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Pediatric Non-Alcoholic Fatty Liver Disease: Etiologies, Features, Treatment and Implications for the RD

Pediatric Non-Alcoholic Fatty Liver Disease: Etiologies, Features, Treatment and Implications for the RD. Deborah Cohen, DCN, RD Assistant Professor UNM Nutrition Program. Objectives. Discuss the prevalence of pediatric non-alcoholic fatty liver disease (NAFLD) in the United States .

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Pediatric Non-Alcoholic Fatty Liver Disease: Etiologies, Features, Treatment and Implications for the RD

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  1. Pediatric Non-Alcoholic Fatty Liver Disease: Etiologies, Features, Treatment and Implications for the RD Deborah Cohen, DCN, RD Assistant Professor UNM Nutrition Program

  2. Objectives • Discuss the prevalence of pediatric non-alcoholic fatty liver disease (NAFLD) in the United States. • Identify the major risk factors that contribute to the development of NAFLD. • Review the biochemical and anthropometric features of pediatric NAFLD. • Discuss the recommendations for preventing and treating pediatric NAFLD, based on the current research.

  3. 25,000 U.S. Deaths Linked to Sugary Drinks | ABC News – Wed, Mar 20, 2013 12:29 AM EDT

  4. Non-alcoholic fatty liver disease (NAFLD) Describes a spectrum of steatotic liver disease generally associated with obesity and metabolic syndrome HTN, dyslipidemia, increased waist circumference, insulin resistance

  5. Prevalence Most common pediatric chronic liver disease in US and globally 2.6%-9.6% Prevalence depends on population studied Studies from Europe, Asia, America: Overweight and obese children 24%-77% (severe obesity: up to 90%) More common in boys vs. girls

  6. Study of Child and Adolescent Liver Epidemiology (SCALE) • Retrospective autopsy study (n=742, ages 2-19, 1993-2003, San Diego County) • Fatty liver (≥5% of hepatocytes containing macrovesicularfat) was present in 13% of subjects • Prevalence of fatty liver (adjusted for age, gender, race, and ethnicity) estimated to be 9.6% • Prevalence differed significantly by race and ethnicity • Asian: 10.2%; Black: 1.5%; Hispanic: 11.8%; White: 8.6% • The highest rate of fatty liver seen in obese children (38%). Schwimmer et al. Prevalence of fatty liver in children and adolescents. Pediatrics. 2006;118(4):1388-1393.

  7. Risk Factors Associated with NAFLD Chalasani et al. The Diagnosis and Management of Non-Alcoholic Fatty Liver Disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55(6): 2005-2023.

  8. Progression of fatty liver disease Nonalcoholic fatty liver (NAFL) Progression of hepatic steatosis with no evidence of hepatocellular injury. Nonalcoholic steatohepatitis (NASH) Presence of hepatic steatosis with hepatocellular injury (ballooning) with or without fibrosis. NASH Cirrhosis

  9. Pathogenesis De novo lipogenesis (DNL) Role of Insulin Resistance “Two Hit” Theory Cytokines & Oxidative Stress

  10. There are 3major sources for the increased TG deposition in the liver: Rate of FFA uptake and synthesis > need for FFA for essential functions Impaired VLDL export Increased de novo lipogenesis (DNL) synthesis of FA from CHO in the liver

  11. Role of Insulin Resistance The liver is the main site of insulin action, in addition to skeletal muscle and adipose tissue. Fatty liver: ability of insulin to inhibit hepatic glucose production is impaired (hyperglycemia). Insulin resistance hyperglycemia, hyperinsulinemia…both stimulate DNL by activation of the transcription factors carbohydrate regulatory element-binding protein (ChREBP) & sterol regulatory element-binding proteins (SREBP-1c). Insulin resistance stimulates the liver to overproduce TG rich VLDL in the fasting state.

  12. The metabolic consequences of insulin resistance include: Persistent hyperglycemia Hyperinsulinemia Elevated serum FFA’s Hypertriglyceridemia

  13. It is unclear if insulin resistance and hyperglycemiacauseNAFLD or are the consequencesof the disease. NAFLD can be considered the hepatic manifestation of metabolic syndrome.

  14. “Two Hit” Theory The first “hit” involves the accumulation of fat in the hepatocytes. Subsequent “hits” involve: chronic oxidative stress with the production of reactive oxygen species (ROS) secretion of pro-inflammatory cytokines mitochondrial dysfunction liver injury, hepatic apoptosis (liver cell death) and fibrosis

  15. Pro-inflammatory cytokines (TNF-α) are produced directly by hepatocytes in response to an increased supply of FFA and/or by adipose tissue macrophages that increase during obesity. Fibrosis is thought to arise as part of the normal healing response to inflammation and injury.

  16. Cytokines and Oxidative Stress Adiponectin: Inversely associated with obesity, BMI, metabolic syndrome, visceral adiposity, NAFLD IL-6: Implicated in insulin resistance, NASH TNF-α: Elevated levels with insulin resistance, metabolic syndrome CRP: May be a marker for hepatic steatosis --- but not of severity of NAFLD Pearce S et al. Noninvasive biomarkers for the diagnosis of steatohepatitisand advanced fibrosis in NAFLD. Biomarker Research.2013;1:7.

  17. Role of Genetics Global patterns of racial and ethnic distributions. United States: Prevalence in Hispanic Americans, Asians and Native Americans higher than in Caucasians & African-Americans. Schwimmer et al. Prevalence of fatty liver in children and adolescents. Pediatrics 2006;118(4):1388-1393.

  18. Several gene polymorphisms are associated with NAFLD & genes that influence: insulin signaling and the regulation of fat metabolism oxidative stress responses to endotoxins release of cytokines severity of fibrosis Genetic factors may also predispose certain individuals to environmental influences that promote the development of NAFLD. Alisiet al. Nonalcoholic fatty liver disease and metabolic syndrome in adolescents: Pathogenetic role of genetic background and intrauterine environment. Ann Med. 2012;44(1)29-40.

  19. Polymorphisms (single nucleotide polymorphisms or SNPs) in genes encoding proteins involved in the synthesis, storage, and export of TG may play a role in NAFLD susceptibility.

  20. PNPLA3 (patatin-like phospholipase domain-containing protein 3,Adiponutrin) Function not entirely known but is reported to have lipase-like activity and to promote TG hydrolysis in the liver. • SNP (methionine substituted for isoleucine at codon 148 in the gene PNPLA3 has been determined to regulate a variety of the mechanisms involved with the development of NAFLD HFE gene (human hemochromatosis protein) Gene involved with insulin sensitivity, oxidative stress.

  21. Several investigators have found a genetic association between PNPLA3 polymorphisms and elevated plasma liver enzymes in Hispanic populations. Romeo et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nature Genetics. 2008.40(2):1461-1465. Quan et al. PNPLA3polymorphisms and liver aminotransferase levels in a Mexican American population.Clin Invest Med. 2012 August 4; 35(4): E237.

  22. Romeo et al. The 148M allele of the PNPLA3 gene is associated with indices of liver damage early in life. J Hepatol. 2010;53:35-338. • N = 475 overweight/obese children & adolescents (Italy) age 10 ± 3; genotyped; anthropometric, biochemical and US data obtained • Carriers of two 148M alleles had a 52% increase in circulating ALT levels compared to carriers of two 148I alleles. • Liver steatosis was more prevalent in carriers of two 148M alleles. • Glucose tolerance and insulin sensitivity were similar across all three genotypes. Carriers of the PNPLA3 148M allele: more likely to exhibit hepatic damage at an early age.

  23. Genetics may play an important role particularly at early onset disease. Use of genetic analysis and genotyping has the potential to become an important noninvasive tool for the screening and diagnosis of NAFLD.

  24. Histological NAFL presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes. NASH hepatic steatosis and inflammation with hepatocyte injury (ballooning) with or without fibrosis.

  25. Spectrum of disease in NAFLD A: Nonalcoholic fatty liver (NAFL) B: Nonalcoholic steatohepatitis (NASH) C: Cirrhosis

  26. Histological Features Brunt EM et al. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94(9):2467-2474. Kleiner DE et al. Nonalcoholic Steatohepatitis Clinical Research network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41(6):1313-1321.

  27. Biochemical Features Elevated serum TG > 150 mg/dL Elevated ALT • No universal standards for children • 30-45 U/L most commonly used cutoff for abnormal ALT • ALT may be normal • Current standards controversial—range may be too high

  28. Insulin resistance Homeostatic Model Assessment Insulin Resistance (HOMA-IR) fasting glucose (mg/dl) × fasting insulin (μU/ml) 405 >3

  29. Anthropometric Features Abdominal obesity WC > 90th percentile Overweight BMI >95th percentile Obesity BMI >95th percentile

  30. International Diabetes Federation (IDF) Criteria for the Classification of Metabolic Syndrome in Children

  31. Clinical Features Acanthosisnigricans Hepatomegaly on palpation

  32. Diagnosis Liver biopsy invasive, risks, expensive

  33. Diagnostic Imaging Magnetic Resonance Imaging (MRI) no exposure to ionizing radiation expensive! Computerized Tomography (CT) exposure to ionizing radiation Ultrasound accessible, no ionizing radiation exposure low sensitivity: mild-moderate steatosis limited beam penetration in obese individuals

  34. Ultrasound image of the Liver MRI of the Liver CT image of the Liver

  35. Dietary Characteristics overconsumption of fructose & soft drinks lower consumption of fiber overconsumption of meat/saturated fat/cholesterol lower consumption of fish, omega-3 fatty acids, and lower consumption of some vitamins (vitamin E) Zelber-Sagi et al. Nutrition and physical activity in NAFLD: An overview of the epidemiological evidence. World J Gastroenterol. 2011; 17(29): 3377–3389.

  36. Nutritional Factors Role of CHO Sucrose Increases hepatic TG synthesis Fructose Increases DNL & insulin resistance in animal models Fructose overfeeding increases fasting and postprandial plasma TG hepatic DNL, VLDL-TG secretion & decreased VLDL-TG clearance TappyL. Does fructose consumption contribute to non-alcoholic fatty liver disease? Clinics Res GastroentHepatol. 2012;36(6):554-560.

  37. A possible explanation: Insulin resistance and hyperglycemia develops primarily in presence of sustained fructose exposures associated with changes in body composition. Tappy L. Does fructose consumption contribute to non-alcoholic fatty liver disease? Clinics Res GastroentHepatol. 2012;36(6):554-560.

  38. Bravo et al. Consumption of sucrose and high fructose corn syrup does not increase liver fat or ectopic fat deposition in muscles. ApplPhysiolNutrMetab. Doi: 10.1139/apnm-2012-0322. Objective To evaluate the effect of the addition of commonly consumed fructose/glucose containing sugars in the usual diet on liver fat and intramuscular adipose tissue (IMAT) Materials & Methods • 64 adults, consumed low fat milk sweetened with either HFCS or sucrose at different levels for 10 weeks • CT: liver fat • MRI: IMAT

  39. Results • No increase in liver fat or IMAT Authors Conclusions • When fructose consumed as part of a typical diet as sucrose or HFCS, liver fat storage is not promoted. Limitations?

  40. Sugar sweetened beverages Increased soda consumption in US children and adults ~175 calories/day. Duffeyet al. Shifts in patterns and consumption of beverages between 1965 and 2002. Obesity. 2007;15:2739–2747. Caramel coloring (contains advanced glycation end products) which can increase insulin resistance and inflammation. Gaby AR. Adverse effects of dietary fructose. Altern Med Rev. 2005;10:294–306.

  41. Zelber-Sagi S et al. Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population based study. J Hepatol. 2007;47:711–717. • cross-sectional study of a sub-sample (n = 375) from the Israeli National Health and Nutrition Survey (1999-2001). • semi-quantitative FFQ, abdominal US, biochemical, anthropometrics • The NAFLD group consumed: • almost twice the amount of soft drinks (P = 0.03) • 27% more meat (P < 0.001) • Subjects with NAFLD had a higher intake of soft drinks • Higher intake of soft drinks was associated with an increased risk of NAFLD, independent of age, gender, BMI, and total calorie intake.

  42. Polyunsaturated n-3 and n-6 fatty acids Animal models: reduction of steatosis Studies in adults with NAFLD: improved lipid profiles, reduced inflammation 2 gm fish oil (6 mos, n=40 adults) reduced serum TG, liver enzymes, and TNF-α; regression of steatosis (US) Spadaro L et al. Omega-3 polyunsaturated fatty acids: a pilot trial in non-alcoholic fatty liver disease. J Hepatol. 2006;44:S264

  43. Treatment Bariatric surgery Lifestyle Interventions Physical activity Weight loss Pharmacologic agents Metformin Vitamin E, omega 3 fats

  44. Physical activity Exercise alone increases LBM, reduces adipose, improves insulin resistance.

  45. Weight loss As little as a 7-10% reduction in total body weight (regardless of diet composition) may reduce hepatic fat accumulation in obese adults and adolescents. Promrat K et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis (NASH). Hepatology. 2010;51(1):121-129.

  46. Reduction in intrahepatic fat has been reported to occur in obese adults with type 2 diabetes in as little as the two weeks of dietary restriction + exercise. Tamura Y et al. Effects of diet ad exercise on muscle and liver intracellular lipid contents and insulin sensitivity in type 2 diabetic patients. J EndocrinolMetab. 2005;90(6):3191-3196. Rapid weight loss >1.6 kg per week is not recommended due to the risk of liver damage.

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