Nonalcoholic fatty liver disease in children and adolescents
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.
5.
6. Cohen, et al, Human Fatty Liver Disease: Old Questions and New Insights, Science, June 2011.
7. 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?
8. 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?
15. 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
16. 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?
17. Figure 1. CONSORT Flow Diagram of TONIC Trial Participants
Lavine, J. E. et al. JAMA 2011;305:1659-1668
18. Table 1. Baseline Characteristics by Treatment Group.
Lavine, J. E. et al. JAMA 2011;305:1659-1668
19. Table 2. Primary Outcome: Sustained Reduction in ALT Level by Treatment Group.
Lavine, J. E. et al. JAMA 2011;305:1659-1668
20. 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
21. 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.
22. 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.
23. 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.
25. 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.