nonalcoholic fatty liver disease in children and adolescents
TRANSCRIPT
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Nonalcoholic Fatty Liver Disease in Children and Adolescents
Peds GI Conference
Joanna Yeh
December 22, 2011
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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.
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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.
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Cohen, et al, Human Fatty Liver Disease: Old Questions and New Insights, Science, June 2011.
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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?
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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?
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UCLA “Pediatric Obesity Clinical Decision Tool”
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Cincinnati Children’s Protocol
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Cincinnati Children’s Protocol
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NASPGHAN Module
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Beyond healthy lifestyle changes, no good therapeutic options available…
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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
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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?
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Figure 1. CONSORT Flow Diagram of TONIC Trial Participants
Lavine, J. E. et al. JAMA 2011;305:1659-1668
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Table 1. Baseline Characteristics by Treatment Group.
Lavine, J. E. et al. JAMA 2011;305:1659-1668
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Table 2. Primary Outcome: Sustained Reduction in ALT Level by Treatment Group.
Lavine, J. E. et al. JAMA 2011;305:1659-1668
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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
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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.
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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.
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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.
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Many questions, no clear answers.
No good guidelines.
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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.