title: Fructose, high-fructose corn syrup, sucrose, and nonalcoholic fatty liver disease or indexes of liver health: a systematic review and meta-analysis.
abstract: BACKGROUND
  Concerns have been raised about the concurrent temporal trend between simple sugar intakes, especially of fructose or high-fructose corn syrup (HFCS), and rates of nonalcoholic fatty liver disease (NAFLD) in the United States.
  
  
  OBJECTIVE
  We examined the effect of different amounts and forms of dietary fructose on the incidence or prevalence of NAFLD and indexes of liver health in humans.
  
  
  METHODS
  We conducted a systematic review of English-language, human studies of any design in children and adults with low to no alcohol intake and that reported at least one predetermined measure of liver health. The strength of the evidence was evaluated by considering risk of bias, consistency, directness, and precision.
  
  
  RESULTS
  Six observational studies and 21 intervention studies met the inclusion criteria. The overall strength of evidence for observational studies was rated insufficient because of high risk of biases and inconsistent study findings. Of 21 intervention studies, 19 studies were in adults without NAFLD (predominantly healthy, young men) and 1 study each in adults or children with NAFLD. We found a low level of evidence that a hypercaloric fructose diet (supplemented by pure fructose) increases liver fat and aspartate aminotransferase (AST) concentrations in healthy men compared with the consumption of a weight-maintenance diet. In addition, there was a low level of evidence that hypercaloric fructose and glucose diets have similar effects on liver fat and liver enzymes in healthy adults. There was insufficient evidence to draw a conclusion for effects of HFCS or sucrose on NAFLD.
  
  
  CONCLUSIONS
  On the basis of indirect comparisons across study findings, the apparent association between indexes of liver health (ie, liver fat, hepatic de novo lipogenesis, alanine aminotransferase, AST, and γ-glutamyl transpeptase) and fructose or sucrose intake appear to be confounded by excessive energy intake. Overall, the available evidence is not sufficiently robust to draw conclusions regarding effects of fructose, HFCS, or sucrose consumption on NAFLD.
authors.affiliation: From the Center for Clinical Evidence Synthesis, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA (MC, KP, SB, and JL); the Nutrition/Infection Unit, Department of Public Health and Community Medicine, School of Medicine, Tufts University, Boston, MA (MC); the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA (JM and AHL); and the Center for Evidence-based Medicine, School of Public Health, Brown University, Providence, RI (JL).
authors.forename: Mei
authors.initials: M
authors.lastname: Chung
authors.affiliation: From the Center for Clinical Evidence Synthesis, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA (MC, KP, SB, and JL); the Nutrition/Infection Unit, Department of Public Health and Community Medicine, School of Medicine, Tufts University, Boston, MA (MC); the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA (JM and AHL); and the Center for Evidence-based Medicine, School of Public Health, Brown University, Providence, RI (JL).
authors.forename: Jiantao
authors.initials: J
authors.lastname: Ma
authors.affiliation: From the Center for Clinical Evidence Synthesis, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA (MC, KP, SB, and JL); the Nutrition/Infection Unit, Department of Public Health and Community Medicine, School of Medicine, Tufts University, Boston, MA (MC); the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA (JM and AHL); and the Center for Evidence-based Medicine, School of Public Health, Brown University, Providence, RI (JL).
authors.forename: Kamal
authors.initials: K
authors.lastname: Patel
authors.affiliation: From the Center for Clinical Evidence Synthesis, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA (MC, KP, SB, and JL); the Nutrition/Infection Unit, Department of Public Health and Community Medicine, School of Medicine, Tufts University, Boston, MA (MC); the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA (JM and AHL); and the Center for Evidence-based Medicine, School of Public Health, Brown University, Providence, RI (JL).
authors.forename: Samantha
authors.initials: S
authors.lastname: Berger
authors.affiliation: From the Center for Clinical Evidence Synthesis, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA (MC, KP, SB, and JL); the Nutrition/Infection Unit, Department of Public Health and Community Medicine, School of Medicine, Tufts University, Boston, MA (MC); the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA (JM and AHL); and the Center for Evidence-based Medicine, School of Public Health, Brown University, Providence, RI (JL).
authors.forename: Joseph
authors.initials: J
authors.lastname: Lau
authors.affiliation: From the Center for Clinical Evidence Synthesis, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA (MC, KP, SB, and JL); the Nutrition/Infection Unit, Department of Public Health and Community Medicine, School of Medicine, Tufts University, Boston, MA (MC); the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA (JM and AHL); and the Center for Evidence-based Medicine, School of Public Health, Brown University, Providence, RI (JL).
authors.forename: Alice H
authors.initials: AH
authors.lastname: Lichtenstein
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D019422:Dietary Sucrose / Q000009:adverse effects*; D002149:Energy Intake; D019317:Evidence-Based Medicine; D005632:Fructose / Q000009:adverse effects*; D066248:High Fructose Corn Syrup / Q000009:adverse effects*; D006801:Humans; D006963:Hyperphagia / Q000503:physiopathology; D008099:Liver / Q000503:physiopathology*; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D064427:Nutritive Sweeteners / Q000009:adverse effects*
chemical_list: D015415:Biomarkers; D019422:Dietary Sucrose; D066248:High Fructose Corn Syrup; D064427:Nutritive Sweeteners; D005632:Fructose
references.citation: J Am Diet Assoc. 1988 Aug;88(8):932-8
references.pmid: 3294273
references.citation: Am J Clin Nutr. 2010 Dec;92(6):1522-7
references.pmid: 20962157
references.citation: BMC Gastroenterol. 2010 Aug 25;10:98
references.pmid: 20738844
references.citation: Exp Diabetes Res. 2012;2012:361863
references.pmid: 22203835
references.citation: Br J Nutr. 2011 Jul;106(1):79-86
references.pmid: 21396140
references.citation: Best Pract Res Clin Gastroenterol. 2004 Dec;18(6):1105-16
references.pmid: 15561641
references.citation: J Nutr. 2009 Nov;139(11):2067-71
references.pmid: 19776184
references.citation: J Clin Invest. 2009 May;119(5):1322-34
references.pmid: 19381015
references.citation: Int J Obes (Lond). 2010 Mar;34(3):454-61
references.pmid: 20029377
references.citation: J Clin Gastroenterol. 2006 Mar;40 Suppl 1:S39-43
references.pmid: 16540766
references.citation: Curr Opin Lipidol. 2008 Feb;19(1):25-9
references.pmid: 18196983
references.citation: Control Clin Trials. 1986 Sep;7(3):177-88
references.pmid: 3802833
references.citation: Am J Clin Nutr. 2010 Aug;92(2):273-6
references.pmid: 20504974
references.citation: Br J Nutr. 2010 Apr;103(7):939-43
references.pmid: 19930762
references.citation: J Hepatol. 2008 Jun;48(6):993-9
references.pmid: 18395287
references.citation: Clin Gastroenterol Hepatol. 2011 Jun;9(6):524-530.e1; quiz e60
references.pmid: 21440669
references.citation: Am J Physiol Endocrinol Metab. 2005 Feb;288(2):E462-8
references.pmid: 15339742
references.citation: World J Gastroenterol. 2012 May 21;18(19):2300-8
references.pmid: 22654421
references.citation: J Pediatr. 2013 Mar;162(3):496-500.e1
references.pmid: 23084707
references.citation: Arterioscler Thromb Vasc Biol. 2008 Jan;28(1):27-38
references.pmid: 17690317
references.citation: Gastroenterology. 2011 Jan;140(1):124-31
references.pmid: 20858492
references.citation: Adv Nutr. 2013 Mar 01;4(2):246-56
references.pmid: 23493541
references.citation: PLoS Med. 2009 Jul 21;6(7):e1000097
references.pmid: 19621072
references.citation: Diabetes Care. 2007 Sep;30(9):e94; author reply e95
references.pmid: 17726184
references.citation: Am J Clin Nutr. 2009 Mar;89(3):728-33
references.pmid: 19176732
references.citation: Diabetes Metab. 2010 Jun;36(3):244-6
references.pmid: 20483648
references.citation: Eur J Clin Nutr. 2014 Apr;68(4):416-23
references.pmid: 24569542
references.citation: N Engl J Med. 2002 Apr 18;346(16):1221-31
references.pmid: 11961152
references.citation: Hypertension. 2012 Apr;59(4):787-95
references.pmid: 22331380
references.citation: Am J Clin Nutr. 2009 Jun;89(6):1760-5
references.pmid: 19403641
references.citation: Diabetes Care. 2008 Jun;31(6):1254-6
references.pmid: 18332156
references.citation: Clin Sci (Lond). 2014 Dec;127(12):655-63
references.pmid: 24738611
references.citation: Diabetes. 2005 Jul;54(7):1907-13
references.pmid: 15983189
references.citation: Horm Metab Res. 2005 Jan;37(1):32-5
references.pmid: 15702436
references.citation: J Nutr. 2008 Aug;138(8):1452-5
references.pmid: 18641190
references.citation: Br J Nutr. 2013 Sep 14;110(5):918-25
references.pmid: 23340336
references.citation: Am J Med. 1983 Oct;75(4):624-30
references.pmid: 6624769
references.citation: Hepatol Res. 2011 Jul;41(7):670-4
references.pmid: 21711426
references.citation: Clin Biochem. 2010 Jul;43(10-11):815-21
references.pmid: 20398645
references.citation: J Nutr. 2008 Dec;138(12):2297-306
references.pmid: 19022948
references.citation: J Am Diet Assoc. 2010 Sep;110(9):1307-21
references.pmid: 20800122
references.citation: Br J Nutr. 2012 Aug;108(3):418-23
references.pmid: 22354959
references.citation: Am J Clin Nutr. 2011 Sep;94(3):726-34
references.pmid: 21753067
references.citation: BMJ. 2011 Nov 18;343:d6891
references.pmid: 22102439
references.citation: Ann Intern Med. 2012 Feb 21;156(4):291-304
references.pmid: 22351714
references.citation: Am Fam Physician. 1999 Apr 15;59(8):2223-30
references.pmid: 10221307
references.citation: J Nutr. 2007 Jun;137(6):1447-54
references.pmid: 17513405
references.citation: Evid Rep Technol Assess (Full Rep). 2009 Aug;(183):1-420
references.pmid: 20629479
references.citation: J Clin Invest. 2006 Jul;116(7):1793-801
references.pmid: 16823477
references.citation: Diabetes Care. 2009 Oct;32(10):1930-7
references.pmid: 19592634
references.citation: Eur J Nutr. 2013 Mar;52(2):527-35
references.pmid: 22543623
references.citation: Br J Clin Pharmacol. 2004 Feb;57(2):199-208
references.pmid: 14748819
references.citation: Ann Intern Med. 2011 Nov 1;155(9):616-24
references.pmid: 22041950
references.citation: Am J Clin Nutr. 2004 Apr;79(4):537-43
references.pmid: 15051594
references.citation: Science. 2011 Jun 24;332(6037):1519-23
references.pmid: 21700865
references.citation: Eur J Clin Nutr. 2010 Jun;64(6):628-35
references.pmid: 20216561
references.citation: BMJ. 2011 Oct 18;343:d5928
references.pmid: 22008217
references.citation: Am J Clin Nutr. 2006 Dec;84(6):1374-9
references.pmid: 17158419
references.citation: Hypertension. 2005 May;45(5):1012-8
references.pmid: 15824194
references.citation: J Med Food. 2003 Summer;6(2):135-40
references.pmid: 12935325
references.citation: Am J Gastroenterol. 2005 May;100(5):1082-90
references.pmid: 15842582
references.citation: Hepatology. 2012 Jun;55(6):2005-23
references.pmid: 22488764
references.citation: Arch Pediatr Adolesc Med. 2009 Jul;163(7):674-5
references.pmid: 19581556
references.citation: BMJ. 2010 Feb 15;340:c365
references.pmid: 20156912
references.citation: Am J Clin Nutr. 2012 Feb;95(2):283-9
references.pmid: 22205311
references.citation: Liver Int. 2011 Mar;31(3):412-6
references.pmid: 21281435
references.citation: J Nutr. 2012 May;142(5):916-23
references.pmid: 22457397
references.citation: Dig Dis Sci. 2012 Jul;57(7):1932-41
references.pmid: 22427130
references.citation: Aliment Pharmacol Ther. 2011 Aug;34(3):274-85
references.pmid: 21623852
references.citation: BMC Gastroenterol. 2006 Nov 02;6:33
references.pmid: 17081293
references.citation: Clin Biochem. 2005 Jun;38(6):540-7
references.pmid: 15885234
references.citation: Am J Clin Nutr. 2012 Nov;96(5):1008-16
references.pmid: 23034968
references.citation: Appl Physiol Nutr Metab. 2013 Jun;38(6):681-8
references.pmid: 23724887
references.citation: Am J Clin Nutr. 2007 Aug;86(2):285-300
references.pmid: 17684197
references.citation: Gastroenterology. 2013 Nov;145(5):1016-1025.e2
references.pmid: 23872500
references.citation: Gastroenterology. 2008 May;134(6):1682-98
references.pmid: 18471547
references.citation: Clin Liver Dis. 2004 Aug;8(3):521-33, viii
references.pmid: 15331061
references.citation: Am J Clin Nutr. 1974 Sep;27(9):926-36
references.pmid: 4412810
references.citation: Indian J Pediatr. 2007 Jul;74(7):663-71
references.pmid: 17699976
references.citation: Nutr Metab (Lond). 2012 Jul 24;9(1):68
references.pmid: 22828276
references.citation: Am J Clin Nutr. 2011 Aug;94(2):479-85
references.pmid: 21677052
references.citation: BMJ. 2003 Sep 6;327(7414):557-60
references.pmid: 12958120