PORNTITA WIBOONTHANASARN, MD 21 NOVEMBER 2012 Pediatric nonalcoholic fatty liver disease.
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PORNTITA WIBOONTHANASARN, MD 21 NOVEMBER 2012 Pediatric nonalcoholic fatty liver disease Slide 2 Outline Definition Epidemiology Etiopathogenesis Risk factors Clinical features Diagnosis Treatment Prognosis Slide 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 2030% of adults and 310% of children in Western countries Nature Review, MARCH 2012, VOLUME 9 Slide 4 Definitions of the spectrum of NAFLD JPGN Volume 54, Number 5, May 2012 Slide 5 Slide 6 Epidemiology widely distributed worldwide variable in prevalence (310% in all individuals from South and North America, Europe, Asia and Australia) 7080% in obese male-to-female ratio of 2:1 more prevalent in adolescents BUT can occur in very young children WHO : next 1020 yrs, many low-income and middle- income countries will experience the double burden of the diseaseundernutrition and obesity coexisting in the same population. Nature Review, MARCH 2012, VOLUME 9 Slide 7 Etiology 9 th SLEISENGER AND FORDTRAN chapter 85 Slide 8 Pathogenesis The two-hit theory I. intrahepatic lipid accumulation (hepatic steatosis) II. inflammatory progression to nonalcoholic steatohepatitis (NASH) In the first hit hepatic metabolism of fructose promotes de novo lipogenesis and intrahepatic lipid, inhibition of mitochondrial -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 Slide 9 Pathogenesis 9 th SLEISENGER AND FORDTRAN chapter 85 Slide 10 Pathogenesis The Annual Review of Pathology: Mechanisms of Disease 2010 Slide 11 Risk factors obesity/visceral adiposity sedentary lifestyle insulin resistance predisposing genetic background : race ethnicity age and gender Nature Review, MARCH 2012, VOLUME 9 Slide 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 Slide 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 Slide 14 Clinical features 2080% 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 Slide 15 Clinical features 9 th SLEISENGER AND FORDTRAN chapter 85 Slide 16 Investigation JPGN Volume 54, Number 5, May 2012 Slide 17 Diagnostic tool Nature Review, MARCH 2012, VOLUME 9 Slide 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 Slide 19 Liver histology nonalcoholic steatohepatitis simple steatosis (fatty liver) 9 th SLEISENGER AND FORDTRAN chapter 85 Slide 20 JPGN Volume 54, Number 5, May 2012 Slide 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 Slide 22 Imaging method Ultrasonography Unenhanced computed tomography MRI Fibroscan Magnetic resonance elastography (MRE) Nature Review, MARCH 2012, VOLUME 9 Slide 23 Differential diagnosis JPGN Volume 54, Number 5, May 2012 Slide 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 Slide 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 Slide 26 Dietary modification Circulation journal of the American Heart Association 2005 Slide 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 Slide 28 Insulin sensitizing agent Metformin First line for type 2 DM Increase activity of 5AMP-activated protein kinase Decrease hepatic glucose production & hepatic insulin resistance Thiazolidinedione Selective agonist for peroxisome proliferator activated nuclear receptor- Decrease hepatic FFA (decrease lipolysis & increase oxidation), redistribute fat content from liver to peripheral adipose tissue, promote insulin sensitivity Gastroenterol Clin N Am 40, 2011, page 541 559 Slide 29 Antioxidant Vit E its function as a free radical scavenger or ability to inhibit cytokines such as transforming growth factor (TGF-) Caution : High-dose vitamin E therapy has been associated with increased mortality Gastroenterol Clin N Am 40, 2011, page 541 559 Slide 30 Slide 31 Slide 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. Slide 33 Conclusion: metformin did not appear more effective than lifestyle intervention in ameliorating levels of aminotransferases, steatosis and liver histology in children with NAFLD. Slide 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 -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 Slide 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 Slide 36 Prognosis 9 th SLEISENGER AND FORDTRAN chapter 85 Slide 37 Reference Pediatric nonalcoholic fatty liver disease: a multidisciplinary approach NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY, VOLUME 9, MARCH 2012, page 152-161 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 FORDTRANS 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 541559