Стеатогепатит у детей с ожирением

В статье обсуждаются вопросы развития, диагностики и терапии стеатогепатита у детей. Стеатогепатит является одной из форм неалкогольной жировой болезни печени, диагностируемой у 12–26% детей с ожирением. В числе патогенетических факторов определены оксидативный стресс, генетическая предрасположенность, нарушения микробиоты, дефицит витамина D. Приведены сведения по алгоритму диагностики в соответствии с рекомендациями Евро пейского и Северо-Американского обществ детских гастроэнтерологов, гепатологов и нутрициологов. Дана характеристика инструментальным методам диагностики стеатогепатита (биопсия, ультразвук, магнитно-резонансная и компьютерная томография, эластография, биохимические тесты), определены показания для их применения в детском возрасте. Приводятся данные по лечению стеатогепатита, которое включает диету и физическую активность, а также обсуждаются возможности применения у детей гепатопротекторов (урсодезоксихолевой кислоты, эссенциальных фосфолипидов) и биологически активных веществ. 

1. Vos MB, Abrams SH, Barlow SE, et al. NASPGHAN Clinical Practice Guideline for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Children: Recommendations from the Expert Committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). J Pediatr Gastroenterol Nutr. 2017;64(2):319–334. doi: 10.1097/MPG.0000000000001482

2. Sahota AK, Shapiro WL, Newton KP, et al. Incidence of Nonalcoholic Fatty Liver Disease in Children: 2009–2018. Pediatrics. 2020;146(6):e20200771. doi: 10.1542/peds.2020-0771

3. Рекомендации по диагностике, лечению и профилактике ожирения у детей и подростков. — М.: Практика; 2015. — С. 19.

4. 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):700–713. doi: 10.1097/MPG.0b013e318252a13f

5. Rito AI, Buoncristiano M, Spinelli A, et al. Association between Characteristics at Birth, Breastfeeding and Obesity in 22 Countries: The WHO European Childhood Obesity Surveillance Initiative — COSI 2015/2017. Obes Facts. 2019;12(2):226–243. doi: 10.1159/000500425

6. Намазова-Баранова Л.С., Елецкая К.А., Кайтукова Е.В., Макарова С.Г. Оценка физического развития детей среднего и старшего школьного возраста: анализ результатов одномоментного исследования // Педиатрическая фармакология. — 2018. — Т. 15. — № 4. — С. 333–342. doi: 10.15690/pf.v15i4.1948

7. Mapping the health system response to childhood obesity in the WHO European Region. An overview and country perspectives. Copenhagen: World Health Organization Regional Office for Europe; 2019. 4 p. Available online: https://www.euro.who.int/__data/assets/pdf_file/0019/401176/Childhood-obesity-web.pdf. Accessed on June 23, 2021.

8. Neuschwander-Tetri BA. Non-alcoholic fatty liver disease. BMC Med. 2017;15(1):45. doi: 10.1186/s12916-017-0806-8

9. Ling JR, Zhang YJ, Zhang ZH, et. al. Specific changes of intestinal microflora in children with nonalcoholic fatty liver disease. Zhonghua Er Ke Za Zhi. 2018;56(11):850–855. doi: 10.3760/cma.j.issn.0578-1310.2018.11.011

10. Yang F, Dai Y, Min C, Li X. Neonatal overfeeding induced glucocorticoid overexposure accelerates hepatic lipogenesis in male rats. Nutr Metab (Lond). 2018;15:30 doi: 10.1186/s12986-018-0272-0

11. Flisiak-Jackiewicz M, Lebensztejn DM. Update on pathogenesis, diagnostics and therapy of nonalcoholic fatty liver disease in children. Clin Exp Hepatol. 2019;5(1):11–21. doi: 10.5114/ceh.2019.83152

12. Богомолов П.О., Кокина К.Ю., Майоров А.Ю., Мишина Е.Е. Генетические аспекты неалкогольной жировой болезни печени // Вопросы современной педиатрии. — 2018. — Т. 17. — № 6. — С. 442–448. doi: 10.15690/vsp.v17i6.1974

13. Nikolaou N, Gathercole L, Marchand L, et al. AKR1D1 is a novel regulator of metabolic phenotype in human hepatocytes and is dysregulated in non-alcoholic fatty liver disease. Metabolism. 2019;99:67–80. doi: 10.1016/j.metabol.2019.153947

14. Wang X, Zhou Y, Zhang M, et al. The methylenetetrahydrofolate reductase genotype 677CT and non-alcoholic fatty liver disease have a synergistic effect on the increasing homocysteine levels in subjects from Chongqing, China. Genes Dis. 2018;6(1):88–95. doi: 10.1016/j.gendis.2018.07.003

15. Kong M, Longdong Zhu, Bai L, et al. Vitamin D deficiency promotes nonalcoholic steatohepatitis through impaired enterohepatic circulation in animal model. Am J Physiol Gastrointest Liver Physiol. 2014;307(9):G883–G893. doi: 10.1152/ajpgi.00427.2013

16. Cimini FA, Barchetta I, Carotti S, et al. Relationship between adipose tissue dysfunction, vitamin D deficiency and the pathogenesis of non-alcoholic fatty liver disease. World J Gastroenterol. 2017;23(19):3407–3417. doi: 10.3748/wjg.v23.i19.3407

17. Yodoshi, T, Orkin S, Arce-Clachar AC, et al. Vitamin D deficiency: prevalence and association with liver disease severity in pediatric nonalcoholic fatty liver disease. Eur J Clin Nutr. 2020;74(3): 427–435. doi: 10.1038/s41430-019-0493-y

18. Schwimmer JB, Newton KP, Awai HI, et al. Paediatric gastroenterology evaluation of overweight and obese children referred from primary care for suspected non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2013;38(10):1267–1277. doi: 10.1111/apt.12518

19. Chen J, Chen J, Fu H, et al. Hypoxia exacerbates non-alcoholic fatty liver disease via HIF-2α/PPARα pathway. Am J Physiol Endocrinol Metab. 2019;317(4):E710–E722. doi: 10.1152/ajpendo.00052.2019

20. Elkabany ZA, Hamza RT, Ismail EAR, et al. Serum visfatin level as a noninvasive marker for nonalcoholic fatty liver disease in children and adolescents with obesity: relation to transient elastography with controlled attenuation parameter. Eur J Gastroenterol Hepatol. 2020;32(8):1008–1016. doi: 10.1097/MEG.0000000000001608

21. Wen H, Wang HJ, Dong B, Ma J. Relationship between serum visfatin level and children and adolescent obesity and non-alcoholic fatty liver disease. Zhonghua Liu Xing Bing Xue Za Zhi. 2012;33(3):269–272.

22. Cura-Esquivel I, Cordero-Pérez P, Torres-González L, Muñoz-Espinosa LE. Acute phase markers in obese children and adolescents with metabolic disorders. Arch Argent Pediatr. 2018;116(4): 275–282. doi: 10.5546/aap.2018.eng.275

23. Hua M, Huang J-L, Hu C-C, et al. Including Fibroblast Growth Factor-21 in Combined Biomarker Panels Improves Predictions of Liver Steatosis Severity in Children. Front Pediatr. 2019;7:420. doi: 10.3389/fped.2019.00420

24. Aksoy GK, Artan R, Aksoy C, et al. Role of Soluble Adiponectin Receptor 2 in Non-Alcoholic Fatty Liver Disease in Children. Pediatr Gastroenterol Hepatol Nutr. 2019;22(5):470–478. doi: 10.5223/pghn.2019.22.5.470

25. Mann JP, Raponi M, Nobili V. Clinical implications of understanding the association between oxidative stress and pediatric NAFLD. Expert Rev Gastroenterol Hepatol. 2017;11(4):371–382. doi: 10.1080/17474124.2017.1291340

26. Tilg H, Hotamisligil GS. Nonalcoholic fatty liver disease: cytokine–adipokine interplay and regulation of insulin resistance. Gastroenterology. 2006;131(3):934–945. doi: 10.1053/j.gastro.2006.05.054

27. Ballestri S, Lonardo A, Romagnoli D, et al. Ultrasonographic fatty liver indicator, a novel score which rules out NASH and is correlated with metabolic parameters in NAFLD. Liver Int. 2012;32(8): 1242–1252. doi: 10.1111/j.1478-3231.2012.02804.x

28. Liu H, Yang MC, Su YT, et al. Novel Ultrasonographic Fatty Liver Indicator Can Predict Hepatitis in Children With Non-alcoholic Fatty Liver Disease. Front Pediatr. 2019;6:416. doi: 10.3389/fped.2018.00416

29. Kwon YD, Ko KO, Lim JW, et al. Usefulness of Transient Elastography for Non-Invasive Diagnosis of Liver Fibrosis in Pediatric Non-Alcoholic Steatohepatitis. J Korean Med Sci. 2019;34(23):e165. doi: 10.3346/jkms.2019.34.e165

30. Bedossa P. Current histological classification of NAFLD: strength and limitations. Hepatol Int. 2013;7(2):765–770. doi: 10.1007/s12072-013-9446-z

31. Poynard T, Lassailly G, Diaz E, et al. Performance of biomarkers FibroTest, ActiTest, SteatoTest, and NashTest in patients with severe obesity: meta analysis of individual patient data. PLoS One. 2012;7(3):e30325. doi: 10.1371/journal.pone.0030325

32. Lin HZ, Yang SQ, Chuckaree C, et al. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med. 2000;6(9): 998–1003. doi: 10.1038/79697

33. Bugianesi E, Gentilcore E, Manini R, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol. 2005;100(5):1082–1090. doi: 10.1111/j.1572-0241.2005.41583.x

34. 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):1659–1668. doi: 10.1001/jama.2011.520

35. Ratziu V, de Ledinghen V, Oberti F, et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol. 2011;54(5):1011–1019. doi: 10.1016/j.jhep.2010.08.030

36. Рейзис А.Р. Неалкогольная жировая болезнь печени в свете проблемы гепатитов невыясненной этиологии у детей и подростков // РМЖ. — 2019. — № 7. — С. 26–29.

37. Dufour JF, Oneta CM, Gonvers JJ, et al. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2006;4(12): 1537–1543. doi: 10.1016/j.cgh.2006.09.025

38. Казюлин А.Н. Место урсодезоксихолевой кислоты в терапии неалкогольной жировой болезни печени на разных стадиях заболевания: стеатоз, стеатогепатит, фиброз/цирроз // РМЖ. — 2017. — № 17. — С. 1248–1257.

39. Caro-Sabido EA, Larrosa-Haro A. Efficacy of dietary intervention and physical activity in children and adolescents with nonalcoholic fatty liver disease associated with obesity: A scoping review. Rev Gastroenterol Mex. 2019;84(2):185–194. doi: 10.1016/j.rgmx.2019.02.001

40. Pervez MA, Khan DA, Ijaz A, Khan S. Effects of Delta-tocotrienol Supplementation on Liver Enzymes, Inflammation, Oxidative stress and Hepatic Steatosis in Patients with Nonalcoholic Fatty Liver Disease. Turk J Gastroenterol. 2018;29(2):170–176. doi: 10.5152/tjg.2018.17297

41. 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):740–743. doi: 10.1097/MPG.0b013e31821f9b85

42. Eslamparast T, Poustchi H, Zamani F, et al. Synbiotic supplementation in nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled pilot study. Am J Clin Nutr. 2014; 99(3):535–542. doi: 10.3945/ajcn.113.068890

43. Павловская Е.В., Строкова Т.В., Багаева М.Э. и др. Эффективность пробиотиков в лечении неалкогольной жировой болезни печени у детей с ожирением // РМЖ. — 2020. — № 2. — С. 7–10.

44. Spahis S, Alvarez F, Ahmed N, Dubois J, et al. Non-alcoholic fatty liver disease severity and metabolic complications in obese children: impact of omega-3 fatty acids. J Nutr Biochem. 2018;58:28–36. doi: 10.1016/j.jnutbio.2018.03.025