Pediatric Non-Alcoholic Fatty Liver Disease: Implications for the RD Dr. Deborah Cohen, DCN, RD Dr. Jane Ziegler, DCN, RD, LDN October 20, 2013

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1 DISCLOSURE Dr. Jane Ziegler Pediatric Non-Alcoholic Fatty Liver Disease: Implications for the RD Dr. Deborah Cohen, DCN, RD Dr. Jane Ziegler, DCN, RD, LDN October 20, 2013 Nothing to disclose OBJECTIVES At the end of this presentation, the attendee should be able to: Identify the incidence and prevalence of pediatric non-alcoholic fatty liver disease Identify the major risk factors that contribute to the development of NAFLD Interpret the biochemical and anthropometric features of pediatric NAFLD Describe and apply the recommendations for preventing and treating pediatric NAFLD based on the current research evidence. NAFLD Background Rapid emergence to become the most common form of chronic liver disease Rapid, widespread increase in overweight and obesity A spectrum of steatotic liver pathologies Associated with severe metabolic impairments: Abdominal obesity, HTN, dyslipidemia, insulin resistance, increased waist circumference Increased risk of CVDs, T2DM and metabolic syndrome Can evolve to cirrhosis and heptocellular carcinoma and resultant liver transplantation Genetic and environmental factors involved in development and progression of disease Natural history poorly understood, large, long term studies are limited in children Long term outcome not known, but likely to be worse due to anticipated lifespan of typical adolescent Risk Factors Associated with NAFLD Conditions with established association Truncal obesity and insulin resistance T2DM Dyslipidemia - hypertriglyceridemia Metabolic syndrome Conditions with emerging association Polycystic ovary syndrome Hypothyroidism Obstructive sleep apnea Hypopituitarism Hypogonadism Pancreatico-duodenal resection Masuoka HC, Chalasani N. Nonalcoholic fatty liver disease: an emerging threat to obese and diabetic individuals. Ann N Y Acad Sci. 2013;1281: Pediatric Non-Alcoholic Fatty Liver Disease: Prevalence Most prevalent form of liver disease in children Difficult to estimate prevalence: influenced by the population, lifestyle habits, and diagnostic method of detection. Incidence mirrors global increase in obesity Adolescents - more than doubled over the past 3 decades 3.9% ( ) 10.7% ( ) Increases occurred among all Race/ethnic subgroups Males and females Those already obese Increased by 50% among male adolescents 1 Children Estimated to be between 3 and 10% 1. Welsh JA et al. Increasing prevalence of fatty liver disease among United States Adolescents, to J Peds 2013;162(3): eds

2 Prevalence cont. More common in boys than girls (2:1) Ethnicity More common among Hispanic than Caucasian Differences may be due to IR, visceral adiposity at equivalent BMI, socioeconomic factors (diet, exercise choice, environment) African-American children may present with more risk factors (obesity, IR, T2DM) rate of NAFLD is lower. Asians > Hispanics > Caucasian > African - Americans Estimate of Pediatric Obesity Prevalence: mages/news_and_events/news/winter08_tt2. gif Mencin AA, Lavine JE. Advances in pediatric nonalcoholic fatty liver disease. Pediatr Clin N Am 2011;58: Natural History of Pediatric NAFLD Poorly understood Case reports of rapid progression to cirrhosis 1 A-Kader et al studied 106 NAFLD children (mean age of 13.4 years) 2 Baseline liver biopsy for confirmation of NAFLD 18 repeat biopsies, mean 28 months 8 no change in fibrosis 7 with worsening fibrosis 3 patients with improved fibrosis (ALL lost weight) 1.Molleston JP et al. Obese children with steatohepatitis can develop cirrhosis in childhood. Am J Gastroent. 2002;97(9): A-Kader HH et al. Nonalcoholic fatty liver disease in children: a single center experience. Clin Gatroent & Hepatol. 2008:6: SCALE Study 742 children 2-19 years Traumatic death (MVA, accidents, homicide, suicide) Exclusions factors that potentially influence liver histology Although previously healthy 9.6% had fatty infiltration of liver NAFLD more prevalent among older, overweight, known associations with IR More common among Hispanics (11.8% vs 1.5% in Blacks, 8.6% in non-hispanic whites) More common among males 11.1% vs. 7.9% females Liver inflammation (steatohepatitis, NASH) found in 23% of children with NAFLD and 3% of total biopsies Data is consistent with smaller studies and confirmed that Hispanics are more likely to develop advanced liver fibrosis. Schwimmer JB et al, Pediatrics 2006;118: Progression of NAFLD Mechanisms of Pathogenesis Defects at multiple levels tip metabolic balance towards hepatic fat accumulation Excessive substrate to liver Intrahepatic disparity between lipid synthesis and oxidation Inadequate export to peripheral tissues Adipose Tissue Insulin Resistance (IR) Metabolic Syndrome Change in lipogenesis Mitochondrial dysfunction Two-hit model McCullough AJ. J Clin Gastroenterol; 2006;40:S17-S29 Inflammation 2

3 Obesity and Multi-Organ Dysfunction Fat mass Increase in fat mass assumes great significance Adipocyte is an endocrine organ not just storage depot As a result of expansion of fat mass and inflammation and adipocyte differentiation a variety of cytokines are produced Increased production of Leptin, resistin, angiotensinogen, TNF-α, and FFAs Decreased production of Adiponectin Cusi K. Gastroenterology 2012;142: McCullough AJ J Clin Gastroenterol. 2006;40:S17-S29 Adipose Tissue and Metabolic Dysregulation Insulin resistance (IR) Critical to pathogenesis of pediatric NAFLD Present in ~ 95% of biopsy proven NAFLD Associated with multiple metabolic abnormalities Metabolic syndrome Abnormal glucose metabolism Reproductive abnormalities in females Cutaneous abnormalities Acanthosis nigricans Skin tags Schwimmer JB J Peds 2003; Cusi K. Curr Diab Rep. 2010;10: Insulin Resistance Impaired suppression of lipolysis in adipose tissue Increased levels of circulating nonesterified or free fatty acids (FFAs) Excess saturated FFAs overwhelm capacity of liver to esterify FFAs Reduction of glucose uptake in skeleton muscle hyperglycemia and hyperinsulinemia Hyperinsulinemia stimulates liver to synthesize TGs and incorporation of TGs into VLDL for secretion into systemic circulation Lipotoxicity is induced Magnitude of the TGs likely serves as biomarker for flux of FFAs delivered to liver Disease severity is directly proportional to level of circulating FFAs Cusi K Gastroenterology 2012;142: Pathophysiology of NAFLD and Insulin Resistance McCullough AJ. J Clin Gastroenterology 2006;40:S17-S29 3

4 NAFLD and Metabolic Syndrome NAFLD closely associated with Abdominal obesity Atherogenic dyslipidemia Hypertension Insulin resistance Impaired glucose tolerance All features of MetS Emerging evidence for relationship in children Compelling data supports a significant relationship between NAFLD and MetS which is not explicable merely by coexistence of overweight or obesity Supports the hypothesis that fat accumulation in liver has important role in pathogenesis of other obesity related conditions Cusi K Clin Liver Dis 2009;13: Homeostasis of Hepatic Lipids Result of balance of several pathways Fatty acid uptake De novo synthesis Oxidation VLDL secretion Fatty Acid Uptake in liver Four FFA transporters CD36, FABPpm, SLC27A2, and SLC27A5 - Mediate FFA uptake FA uptake depends on the concentration of the plasma FA and capacity of the uptake transporter systems Very elevated plasma FFA concentration in NASH suggest transport systems are saturated Capacity (quantity) of FFA transporters is rate-limiting factor Increased expression of all these transporters has been observed in NASH liver with CD36 exhibiting the highest increase De Novo synthesis Rate limiting reaction is the carboxylation of acetyl-coenzyme A (CoA) Catalyzed by acetyl-coa carboxylase β (ACACB) Elevated gene expression was also observed for genes involved in fatty acid de novo synthesis Results in up-regulation of de novo FA synthesis FA oxidation NASH livers feature elevated FA oxidation an effort to reduce lipid load toward a normal level FA oxidation appears to be increased in NASH but to a level insufficient to compensate for the import/synthesis of FA. VLDL secretion Dysfunctional VLDL synthesis and release might be a key factor in NASH pathogenesis. 4

5 Altered Lipid Metabolism Majority of hepatic lipids in NAFLD stored as TG Circulating FFAs from adipose tissue critical role in steatosis development Contribute to 60% of hepatic fat content De novo lipogenesis ~ 30% of stored hepatic fat Dietary lipid ~ 10% of lipid content Decreased export of TGs via VLDLs and decreased oxidation of FAs (at level of mitochrondria) may play a role in genetic susceptibility FFAs increased in NASH, correlate with disease severity Saturated FFAs more hepatotoxic than unsaturated FFAs Pathophysiology from Adipose Tissue to NASH Adipose tissue IR creates a lipotoxic environment supplies liver with FFA and compensatory hyperinsulinemia stimulates lipogenesis. Development of hepatic steatosis and of a lipid pool from where lipid-derived toxic metabolites may activate inflammatory pathways Progression from simple steatosis to active necroinflammation depends on ability of liver to adapt to longstanding TG accumulation Failure to adapt FFA-induced lipotoxicity with mitochrondrial dysfunction, ER stress, ROS formation and chronic necroinflammation Fibrosis Progression of NAFLD NAFLD and CVD Data on prognosis and clinical complications of NAFLD in children are limited Relationship between obesity and atherosclerosis development has been evaluated in many studies In an autopsy study (Schwimmer 2003) with 817 children (2-19 years) who died of external causes Atherosclerosis was increased by a factor of 2 among those with NAFLD Fatty liver present in 15% Mild atherosclerosis in 21% Moderate to severe atherosclerosis in 2% For obese subjects the odds of atherosclerosis was more than 6 times higher in children with NAFLD Cusi K Clin Liver Dis 2009;13: Mechanisms linking NAFLD to atherosclerosis Still poorly understood. Increased visceral adipose tissue IR Inflammation with resultant proinflammatory cytokines NAFLD may act as stimulus for additional IR and dyslipidemia accelerating atherosclerosis Impaired ability of liver to export TG and cholesterol esters. Impaired VLDL secretion result in increased levels of atherogenic TG and cholesterol rich remnant particles. Cardiovascular Rick Factors Coexisting with NAFLD Cusi K. Gastroenterology 2012;142:

6 The two hits hypothesis Giorgio V et al. Pediatric non alcoholic fatty liver disease: old and new concepts on development, progression, metabolic insight and potential treatment targets BMC Pediatrics 2013;13:4050 Cusi K Clin Liver Dis 2009;13: Genetic Predisposition Evidence suggests that only a minority of patients with NAFLD progress to NASH Disease progression is likely to depend on complex interplay between environmental and genetic predisposition 2 recent cohort studies and one community-based study (different ethnicities) estimated the heritability of NAFLD at ~ 35-49% of the total predisposition, after adjusting for age, gender, race and BMI Genetics Supported by increased prevalence in boys, certain ethnicities and races and family clustering Family Studies Rates of NAFLD higher in family members of children with a diagnosis of NAFLD Important to screen family members In children with Bx proven NAFLD, 59% siblings and 78% parents evidence of fatty liver on MRI Interethnic variations NAFLD and NAFLD-related cryptogenic cirrhosis Hispanic Potential Genetic Contributors Susceptibility to NAFLD/NASH associated with genes influencing: Regulation of FA metabolism (hepatic lipid synthesis, storage and export) Insulin sensitivity Immune regulation Oxidative stress Fibrosis development Genetic factors may predispose certain individuals to environmental influences that promote the development of NAFLD Alisi A, Nobili V. Nonalcoholic liver disease in children now: Lifestyles changes and pharmacologic interventions.nutrition. 2012;28: Common Variants Associated with NAFLD Gene Protein Function Allele variant PNPLA3 Patatin-like phospholipase domain TG hydrolase? rs containing protein 3 l148m PPP1R3B Glycogen binding subunit of Enhances protein phosphatase 1 rs protein phosphatase 1 activatons of glycogen synthase NCAN Neurocan Unknown rs P925 GCKR Glucokinase regulatory protein Negative regulator of rs glucokinase P446L LYPLAL1 Lysophospholipase-like 1 Unknown rs APOC3 Apolipoprotein C3 Limits hydrolysis of TG in rs circulating lipoproteins rs Cohen JC et al. Human fatty liver disease: old questions and new insights. Science. 2011;332:

7 PNPLA3 (Adiponutrin) Consistently associated with NAFLD; steatosis, elevated ALT and NASH Relationship with hepatic TG content Accounts for ~70% of differences in frequency of hepatic steatosis between Hispanics, African Americans and individuals of European descent Homozygotes for the risk alelle PNPLA3 have ~ 2 fold higher hepatic TG content (magnitude of effect is strongly influenced by adiposity and IS) PNPLA3 is highly expressed in adipose tissue and liver Other genomic regions are associated with hepatic steatosis Elucidation of the roles of these genes may provide new insights into metabolic pathways that contribute to NAFLD Pediatric Non-Alcoholic Fatty Liver Disease: Implications for the RD Deborah Cohen, DCN, RD Assistant Professor University of New Mexico October 20, 2013 Cohen JC et al. Human fatty liver disease: old questions and new insights. Science. 2011;332: DISCLOSURE Nothing to disclose Deborah Cohen OBJECTIVES 1. Identify the incidence and prevalence of pediatric non-alcoholic fatty liver disease (NAFLD) in the United States. 2. Identify the major risk factors that contribute to the development of NAFLD. 3. Interpret the biochemical and anthropometric features of pediatric NAFLD. 4. Describe and apply the recommendations for preventing and treating pediatric NAFLD, based on the current research. Features Histologic Progression of NAFLD Histological classification of steatosis Biochemical insulin resistance hypertriglyceridemia elevated ALT Anthropometrics overweight/obese abdominal obesity Clinical Acanthosis nigricans 7

8 Histologic Features Histologic Steatosis Grades Fatty liver macrovesicular steatosis Nonalcoholic steatohepatitis (NASH) fat, inflammation, fibrosis Grade 0: normal Grade 1: mild Grade 2: moderate Grade 3: severe <5% of hepatocytes affected 5-33% of hepatocytes affected 34-66% of hepatocytes affected >67% of hepatocytes affected Cirrhosis Biochemical Features Elevated serum TG >150 mg/dl Acceptable levels for children and adolescents ages 2-19 Total Cholesterol <170 mg/dl Biochemical Elevated ALT No universal standards for children U/L commonly used cutoff for abnormal ALT HDL-C LDL-C TG >45 mg/dl <110 mg/dl < 115 mg/dl (young adults) ALT may be normal Current standards controversial range may be too high Biochemical SAFETY Study Schwimmer et al. SAFETY study: alanine aminotransferase cutoff values are set too high for reliable detection of pediatric chronic liver disease. Gastroenterol. 2010;138: Data from National Health and Nutrition Examination Survey (NHANES, ) and 43 acute care children s hospitals in the U.S. Median upper limit at children s hospitals: 53 U/L NHANES: 95 th percentile healthy weight, metabolically normal, liver disease free: boys 25.8 U/L girls 22.1 U/L Biochemical U.S. data regarding prevalence of elevated ALT >30 U/L in adolescents: Caucasian: 10.1% Mexican American: 15.2% Black: 9.7% Welsh JA et al. Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, to J Pediatr. 2013;162:

9 Biochemical Insulin Resistance Homeostatic Model Assessment Insulin Resistance (HOMA-IR) Optimal <3 fasting glucose (mg/dl) fasting insulin (μu/ml) 405 Biochemical Insulin Resistance Fasting Serum insulin (μiu/ml) Tanner Stage I (pre-pubertal) Tanner Stage II Tanner Stage III May be dependent on ethnicity Cytokines Adiponectin Inversely associated with obesity, BMI, metabolic syndrome, NAFLD, visceral adiposity Leptin Elevated levels associated with NAFLD, early stage NASH TNF-α Elevated levels with insulin resistance, metabolic syndrome IL-6 Implicated in insulin resistance, NASH IL-10 Inverse correlation with metabolic syndrome Biochemical Scores for Pediatric NAFLD Pediatric NAFLD Fibrosis Index (PNFI) Based on age, WC, TG Pediatric NAFLD Histological Score (PNHS) Based on Brunt's histological score Biochemical Novel Noninvasive Biomarkers Cytokeratin 18 Marker of hepatic apoptosis Plasma levels correlate with liver damage; independently predict NASH Not available commercially 9

10 Anthropometric Features Abdominal obesity Waist circumference (WC) surrogate marker for visceral adiposity Anthropometric Visceral adiposity & fatty liver disease Visceral Fat: more abundant cytokine expression compared to other fat depots Visceral fat associated with elevated ALT and IR, hypoadiponectinemia Strong association between higher trunk fat mass and elevated ALT levels Anthropometrics Pediatric Waist circumference percentiles: Fernandez JR, et al. Waist circumference percentiles in nationally representative samples of African-American, European-American, and Mexican-American children and adolescents. J Pediatr 2004;145(4): Anthropometrics Mager DR et al. Anthropometric Measures of visceral and subcutaneous fat are important in the determination of metabolic dysregulation in boys and girls at risk for nonalcoholic fatty liver disease. Nutr Clin Pract. 2013;28: Objectives To describe and contrast body composition and its interrelationships to biomarkers of liver disease, IR, lipids and cytokine expression in youth with and without NAFLD. N = 44 children and adolescents n=16 with NAFLD n=11 obese n=17 lean controls Age 7-18 years Anthropometrics: height, weight, BMI, WC, air displacement plethysmography (ADP), skinfolds Biochemical: fasting lipids, ALT, hs-crp, HOMA-IR, leptin, adiponectin, TNF-α, IL-6, IL-10 10

11 Results WC >97 th percentile in boys and girls with NALFD No differences in %FM, FFM, total BF as measured by ADP, skinfolds Biochemical NAFLD/obese: higher plasma insulin, TG, CRP NAFLD: higher ALT Obese: higher leptin Results Relationships Strong correlation between ALT and skinfolds (subscapular, abdominal, sum of trunk), WC and waist- toheight ratio (WHTR) Strong correlation between anthropometric and skinfolds: HOMA-IR, TG, HDL (inverse) and IL-10 (inverse) Strong correlation between somatotype & markers of visceral fat (WC, WHTR) for endomorphic, ectomorphic and mesomorphic somatotypes Anthropometrics Conclusions Obese children with NAFLD: higher levels of visceral adiposity, especially in boys which was also correlated with IR, TG, LDL and inflammatory cytokines Overweight and Obesity overweight >85 th percentile obese >95 th percentile Abdominal obesity is more closely associated with NAFLD than BMI Clinical Features Acanthosis nigricans associated with insulin resistance may be difficult to detect in darker skinned individuals Clinical Features Vague symptoms nausea, fatigue, right upper quadrant (RUQ) pain Hepatomegaly on palpation may be difficult to assess in obese individuals 11

12 Diagnostic Imaging and Procedures Computerized Tomography (CT) Ultrasound Magnetic Resonance Imaging (MRI) Magnetic Resonance Spectroscopy (MRS) Liver Biopsy Diagnostic flowchart based on the ESPGHAN practice guideline for NAFLD. Alisi A et al. Curr Opin Gastroenterol. 2013;29(3): Diagnostic Imaging Computerized Tomography (CT) Sensitivity low; Specificity high Exposure to ionizing radiation Diagnostic Imaging Ultrasound Feasible, available at most institutions Relatively inexpensive No exposure to ionizing radiation Diagnostic Imaging Ultrasound Low sensitivity & specificity sensitivity 60-90% specificity 66-95% Cannot detect steatosis <20% Operator dependent Limited beam penetration in obese individuals Diagnostic Imaging Magnetic Resonance Imaging (MRI) No exposure to ionizing radiation Able to quantify fat Can differentiate the different types of fat (subcutaneous versus visceral adipose) 12

13 Diagnostic Imaging Magnetic Resonance Imaging (MRI) Long scan times difficult for young children Weight limits (<440 pounds) Requires highly trained individuals to read scans Expensive Diagnostic Imaging Magnetic Resonance Spectroscopy (MRS) Relies on the concept of chemical shift refers to the differences in the frequencies given off by the lipid and water components of cells. Gold standard (imaging) Sensitivity 95% Specificity 95% Requires trained individuals to read scans Not readily available MRI of the liver Ultrasound of the liver Diagnostic Procedure Liver Biopsy Definitive diagnosis Invasive Surgical risks Expensive Not warranted for use as a screening tool at this time CT of the liver Nutritional Factors CHO fructose Fat omega 3 fatty acids Antioxidants vitamin E Nutritional Factors Dietary Characteristics of Children & Adolescents with NAFLD Overconsumption fructose soft drinks meat saturated fat cholesterol Low consumption fiber fish omega 3 fats vitamin E Zelber-Sagi et al. Nutrition and physical activity in NAFLD: An overview of the epidemiological evidence. World J Gastroenterol 2011; 17(29):

14 Nutritional Factors Adolescents consume ~155 calories per day from sugar sweetened beverages ( NHANES). Nutritional Factors Role of CHO Fructose Increases serum TG Increases insulin resistance Increases hepatic de novo lipogenesis Increases visceral adiposity (adult & animal models) May alter the gut microbiome Kit BK et al. Trends in sugar-sweetened beverage consumption among youth and adults in the United States: AJCN 2013;98(1): Vos MB, Lavine JE. Dietary fructose in nonalcoholic fatty liver disease. Hepatology 2013;57: Dietary fructose in nonalcoholic fatty liver disease Mager DR et al. The effect of a low fructose and Low glycemic index/load (FRAGILE) dietary intervention on indices of liver function, cardiometabolic risk factors, and body composition in children and adolescents with nonalcoholic fatty liver disease (NAFLD). J Parenter Enteral Nutr August 2013 doi: / N=26 children (NASH n=4, n=8 simple steatosis, n=14 healthy lean controls) Age 7-18 years Anthropometrics (wt, BMI, skinfolds) Labs (lipid panel, cytokines, HOMA-IR, ALT) Diet assessment (3 day food records baseline, 3 & 6 months) Physical activity assessment Diet Intervention: Low GI (45-55), GL (<80) and fructose (<7% of energy intake) Vos MB, Lavine JE. Hepatology 2013;57(6): DOI: /hep Results No significant differences in weight, BMI z scores Significant reductions in BP % body fat, ALT, HOMA-IR at 3 and 6 months Modest reduction in fructose, GI, and GL result in improvements in plasma markers of liver dysfunction and cardiometabolic risk. Nutritional Factors Omega 3 Fats Meta analysis Inclusion criteria: Adults > 18 years Outcomes: liver biopsy, MRS, ultrasound, ALT 9 studies met criteria Dose Median: 4 gms/day (range gms/day) Median duration: 6 months 14

15 Results Reduction of steatosis Decrease in ALT Omega 3 fats offer a potential pharmacological treatment of NAFLD ---in addition to diet and lifestyle modifications Conclusions Current data are not sufficient to set optimal dose More RCT s needed Parker HM et al. Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol 2012;56: Nutritional Factors Vitamin E Antioxidant Reactive oxygen species (ROS) scavenger ROS overproduction enhances lipid peroxidation and increases production of cytokines, including TNF-α Lipid peroxidation products and cytokines damage mitochondrial DNA, generate more ROS production potentially inducing apoptosis, inflammation and liver fibrosis Decreased intake and levels in NASH patients compared with healthy controls Animal models Decreased oxidative stress in diet induced obese rats and improvement of antioxidant activity after Vitamin E supplementation. Shen XH et al. Vitamin E regulates adipocytokine expression in a rat model of dietary-induced obesity. Exp Biol Med 2010;235: Vitamin E supplementation provided protection against bile induced hepatocyte injury in leptin-deficient Zucker rats. Soden JS et al. Subcutaneous vitamin E ameliorates liver injury in an in vivo model of steatocholestasis. Hepatology 2007;46: Human studies Conflicting results small sample sizes, varying Vitamin E formulations 2 major RCT s PIVENS Study, TONIC Study Vitamin E PIVENS Trial Sanyal AJ et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. NEJM 2010;362(18): N=247 adults with NASH (multicenter) Random assignment: 30 mg pioglitazone (n=80) 800 IU vitamin E (n=84) Placebo (n=83) 96 weeks 15

16 Primary outcome Improvement in histologic findings Secondary outcomes Changes in overall NAFLD activity score, ALT levels, anthropometric findings, IR, lipid profiles Results Vitamin E vs. placebo: significant improvement in NASH, steatosis, ALT No benefit of pioglitazone over placebo for primary outcome; significant benefits observed for some secondary outcomes reduction in steatosis, inflammation, improvements in IR, ALT (though subjects did experience weight gain) TONIC Trial Lavine JE et al. Effect of Vitamin E or Metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: The TONIC randomized controlled trial. JAMA 2011;305(16): Objective: To determine whether children with NAFLD would improve from therapeutic intervention with vitamin E or Metformin. Design, Setting, and Patients: Interventions Daily dosing of 800 IU of vitamin E (n=58) 1000 mg of Metformin (n=57) Placebo (n=58) 96 weeks Randomized, double-blind, double-dummy, placebo-controlled clinical trial (multicenter) N = 173 (age 8-17 years) Biopsy-confirmed NAFLD Sept Mar 2010 Main Outcome Measures: Sustained reduction in ALT defined as 50% or less of the baseline level or 40 U/L or less at visits every 12 weeks from 48 to 96 weeks of treatment. Improvements in histological features of NAFLD and resolution of NASH were secondary outcome measures. Conclusions: Vitamin E Vos MB, et al. Correlation of vitamin E, uric acid, and diet composition with histologic features of pediatric NAFLD. JPGN 2012;54: Objectives To examine dietary data from a large cohort with NAFLD patients and correlate diet variables with specific histopathologic features Neither vitamin E nor Metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with NAFLD. 16

17 NAFLD and NASH diagnosed via liver biopsy Block FFQ (77 food items) N=149 children (73% boys), 53% Hispanic, mean age 13±2.6 years, mean BMI z-score 2.3±0.4 Results Mean energy intake lower than previously reported (NASH: calories; No NASH: 1526 calories) Mean CHO intake: 50.4% of total calories Mean fat intake: 35% of total calories Results (continued) Vitamin E was lower in children with higher grade steatosis (P=0.05) No differences in reported SSB intake between those with NAFLD and NASH Uric acid, a surrogate marker of dietary fructose, was significantly increased in those children with NASH Conclusions More studies that evaluate diet and NAFLD are needed Treatment Lifestyle Interventions physical activity, weight loss Pharmacologic Agents insulin sensitizers Probiotics Physical Activity Reduces adipose Increases lean body mass Improves insulin resistance Role of Bariatric Surgery Diet 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. Weight loss Reduction in intrahepatic fat has been reported to occur in obese adults with type 2 diabetes in as little as 2 weeks of dietary restriction + exercise. Tamura Y et al. Effects of diet and exercise on muscle and liver intracellular lipid contents and insulin sensitivity in type 2 diabetic patients. J Endocrinol Metab 2005;90(6):

18 Pharmacologic Agents Rapid weight loss >1.6 kg per week is not recommended-- risk of liver damage Insulin sensitizers Metformin Early trials: reduction in IR, ALT Trials have found only modest improvements in steatosis and inflammation Meta analysis: no major significant improvements in liver histology or aminotransferases Safety profile in children, adolescents?? Vernon G et al. Systematic review: the epidemiology and natural history of nonalcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34: Probiotics Gut Liver Axis Liver: major filter organ, 1 st line of defense Liver is constantly exposed to gut-bacteria bacterial products and metabolites Gut microbiome alterations increased mucosal permeability Possible Mechanisms: Gut is the primary source of Lipopolysaccharide (LPS) Endotoxin in gram negative bacteria produced upon bacterial death Translocated through intestinal capillaries to target tissues LPS, through activation of TLR-4 inflammatory signaling cascade leads to IR and TNF-α mediated inflammation High fat intake may increase intestinal translocation of endotoxin; reduce intestinal content of Bifidobacteria Disturbance in choline metabolism (VLDL assembly lipid export from the liver) Changes in bile acid patterns Animal studies small intestinal bacterial overgrowth (SIBO) associated with NASH histology Human studies NAFLD, NASH associated with SIBO and increased permeability Antibiotic therapy improves steatosis (animal and human studies) Obese individuals have different gut bacteria compared to lean individuals & diet induced weight loss affects gut bacteria composition 18

19 Humans 4 pilot studies to date evaluating effects of probiotics & NAFLD Short duration (2-4 months), small sample sizes Loguercio C et al. Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol 2005;39(6): Loguercio C et al. Gut liver axis: a new point of attack to treat chronic liver damage? Am J Gastroenterol 2002;97(8): Aller et al. Effect of a probiotic on liver aminotransferases in nonalcoholic fatty liver disease patients: a double blind randomized clinical trial. Eur Rev Med Pharmacol Sci. 2011;15(9): Solga et al. The effect of a probiotic on hepatic steatosis. J Clin Gastroenterol. 2008;42(10): Probiotics as Tx of NAFLD No RCT s therefore, currently Cochrane and ESPGHAN do not support the use of probiotics Probiotics well tolerated and may improve liver function tests (ALT) Role of Bariatric Surgery Assessment Lap bands not FDA approved for <18 years American Academy of Pediatrics Criteria (2004): failed >6 months of organized attempts at weight management attained or nearly attained physiologic or skeletal maturity BMI >40 (with serious obesity related conditions) or have a BMI >50 with less severe obesity-related problems Proposed as a potential treatment for NASH in adolescents Inge TH et al. Bariatric surgery for severely overweight adolescents: concerns and recommendations. Pediatrics 2004;114(1): Anthropometrics Biochemical height, weight, BMI calculation waist circumference skinfolds (?) ALT Lipid panel HDL, LDL, TG FBG Fasting Serum insulin (μiu/ml) Tanner Stage I Tanner Stage II Tanner Stage III HOMA-IR 19

20 Clinical Acanthosis nigricans PMH: PCOS type 2 diabetes insulin resistance Diet FFQ questions SSB, fruits, vegetables 3, 5 day food records (if possible) <12 years: caregiver Assess intake of sugar sweetened beverages sodas, sweetened waters, teas, flavored milk, fruit juices, fruit drinks, energy drinks, sports drinks, etc Implications for Dietetics Professionals No consensus as to what diet or lifestyle approach is most effective due to lack of scientific evidence. The type of fat (saturated vs. PUFA vs. omega 3) Fiber intake Universally recommended Omega 3 fats Fruits, vegetables High fiber Vitamin E sources Reduce intake of saturated fats/ simple CHO/sweetened beverages Weight loss Physical activity Lifestyle Recommendations Concluding Statements Prevention of overweight and obesity are KEY. In obese children with risk factors suggestive of Metabolic Syndrome, NAFLD should also be suspected. 20

21 NAFLD Case Study - JJ Patient Profile Adolescent male Birth date: 3/27/1999 Current Age: ~14.5 years Race - Hispanic FMH: strong FH of HTN, dyslipidemia and obesity, mother T2DM PMH: BW 7.5#, FFT at 1 yr of age (15#) Medical Diagnoses: Obesity, HTN, Acanthosis nigricans, dyslipidemia, ALT, OSA, Asthma, Allergies Healthy Fit Clinic Visit 6/ years old Progressively increasing BMI Diet: +SSB, 2 svgs F/V/D, B/L school, starch, Ø fast food Diet per mom: CHO, Salt Screen time: ~ 2-3 hours/day Exercise per mom: ~ 3-4 hours/day of play Meds: albuterol, flovent, Flonase BP: 119/71 4+ acanthosis nigricans Readiness to change: 10 mother and JJ Physical exam WNL Referral to RD Assessment and Intervention Initial RD Visit Excessive calorie intake related to inadequate knowledge as evidenced by BMI z-score. Treatment: Nutrition education with RD Salt restriction F/V to 5 x/d Grain intake SSB physical activity BP monitoring screen time Healthy Fit Clinic Visit 11/2009 Screen time 3 hours/day 12 oz. diet soda/d, increased intake of water Increased intake of F/V Portion sizes more appropriate Appropriate snack choices Exercise: Wrestling program at school 3 x week Aggressive nutrition and exercise interventions by RD Healthy Fit Clinic 03/2010 Following lifestyle recommendations by MD and RD Continues with Wrestling team activities 3 x week with weekend competitions Meds remain the same BMI z-score decreasing BP WNL ALT decreased Improvement in dyslipidemia Continue with lifestyle interventions and RD follow-up Healthy Fit Clinic 09/2010 Multiple visits to RD prior to clinic visit Exercise: water polo, Zumba (wrestling to start again soon) Diet inconsistent was in Mexico for two months visiting family BMI z-score continues to improve Slight increase in LDL and ALT from last visit Reinforced lifestyle interventions 21

22 Healthy Fit Clinic 03/2011 Screen time < 1 hour/day Continues with lifestyle interventions Wrestling activities just ended Increase in BMI z-score ALT WNL, TG and LDL elevated Review of exercise and nutrition recommendations Coach of wrestling team had encouraged JJ to gain weight to compete at higher weight level MD contacted coach to discuss health concerns Healthy Fit Clinic 08/2011 Spent summer in Mexico Swimming 2-3 hours/day, Zumba classes, running and biking Wrestling to start in one month Dietary intake altered over the summer to include more sweets and higher carbohydrate containing foods. Improvement in ALT, HTN Healthy Fit Clinic 08/2012 Continues with wrestling and lifestyle interventions Resolved dyslipidemia Resolved suspected NAFLD Screen time < 1 hour/day Date Age Height (cm) 11/ (-0.055) 2/ (+0.27) 6/ (+0.17) Weight (kg) 54 (+2.327) 60 (+2.50) 58.5 (+2.31) BMI/ WC (cm) 29 (+2.4) 30.6 (+2.46) 30.5 (+2.36) ALT (U/L) TC (mg/ dl) HDL (mg/ dl) (borde rline) LDL (mg/ dl) TG (mg/ dl) FBG (mg/dl) Insulin (mcu/ml) 3/ (-0,10) 60.1 (+2.14) 29.6/90 (+2.31)/ (>90 th ) / (+0.00) 52 (+1.41) 29.09/92 (+1.75) /(>90 th ) / (+0.02) 64 (+1.95) 28.83/93 (+2.16) /(>90 th ) / (-0.83) 68.7 (+1.65) 29.46/95 (+2.09)/ (>90 th ) HgA1c 5.7 Mean FBG JJ BMI for Age Growth Chart RD Intervention This case demonstrates the impact of RD intervention in a child with obesity, dyslipidemia, elevated ALT and suspected NAFLD, OSA, HTN with resolution of dyslipidemia, decrease in ALT, improvement in HTN and decease in BMI z-score after a period of aggressive nutrition and exercise intervention. 22

23 PRACTICE APPLICATIONS Assessment of anthropometric and biochemical indicators should be conducted to identify those pediatric patients at high risk for NAFLD. Pediatric patients with history of insulin resistance, high waist circumference and high triglycerides are at high risk for NAFLD. Aggressive diet and exercise interventions can reduce the risk of adverse health outcomes associated with NAFLD. 23