Nonalcoholic fatty liver disease in children and adolescents

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  • 1.Nonalcoholic Fatty Liver Disease in Children and Adolescents Peds GI Conference Joanna Yeh December 22, 2011

2. Goals Basics and background of NAFLD. Discuss who should be screened and then worked up for NAFLD and how. Discuss recent JAMA article (April 2011) regarding treatment of NAFLD with vitamin E and metformin. 3. Background NAFLD is the most common cause of chronic liver disease in children and adults. In the U.S., ~30% of children and adolescents are overweight, ~15% are obese. Adult data indicate 1/3 of patient with early NASH will have cirrhosis in 5-10 years. Prevalence of NAFLD in children: ~10% overall (6 million), ~40% obese. 4. Cohen, et al, Human Fatty Liver Disease: Old Questions and New Insights, Science, June 2011. 5. Who should be screened? Average age at diagnosis is 12 years. Earliest reported case around 2 years. More common in Hispanic Americans, then Asians and Whites compared to African Americans. Hispanic adolescents more likely to develop significant liver fibrosis. Boys more likely to have steatosis . 10% of NAFLD cases are non-overweight. Other risk factors? Genetics? 6. How should we screen? AST/ALT Ultrasound MRI Measurements for fibrosis. PNFI: Pediatric NAFLD fibrosis index (age, waist circumference, TG level) ELF: Enhanced liver fibrosis test (hyaluronic acid, aminoterminal propeptide of type 3 collagen, tissue inhibitor of metalloproteinase 1) Fibroscan (transient elastography) Gold standard for staging and grading is liver biopsy. Who gets liver biopsy? 7. UCLA Pediatric Obesity Clinical Decision Tool 8. Cincinnati Childrens Protocol 9. Cincinnati Childrens Protocol 10. NASPGHAN Module 11. Beyond healthy lifestyle changes, no good therapeutic options available 12. TONIC (Treatment of NAFLD in Children) Randomized Controlled Trial Published in JAMA, April 2011. Design: Randomized, double-blind, double-dummy, placebo- controlled clinical trial 10 university clinical research centers 173 patients age 8-17 years with biopsy proven NAFLD between Sept 2005-March 2010 Vitamin E 400 IU bid Metformin 500 mg bid Outcome: Primary: sustained reduction in ALT (50% or less of baseline level or 40 U/L or less from 48-96 weeks after treatment Secondary: histological improvements or resolution 13. Methods Definition of NAFLD: liver biopsy with >5% steatosis. Inclusions: NAFLD + persistent elevation of serum ALT. Exclusions: diabetes mellitus or cirrhosis, less than 8 years old. Liver biopsy at 96 weeks was done. Why was primary outcome ALT improvement? 14. Figure 1. CONSORT Flow Diagram of TONIC Trial Participants Lavine, J. E. et al. JAMA 2011;305:1659-1668 15. Table 1. Baseline Characteristics by Treatment Group. Lavine, J. E. et al. JAMA 2011;305:1659-1668 16. Table 2. Primary Outcome: Sustained Reduction in ALT Level by Treatment Group. Lavine, J. E. et al. JAMA 2011;305:1659-1668 17. Table 3. Change From Baseline to End of Treatment in Liver Histology by Treatment Group. Lavine, J. E. et al. JAMA 2011;305:1659-1668 18. Article Conclusions Neither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD. Children treated with vitamin E showed improvements in terms of resolution of NASH in those with NASH or borderline NASH at baseline compared with placebo. 19. Critiques Metformin dose adequate? No data provided on adherence/compliance. Possible false negative due to under enrollment. Enrolling children with NAFLD but no requiring NASH may have limited the amount of improvement that could be achieved with treatment. How about children with NAFLD but lesser ALT elevations? Secondary outcome analysis based on completers rather than intention to treat. 20. Take home points ALT may not correlate well with disease. Liver biopsy is required for NASH diagnosis. Weight loss is currently the only long term solution. Vitamin E may be appropriate for biopsy- proven NASH. 21. Many questions, no clear answers. No good guidelines. 22. References Cohen, et al, Human Fatty Liver Disease: Old Questions and New Insights, Science June 2011. Mencin and Lavine, Nonalcoholic Fatty Liver Disease in Children, Curr Opin Clin Nutr Metab Care, Mar 2011. Barlow, Expert Committee Recommendations Regarding the Prevention, Assessment, and Treatment of Child and Adolescent Overweight and Obesity: Summary Report, Pediatrics, 2007. Schwimmer, et al, Prevalence of Fatty Liver in Children and Adolescents, Pediatrics, 2006. Alkhouri, et al, A Combination of the Pediatric NAFLD Fibrosis Index and Enhanced Liver Fibrosis Test Identifies Children with Fibrosis, Clinical Gastro and Hepatology, Feb 2011. Lavine, et al, Effect of Vitamin E or Metformin for Treatment of Nonalcoholic Fatty Liver Disease in Children and Adolescents, JAMA, April 2011.