儿童非酒精性脂肪性肝病危险因素的研究进展

doi:10.11852/zgetbjzz2023-0676

摘要/Abstract

摘要： 非酒精性脂肪性肝病(NAFLD)已成为全球儿童慢性肝病的主要原因,且发病率呈逐年上升的趋势。导致儿童NAFLD发病的危险因素是多样化的,且与成人有诸多不同,目前大多数医疗机构对儿童NAFLD的重视度仍不高。本文归纳了导致儿童NAFLD的相关危险因素及机制,包含基因多态性、母体及胎儿情况、饮食和生活习惯、环境暴露、代谢综合征、内分泌相关机制和肠道微生态等,旨在为儿童NAFLD的预防及管理提供参考依据。

关键词: 非酒精性脂肪性肝病, 慢性肝病, 儿童

Abstract: Non-alcoholic fatty liver disease(NAFLD) has become the main cause of chronic liver disease in children worldwide, and the incidence of NAFLD shows an increasing trend year by year. The risk factors leading to the onset of NAFLD in children are diversified and different from those in adults. At present, most medical institutions still pay little attention to NAFLD in children. This paper summarizes the risk factors and mechanisms for NAFLD in children, including gene polymorphism, maternal and fetal conditions, diet and living habits, environmental exposure, metabolic syndrome, endocrine-related mechanisms and intestinal microecology, in order to provide reference for the prevention and management of childhood NAFLD.

Key words: non-alcoholic fatty liver disease, chronic liver disease, children

中图分类号:

R725.7

耿坐涛, 张丹, 朱筱桐, 李兰怡, 李雪海, 杨永礼. 儿童非酒精性脂肪性肝病危险因素的研究进展[J]. 中国儿童保健杂志, 2024, 32(4): 412-418.

GENG Zuotao, ZHANG Dan, ZHU Xiaotong, LI Lanyi, LI Xuehai, YANG Yongli. Risk factors of non-alcoholic fatty liver disease in children[J]. Chinese Journal of Child Health Care, 2024, 32(4): 412-418.

参考文献

[1] Hsu E, Murray K. Is nonalcoholic fatty liver disease in children the same disease as in adults?[J]. Clin Liver Dis, 2012, 16(3):587-598.
[2] Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: Trends, predictions, risk factors and prevention[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(4):223-238.
[3] Mosca A, Panera N, Maggiore G, et al. From pregnant women to infants: Non-alcoholic fatty liver disease is a poor inheritance[J]. J Hepatol, 2020, 73(6):1590-1592.
[4] Sharpton S, Shan K, Bettencourt R, et al. Prevalence and factors associated with liver fibrosis among first‐degree relatives of Mexican Americans with hepatocellular carcinoma[J]. Aliment Pharmacol Ther, 2023, 57(4):378-386.
[5] Valenti L, Alisi A, Galmozzi E, et al. I148M patatin-like phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease[J]. Hepatology, 2010, 52(4):1274-1280.
[6] Nobili V, Alisi A, Valenti L, et al. NAFLD in children: new genes, new diagnostic modalities and new drugs[J]. Nat Rev Gastroenterol Hepatol, 2019, 16(9):517-530.
[7] Barbieri E, Santoro N, Umano GR. Clinical features and metabolic complications for non-alcoholic fatty liver disease(NAFLD) in youth with obesity[J]. Front Endocrinol(Lausanne), 2023, 14:1062341.
[8] Santoro N, Zhang CK, Zhao H, et al. Variant in the glucokinase regulatory protein(GCKR) gene is associated with fatty liver in obese children and adolescents[J]. Hepatology, 2012, 55(3):781-789.
[9] Meroni M, Dongiovanni P, Longo M, et al. Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes[J]. EBioMedicine, 2020, 52:102658.
[10] Jiao TY, Ma YD,Guo XZ, et al. Bile acid and receptors: Biology and drug discovery for nonalcoholic fatty liver disease[J]. Acta Pharmacol Sin, 2022, 43(5):1103-1119.
[11] Dongiovanni P, Crudele A, Panera N, et al. beta-Klotho gene variation is associated with liver damage in children with NAFLD[J]. J Hepatol, 2020, 72(3):411-419.
[12] Galvan-Martinez DH,Bosquez-Mendoza VM, Ruiz-Noa Y, et al. Nutritional, pharmacological, and environmental programming of NAFLD in early life[J]. Am J Physiol Gastrointest Liver Physiol, 2023, 324(2):G99-G114.
[13] Wesolowski SR, Kasmi KC, Jonscher KR, et al. Developmental origins of NAFLD:A womb with a clue[J]. Nat Rev Gastroenterol Hepatol, 2017, 14(2):81-96.
[14] Geurtsen ML, Wahab RJ, Felix JF, et al. Maternal early-pregnancy glucose concentrations and liver fat among school-age children[J]. Hepatology, 2021, 74(4):1902-1913.
[15] Smith EVL, Dyson RM, Berry MJ, et al. Fructoseconsumption during pregnancy influences milk lipid composition and offspring lipid profiles in guinea pigs[J]. Front Endocrinol(Lausanne), 2020, 11:550.
[16] Nobili V, Schwimmer JB, Vajro P. Breastfeeding and NAFLD from the maternal side of the mother-infant dyad[J]. J Hepatol, 2019, 70(1):13-14.
[17] Abeysekera KW, Orr JG, Madley-Dowd P, et al. Association of maternal pre-pregnancy BMI and breastfeeding with NAFLD in young adults: A parental negative control study[J]. Lancet Reg Health Eur, 2021, 10:100206.
[18] Hagstrom H, Simon TG, Roelstraete B, et al. Maternal obesity increases the risk and severity of NAFLD in offspring[J]. J Hepatol, 2021, 75(5):1042-1048.
[19] Bugianesi E, Bizzarri C, Rosso C, et al. Low birthweight increases the likelihood of severe steatosis in pediatric non-alcoholic fatty liver disease[J]. Am J Gastroenterol, 2017, 112(8):1277-1286.
[20] Faienza MF, Brunetti G, Ventura A, et al. Nonalcoholic fatty liver disease in prepubertal children born small for gestational age:Influence of rapid weight catch-up growth[J]. Horm Res Paediatr, 2013, 79(2):103-109.
[21] Liu X,Peng Y, Chen S, et al. An observational study on the association between major dietary patterns and non-alcoholic fatty liver disease in Chinese adolescents[J]. Medicine(Baltimore), 2018, 97(17):e0576.
[22] Softic S, Stanhope KL, Boucher J, et al. Fructose and hepatic insulin resistance[J]. Crit Rev Clin Lab Sci, 2020, 57(5):308-322.
[23] Nobili V, Svegliati-Baroni G, Alisi A, et al. A 360-degree overview of paediatric NAFLD: Recent insights[J]. J Hepatol, 2013, 58(6):1218-1229.
[24] Zhu S, Wang Y,Luo F, et al. The level of vitamin D in children and adolescents with nonalcoholic fatty liver disease: A Meta-analysis[J]. Biomed Res Int, 2019, 2019:7643542.
[25] Mandala A, Janssen RC,Palle S, et al. Pediatric non-alcoholic fatty liver disease: Nutritional origins and potential molecular mechanisms[J]. Nutrients, 2020, 12(10):3166.
[26] Labayen I, Medrano M, Arenaza L, et al. Effects of exercise in addition to a family-based lifestyle intervention program on hepatic fat in children with overweight[J]. Diabetes Care, 2020, 43(2):306-313.
[27] Trevino LS, Katz TA. Endocrinedisruptors and developmental origins of nonalcoholic fatty liver disease[J]. Endocrinology,2018, 159(1):20-31.
[28] Wahlang B, Jin J, Beier JI, et al. Mechanisms of environmental contributions to fatty liver disease[J]. Curr Environ Health Rep, 2019, 6(3):80-94.
[29] Attanasio R. Sex differences in the association between perfluoroalkyl acids and liver function in US adolescents: Analyses of NHANES 2013—2016[J]. Environ Pollut, 2019, 254(Pt B):113061.
[30] DiNisio A, Sabovic I, Valente U, et al. Endocrine disruption of androgenic activity by perfluoroalkyl substances: Clinical and experimental evidence[J]. J Clin Endocrinol Metab, 2019, 104(4):1259-1271.
[31] Hong L,Xu Y, Wang D, et al. Sulforaphane ameliorates bisphenol A-induced hepatic lipid accumulation by inhibiting endoplasmic reticulum stress[J]. Sci Rep, 2023, 13(1):1147.
[32] Stratakis N, Golden-Mason L, Margetaki K, et al. In utero exposure to mercury is associated with increased susceptibility to liver injury and inflammation in childhood[J]. Hepatology, 2021, 74(3):1546-1559.
[33] Caglayan C, Kandemir FM, Darendelioglu E, et al. Rutin ameliorates mercuric chloride-induced hepatotoxicity in rats via interfering with oxidative stress, inflammation and apoptosis[J]. J Trace Elem Med Biol, 2019, 56:60-68.
[34] Betanzos-Robledo L, Cantoral A, Peterson KE, et al. Association between cumulative childhood blood lead exposure and hepatic steatosis in young Mexican adults[J]. Environ Res, 2021, 196:110980.
[35] Wang CW, Chuang HY, Liao KW, et al. Urinarythiodiglycolic acid is associated with increased risk of non-alcoholic fatty liver disease in children living near a petrochemical complex[J]. Environ Int, 2019, 131:104978.
[36] Nobili V, Alkhouri N, Alisi A, et al. Nonalcoholic fatty liver disease:A challenge for pediatricians[J]. JAMA Pediatr, 2015, 169(2):170-176.
[37] Karaman ZF, Hatipoglu N, Kardas F, et al. Identifying the effects of excess weight, metabolic syndrome and insulin resistance on liver stiffness using ultrasound elastography in children[J]. Turk J Pediatr, 2022, 64(4):671-682.
[38] Prokopowicz Z, Malecka-Tendera E, Matusik P. Predictive value of adiposity level, metabolic syndrome, and insulin resistance for the risk of nonalcoholic fatty liver disease diagnosis in obese children[J]. Can J Gastroenterol Hepatol, 2018, 2018:9465784.
[39] Scapaticci S, D'Adamo E, Mohn A, et al. Non-alcoholic fatty liver disease in obese youth with insulin resistance and type 2 diabetes[J]. Front Endocrinol(Lausanne),2021, 12:639548.
[40] Beauchamp G, Barr MM,Vergara A, et al. Treatment of hyperglycemia not associated with NAFLD improvement in children with type 2 diabetes mellitus[J]. Int J Pediatr Adolesc Med, 2022, 9(2):83-88.
[41] Schwimmer JB, Zepeda A, Newton KP, et al. Longitudinal assessment of high blood pressure in children with nonalcoholic fatty liver disease[J]. PLoS One, 2014, 9(11):e112569.
[42] Lim CYS, Foo YW,Tok CLX, et al. Screening for metabolic complications of childhood and adolescent obesity: A scoping review of national and international guidelines[J]. Obes Rev, 2022, 23(12):e13513.
[43] Suzuki A,Abdelmalek MF, Schwimmer JB, et al. Association between puberty and features of nonalcoholic fatty liver disease[J]. Clin Gastroenterol Hepatol, 2012, 10(7):786-794.
[44] Shaunak M, Byrne CD, Davis N, et al. Non-alcoholic fatty liver disease and childhood obesity[J]. Arch Dis Child, 2021, 106(1):3-8.
[45] Mueller NT, Liu T, Mitchel EB, et al. Sexhormone relations to histologic severity of pediatric nonalcoholic fatty liver disease[J]. J Clin Endocrinol Metab, 2020, 105(11):3496-3504.
[46] Xue J, Liang S, Ma J, Xiao Y et al. Effect of growth hormone therapy on liver enzyme and other cardiometabolic risk factors in boys with obesity and nonalcoholic fatty liver disease[J]. BMC Endocr Disord, 2022, 22(1):49.
[47] ElAmrousy D, El-Afify D. Osteocalcin and osteoprotegerin levels and their relationship with adipokines and proinflammatory cytokines in children with nonalcoholic fatty liver disease[J]. Cytokine, 2020, 135:155215.
[48] Leung DH,Yimlamai D. The intestinal microbiome and paediatric liver disease[J]. Lancet Gastroenterol Hepatol, 2017, 2(6):446-455.
[49] Schwimmer JB, Johnson JS, Angeles JE, et al. Microbiome signatures sssociated with steatohepatitis and moderate to severe fibrosis in children with nonalcoholic fatty liver disease[J]. Gastroenterology, 2019, 157(4):1109-1122.
[50] Zhu L, Baker RD, Zhu R, et al. Sequencing the gutmetagenome as a noninvasive diagnosis for advanced nonalcoholic steatohepatitis[J]. Hepatology, 2017, 66(6):2078-2080.
[51] Hofer U. Microbiome: Pro-inflammatory prevotella?[J]. Nat Rev Microbiol, 2014, 12(1):5.
[52] Lin YC, Lin HF, Wu CC, et al. Pathogenic effects of desulfovibrio in the gut on fatty liver in diet-induced obese mice and children with obesity[J]. J Gastroenterol, 2022, 57(11):913-925.
[53] Li Q, Tan Y, Chen S, et al. Irisin alleviates LPS-induced liver injury and inflammation through inhibition of NLRP3 inflammasome and NF-κB signaling[J]. J Recept Signal Transduct Res, 2023, 41(3):294-303.
[54] Giorgio V,Miele L, Principessa L, et al. Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with liver disease severity[J]. Dig Liver Dis, 2014, 46(6):556-560.
[55] Xu J, Lai KKY, Verlinsky A, et al. Synergistic steatohepatitis by moderate obesity and alcohol in mice despite increased adiponectin and p-AMPK[J]. J Hepatol, 2011, 55(3):673-682.
[56] Zhu L, Baker RD, Baker SS. Gutmicrobiome and nonalcoholic fatty liver diseases[J]. Pediatr Res, 2015, 77(1-2):245-251.
[57] Giuffrè M, Gazzin S, Zoratti C, et al. Celiac disease and neurological manifestations: From gluten to neuroinflammation[J]. Int J Mol Sci, 2022, 23(24):15564.
[58] Manka P, Sydor S, Schänzer-Ocklenburg JM, et al. A potential role for bile acid signaling in celiac disease-associated fatty liver[J]. Metabolites, 2022, 12(2):130.
[59] Scapaticci S, Venanzi A, Chiarelli F, et al. MAFLD and celiac disease in children[J]. Int J Mol Sci, 2023, 24(2):1764.
[60] Sundaram SS, Sokol RJ, Capocelli KE, et al. Obstructive sleep apnea and hypoxemia are associated with advanced liver histology in pediatric nonalcoholic fatty liver disease[J]. J Pediatr, 2014, 164(4):699-706.