1. Pediatric nonalcoholic fatty liver disease
PORNTITA WIBOONTHANASARN, MD
21 NOVEMBER 2012

2. Outline Definition Epidemiology Etiopathogenesis Risk factors
Clinical features
Diagnosis
Treatment
Prognosis

3. NAFLD/ NASH
Nonalcoholic fatty liver disease (NAFLD) is a multifactorial condition, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis
Etiopathogenesis of primary NAFLD in children is unknown
The most common causes of chronic liver disease worldwide
20–30% of adults and 3–10% of children in Western countries
Nature Review , MARCH 2012, VOLUME 9

4. Definitions of the spectrum of NAFLD
JPGN Volume 54, Number 5, May 2012

6. Epidemiology widely distributed worldwide
variable in prevalence (3–10% in all individuals from South and North America, Europe, Asia and Australia)
70–80% in obese
male-to-female ratio of 2:1
more prevalent in adolescents BUT can occur in very young children
WHO : next 10–20 yrs, many low-income and middle- income countries will experience the ‘double burden’ of the disease—undernutrition and obesity coexisting in the same population.
Nature Review , MARCH 2012, VOLUME 9

7. Etiology
9th SLEISENGER AND FORDTRAN chapter 85

8. Pathogenesis The ‘two-hit’ theory In the first ‘hit’
intrahepatic lipid accumulation (hepatic steatosis)
inflammatory progression to nonalcoholic steatohepatitis (NASH)
In the first ‘hit’
hepatic metabolism of fructose promotes de novo lipogenesis and intrahepatic lipid, inhibition of mitochondrial β-oxidation of long-chain fatty acids, triglyceride formation and steatosis, hepatic and skeletal muscle insulin resistance, and hyperglycemia.
In the second ‘hit’
owing to the molecular instability of its five-membered furanose ring, fructose promotes protein fructosylation and formation of reactive oxygen species (ROS), which require quenching by hepatic antioxidants.
Many patients with NASH also have micronutrient deficiencies and do not have enough antioxidant capacity to prevent synthesis of ROS, resulting in necroinflammation.
Nature Review , MARCH 2012, VOLUME 9

9. Pathogenesis
9th SLEISENGER AND FORDTRAN chapter 85

10. Pathogenesis
The Annual Review of Pathology: Mechanisms of Disease 2010

11. Risk factors obesity/visceral adiposity sedentary lifestyle
insulin resistance
predisposing genetic background : race ⁄ ethnicity
age and gender
Nature Review , MARCH 2012, VOLUME 9

12. Genetic factor
Role of PNPLA3 in lipid processing is not known, but this protein may also affect other ectopic lipid depots, as visceral adipose tissue is related to intrahepatic lipid accumulation
Nature Review , MAY 2010, VOLUME 7

13. Clinical features
most children have asymptomatic or signs of liver disease, despite histological damage.
Few of them complain of fatigue and/or vague RUQ discomfort
accidental finding by USG performed for other clinical indications or by a routine laboratory assessment showing hypertransaminasemia
PE : hepatomegaly is often , acanthosis nigricans, a sign related to hyperinsulinemia (50% of cases of pediatric NASH)
JPGN Volume 54, Number 5, May 2012

14. Clinical features
20–80% of children with NAFLD can present with hypertriglyceridemia and/or hypercholesterolemia
several metabolic impairments (increased baseline waist circumference, hypertension and insulin resistance)
increase the risk of developing type 2DM , metabolic syndrome and cardiovascular disease
Nature Review , MARCH 2012, VOLUME 9

15. Clinical features
9th SLEISENGER AND FORDTRAN chapter 85

16. Investigation
JPGN Volume 54, Number 5, May 2012

17. Diagnostic tool
Nature Review , MARCH 2012, VOLUME 9

18. Liver biopsy the gold standard for assessing NAFLD
distinguish between NASH and hepatic steatosis, determine the severity of liver damage and the presence and extent of fibrosis, rule out other diagnoses such as autoimmune hepatitis and Wilson disease
minimum criterion for the diagnosis of NAFLD in both adults and children is the presence of steatosis in >5% of hepatocytes
Nature Review , MARCH 2012, VOLUME 9

19. simple steatosis (fatty liver)
Liver histology
simple steatosis (fatty liver)
nonalcoholic steatohepatitis
9th SLEISENGER AND FORDTRAN chapter 85

20. JPGN Volume 54, Number 5, May 2012

21. NOVEL NONINVASIVE LABORATORY ASSESSMENT OF NAFLD STAGES AND GRADES
Serum Markers of Hepatic Inflammation
Markers of Oxidative Stress
hepatic lipid peroxidation
Markers of Apoptosis
Caspase-cleaved CK18 fragments
Markers of Hepatic Fibrosis
The pediatric NAFLD fibrosis index
The European liver fibrosis (ELF) panel
OTHER BIOCHEMICAL PREDICTORS
JPGN Volume 54, Number 5, May 2012

22. Imaging method Ultrasonography Unenhanced computed tomography MRI
Fibroscan
Magnetic resonance elastography (MRE)
Nature Review , MARCH 2012, VOLUME 9

23. Differential diagnosis
JPGN Volume 54, Number 5, May 2012

24. Treatment
no guidelines for the management of NAFLD, both in adults and in children
Lifestyle changes : improves aminotransferases and liver histology in children with NAFLD and should be the first line of treatment
Dietary modification
Physical activity
Pharmacological : aimed to improving insulin sensitivity and reducing oxidative stress
Nature Review , MARCH 2012, VOLUME 9

25. Dietary modification
No information exists on recommending any particular type of diet or exercise
Recommendations for overweight pediatric NAFLD patients should include consultation with a registered dietitian to assess quality of diet and measurement of caloric intake, adoption of American Heart Association dietary strategies, and regular aerobic exercise
AASLD PRACTICE GUIDELINE, HEPATOLOGY, June 2012

26. Dietary modification
Circulation journal of the American Heart Association 2005

27. Dietary modification A pragmatic approach may be to recommend
reduced caloric and balanced diet, 20% fats, 50%–55% carbohydrates, 15%–30% proteins
consumption of low-glycemic index foods and polyunsaturated fats from fish and flax seed oils
reduced fructose intake
Dietary polyunsatured fatty acid of the N-6 and N-3 families is a well-established down-regulator of lipogenesis.
docosahexaenoic acid supplementation in children with NAFLD improves liver steatosis and insulin sensitivity

28. Insulin sensitizing agent
Metformin
First line for type 2 DM
Increase activity of 5’AMP-activated protein kinase
Decrease hepatic glucose production & hepatic insulin resistance
Thiazolidinedione
Selective agonist for peroxisome proliferator activated nuclear receptor-γ
Decrease hepatic FFA (decrease lipolysis & increase β oxidation) , redistribute fat content from liver to peripheral adipose tissue, promote insulin sensitivity
Gastroenterol Clin N Am 40 , 2011, page 541–559

29. Antioxidant
Vit E
its function as a free radical scavenger or ability to inhibit cytokines such as transforming growth factor (TGF-β)
Caution : High-dose vitamin E therapy has been associated with increased mortality
Gastroenterol Clin N Am 40 , 2011, page 541–559

32. Conclusion
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.

33. Conclusion:
metformin did not appear more effective than lifestyle intervention in ameliorating levels of aminotransferases , steatosis and liver histology in children with NAFLD.

34. Summary in treatment Recommendations
Intensive lifestyle modification improves aminotransferases and liver histology in children with NAFLD and thus should be the first line of treatment.
Metformin at 500 mg twice daily offers no benefit to children with NAFLD and thus should not be prescribed. The effect of metformin administered at a higher dose is not known.
Vitamin E 800 IU/day (RRR α-tocopherol) offers histological benefits to children with biopsyproven NASH or borderline NASH but confirmatory studies are needed before its use can be recommended in clinical practice
AASLD PRACTICE GUIDELINE, HEPATOLOGY, June 2012

35. Prognosis
The prognosis of pediatric NAFLD with advanced fibrosis or cirrhosis : unknown owing to the limited numbers of studies with long-term follow-up.
any stage of NAFLD often develop cirrhosis in adulthood
No clinical or laboratory data reliably predicted the course of liver disease
Nature Review , MARCH 2012, VOLUME 9

36. Prognosis
9th SLEISENGER AND FORDTRAN chapter 85

37. Reference
Pediatric nonalcoholic fatty liver disease: a multidisciplinary approach
NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY , VOLUME 9, MARCH 2012 , page
Diagnosis of Nonalcoholic Fatty Liver Disease in Children and Adolescents
Position Paper of the ESPGHAN Hepatology Committee , JPGN Volume 54,
Number 5, May 2012
SLEISENGER AND FORDTRAN’S GASTROINTESTINAL AND LIVER DISEASE: PATHOPHYSIOLOGY ninth edition chapter 85
Nonalcoholic Fatty Liver Disease: Pathology and Pathogenesis
The Annual Review of Pathology: Mechanisms of Disease 2010
The Diagnosis and Management of Non-Alcoholic Fatty Liver Disease: Practice Guideline by the AASLD, ACG and AGA, HEPATOLOGY, June 2012
Nonalcoholic Fatty Liver Disease: Pharmacologic and Surgical Options , Gastroenterol Clin N Am 40 (2011) page 541–559