Invited Review
Updates in Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) in Children
Kushila Rupasinghe BSc (Hons), MBBS, MRCPCH, MSc,
Jonathan Hind BMedSci, BMBS, FRCPCH,
Robert Hegarty MBBS, MD (Res),
Corresponding Author
Kushila Rupasinghe BSc (Hons), MBBS, MRCPCH, MSc
Paediatric Liver, GI and Nutrition Centre, King's College Hospital, London, UK
Address correspondence and reprint requests to Kushila Rupasinghe, BSc (hons), MBBS, MRCPCH, MSc, Paediatric Liver, GI and Nutrition Centre, King's College Hospital, London SE5 9RS, UK (e-mail: [email protected]).Search for more papers by this authorJonathan Hind BMedSci, BMBS, FRCPCH
Paediatric Liver, GI and Nutrition Centre, King's College Hospital, London, UK
Search for more papers by this authorRobert Hegarty MBBS, MD (Res)
Paediatric Liver, GI and Nutrition Centre, King's College Hospital, London, UK
Search for more papers by this authorKushila Rupasinghe BSc (Hons), MBBS, MRCPCH, MSc,
Jonathan Hind BMedSci, BMBS, FRCPCH,
Robert Hegarty MBBS, MD (Res),
Corresponding Author
Kushila Rupasinghe BSc (Hons), MBBS, MRCPCH, MSc
Paediatric Liver, GI and Nutrition Centre, King's College Hospital, London, UK
Address correspondence and reprint requests to Kushila Rupasinghe, BSc (hons), MBBS, MRCPCH, MSc, Paediatric Liver, GI and Nutrition Centre, King's College Hospital, London SE5 9RS, UK (e-mail: [email protected]).Search for more papers by this authorJonathan Hind BMedSci, BMBS, FRCPCH
Paediatric Liver, GI and Nutrition Centre, King's College Hospital, London, UK
Search for more papers by this authorRobert Hegarty MBBS, MD (Res)
Paediatric Liver, GI and Nutrition Centre, King's College Hospital, London, UK
Search for more papers by this authorThe authors report no conflicts of interest.
Abstract
The obesity epidemic is one of the major health concerns of the 21st century. Nonalcoholic fatty liver disease (NAFLD) is linked with the increased adiposity associated with obesity. NAFLD has become the most frequent cause of chronic liver disease in adults and children worldwide. Metabolic dysfunction-associated fatty liver disease (MAFLD) also known in children as pediatric fatty liver disease (PeFLD) type 2 has begun to supersede NAFLD as the preferred nomenclature in the pediatric population. Evidence suggests the etiology of MAFLD is multifactorial, related to the complex interplay of hormonal, nutritional, genetic, and environmental factors. Current limitations in accurate diagnostic biomarkers have rendered it a diagnosis of exclusion and it is important to exclude alternative or coexisting causes of PeFLD. Lifestyle changes and modifications remains the primary treatment modality in MAFLD in children. Weight loss of 7%–10% is described as reversing MAFLD in most patients. The Mediterranean diet also shows promise in reversing MAFLD. Pharmacological intervention is debatable in children, and though pediatric trials have not shown promise, other agents undergoing adult clinical trials show promise. This review outlines the latest evidence in pediatric MAFLD and its management.
REFERENCES
- 1Anderson EL, Howe LD, Fraser A et al. Weight trajectories through infancy and childhood and risk of non-alcoholic fatty liver disease in adolescence: the ALSPAC study. J Hepatol. 2014; 61: 626–32. doi:10.1016/j.jhep.2014.04.018.
- 2Nobili V, Alisi A, Valenti L, Miele L, Feldstein AE, Alkhouri N. NAFLD in children: new genes, new diagnostic modalities and new drugs. Nat Rev Gastroenterol Hepatol. 2019; 16: 517–30. doi:10.1038/s41575-019-0169-z.
- 3Nobili V, Pinzani M. Alcoholic and non-alcoholic fatty liver in adolescents: a worrisome convergence. Alcohol Alcohol. 2011; 46: 627–9. doi:10.1093/alcalc/agr074.
- 4Shaunak M, Byrne CD, Davis N, Afolabi P, Faust SN, Davies JH. Non-alcoholic fatty liver disease and childhood obesity. Arch Dis Child. 2021; 106: 3–8. doi:10.1136/archdischild-2019-318063.
- 5Eslam M, Newsome PN, Sarin SK et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J Hepatol. 2020; 73: 202–9. doi:10.1016/j.jhep.2020.03.039.
- 6Eslam M, Alkhouri N, Vajro P et al. Defining paediatric metabolic (dysfunction)-associated fatty liver disease: an international expert consensus statement. Lancet Gastroenterol Hepatol. 2021; 6: 864–73. doi:10.1016/S2468-1253(21)00183-7.
- 7Hegarty R, Deheragoda M, Fitzpatrick E, Dhawan A. Paediatric fatty liver disease (PeFLD): all is not NAFLD – pathophysiological insights and approach to management. J Hepatol. 2018; 68: 1286–99. doi:10.1016/j.jhep.2018.02.006.
- 8Zhang X, Wu M, Liu Z et al. Increasing prevalence of NAFLD/NASH among children, adolescents and young adults from 1990 to 2017: a population-based observational study. BMJ Open. 2021; 11: e042843. doi:10.1136/bmjopen-2020-042843.
- 9 GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020; 396: 1204–22. doi:10.1016/S0140-6736(20)30925-9.
- 10Abeysekera KWM, Fernandes GS, Hammerton G et al. Prevalence of steatosis and fibrosis in young adults in the UK: a population-based study. Lancet Gastroenterol Hepatol. 2020; 5: 295–305. doi:10.1016/S2468-1253(19)30419-4.
- 11Anderson EL, Howe LD, Jones HE, Higgins JP, Lawlor DA, Fraser A. The prevalence of non-alcoholic fatty liver disease in children and adolescents: a systematic review and meta-analysis. PLoS One. 2015; 10: e0140908. doi:10.1371/journal.pone.0140908.
- 12Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics. 2006; 118: 1388–93. doi:10.1542/peds.2006-1212.
- 13Mann JP, Valenti L, Scorletti E, Byrne CD, Nobili V. Nonalcoholic fatty liver disease in children. Semin Liver Dis. 2018; 38: 1–13. doi:10.1055/s-0038-1627456.
- 14Lawlor DA, Callaway M, Macdonald-Wallis C et al. Nonalcoholic fatty liver disease, liver fibrosis, and cardiometabolic risk factors in adolescence: a cross-sectional study of 1874 general population adolescents. J Clin Endocrinol Metab. 2014; 99: E410–7. doi:10.1210/jc.2013-3612.
- 15Arshad T, Paik JM, Biswas R, Alqahtani SA, Henry L, Younossi ZM. Nonalcoholic fatty liver disease prevalence trends among adolescents and young adults in the United States, 2007–2016. Hepatol Commun. 2021; 5: 1676–88. doi:10.1002/hep4.1760.
- 16Flores-Calderón J, Gómez-Díaz RA, Rodríguez-Gómez G, Morán-Villota S. Frequency of increased aminotransferases levels and associated metabolic abnormalities in obese and overweight children of an elementary school in Mexico City. Ann Hepatol. 2005; 4: 279–83.
- 17Franzese A, Vajro P, Argenziano A et al. Liver involvement in obese children. Ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population. Dig Dis Sci. 1997; 42: 1428–32. doi:10.1023/a:1018850223495.
- 18Bedogni G, Gastaldelli A, Manco M et al. Relationship between fatty liver and glucose metabolism: a cross-sectional study in 571 obese children. Nutr Metab Cardiovasc Dis. 2012; 22: 120–6. doi:10.1016/j.numecd.2010.05.003.
- 19Caserta CA, Pendino GM, Amante A et al. Cardiovascular risk factors, nonalcoholic fatty liver disease, and carotid artery intima-media thickness in an adolescent population in southern Italy. Am J Epidemiol. 2010; 171: 1195–202. doi:10.1093/aje/kwq073.
- 20Song K, Yang J, Lee HS et al. Changes in the prevalences of obesity, abdominal obesity, and non-alcoholic fatty liver disease among Korean children during the COVID-19 outbreak. Yonsei Med J. 2023; 64: 269–77. doi:10.3349/ymj.2022.0540.
- 21Song P, Yu J, Wang M, Chang X, Wang J, An L. Prevalence and correlates of suspected nonalcoholic fatty liver disease in Chinese children. Int J Environ Res Public Health. 2017; 14: 465. doi:10.3390/ijerph14050465.
- 22Zhang X, Wan Y, Zhang S et al. Nonalcoholic fatty liver disease prevalence in urban school-aged children and adolescents from the Yangtze River delta region: a cross-sectional study. Asia Pac J Clin Nutr. 2015; 24: 281–8. doi:10.6133/apjcn.2015.24.2.13.
- 23Mburu AN, Laving A, Macharia WM, Sande J. Prevalence of non-alcoholic fatty liver disease in overweight and obese children seeking ambulatory healthcare in Nairobi, Kenya. BMJ Open Gastroenterol. 2023; 10: e001044. doi:10.1136/bmjgast-2022-001044.
- 24Ayonrinde OT, Olynyk JK, Beilin LJ et al. Gender-specific differences in adipose distribution and adipocytokines influence adolescent nonalcoholic fatty liver disease. Hepatology. 2011; 53: 800–9. doi:10.1002/hep.24097.
- 25Benetolo PO, Fernandes MIM, Ciampo IRLD, Elias-Junior J, Sawamura R. Evaluation of nonalcoholic fatty liver disease using magnetic resonance in obese children and adolescents. J Pediatr (Rio J). 2019; 95: 34–40. doi:10.1016/j.jped.2017.12.010.
- 26Song K, Park G, Lee HS et al. Trends in prediabetes and non-alcoholic fatty liver disease associated with abdominal obesity among Korean children and adolescents: based on the Korea National Health and Nutrition Examination Survey between 2009 and 2018. Biomedicines. 2022; 10: 584. doi:10.3390/biomedicines10030584.
- 27Zelber-Sagi S, Ratziu V, Oren R. Nutrition and physical activity in NAFLD: an overview of the epidemiological evidence. World J Gastroenterol. 2011; 17: 3377–89. doi:10.3748/wjg.v17.i29.3377.
- 28Barrera F, George J. The role of diet and nutritional intervention for the management of patients with NAFLD. Clin Liver Dis. 2014; 18: 91–112. doi:10.1016/j.cld.2013.09.009.
- 29 European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. Diabetologia. 2016; 59: 1121–40. doi:10.1007/s00125-016-3902-y.
- 30Ouyang X, Cirillo P, Sautin Y et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. 2008; 48: 993–9. doi:10.1016/j.jhep.2008.02.011.
- 31Jensen T, Abdelmalek MF, Sullivan S et al. Fructose and sugar: a major mediator of non-alcoholic fatty liver disease. J Hepatol. 2018; 68: 1063–75. doi:10.1016/j.jhep.2018.01.019.
- 32Lanaspa MA, Sanchez-Lozada LG, Choi YJ et al. Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver. J Biol Chem. 2012; 287: 40732–44. doi:10.1074/jbc.M112.399899.
- 33Muriel P, López-Sánchez P, Ramos-Tovar E. Fructose and the liver. Int J Mol Sci. 2021; 22: 6969. doi:10.3390/ijms22136969.
- 34Nobili V, Liccardo D, Bedogni G et al. Influence of dietary pattern, physical activity, and I148M PNPLA3 on steatosis severity in at-risk adolescents. Genes Nutr. 2014; 9: 392. doi:10.1007/s12263-014-0392-8.
- 35Schwimmer JB, Ugalde-Nicalo P, Welsh JA et al. Effect of a low free sugar diet vs usual diet on nonalcoholic fatty liver disease in adolescent boys: a randomized clinical trial. JAMA. 2019; 321: 256–65. doi:10.1001/jama.2018.20579.
- 36Chen LH, Wang YF, Xu QH, Chen SS. Omega-3 fatty acids as a treatment for non-alcoholic fatty liver disease in children: a systematic review and meta-analysis of randomized controlled trials. Clin Nutr. 2018; 37: 516–21. doi:10.1016/j.clnu.2016.12.009.
- 37Santoro N, Caprio S, Pierpont B, Van Name M, Savoye M, Parks EJ. Hepatic De novo lipogenesis in obese youth is modulated by a common variant in the GCKR gene. J Clin Endocrinol Metab. 2015; 100: E1125–32. doi:10.1210/jc.2015-1587.
- 38Green CJ, Hodson L. The influence of dietary fat on liver fat accumulation. Nutrients. 2014; 6: 5018–33. doi:10.3390/nu6115018.
- 39Thoma C, Day CP, Trenell MI. Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review. J Hepatol. 2012; 56: 255–66. doi:10.1016/j.jhep.2011.06.010.
- 40Ryan MC, Itsiopoulos C, Thodis T et al. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol. 2013; 59: 138–43. doi:10.1016/j.jhep.2013.02.012.
- 41Anania C, Perla FM, Olivero F, Pacifico L, Chiesa C. Mediterranean diet and nonalcoholic fatty liver disease. World J Gastroenterol. 2018; 24: 2083–94. doi:10.3748/wjg.v24.i19.2083.
- 42Hoyles L, Fernández-Real JM, Federici M et al. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat Med. 2018; 24: 1070–80. doi:10.1038/s41591-018-0061-3.
- 43Soderborg TK, Clark SE, Mulligan CE et al. The gut microbiota in infants of obese mothers increases inflammation and susceptibility to NAFLD. Nat Commun. 2018; 9: 4462. doi:10.1038/s41467-018-06929-0.
- 44Schwimmer JB, Johnson JS, Angeles JE et al. Microbiome signatures associated with steatohepatitis and moderate to severe fibrosis in children with nonalcoholic fatty liver disease. Gastroenterology. 2019; 157: 1109–22. doi:10.1053/j.gastro.2019.06.028.
- 45Wesolowski SR, Kasmi KC, Jonscher KR, Friedman JE. Developmental origins of NAFLD: a womb with a clue. Nat Rev Gastroenterol Hepatol. 2017; 14: 81–96. doi:10.1038/nrgastro.2016.160.
- 46Loomba R, Schork N, Chen CH et al. Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterology. 2015; 149: 1784–93. doi:10.1053/j.gastro.2015.08.011.
- 47Speliotes EK, Yerges-Armstrong LM, Wu J et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011; 7: e1001324. doi:10.1371/journal.pgen.1001324.
- 48Goyal NP, Rosenthal SB, Nasamran C et al. Nonalcoholic fatty liver disease risk and histologic severity are associated with genetic polymorphisms in children. Hepatology. 2022; 77: 197–212. doi:10.1002/hep.32570.
- 49Meroni M, Dongiovanni P, Longo M et al. Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes. EBioMedicine. 2020; 52: 102658. doi:10.1016/j.ebiom.2020.102658.
- 50Thangapandi VR, Knittelfelder O, Brosch M et al. Loss of hepatic Mboat7 leads to liver fibrosis. Gut. 2021; 70: 940–50. doi:10.1136/gutjnl-2020-320853.
- 51Hegarty R, Kyrana E, Fitzpatrick E, Dhawan A. Fatty liver disease in children (MAFLD/PeFLD Type 2): unique classification considerations and challenges. Ther Adv Endocrinol Metab. 2023; 14:20420188231160388. doi:10.1177/20420188231160388.
- 52Vos 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: 319–34. doi:10.1097/MPG.0000000000001482.
- 53Chrysavgis L, Ztriva E, Protopapas A, Tziomalos K, Cholongitas E. Nonalcoholic fatty liver disease in lean subjects: prognosis, outcomes and management. World J Gastroenterol. 2020; 26: 6514–28. doi:10.3748/wjg.v26.i42.6514.
- 54Ye Q, Zou B, Yeo YH et al. Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2020; 5: 739–52. doi:10.1016/S2468-1253(20)30077-7.
- 55Conjeevaram Selvakumar PK, Kabbany MN, Lopez R, Rayas MS, Lynch JL, Alkhouri N. Prevalence of suspected nonalcoholic fatty liver disease in lean adolescents in the United States. J Pediatr Gastroenterol Nutr. 2018; 67: 75–9. doi:10.1097/MPG.0000000000001974.
- 56Fishbein MH, Mogren C, Gleason T, Stevens WR. Relationship of hepatic steatosis to adipose tissue distribution in pediatric nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2006; 42: 83–8.
- 57Vajro 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: 700–13. doi:10.1097/MPG.0b013e318252a13f.
- 58Schwimmer JB, Behling C, Newbury R et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology. 2005; 42: 641–9. doi:10.1002/hep.20842.
- 59Carter-Kent C, Yerian LM, Brunt EM et al. Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study. Hepatology. 2009; 50: 1113–20. doi:10.1002/hep.23133.
- 60Kleiner DE, Brunt EM, Van Natta M et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005; 41: 1313–21. doi:10.1002/hep.20701.
- 61Alkhouri 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: 1312–8. doi:10.1016/j.jhep.2012.07.027.
- 62Kleiner DE, Makhlouf HR. Histology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in adults and children. Clin Liver Dis. 2016; 20: 293–312. doi:10.1016/j.cld.2015.10.011.
- 63Fitzpatrick E, Dhawan A. Noninvasive biomarkers in non-alcoholic fatty liver disease: current status and a glimpse of the future. World J Gastroenterol. 2014; 20: 10851–63. doi:10.3748/wjg.v20.i31.10851.
- 64Lee J, Vali Y, Boursier J et al. Accuracy of cytokeratin 18 (M30 and M65) in detecting non-alcoholic steatohepatitis and fibrosis: a systematic review and meta-analysis. PLoS One. 2020; 15: e0238717. doi:10.1371/journal.pone.0238717.
- 65Nobili 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: 160–7. doi:10.1053/j.gastro.2008.09.013.
- 66Alkhouri 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: 150–5. doi:10.1016/j.cgh.2010.09.015.
- 67Sasso M, Beaugrand M, de Ledinghen V et al. Controlled attenuation parameter (CAP): a novel VCTE™ guided ultrasonic attenuation measurement for the evaluation of hepatic steatosis: preliminary study and validation in a cohort of patients with chronic liver disease from various causes. Ultrasound Med Biol. 2010; 36: 1825–35. doi:10.1016/j.ultrasmedbio.2010.07.005.
- 68Cao YT, Xiang LL, Qi F, Zhang YJ, Chen Y, Zhou XQ. Accuracy of controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) for assessing steatosis and fibrosis in non-alcoholic fatty liver disease: a systematic review and meta-analysis. EClinicalMedicine. 2022; 51: 101547. doi:10.1016/j.eclinm.2022.101547.
- 69Desai NK, Harney S, Raza R et al. Comparison of controlled attenuation parameter and liver biopsy to assess hepatic steatosis in pediatric patients. J Pediatr. 2016; 173: 160–164.e1. doi:10.1016/j.jpeds.2016.03.021.
- 70Imajo 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. 2016; 150: 626–637.e7. doi:10.1053/j.gastro.2015.11.048.
- 71Jia S, Zhao Y, Liu J et al. Magnetic resonance imaging-proton density fat fraction vs. transient elastography-controlled attenuation parameter in diagnosing non-alcoholic fatty liver disease in children and adolescents: a meta-analysis of diagnostic accuracy. Front Pediatr. 2021; 9: 784221. doi:10.3389/fped.2021.784221.
- 72Caussy C, Reeder SB, Sirlin CB, Loomba R. Noninvasive, quantitative assessment of liver fat by MRI-PDFF as an endpoint in NASH trials. Hepatology. 2018; 68: 763–72. doi:10.1002/hep.29797.
- 73Schwimmer JB, Behling C, Angeles JE et al. Magnetic resonance elastography measured shear stiffness as a biomarker of fibrosis in pediatric nonalcoholic fatty liver disease. Hepatology. 2017; 66: 1474–85. doi:10.1002/hep.29241.
- 74Di Martino M, Pacifico L, Bezzi M et al. Comparison of magnetic resonance spectroscopy, proton density fat fraction and histological analysis in the quantification of liver steatosis in children and adolescents. World J Gastroenterol. 2016; 22: 8812–9. doi:10.3748/wjg.v22.i39.8812.
- 75Draijer L, Benninga M, Koot B. Pediatric NAFLD: an overview and recent developments in diagnostics and treatment. Expert Rev Gastroenterol Hepatol. 2019; 13: 447–61. doi:10.1080/17474124.2019.1595589.
- 76Nobili V, Marcellini M, Devito R et al. NAFLD in children: a prospective clinical-pathological study and effect of lifestyle advice. Hepatology. 2006; 44: 458–65. doi:10.1002/hep.21262.
- 77Koot BG, van der Baan-Slootweg OH, Tamminga-Smeulders CL et al. Lifestyle intervention for non-alcoholic fatty liver disease: prospective cohort study of its efficacy and factors related to improvement. Arch Dis Child. 2011; 96: 669–74. doi:10.1136/adc.2010.199760.
- 78Dowla S, Pendergrass M, Bolding M et al. Effectiveness of a carbohydrate restricted diet to treat non-alcoholic fatty liver disease in adolescents with obesity: trial design and methodology. Contemp Clin Trials. 2018; 68: 95–101. doi:10.1016/j.cct.2018.03.014.
- 79Yaskolka Meir A, Rinott E, Tsaban G et al. Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial. Gut. 2021; 70: 2085–95. doi:10.1136/gutjnl-2020-323106.
- 80Famouri F, Shariat Z, Hashemipour M, Keikha M, Kelishadi R. Effects of probiotics on nonalcoholic fatty liver disease in obese children and adolescents. J Pediatr Gastroenterol Nutr. 2017; 64: 413–7. doi:10.1097/MPG.0000000000001422.
- 81Alisi 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: 1276–85. doi:10.1111/apt.12758.
- 82Vajro 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: 740–3. doi:10.1097/MPG.0b013e31821f9b85.
- 83Gkiourtzis Ν, Kalopitas G, Vadarlis A et al. The benefit of probiotics in pediatric nonalcoholic fatty liver disease: a meta-analysis of randomized control trials. J Pediatr Gastroenterol Nutr. 2022; 75: e31–7. doi:10.1097/MPG.0000000000003537.
- 84Ranucci G, Spagnuolo MI, Iorio R. Obese children with fatty liver: between reality and disease mongering. World J Gastroenterol. 2017; 23: 8277–82. doi:10.3748/wjg.v23.i47.8277.
- 85Dhana K, Haines J, Liu G et al. Association between maternal adherence to healthy lifestyle practices and risk of obesity in offspring: results from two prospective cohort studies of mother-child pairs in the United States. BMJ. 2018; 362: k2486. doi:10.1136/bmj.k2486.
- 86Kovács E, Siani A, Konstabel K et al. Adherence to the obesity-related lifestyle intervention targets in the IDEFICS study. Int J Obes (Lond). 2014; 38(suppl 2): S144–51. doi:10.1038/ijo.2014.145.
- 87Lavine 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: 1659–68. doi:10.1001/jama.2011.520.
- 88Younossi ZM, Ratziu V, Loomba R et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2019; 394: 2184–96. doi:10.1016/S0140-6736(19)33041-7.
- 89Goldberg IJ, Huang LS, Huggins LA et al. Thyroid hormone reduces cholesterol via a non-LDL receptor-mediated pathway. Endocrinology. 2012; 153: 5143–9. doi:10.1210/en.2012-1572.
- 90Harrison SA, Bashir MR, Guy CD et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019; 394: 2012–24. doi:10.1016/S0140-6736(19)32517-6.
- 91Younossi ZM, Stepanova M, Taub RA, Barbone JM, Harrison SA. Hepatic fat reduction due to resmetirom in patients with nonalcoholic steatohepatitis is associated with improvement of quality of life. Clin Gastroenterol Hepatol. 2022; 20: 1354–1361.e7. doi:10.1016/j.cgh.2021.07.039.
- 92Ratziu V, de Guevara L, Safadi R et al. Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial. Nat Med. 2021; 27: 1825–35. doi:10.1038/s41591-021-01495-3.
- 93Bril F, Kalavalapalli S, Clark VC et al. Response to pioglitazone in patients with nonalcoholic steatohepatitis with vs without type 2 diabetes. Clin Gastroenterol Hepatol. 2018; 16: 558–566.e2. doi:10.1016/j.cgh.2017.12.001.
- 94Armstrong MJ, Gaunt P, Aithal GP et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016; 387: 679–90. doi:10.1016/S0140-6736(15)00803-X.
- 95Kuchay MS, Krishan S, Mishra SK et al. Effect of dulaglutide on liver fat in patients with type 2 diabetes and NAFLD: randomised controlled trial (D-LIFT trial). Diabetologia. 2020; 63: 2434–45. doi:10.1007/s00125-020-05265-7.
- 96Newsome PN, Buchholtz K, Cusi K et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021; 384: 1113–24. doi:10.1056/NEJMoa2028395.
- 97Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia. 2017; 60: 215–25. doi:10.1007/s00125-016-4157-3.
- 98Kuchay MS, Krishan S, Mishra SK et al. Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E-LIFT Trial). Diabetes Care. 2018; 41: 1801–8. doi:10.2337/dc18-0165.
- 99Cusi K, Bril F, Barb D et al. Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes. Diabetes Obes Metab. 2019; 21: 812–21. doi:10.1111/dom.13584.
- 100Malehmir M, Pfister D, Gallage S et al. Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nat Med. 2019; 25: 641–55. doi:10.1038/s41591-019-0379-5.
- 101Merat S, Jafari E, Radmard AR et al. Polypill for prevention of cardiovascular diseases with focus on non-alcoholic steatohepatitis: the PolyIran-Liver trial. Eur Heart J. 2022; 43: 2023–33. doi:10.1093/eurheartj/ehab919.
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