Non Alcoholic Fatty Liver (NAFLD) in as a Pediatric Disease SHIMON REIF, MD DEPARTMENT OF PEDIATRICS HADASSAH MEDICAL CENTER

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1 Non Alcoholic Fatty Liver (NAFLD) in as a Pediatric Disease SHIMON REIF, MD DEPARTMENT OF PEDIATRICS HADASSAH MEDICAL CENTER

2 NAFLD IN CHILDREN Most asymptomatic Non specific abdominal pain or fatigue Referred due to abnormal liver enzymes or Incidental US finding PE Hepatomegaly, no splenomegaly acanthocytosis nigricans Autoantibodies presents in 20% of NAFLD Do not correlate with severity of disease

3 Epidemiology NAFLD/NASH is the most common liver abnormalities in children aged 2-19 years Reported in 10-15% of American children Over weight & obesity 30% NAFLD has been reported in children as young as 2 yrs of age, and NASH-related cirrhosis as early as 8 yrs of age Chalasani N, et al. Hepatology

4 NAFLD IN CHILDREN Rising rate of obesity, type II DM Unknown factors More frequent in male May appear at age 5-10 years High proportion of steatohepatitis (70%) In adult main DD is alcoholic fatty liver In children inflammatory/genetic disease

5 Metabolic diseases associated with steatosis Relatively common CF Wilson Disease α1 antitrypsin def Fructose intolerance Galactosemia GSD Familial hyperliproteinemia Less common Sialidosis Mannosidosis Fucosidosis Tyrosinemia type I Homocystinuria Abeta lipoproteinemia Tangier disease Citrulinemia Porphyria cutanea tarda

6 NON GENETIC DISEASES AND NAFLD Hepatitis C Celiac Schwachman Diamond IBD Nephrotic syndrome Drugs - methotrexate

7 הקשר בין מבנה הכבד ואנזימי הכבד ובין הופעת סיבוכי השמנה % 80.00% 60.00% 79.20% 63% 81.80% 40.00% 20.00% 20.80% 37% 18.20% ללא סיבוכי השמנה עם סיבוכי השמנה 0.00% כבד שומני ואנזימי כבד מופרעים כבד שומני וללא הפרעה באנזימי כבד כבד תקין וללא הפרעה באנזימי כבד Sagi, Reif, Phillip, Shalitin et al Acta Pediatric Scandinavica, 2007

8 NAFLD in obese children and adolescents in Israel שכיחות כבד שומני במחקר 59.7% בקורלציה עם BMI-SDS אנזימי כבד מוגברים נמצאו רק ב 27.5% מכלל מקרי כבד שומני דומה למדווח בספרות Franzese et al. Dig. Sci 25% היו שכיחים יותר בקבוצת כבד שומני קשה בהשוואה לקבוצת כבד שומני קל 45% Vs 10% בדיקת אנזימי כבד אינה מהווה מדד מספיק לאבחון כבד שומני ALT/AST > 1

9 NAFLD in obese children and adolescents in Israel גורמים מנבאים אפשרים לכבד שומני קשה: BMI-SDS מין זכר גבוה רמות אנזימי כבד מוגברות שיעור גבוה של סיבוכי השמנה רמות גבוהות של אינסולין בצום TG מוגברים Sagi, Reif, Phillip, Shalitin Acta Pediatric Scandinavica, 2007

10 AST (U/L) ALT (U/L) Limited Value of AST or ALT to Establish NASH Severity in Children Prospective study of 176 children with NAFLD and available liver biopsies NAFLD Activity Score NAFLD Activity Score Patton HM, et al. Gastroenterology. 2008;135:

11 AST (U/L) ALT (U/L) Limited Value of AST or ALT to Establish NASH Severity in Children: Fibrosis Stage N = Fibrosis Stage 400 Fibrosis Stage None Mild Mod Bridging 0 None Mild Mod Bridging Patton HM, et al. Gastroenterology. 2008;135:

12 Pediatric NASH: Multiple Risk Factors Male sex Race/ethnicity Family history Intrauterine environment Early infant feeding Sedentary lifestyle SNPs PNPLA3: TNF IL-6, KLF-6, INSIG Dietary Higher saturated fatty acids/cholesterol Lower PUFA antioxidants, zinc, and fiber More meat and soft drinks Fructose Nobili, et al. JAMA Pediatr. 2015;169:

13 Screening Recommendations Biannual screening starting at 10 yrs of age for children with: BMI of 95th percentile BMI of 85th to 94th percentile who have other risk factors Pediatric risk groups Metabolic syndrome Insulin resistance: acanthosis nigricans Type 2 diabetes: family history, FPG, A1C Central obesity and other features of metabolic syndrome canthosis Nigricans: Best Predictor of Insulin Resistance in Pediatric NAFLD Schuppan J Gastroenterol Hepatol 2013

14 Pts (n) NASH in Children With OSA Often Associated With Worse Liver Fibrosis Prospective study of obese children (N = 25) aged yrs with liver biopsy proven NAFLD 10 8 No OSA/Hypoxia 8 P =.03 OSA/Hypoxia Fibrosis Stage Sundaram SS, et al. J Pediatr. 2014;164:

15 When to Obtain a Liver Biopsy For Suspected Pediatric NAFLD Rule out other treatable diseases Unclear diagnosis (AIH, DILI, metabolic liver diseases) Possibility of multiple diagnoses (NAFLD + AIH) In suspected advanced disease Type 2 DM, metabolic syndrome, evidence of advanced liver disease (low platelets, splenomegaly) Before pharmacologic or surgical treatment, bariatric surgery In clinical trials Vajro P, et al. J Pediatr Gastroenterol Nutr Chalasani N, et al. Hepatology

16 Determine the Severity of NAFLD: Presence of NASH Type 1 NASH (Adult) Type 2 NASH (Pediatric) Mencin A, et al. Nat Rev Gastroenterol Hepatol. 2015

17 CK-18 Tune-Positive Rate CK-18 for Prediction of NASH in Children CK-18 Levels in Children With vs Without NASH P < Performance of CK-18 Level for Diagnosis of NASH NASH Not NASH Apparent ROC = Bias-corrected ROC = False-Positive Rate Feldstein AE, et al. Am J Gastroenterol

18 Vitamin E treatment of NAFLD in children Positive effect on steatosis (transaminases), not on fibrosis Lavine et al, J Pediatr

19 TONIC: Vitamin E or Metformin for Treatment of Pediatric NAFLD Double-blind, placebo-controlled, randomized, multicenter phase II trial Biopsy at Wk 0 Biopsy at Wk 96 Children aged 8-17 yrs with NAFLD, no diabetes or cirrhosis (N = 173) Vitamin E 400 IU twice daily (n = 58) Metformin 500 mg twice daily (n = 57) Placebo (n = 58) Lavine JE, et al. JAMA. 2011

20 Mean Change in ALT (U/L) Primary Endpoint: Reduction in ALT: Wk 96 No significant difference between vitamin E and placebo or metformin and placebo Subjects With Paired Biopsies Vitamin E n = 50 Metformin Placebo n = 50 n = Wks Lavine JE, et al. JAMA. 2011;305:

21 Take Home Messages Assessment of children with suspected NAFLD Rule out other etiologies of chronic liver disease Evaluate for comorbidities Liver biopsy remains the gold standard for diagnosing NASH and staging fibrosis, and is recommended: When diagnosis is unclear Before treatment Noninvasive markers and imaging studies are urgently needed to stage the severity of NAFLD and determine response to new therapeutic agents

22 Pediatric NAFLD Therapeutic Summary First-line treatment: intensive lifestyle modification VITAMIN E improved NAS and resolution of pediatric NASH vs placebo No change in ALT vs placebo Metformin at 1000 mg/day showed no improvement Obeticholic aimproved NAS vs placebo (in adults) No data in children Cys Cysteamine showed no improvement in NAS vs placebo Sustained improvement in ALT, AST

23 SO UNFORTUNATELY FATTY LIVER IS INDEED A PEDIATRIC DISEASE

24 THANK YOU