Nonalcoholic Fatty Liver Disease in Children: Where Are We?

Nonalcoholic fatty liver disease (NAFLD) affects both children and adults, especially those with risk factors such as obesity, sedentary lifestyle, and diabetes. As the prevalence of obesity increases in the pediatric population, NAFLD has quickly become the most common chronic liver disease in children and an increasing global health problem.1Le M.H. Yeo Y.H. Li X. et al.2019 Global NAFLD prevalence: a systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2021; (Epub ahead of print)Abstract Full Text Full Text PDF Scopus (129) Google Scholar Differences in study design and diagnostic methods in NAFLD all have contributed to uncertainty regarding the exact prevalence of NAFLD in children and adolescents. Our previous study indicated that, in the United States, NAFLD prevalence in individuals aged 12 to 21 years increased almost 40% in recent years, from 8.54% in 1999 to 2004 to 10.1% in 2005 to 2010 and 11.8% in 2011 to 2016.2Li J. Le M.H. Barakat M.T. et al.The changing epidemiology of liver disease among US children and adolescents from 1999 to 2016.Am J Gastroenterol. 2021; 116: 2068-2078Crossref PubMed Scopus (13) Google Scholar Children with NAFLD usually are asymptomatic and NAFLD generally is diagnosed incidentally through screening tests in overweight or obese children.3Goldner D. Lavine J.E. nonalcoholic fatty liver disease in children: unique considerations and challenges.Gastroenterology. 2020; 158: 1967-1983.e1961Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Some pediatric NAFLD patients present with nonspecific symptoms such as abdominal discomfort or fatigue. Children with NAFLD may have mildly abnormal liver enzyme levels (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]). Comorbid conditions, including metabolic syndrome, insulin resistance, essential hypertension, and central adiposity, are associated with the development of NAFLD in children, similar to that in adults.4Shaunak M. Byrne C.D. Davis N. et al.Non-alcoholic fatty liver disease and childhood obesity.Arch Dis Childhood. 2021; 106: 3-8Crossref PubMed Scopus (43) Google Scholar NAFLD in both children and adults is defined histologically as macrovesicular steatosis in 5% or more of hepatocytes in the absence of other known causes of fatty liver. Similar to adults, children with NAFLD have the full spectrum of liver disease from simple steatosis to steatohepatitis to cirrhosis. Yet, there are also significant differences in liver histology between adults and children. Nonalcoholic steatohepatitis (NASH), rather than simple steatosis, is more commonly seen in children and adolescents.5Nobili V. Alisi A. Valenti L. et al.NAFLD in children: new genes, new diagnostic modalities and new drugs.Nat Rev Gastroenterol Hepatol. 2019; 16: 517-530Crossref PubMed Scopus (156) Google Scholar Children younger than 12 years of age usually present with type 2 NASH, in which the pattern of injury typically is centered in zone 1, with the combination of steatosis, parenchymal inflammation, ballooning, and perisinusoidal fibrosis. In contrast, teenagers are more likely to have type 1 NASH with injury typically centered in zone 3, similar to adults.6Kleiner D.E. Makhlouf H.R. Histology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in adults and children.Clin Liver Dis. 2016; 20: 293-312Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar Although liver histology is considered the gold standard for assessing NAFLD, performing a liver biopsy to determine disease prevalence is not feasible in children; thus, alternative indirect approaches are needed.7Li J. Nguyen M.H. Non-invasive diagnosis methods are needed in paediatric non-alcoholic fatty liver disease.Liver Int. 2021; 41: 1161Crossref PubMed Scopus (3) Google Scholar Various noninvasive methods for quantifying and monitoring fatty changes and fibrosis in liver included scoring systems based on laboratory data, radiologic tests, and novel biomarkers. Recently, a study using data from the Cysteamine Bitartrate Delayed-Release for the Treatment of NAFLD in Children clinical trial indicated that the dynamic changes in serum ALT and γ-glutamyl transferase (GGT) levels are associated strongly with changes in liver histology and may be useful as an indicator of histologic response. Specifically, GGT may best reflect improvement in the NAFLD activity score and ALT may reflect improvement in borderline zone 1 NASH and fibrosis.8Newton K.P. Lavine J.E. Wilson L. et al.Alanine aminotransferase and gamma-glutamyl transpeptidase predict histologic improvement in pediatric nonalcoholic steatohepatitis.Hepatology. 2021; 73: 937-951Crossref PubMed Scopus (26) Google Scholar In addition, several scores, which include other laboratory variables (AST, GGT, platelet count) and metabolic parameters (body mass index, insulin resistance, hemoglobin A1c) for ruling out advanced fibrosis in adults, also have been validated in children, including the NAFLD fibrosis score, Fibrosis-4 score, AST/ALT ratio, AST/platelet ratio index, and pediatric NAFLD fibrosis index score.9Younossi Z. Anstee Q.M. Marietti M. et al.Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.Nat Rev Gastroenterol Hepatol. 2018; 15: 11-20Crossref PubMed Scopus (2764) Google Scholar However, none of the scores can differentiate the severity of fibrosis well and overall performance has been poor.10Suri A. Song E. van Nispen J. et al.Advances in the epidemiology, diagnosis, and management of pediatric fatty liver disease.Clin Ther. 2021; 43: 438-454Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Novel markers such as leptin, adiponectin, tumor necrosis factor α, interleukin-6, cytokeratin-18, and fibroblast growth factor 21 have been studied in children over the past decade. Although some have shown promise, all seem to lack the sensitivity and specificity required for the accurate diagnosis of NAFLD. Ultrasound has been shown to have a high sensitivity and specificity for moderate to severe steatosis in children, but cannot diagnose mild steatosis or differentiate between simple steatosis and NASH. Transient elastography (TE) and magnetic resonance elastography both have been used for the noninvasive assessment of liver fibrosis in the pediatric population. Magnetic resonance imaging estimated hepatic proton density fat fraction values show significant correlation with histologic steatosis grade and may be useful in defining early disease.11Middleton M.S. Van Natta M.L. Heba E.R. et al.Diagnostic accuracy of magnetic resonance imaging hepatic proton density fat fraction in pediatric nonalcoholic fatty liver disease.Hepatology. 2018; 67: 858-872Crossref PubMed Scopus (93) Google Scholar Currently, the natural history and long-term outcome of children with NAFLD are largely unknown owing to the lack of high-quality longitudinal data. It seems reasonable to assume that NAFLD in childhood persisting into adulthood is likely to be a harmful condition because advanced fibrosis and cirrhosis are potential consequences of disease starting in childhood. Children with NASH cirrhosis have been reported. However, the prognosis of pediatric NAFLD with advanced fibrosis or cirrhosis remains unknown owing to the limited numbers of studies with long-term follow-up evaluation. Although rare, cases of hepatocellular carcinoma also have been reported in pediatric NAFLD patients. Without effective treatments, children with NASH are at risk of developing cirrhosis and liver-related mortality in early adulthood. A nationwide cohort study in Sweden with a median follow-up period of 15.8 years found that children with biopsy-confirmed NAFLD and NASH have significantly higher rates of overall, cancer-, liver-, and cardiometabolic-specific mortality.12Simon T.G. Roelstraete B. Hartjes K. et al.Non-alcoholic fatty liver disease in children and young adults is associated with increased long-term mortality.J Hepatol. 2021; 75: 1034-1041Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar Various treatments/interventions have been investigated for the management of pediatric NAFLD including diet and physical activity (Table 1).13Lavine J.E. Schwimmer J.B. Van Natta M.L. 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: 1659-1668Crossref PubMed Scopus (837) Google Scholar, 14Della Corte C. Carpino G. De Vito R. et al.Docosahexanoic acid plus vitamin D treatment improves features of NAFLD in children with serum vitamin D deficiency: results from a single centre trial.PLoS One. 2016; 11e0168216Crossref PubMed Scopus (80) Google Scholar, 15Schwimmer J.B. Lavine J.E. Wilson L.A. et al.In children with nonalcoholic fatty liver disease, cysteamine bitartrate delayed release improves liver enzymes but does not reduce disease activity scores.Gastroenterology. 2016; 151: 1141-1154.e1149Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 16Vos M.B. Jin R. Konomi J.V. et al.A randomized, controlled, crossover pilot study of losartan for pediatric nonalcoholic fatty liver disease.Pilot Feasibility Stud. 2018; 4: 109Crossref PubMed Scopus (15) Google Scholar, 17Dohil R. Schmeltzer S. Cabrera B.L. et al.Enteric-coated cysteamine for the treatment of paediatric non-alcoholic fatty liver disease.Aliment Pharmacol Ther. 2011; 33: 1036-1044Crossref PubMed Scopus (63) Google Scholar, 18Janczyk W. Lebensztejn D. Wierzbicka-Rucińska A. et al.Omega-3 fatty acids therapy in children with nonalcoholic fatty liver disease: a randomized controlled trial.J Pediatr. 2015; 166 (e1351–1353): 1358-1363Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 19Yurtdaş G. Akbulut G. Baran M. et al.The effects of Mediterranean diet on hepatic steatosis, oxidative stress, and inflammation in adolescents with non-alcoholic fatty liver disease: a randomized controlled trial.Pediatr Obes. 2021; (Epub ahead of print)e12872PubMed Google Scholar, 20Schwimmer J.B. Ugalde-Nicalo P. Welsh J.A. 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: 256-265Crossref PubMed Scopus (136) Google Scholar One of the largest randomized control trials is the Treatment of NAFLD in Children study, which found patients on vitamin E (800 IU) treatment had greater resolution of NASH (58% with vitamin E vs 28% with placebo; P = .006) with statistically significant improvements in histologic activity scores (-0.7 with placebo vs -1.8 with vitamin E; P = .02).13Lavine J.E. Schwimmer J.B. Van Natta M.L. 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: 1659-1668Crossref PubMed Scopus (837) Google Scholar Omega-3 fatty acids (specifically docosahexaenoic acid) plus vitamin D treatment also have shown beneficial effects on NAFLD activity score because docosahexaenoic acid might improve hepatic fatty acid metabolism by inhibiting lipogenesis and stimulating fatty acid oxidation.14Della Corte C. Carpino G. De Vito R. et al.Docosahexanoic acid plus vitamin D treatment improves features of NAFLD in children with serum vitamin D deficiency: results from a single centre trial.PLoS One. 2016; 11e0168216Crossref PubMed Scopus (80) Google Scholar One-year treatment of cysteamine bitartrate delayed release in children did not improve overall histologic markers of NAFLD compared with placebo but showed significant reductions in serum AST levels and lobular inflammation (36% of patients in the cysteamine bitartrate delayed release group vs 21% of patients in the placebo group; P = .03).15Schwimmer J.B. Lavine J.E. Wilson L.A. et al.In children with nonalcoholic fatty liver disease, cysteamine bitartrate delayed release improves liver enzymes but does not reduce disease activity scores.Gastroenterology. 2016; 151: 1141-1154.e1149Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar Other ongoing trials included the use of probiotics, semaglutide, and other dietary (Indo-Mediterranean diet) and exercise (high-intensity interval training) interventions (ClinicalTrials.gov).Table 1Current Completed Clinical Studies of Pediatric Nonalcoholic Fatty Liver Disease From clinicaltrial.govNCT numberStudyPopulation and actual enrollmentIntervention/drug (number completed)PhaseStudy designPrimary outcome measuresResultsNCT00063635Lavine, et al,13Lavine J.E. Schwimmer J.B. Van Natta M.L. 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: 1659-1668Crossref PubMed Scopus (837) Google Scholar 2011173 children aged 8–17 years with biopsy-proven NAFLDVitamin E (800 IU/d) (N = 50), metformin (1000 mg/d) (N = 51), or placebo (N = 49) treatment for 96 weeksPhase 3Randomized, double-blind, double-dummy, placebo-controlledSustained reduction in ALT level to either 50% of baseline value or <40 IU/LSustained reduction in ALT level was similar to placebo (17%) in both the vitamin E (26%; P = .26) and metformin treatment groups (16%; P = .83)The mean change at 96 weeks in hepatocellular ballooning scores was 0.1 with placebo (95% CI, -0.2 to 0.3) vs -0.5 with vitamin E (P = .006) and -0.3 with metformin (P = .04)NCT02098317Della Corte et al,14Della Corte C. Carpino G. De Vito R. et al.Docosahexanoic acid plus vitamin D treatment improves features of NAFLD in children with serum vitamin D deficiency: results from a single centre trial.PLoS One. 2016; 11e0168216Crossref PubMed Scopus (80) Google Scholar 201643 obese children with biopsy-proven NAFLD + vitamin D deficiencyDHA (500 mg/d) + vitamin D (800 IU/d) (N = 18) or placebo (N = 23) for 12 monthsPhase 3Randomized, double-blind placebo-controlledImprovement in liver histology, defined by NASDHA plus vitamin D treatment reduced the NAS in the treatment group (5.4 vs 1.92; P < .001 for baseline vs end of study)NCT01529268Schwimmer et al,15Schwimmer J.B. Lavine J.E. Wilson L.A. et al.In children with nonalcoholic fatty liver disease, cysteamine bitartrate delayed release improves liver enzymes but does not reduce disease activity scores.Gastroenterology. 2016; 151: 1141-1154.e1149Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar 2016169 children with NAS ≥4CBDR (N = 76) vs placebo (N = 78) treatment for 52 weeksPhase 2Randomized, placebo-controlledImprovement in liver histology over 52 weeks, defined as a decrease in the NAS of 2 points or more without worsening fibrosisNo significant difference between groups in the primary outcome (28% in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% CI, 0.8–2.1; P = .34)Children receiving CBDR had significant changes in mean levels of ALT (-53 ± 88 U/L vs -8 ± 77 U/L in the placebo group; P = .02) and AST (-31 ± 52 vs -4 ± 36 U/L in the placebo group; P = .008), and a larger proportion had reduced lobular inflammation (in 36% vs 21% in the placebo group; RR, 1.8; 95% CI, 1.1–2.9; P = .03)NCT01913470Vos et al,16Vos M.B. Jin R. Konomi J.V. et al.A randomized, controlled, crossover pilot study of losartan for pediatric nonalcoholic fatty liver disease.Pilot Feasibility Stud. 2018; 4: 109Crossref PubMed Scopus (15) Google Scholar 201812 children aged 11–19 years with biopsy-proven NASHLosartan (50 mg/d) (N = 5) or placebo (N = 4) treatment for 8 weeksPhase 2aRandomized, double-blind, placebo-controlled, crossover studyChange in ALT level from baseline to end of treatmentMore participants had a decreased ALT level on losartan compared with placebo (89% [8 of 9] vs 56% [5 of 9]); participants’ ALT concentration did not return to baseline level after an 8-week treatment periodNCT00799578Dohil et al,17Dohil R. Schmeltzer S. Cabrera B.L. et al.Enteric-coated cysteamine for the treatment of paediatric non-alcoholic fatty liver disease.Aliment Pharmacol Ther. 2011; 33: 1036-1044Crossref PubMed Scopus (63) Google Scholar 201113 children aged ≥10 years with biopsy-proven NAFLD and ALT ≥60 IU/LEnteric-coated cysteamine (N = 11) treatment for 24 weeksPhase 1Open-label, single-group assignmentSubjects with >50% reduction or normalization of ALT level (≤40 IU/L)For all subjects compared with baseline, there was a significant reduction in the mean ALT level after 24 weeks of EC–cysteamine therapy (120.2 vs 54.5 IU/L; P = .002)The primary end point was reached in 7 and normalization of ALT level occurred in 5NCT01547910Janczyk et al,18Janczyk W. Lebensztejn D. Wierzbicka-Rucińska A. et al.Omega-3 fatty acids therapy in children with nonalcoholic fatty liver disease: a randomized controlled trial.J Pediatr. 2015; 166 (e1351–1353): 1358-1363Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar 201576 overweight or obese children with NAFLDOmega-3 fatty acids (450–1300 mg/d) (N = 30) or placebo (N = 34) for 6 monthsPhase 2Randomized, double-blind, placebo-controlledSerum AST level decreased ≥0.3 times ULNNo significant differences between the 2 groups in the number of patients with decreased ALT level by ≥0.3 times the ULN (24 vs 23)NCT04845373Yurtdaş et al,19Yurtdaş G. Akbulut G. Baran M. et al.The effects of Mediterranean diet on hepatic steatosis, oxidative stress, and inflammation in adolescents with non-alcoholic fatty liver disease: a randomized controlled trial.Pediatr Obes. 2021; (Epub ahead of print)e12872PubMed Google Scholar 202144 adolescents aged 11–18 years with NAFLDMD (N = 22) vs LFD (N = 22) for 12 weeksN/ARandomized, single-blind, 2-arm, parallel dietary interventionChanges in hepatic steatosis, inflammatory parameters, oxidative stress markers, glycemic profile, and liver function testsSeverity of hepatic steatosis, serum aminotransferase levels, and insulin resistance decreased significantly in both groups with no significant differences between groups except for AST levelThe decrease in AST level in the MD group was greater than in the LFD group (P < .05)NCT02513121Schwimmer et al,20Schwimmer J.B. Ugalde-Nicalo P. Welsh J.A. 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: 256-265Crossref PubMed Scopus (136) Google Scholar 201940 boys aged 11–16 years with biopsy-proven NAFLD and current evidence of active disease (hepatic steatosis>10% and AST level 45 U/L)Low-sugar diet (N = 20) vs usual diet (N = 20) for 8 weeksN/ARandomized, open-label, parallel assignmentChange in hepatic steatosis estimated by MR PDFF between baseline and 8 weeksThe mean decreases in hepatic steatosis from baseline to week 8 was significantly greater for the low-sugar diet group (25% to 17%) vs the usual diet group (21% to 20%), and the adjusted week 8 mean difference was -6.23% (95% CI, -9.45% to -3.02%; P < .001)The geometric mean decrease in ALT level from baseline to 8 weeks was significantly greater for the low-sugar diet group (103 U/L to 61 U/L) vs the usual diet group (82 U/L to 75 U/L), and the adjusted ratio of the geometric means at week 8 was 0.65 U/L (95% CI, 0.53–0.81 U/L; P < .001)ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBDR, cysteamine bitartrate delayed release; CI, confidence interval; DHA, docosahexaenoic acid; EC, enteric-coated; LFD, low-fat diet; MD, Mediterranean die; MR, magnetic resonance; N/A, not applicable; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NAS, nonalcoholic fatty liver disease activity score; NCT, National Clinical Trial; PDFF, proton density fat fraction; RR, relative risk; ULN, upper limit of normal. Open table in a new tab ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBDR, cysteamine bitartrate delayed release; CI, confidence interval; DHA, docosahexaenoic acid; EC, enteric-coated; LFD, low-fat diet; MD, Mediterranean die; MR, magnetic resonance; N/A, not applicable; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NAS, nonalcoholic fatty liver disease activity score; NCT, National Clinical Trial; PDFF, proton density fat fraction; RR, relative risk; ULN, upper limit of normal. There is currently no approved pharmacotherapy for pediatric NAFLD, so present management focuses on lifestyle and dietary changes such as the Mediterranean diet19Yurtdaş G. Akbulut G. Baran M. et al.The effects of Mediterranean diet on hepatic steatosis, oxidative stress, and inflammation in adolescents with non-alcoholic fatty liver disease: a randomized controlled trial.Pediatr Obes. 2021; (Epub ahead of print)e12872PubMed Google Scholar and low-sugar diet,20Schwimmer J.B. Ugalde-Nicalo P. Welsh J.A. 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: 256-265Crossref PubMed Scopus (136) Google Scholar and increasing physical activity as the primary intervention with improvement of biomarkers of NAFLD after weight loss; however, data on improvement in liver fibrosis are limited. Within this context, the study by Lefere et al21Lefere S. Dupont E. De Guchtenaere A. et al.Intensive lifestyle management improves steatosis and fibrosis in pediatric nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol. 2022; 20: 2317-2326Abstract Full Text Full Text PDF Scopus (10) Google Scholar published in this issue of Clinical Gastroenterology and Hepatology represents a significant advance. Lefere et al21Lefere S. Dupont E. De Guchtenaere A. et al.Intensive lifestyle management improves steatosis and fibrosis in pediatric nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol. 2022; 20: 2317-2326Abstract Full Text Full Text PDF Scopus (10) Google Scholar performed a prospective study of 204 children and adolescents with severe obesity. A total of 32.8% of patients had at least F2 fibrosis by TE, including 10.3% with TE of 9 kPa or greater. Patients underwent a multimodal intervention focusing on increasing the level of physical activity, dietary intervention, acquiring healthy eating habits, and psychological support. After 6 months of intense residential lifestyle intervention, the median body weight loss was 16.0%: the severity of liver steatosis, both on ultrasound and based on controlled attenuation parameter values, decreased significantly and fibrosis improved in 75.0%. These changes were maintained and consolidated over a 1-year period and coincided with significant weight loss and improvements in liver steatosis, liver enzyme levels, and insulin resistance. The degree of weight loss necessary to improve pediatric NAFLD remains unclear, although data in adults suggest that a 7% to 10% weight loss can reduce the severity of NASH and improve fibrosis. Results from the current study suggest that in pediatric NAFLD patients, a median weight loss of 16.0% at 6 months and 25.6% at 12 months was associated with fibrosis regression. Unfortunately, achieving significant weight loss in an outpatient setting is difficult for most children and adolescents. A lifestyle that leads to obesity/overweight and NAFLD is complex. A multidisciplinary, family centered approach to NAFLD, in which both children and their families are treated at the same time, could help to better manage the disease in children. Limitations of the study included lack of liver histology and limited long-term follow-up evaluation. However, this study showed the effectiveness of a residential program in improving NAFLD in the pediatric population. NAFLD in the pediatric population is the leading cause of chronic liver disease globally and presents an impending social and economic burden. Increasing knowledge of the complex pathophysiology of NAFLD will continue to suggest potential therapeutic targets. The lack of noninvasive tools to stage disease remains a formidable barrier to clinical studies. However, general healthy eating advice and physical activity currently are recommended to promote weight loss in pediatric NAFLD. Intensive Lifestyle Management Improves Steatosis and Fibrosis in Pediatric Nonalcoholic Fatty Liver DiseaseClinical Gastroenterology and HepatologyVol. 20Issue 10PreviewChildhood obesity, with associated comorbidities such as nonalcoholic fatty liver disease (NAFLD), is an increasing global health problem. Although lifestyle management is the mainstay of treatment, its efficacy on liver fibrosis has not yet been established. Full-Text PDF