Docosahexaenoic acid supplementation decreases liver fat content in children with non-alcoholic fatty liver disease: double-blind randomised controlled clinical trial

Objective To investigate whether dietary supplementation with docosahexaenoic acid (DHA) decreases liver fat content in children with non-alcoholic fatty liver disease (NAFLD). Design, setting and patients We performed a randomised controlled trial of DHA supplementation (250 and 500 mg/day) versus placebo in 60 children with biopsy-proven NAFLD (20 children per group). Main outcome measures The main outcome was the change in liver fat content as detected by ultrasonography after 6 months of treatment. Secondary outcomes were the changes in insulin sensitivity index, alanine transaminase, triglycerides and body mass index after 6 months of treatment. Results Blood DHA increased in children supplemented with DHA (0.65%, 95% CI 0.30% to 1.10% for the DHA 250 mg group and 1.15%, 0.87% to 1.43% for the DHA 500 mg group). The odds of more severe versus less severe liver steatosis after treatment was lower in children treated with DHA 250 mg/day (OR = 0.01, 0.002 to 0.11, p <0.001) and DHA 500 mg/day (OR = 0.04, 0.002 to 0.46, p = 0.01) as compared to placebo but there was no difference between the DHA groups (p = 0.4). Insulin sensitivity index increased and triglycerides decreased to a similar degree in both DHA groups as compared to placebo but there was no effect on alanine transaminase and body mass index. Conclusion DHA supplementation improves liver steatosis and insulin sensitivity in children with NAFLD.

[1]  O. Receveur,et al.  Could the Quality of Dietary Fat, and Not Just Its Quantity, Be Related to Risk of Obesity? , 2008, Obesity.

[2]  C. Galli,et al.  A method for the direct evaluation of the fatty acid status in a drop of blood from a fingertip in humans: applicability to nutritional and epidemiological studies. , 2004, Analytical biochemistry.

[3]  S. Piro,et al.  Effects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver disease. , 2008, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[4]  V. Arroyo,et al.  Obesity‐induced insulin resistance and hepatic steatosis are alleviated by ω‐3 fatty acids: a role for resolvins and protectins , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[5]  M. Matsuda,et al.  Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. , 1999, Diabetes care.

[6]  P. Kris-Etherton,et al.  Dietary reference intakes for DHA and EPA. , 2009, Prostaglandins, leukotrienes, and essential fatty acids.

[7]  Joseph M Pappachan,et al.  Omega-3 fatty acids: a comprehensive review of their role in health and disease , 2009, Postgraduate Medical Journal.

[8]  Helen Brown,et al.  Applied Mixed Models in Medicine , 2000, Technometrics.

[9]  T. Lohman,et al.  Anthropometric Standardization Reference Manual , 1988 .

[10]  S. Peltier,et al.  Preferential enrichment of liver phospholipids in docosahexaenoate relative to eicosapentaenoate in omega-3-depleted rats injected with a medium-chain triglyceride: fish oil emulsion. , 2008, Prostaglandins, leukotrienes, and essential fatty acids.

[11]  C. Serhan,et al.  Resolvins , 2002, The Journal of experimental medicine.

[12]  R. Loomba,et al.  Insulin sensitizers in nonalcoholic fatty liver disease and steatohepatitis: Current status , 2009, Advances in therapy.

[13]  T. Harada,et al.  Highly purified eicosapentaenoic acid prevents the progression of hepatic steatosis by repressing monounsaturated fatty acid synthesis in high-fat/high-sucrose diet-fed mice. , 2009, Prostaglandins, leukotrienes, and essential fatty acids.

[14]  H. Szajewska,et al.  Pharmacological Interventions for Nonalcoholic Fatty Liver Disease in Adults and in Children: A Systematic Review , 2009, Journal of pediatric gastroenterology and nutrition.

[15]  P. Ciampalini,et al.  NAFLD in children: A prospective clinical‐pathological study and effect of lifestyle advice , 2006, Hepatology.

[16]  G. Bedogni,et al.  Predictors of non-alcoholic fatty liver disease in obese children , 2007, European Journal of Clinical Nutrition.

[17]  G. Radaelli,et al.  The Relationship of Insulin Resistance With SNP 276G>T at Adiponectin Gene and Plasma Long-Chain Polyunsaturated Fatty Acids in Obese Children , 2009, Pediatric Research.

[18]  Myung‐Sook Choi,et al.  Dietary docosahexaenoic acid-rich diacylglycerols ameliorate hepatic steatosis and alter hepatic gene expressions in C57BL/6J-Lep(ob/ob) mice. , 2008, Molecular nutrition & food research.

[19]  G. Watts,et al.  Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension. , 2002, The American journal of clinical nutrition.

[20]  O. Cummings,et al.  Design and validation of a histological scoring system for nonalcoholic fatty liver disease , 2005, Hepatology.

[21]  J. Heinrich,et al.  Role of FADS1 and FADS2 polymorphisms in polyunsaturated fatty acid metabolism. , 2010, Metabolism: clinical and experimental.

[22]  P. Hayes,et al.  Review article: omega-3 fatty acids - a promising novel therapy for non-alcoholic fatty liver disease. , 2010, Alimentary pharmacology & therapeutics.

[23]  M. Raponi,et al.  Pediatric non-alcoholic fatty liver disease: preventive and therapeutic value of lifestyle intervention. , 2009, World journal of gastroenterology.

[24]  J. Drai,et al.  Plasma fatty acid composition is associated with the metabolic syndrome and low-grade inflammation in overweight adolescents. , 2005, The American journal of clinical nutrition.

[25]  J. Lavine,et al.  Advances in pediatric nonalcoholic fatty liver disease. , 2011, Pediatric clinics of North America.

[26]  P. McCullagh Analysis of Ordinal Categorical Data , 1985 .

[27]  M. Marcovecchio,et al.  Pediatric Nonalcoholic Fatty Liver Disease , 2013 .

[28]  A F Roche,et al.  CDC growth charts: United States. , 2000, Advance data.

[29]  J. Maxwell,et al.  Ultrasound scanning in the detection of hepatic fibrosis and steatosis. , 1986, British medical journal.

[30]  S. Freedman,et al.  Alterations in immune response and PPAR/LXR regulation in cystic fibrosis macrophages. , 2008, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.

[31]  A. Alisi,et al.  Pediatric nonalcoholic fatty liver disease in 2009. , 2009, The Journal of pediatrics.

[32]  P. Flachs,et al.  Cellular and molecular effects of n-3 polyunsaturated fatty acids on adipose tissue biology and metabolism. , 2009, Clinical science.

[33]  Sophia Rabe-Hesketh,et al.  Multilevel and Longitudinal Modeling Using Stata , 2005 .

[34]  C. Corporeau,et al.  N-3 long chain polyunsaturated fatty acids: a nutritional tool to prevent insulin resistance associated to type 2 diabetes and obesity? , 2004, Reproduction, nutrition, development.

[35]  A. Suzuki,et al.  Eicosapentaenoic acid ameliorates steatohepatitis and hepatocellular carcinoma in hepatocyte-specific Pten-deficient mice. , 2009, Journal of hepatology.

[36]  D. Jump,et al.  Docosahexaenoic acid (DHA) and hepatic gene transcription. , 2008, Chemistry and physics of lipids.

[37]  L. Baur,et al.  Does Dietary Fat Influence Insulin Action? a , 1997, Annals of the New York Academy of Sciences.

[38]  Shumei S. Guo,et al.  2000 CDC Growth Charts for the United States: methods and development. , 2002, Vital and health statistics. Series 11, Data from the National Health Survey.

[39]  D. Jump N-3 polyunsaturated fatty acid regulation of hepatic gene transcription , 2008, Current opinion in lipidology.

[40]  H. Tilg,et al.  Insulin resistance, inflammation, and non-alcoholic fatty liver disease , 2008, Trends in Endocrinology & Metabolism.

[41]  Z. Younossi,et al.  Effects of Weight Loss on Nonalcoholic Fatty Liver Disease , 2008, Seminars in liver disease.

[42]  Lucy M. Browning,et al.  n-3 Polyunsaturated fatty acids, inflammation and obesity-related disease , 2003, Proceedings of the Nutrition Society.

[43]  G. Bedogni,et al.  Prolonged n‐3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non‐alcoholic fatty liver disease: a pilot study , 2006, Alimentary pharmacology & therapeutics.