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.

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?

9. UCLA “Pediatric Obesity Clinical Decision Tool”

11. Cincinnati Children’s Protocol

12. Cincinnati Children’s Protocol

13. NASPGHAN Module

14. Beyond healthy lifestyle changes, no
good therapeutic options available…

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.

24. Many questions, no clear answers.
No good guidelines.

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.