnosis of pediatric nonalcoholic fatty liver disease

  • Yang, Hye Ran (Department of Pediatrics, Seoul National University Bundang Hospital, Seoul National University College of Medicine)
  • Received : 2012.09.16
  • Accepted : 2012.10.02
  • Published : 2013.02.15

Abstract

Because nonalcoholic steatohepatitis can progress towards cirrhosis even in children, early detection of hepatic fibrosis and accurate diagnosis of nonalcoholic fatty liver disease (NAFLD) are important. Although liver biopsy is regarded as the gold standard of diagnosis, its clinical application is somewhat limited in children due to its invasiveness. Noninvasive diagnostic methods, including imaging studies, biomarkers of inflammation, oxidative stress, hepatic apoptosis, hepatic fibrosis, and noninvasive hepatic fibrosis scores have recently been developed for diagnosing the spectrum of NAFLD, particularly the severity of hepatic fibrosis. Although data and validation are still lacking for these noninvasive modalities in the pediatric population, these methods may be applicable for pediatric NAFLD. Therefore, noninvasive imaging studies, biomarkers, and hepatic fibrosis scoring systems may be useful in the detection of hepatic steatosis and the prediction of hepatic fibrosis, even in children with NAFLD.

Keywords

References

  1. Clark JM, Brancati FL, Diehl AM. Nonalcoholic fatty liver disease. Gastroenterology 2002;122:1649-57. https://doi.org/10.1053/gast.2002.33573
  2. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980;55:434-8.
  3. Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990;11:74-80. https://doi.org/10.1002/hep.1840110114
  4. Molleston JP, White F, Teckman J, Fitzgerald JF. Obese children with steatohepatitis can develop cirrhosis in childhood. Am J Gastroenterol 2002;97:2460-2. https://doi.org/10.1111/j.1572-0241.2002.06003.x
  5. 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. https://doi.org/10.1136/gut.2008.171280
  6. Takahashi Y, Fukusato T. Pediatric nonalcoholic fatty liver disease: overview with emphasis on histology. World J Gastroenterol 2010; 16:5280-5. https://doi.org/10.3748/wjg.v16.i42.5280
  7. Roberts EA. Pediatric nonalcoholic fatty liver disease (NAFLD): a "growing" problem? J Hepatol 2007;46:1133-42. https://doi.org/10.1016/j.jhep.2007.03.003
  8. Schwimmer JB, Behling C, Newbury R, Deutsch R, Nievergelt C, Schork NJ, et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology 2005;42:641-9. https://doi.org/10.1002/hep.20842
  9. Ko JS, Yoon JM, Yang HR, Myung JK, Kim H, Kang GH, et al. Clinical and histological features of nonalcoholic fatty liver disease in children. Dig Dis Sci 2009;54:2225-30. https://doi.org/10.1007/s10620-009-0949-3
  10. Wieckowska A, McCullough AJ, Feldstein AE. Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future. Hepatology 2007;46:582-9. https://doi.org/10.1002/hep.21768
  11. Torres DM, Harrison SA. Diagnosis and therapy of nonalcoholic steatohepatitis. Gastroenterology 2008;134:1682-98. https://doi.org/10.1053/j.gastro.2008.02.077
  12. Guha IN, Parkes J, Roderick PR, Harris S, Rosenberg WM. Non-invasive markers associated with liver fibrosis in non-alcoholic fatty liver disease. Gut 2006;55:1650-60. https://doi.org/10.1136/gut.2006.091454
  13. Manning DS, Afdhal NH. Diagnosis and quantitation of fibrosis. Gastroenterology 2008;134:1670-81. https://doi.org/10.1053/j.gastro.2008.03.001
  14. Shiha G, Sarin SK, Ibrahim AE, Omata M, Kumar A, Lesmana LA, et al. Liver fibrosis: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL). Hepatol Int 2009;3:323-33. https://doi.org/10.1007/s12072-008-9114-x
  15. Nobili V, Alkhouri N, Alisi A, Ottino S, Lopez R, Manco M, et al. Retinol-binding protein 4: a promising circulating marker of liver damage in pediatric nonalcoholic fatty liver disease. Clin Gast roenterol Hepatol 2009;7:575-9. https://doi.org/10.1016/j.cgh.2008.12.031
  16. Nobili V, Alisi A, Torre G, De Vito R, Pietrobattista A, Morino G, et al. Hyaluronic acid predicts hepatic fibrosis in children with nonalcoholic fatty liver disease. Transl Res 2010;156:229-34. https://doi.org/10.1016/j.trsl.2010.05.008
  17. Iacobellis A, Marcellini M, Andriulli A, Perri F, Leandro G, Devito R, et al. Non invasive evaluation of liver fibrosis in paediatric patients with nonalcoholic steatohepatitis. World J Gastroenterol 2006;12:7821-5. https://doi.org/10.3748/wjg.v12.i48.7821
  18. Yang HR, Kim HR, Kim MJ, Ko JS, Seo JK. Noninvasive parameters and hepatic fibrosis scores in children with nonalcoholic fatty liver disease. World J Gastroenterol 2012;18:1525-30. https://doi.org/10.3748/wjg.v18.i13.1525
  19. Nobili V, Parkes J, Bottazzo G, Marcellini M, Cross R, Newman D, et al. Performance of ELF serum markers in predicting fibrosis stage in pediatric non-alcoholic fatty liver disease. Gastroenterology 2009;136:160-7. https://doi.org/10.1053/j.gastro.2008.09.013
  20. Nobili V, Alisi A, Vania A, Tiribelli C, Pietrobattista A, Bedogni G. The pediatric NAFLD fibrosis index: a predictor of liver fibrosis in children with non-alcoholic fatty liver disease. BMC Med 2009;7:21. https://doi.org/10.1186/1741-7015-7-21
  21. Papandreou D, Rousso I, Mavromichalis I. Update on non-alcoholic fatty liver disease in children. Clin Nutr 2007;26:409-15. https://doi.org/10.1016/j.clnu.2007.02.002
  22. 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. https://doi.org/10.1067/S0022-3476(03)00325-1
  23. Loomba R, Sirlin CB, Schwimmer JB, Lavine JE. Advances in pediatric nonalcoholic fatty liver disease. Hepatology 2009;50: 1282-93. https://doi.org/10.1002/hep.23119
  24. Patton HM, Lavine JE, Van Natta ML, Schwimmer JB, Kleiner D, Molleston J, et al. Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis. Gastroenterology 2008; 135:1961-71. https://doi.org/10.1053/j.gastro.2008.08.050
  25. Carter-Kent C, Yerian LM, Brunt EM, Angulo P, Kohli R, Ling SC, et al. Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study. Hepatology 2009;50:1113-20. https://doi.org/10.1002/hep.23133
  26. Shannon A, Alkhouri N, Carter-Kent C, Monti L, Devito R, Lopez R, et al. Ultrasonographic quantitative estimation of hepatic steatosis in children with NAFLD. J Pediatr Gastroenterol Nutr 2011;53:190-5. https://doi.org/10.1097/MPG.0b013e31821b4b61
  27. Park SE, Yang HR, Chang JY, Ko JS, Seo JK, Lee W, et al. Correlation of body mass index, body fat distribution, aminotranferases and computed tomography in obese children with fatty liver. Korean J Pediatr 2005;48:276-83.
  28. Park SH, Kim PN, Kim KW, Lee SW, Yoon SE, Park SW, et al. Macrovesicular hepatic steatosis in living liver donors: use of CT for quantitative and qualitative assessment. Radiology 2006;239: 105-12. https://doi.org/10.1148/radiol.2391050361
  29. Pacifico L, Martino MD, Catalano C, Panebianco V, Bezzi M, Anania C, et al. T1-weighted dual-echo MRI for fat quantification in pediatric nonalcoholic fatty liver disease. World J Gastroenterol 2011;17:3012-9. https://doi.org/10.3748/wjg.v17.i25.3012
  30. Charatcharoenwitthaya P, Lindor KD. Role of radiologic modalities in the management of non-alcoholic steatohepatitis. Clin Liver Dis 2007;11:37-54. https://doi.org/10.1016/j.cld.2007.02.014
  31. Yoneda M, Yoneda M , Mawatari H, Fujita K, Endo H, Iida H, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with nonalcoholic fatty liver disease (NAFLD). Dig Liver Dis 2008;40:371-8. https://doi.org/10.1016/j.dld.2007.10.019
  32. Nobili V, Vizzutti F, Arena U, Abraldes JG, Marra F, Pietrobattista A, et al. Accuracy and reproducibility of transient elastography for the diagnosis of fibrosis in pediatric nonalcoholic steatohepatitis. Hepatology 2008;48:442-8.
  33. Chen J, Talwalkar JA, Yin M, Glaser KJ, Sanderson SO, Ehman RL. Early detection of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease by using MR elastography. Radiology 2011;259:749-56. https://doi.org/10.1148/radiol.11101942
  34. Binkovitz LA, El-Youssef M, Glaser KJ, Yin M, Binkovitz AK, Ehman RL. Pediatric MR elastography of hepatic fibrosis: principles, technique and early clinical experience. Pediatr Radiol 2012;42:402-9. https://doi.org/10.1007/s00247-011-2298-6
  35. Georgoff P, Thomasson D, Louie A, Fleischman E, Dutcher L, Mani H, et al. Hydrogen-1 MR spectroscopy for measurement and diagnosis of hepatic steatosis. AJR Am J Roentgenol 2012;199:2-7. https://doi.org/10.2214/AJR.11.7384
  36. Vajro P, Lenta S, Socha P, Dhawan A, McKiernan P, Baumann U, et al. Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee. J Pediatr Gastroenterol Nutr 2012;54:700-13. https://doi.org/10.1097/MPG.0b013e318252a13f
  37. Manco M, Marcellini M, Giannone G, Nobili V. Correlation of serum TNF-alpha levels and histologic liver injury scores in pediatric nonalcoholic fatty liver disease. Am J Clin Pathol 2007;127:954-60. https://doi.org/10.1309/6VJ4DWGYDU0XYJ8Q
  38. Yang HR, Ko JS, Seo JK. Role of tumor necrosis factor-alpha promoter polymorphism and insulin resistance in the development of non-alcoholic fatty liver disease in obese children. Pediatr Gastroenterol Hepatol Nutr 2012;15:44-51. https://doi.org/10.5223/pghn.2012.15.1.44
  39. Lebensztejn DM, Wojtkowska M, Skiba E, Werpachowska I, Tobolczyk J, Kaczmarski M. Serum concentration of adiponectin, leptin and resistin in obese children with non-alcoholic fatty liver disease. Adv Med Sci 2009;54:177-82.
  40. Yang HR, Ko JS, Seo JK. The role of adipokines in the pathogenesis of non-alcoholic fatty liver disease in obese children; the relationship between body fat distribution and insulin resistance. Korean J Pediatr Gastroenterol Nutr 2007;10:185-92.
  41. 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. https://doi.org/10.1016/j.jpeds.2005.07.030
  42. Day CP, James OF. Steatohepatitis: a tale of two "hits"? Gastroenterology 1998;114:842-5. https://doi.org/10.1016/S0016-5085(98)70599-2
  43. Bell LN, Molleston JP, Morton MJ, Klipsch A, Saxena R, Vuppalanchi R, et al. Hepatic lipid peroxidation and cytochrome P-450 2E1 in pediatric nonalcoholic fatty liver disease and its subtypes. J Clin Gastroenterol 2011;45:800-7. https://doi.org/10.1097/MCG.0b013e31821377e4
  44. Piemonte F, Petrini S, Gaeta LM, Tozzi G, Bertini E, Devito R, et al. Protein glutathionylation increases in the liver of patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2008;23 (8 Pt 2):e457-64. https://doi.org/10.1111/j.1440-1746.2007.05070.x
  45. Nobili V, Parola M, Alisi A, Marra F, Piemonte F, Mombello C, et al. Oxidative stress parameters in paediatric non-alcoholic fatty liver disease. Int J Mol Med 2010;26:471-6.
  46. Bonnefont-Rousselot D, Ratziu V, Giral P, Charlotte F, Beucler I, Poynard T, et al. Blood oxidative stress markers are unreliable markers of hepatic steatosis. Aliment Pharmacol Ther 2006;23:91-8. https://doi.org/10.1111/j.1365-2036.2006.02719.x
  47. Wieckowska A, Zein NN, Yerian LM, Lopez AR, McCullough AJ, Feldstein AE. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology 2006;44:27-33.
  48. Yilmaz Y, Kedrah AE, Ozdogan O. Cytokeratin-18 fragments and biomarkers of the metabolic syndrome in nonalcoholic steatohepatitis. World J Gastroenterol 2009;15:4387-91. https://doi.org/10.3748/wjg.15.4387
  49. Vos MB, Barve S, Joshi-Barve S, Carew JD, Whitington PF, McClain CJ. Cytokeratin 18, a marker of cell death, is increased in children with suspected nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr 2008;47:481-5. https://doi.org/10.1097/MPG.0b013e31817e2bfb
  50. Fitzpatrick E, Mitry RR, Quaglia A, Hussain MJ, DeBruyne R, Dhawan A. Serum levels of CK18 M30 and leptin are useful predictors of steatohepatitis and fibrosis in paediatric NAFLD. J Pediatr Gastroenterol Nutr 2010;51:500-6. https://doi.org/10.1097/MPG.0b013e3181e376be
  51. Sepulveda-Flores RN, Vera-Cabrera L, Flores-Gutierrez JP, Maldonado-Garza H, Salinas-Garza R, Zorrilla-Blanco P, et al. Obesity-related non-alcoholic steatohepatitis and TGF-beta1 serum levels in relation to morbid obesity. Ann Hepatol 2002;1:36-9.
  52. Miele L, Forgione A, La Torre G, Vero V, Cefalo C, Racco S, et al. Serum levels of hyaluronic acid and tissue metalloproteinase inhibitor-1 combined with age predict the presence of nonalcoholic steatohepatitis in a pilot cohort of subjects with nonalcoholic fatty liver disease. Transl Res 2009;154:194-201. https://doi.org/10.1016/j.trsl.2009.06.007
  53. Lesmana CR, Hasan I, Budihusodo U, Gani RA, Krisnuhoni E, Akbar N, et al. Diagnostic value of a group of biochemical markers of liver fibrosis in patients with non-alcoholic steatohepatitis. J Dig Dis 2009;10:201-6. https://doi.org/10.1111/j.1751-2980.2009.00386.x
  54. Loaeza-del-Castillo A, Paz-Pineda F, Oviedo-Cardenas E, Sanchez-Avila F, Vargas-Vorackova F. AST to platelet ratio index (APRI) for the noninvasive evaluation of liver fibrosis. Ann Hepatol 2008; 7:350-7.
  55. McGoogan KE, Smith PB, Choi SS, Berman W, Jhaveri R. Performance of the AST-to-platelet ratio index as a noninvasive marker of fibrosis in pediatric patients with chronic viral hepatitis. J Pediatr Gastroenterol Nutr 2010;50:344-6. https://doi.org/10.1097/MPG.0b013e3181aed725
  56. Ratziu V, Massard J, Charlotte F, Messous D, Imbert-Bismut F, Bonyhay L, et al. Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol 2006;6:6. https://doi.org/10.1186/1471-230X-6-6
  57. Shah AG, Lydecker A, Murray K, Tetri BN, Contos MJ, Sanyal AJ, et al. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2009;7:1104-12. https://doi.org/10.1016/j.cgh.2009.05.033
  58. Friedrich-Rust M, Rosenberg W, Parkes J, Herrmann E, Zeuzem S, Sarrazin C. Comparison of ELF, FibroTest and FibroScan for the non-invasive assessment of liver fibrosis. BMC Gastroenterol 2010;10:103. https://doi.org/10.1186/1471-230X-10-103
  59. Alkhouri N, Carter-Kent C, Lopez R, Rosenberg WM, Pinzani M, Bedogni G, et al. A combination of the pediatric NAFLD fibrosis index and enhanced liver fibrosis test identifies children with fibrosis. Clin Gastroenterol Hepatol 2011;9:150-5. https://doi.org/10.1016/j.cgh.2010.09.015

Cited by

  1. Intense FDG Activity in Focal Hepatic Steatosis vol.39, pp.7, 2014, https://doi.org/10.1097/rlu.0000000000000472
  2. Improvement of BMI after Lifestyle Intervention Is Associated with Normalisation of Elevated ELF Score and Liver Stiffness in Obese Children vol.2015, pp.None, 2013, https://doi.org/10.1155/2015/457473
  3. Paediatric non-alcoholic fatty liver disease: a practical overview for non-specialists vol.100, pp.7, 2013, https://doi.org/10.1136/archdischild-2014-307985
  4. Shear-wave ultrasound elastography of the liver in normal-weight and obese children vol.58, pp.12, 2017, https://doi.org/10.1177/0284185117695668