26 - World Journal of Gastroenterology

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genesis through the presence of abnormal lipoprotein metabolism, especially during the post-prandial phase [76,77] . Apolipoprotein (APO) B is a large protein involved in the transport of triglycerides and cholesterol from the liver to peripheral tissues. Diminished synthesis of APO B, a rate-determining step in the very low density lipoproteins (VLDL) assembly, would impair the ability of the hepatocyte to export triglycerides and cholesterol esters. Impaired VLDL secretion would also result in increased levels of atherogenic triglyceride- and cholesterol-rich remnant particles. Recent studies have suggested a genetic basis for abnormal lipoprotein metabolism in patients with NAFLD. Two single-nucleotide polymorphisms in the gene encoding APOC3 may be associated with hypertriglyceridemia [78-80] . APOC3 variants C-482T and T-455C lead to increased plasma concentrations of APOC3, which in turn inhibit lipoprotein lipase and triglyceride clearance, thus conferring a predisposition to both fasting and postprandial hypertriglyceridemia due to an increase in chylomicron-remnant particles [81] . THERAPEUTIC APPROACH The only accepted therapy for pediatric NAFLD is lifestyle modification with diet and physical exercise. The close association of NAFLD with MetS and obesity in children provides the rationale for the therapeutic role of weight reduction in the treatment of fatty liver disease. Fortunately, this approach may also be beneficial in improving cardiovascular risk profile. Weight-loss oriented lifestyle interventions in the overweight pediatric population have been shown to increase glucose tolerance and improve the MetS risk factors [82] . In children with presumed NAFLD, several studies demonstrate a normalization of serum ALT associated with weight loss [5,83,84] . However, the relative efficacy of weight loss and degree of weight loss needed to induce histologic improvement in pediatric NAFLD is unknown. Studies in adults with NAFLD suggest that weight loss also leads to significant improvement in liver histology. In particular, a weight loss greater than 5% has been associated with significant improvement in liver histology [85] . There is only one clinical trial using liver histology as the primary end point in children and adolescents with NAFLD [83] . The study demonstrated that 2 years of lifestyle intervention with a diet tailored on individual caloric requirement and increased physical activity was associated with a mean weight loss of approximately 5 kg, resulting in a significant improvement in liver histology as well as in insulin resistance, serum levels of aminotransferases, and lipid levels. No information exists on recommending any type of diet. A low-carbohydrate diet has been shown to lead to a reduction in serum ALT and fatty liver content in adult patients [86] . A randomized controlled study in obese adolescents has demonstrated that a diet based on a reduced glycemic load is more effective than a low fat diet in achieving weight loss [87] , but similar data are not available in children with NAFLD. Current data on the role of a low WJG|www.wjgnet.com Pacifico L et al . Pediatric NAFLD and cardiovascular risk fructose diet in children with NAFLD are inconclusive [71] . A 6-month pilot study in children with NAFLD showed that a low fructose diet was associated with a significant decrease in oxidized LDL-c [88] . However, no effect on serum ALT concentrations was found. N-3 long-chain polyunsaturated fatty acids (LCPUFA) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been reported to control some of the metabolic stigmata of obesity [89] . Dietary N-3 LCPUFA lower blood triglycerides and have anti-inflammatory as well as insulinsensitizing effects [89] . A recent randomised clinical trial has shown that the supplementation of DHA improves liver steatosis and insulin sensitivity in children with NAFLD [90] . Their role in prevention of CVD is also emerging [91] . At this time, however, the available information is insufficient to derive dietary intake recommendations for EPA and DHA [92] . Finally, diet duration and amount of weight loss have not been definitively assessed in children [83,93,94] . A general consensus exists about the key role of physical activity and its synergic effect when combined to diet modifications. Increasing energy expenditure is an additional way to reducing daily calories. Liver biopsy has shown improvement of histologic features in children with NAFLD who were engaged in a moderate daily exercise program (45 min/d aerobic physical exercise) associated to dietary changes [83] . Owing to the likely role of insulin resistance and oxidative stress in the development and progression of NAFLD, most studies on pharmacological treatment have focused on the use of metformin or antioxidants. These drugs have been found to be effective in pilot studies [3] . Recently, in a multicenter, randomized, placebo-controlled clinical trial of treatment with metformin, vitamin E, or placebo for 96 wk in 173 nondiabetic children with histologically confirmed NAFLD, the Nonalcoholic Steatohepatitis Clinical Research Network found that compared with placebo, neither vitamin E nor metformin was associated with a sustained reduction in serum ALT [95,96] . Compared to placebo, vitamin E significantly improved hepatocellular ballooning and NAFLD activity score and, in the subset of children with NASH at baseline, significantly increased resolution of NASH. Metformin had no significant effect on any secondary histologic outcome [96] . Neither vitamin E nor metformin had significant effects on fibrosis, lobular inflammation, or portal inflammation scores. No significant differences in safety were reported between groups [96] . However, the likelihood that vitamin E would need to be taken indefinitely [97] underlines the importance of longterm prospective studies involving patients with NASH to assess the effect of vitamin E on liver-related and cardiovascular mortality [98] . Given the role of obesity in the pathogenesis of NAFLD, bariatric surgery has been proposed as a potential treatment strategy. In obese adult patients, bariatric surgery has been shown to induce weight loss, ameliorate cardiovascular risk factors, resolve hepatic steatosis and, in most studies, inflammation [99-101] . NASH was improved in the majority of affected patients and was intimately associ- 3087 July 14, 2011|Volume 17|Issue 26|
Pacifico L et al . Pediatric NAFLD and cardiovascular risk ated with insulin resistance over both the short and long term [101] . The issue of NAFLD and bariatric surgery in children is complex [71] . Though adolescents are increasingly undergoing surgical treatment of obesity, the guidelines for eligibility are not standardized [102] . In addition, children with a clinical diagnosis of NAFLD are different from those typically undergoing bariatric surgery [103] . Children with a clinical diagnosis of NAFLD tend to be younger and less obese than adolescents undergoing surgical treatment of obesity [103] . Although several studies report resolution or improvement of comorbidities after bariatric surgery in adolescents [104,105] , liver outcome data are needed. In a series of 41 adolescents, Nadler et al [105] reported improvement in liver function enzymes 1 to 2 years after surgery. CONCLUSION The current body of evidence suggests that NAFLD is associated with a significantly greater overall mortality than in the general population, as well as with increased CVD prevalence, independently of classical atherosclerotic risk factors. These observations raise the possibility that NAFLD may be not only a marker but also an early mediator of atherosclerosis. Children with NAFLD may also be at a higher risk for atherosclerosis. Therefore, the rising prevalence of obesityrelated MetS and NAFLD in childhood may lead to a parallel increase in adverse cardiovascular outcomes. In children, the cardiovascular system remains plastic and damagereversible if early and appropriate interventions are established effectively. Therapeutic goals for NAFLD should address nutrition, physical activity and avoidance of smoking to prevent not only end-stage liver disease but also CVD. REFERENCES 1 Barshop NJ, Sirlin CB, Schwimmer JB, Lavine JE. Review article: epidemiology, pathogenesis and potential treatments of paediatric non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2008; 28: 13-24 2 Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346: 1221-1231 3 Loomba R, Sirlin CB, Schwimmer JB, Lavine JE. Advances in pediatric nonalcoholic fatty liver disease. Hepatology 2009; 50: 1282-1293 4 Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics 2006; 118: 1388-1393 5 Franzese A, Vajro P, Argenziano A, Puzziello A, Iannucci MP, Saviano MC, Brunetti F, Rubino A. Liver involvement in obese children. Ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population. Dig Dis Sci 1997; 42: 1428-1432 6 Guzzaloni G, Grugni G, Minocci A, Moro D, Morabito F. Liver steatosis in juvenile obesity: correlations with lipid profile, hepatic biochemical parameters and glycemic and insulinemic responses to an oral glucose tolerance test. Int J Obes Relat Metab Disord 2000; 24: 772-776 7 Tazawa Y, Noguchi H, Nishinomiya F, Takada G. Serum alanine aminotransferase activity in obese children. Acta Paediatr 1997; 86: 238-241 8 Chan DF, Li AM, Chu WC, Chan MH, Wong EM, Liu EK, Chan IH, Yin J, Lam CW, Fok TF, Nelson EA. Hepatic ste- WJG|www.wjgnet.com atosis in obese Chinese children. Int J Obes Relat Metab Disord 2004; 28: 1257-1263 9 Kotronen A, Yki-Jarvinen H. Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol 2008; 28: 27-38 10 Targher G, Bertolini L, Padovani R, Rodella S, Zoppini G, Zenari L, Cigolini M, Falezza G, Arcaro G. Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care 2006; 29: 1325-1330 11 Targher G, Bertolini L, Scala L, Zoppini G, Zenari L, Falezza G. Non-alcoholic hepatic steatosis and its relation to increased plasma biomarkers of inflammation and endothelial dysfunction in non-diabetic men. Role of visceral adipose tissue. Diabet Med 2005; 22: 1354-1358 12 Fracanzani AL, Burdick L, Raselli S, Pedotti P, Grigore L, Santorelli G, Valenti L, Maraschi A, Catapano A, Fargion S. Carotid artery intima-media thickness in nonalcoholic fatty liver disease. Am J Med 2008; 121: 72-78 13 Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363: 1341-1350 14 Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005; 129: 113-121 15 Ekstedt M, Franzén LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, Kechagias S. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006; 44: 865-873 16 Rafiq N, Bai C, Fang Y, Srishord M, McCullough A, Gramlich T, Younossi ZM. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol 2009; 7: 234-238 17 Söderberg C, Stål P, Askling J, Glaumann H, Lindberg G, Marmur J, Hultcrantz R. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010; 51: 595-602 18 Bland J, Skordalaki A, Emery JL. Early intimal lesions in the common carotid artery. Cardiovasc Res 1986; 20: 863-868 19 Stary HC. Lipid and macrophage accumulations in arteries of children and the development of atherosclerosis. Am J Clin Nutr 2000; 72: 1297S-1306S 20 Newman WP, Freedman DS, Voors AW, Gard PD, Srinivasan SR, Cresanta JL, Williamson GD, Webber LS, Berenson GS. Relation of serum lipoprotein levels and systolic blood pressure to early atherosclerosis. The Bogalusa Heart Study. N Engl J Med 1986; 314: 138-144 21 Wissler RW, Strong JP. Risk factors and progression of atherosclerosis in youth. PDAY Research Group. Pathological Determinants of Atherosclerosis in Youth. Am J Pathol 1998; 153: 1023-1033 22 Berenson GS, Srinivasan SR, Bao W, Newman WP, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med 1998; 338: 1650-1656 23 Raitakari OT, Juonala M, Kähönen M, Taittonen L, Laitinen T, Mäki-Torkko, Järvisalo MJ, Uhari M, Jokinen E, Rönnemaa T, Akerblom HK, Viikari JS. Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. JAMA 2003; 290: 2277-2283 24 Magnussen CG, Koskinen J, Chen W, Thomson R, Schmidt MD, Srinivasan SR, Kivimäki M, Mattsson N, Kähönen M, Laitinen T, Taittonen L, Rönnemaa T, Viikari JS, Berenson GS, Juonala M, Raitakari OT. Pediatric metabolic syndrome predicts adulthood metabolic syndrome, subclinical atherosclerosis, and type 2 diabetes mellitus but is no better than body mass index alone: the Bogalusa Heart Study and the Cardiovascular Risk in Young Finns Study. Circulation 2010; 122: 1604-1611 25 Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, 3088 July 14, 2011|Volume 17|Issue 26|
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Page 3 and 4: Robert JL Fraser, Daw Park Jacob Ge
Page 5 and 6: Italy Donato F Altomare, Bari Piero
Page 7 and 8: Fernando Azpiroz, Barcelona Ramon B
Page 9 and 10: S Contents EDITORIAL REVIEW ORIGINA
Page 11 and 12: Contents APPENDIX FLYLEAF EDITORS F
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Page 22 and 23: Table 1 Published studies on the as
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26 - World Journal of Gastroenterology

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