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Meta-Analysis
. 2022 Jul 12;14(14):2846.
doi: 10.3390/nu14142846.

Important Food Sources of Fructose-Containing Sugars and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis of Controlled Trials

Danielle Lee  1   2 , Laura Chiavaroli  1   2 , Sabrina Ayoub-Charette  1   2 , Tauseef A Khan  1   2 , Andreea Zurbau  1   2   3 , Fei Au-Yeung  1   2   3 , Annette Cheung  1   2 , Qi Liu  1   2 , Xinye Qi  1   2 , Amna Ahmed  1   2 , Vivian L Choo  1   2   4 , Sonia Blanco Mejia  1   2 , Vasanti S Malik  1   5 , Ahmed El-Sohemy  1 , Russell J de Souza  1   2   6   7 , Thomas M S Wolever  1   3   8 , Lawrence A Leiter  1   2   8   9   10 , Cyril W C Kendall  1   2   11 , David J A Jenkins  1   2   8   9   10 , John L Sievenpiper  1   2   8   9   10
Affiliations
Meta-Analysis

Important Food Sources of Fructose-Containing Sugars and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis of Controlled Trials

Danielle Lee et al. Nutrients. .

Abstract

Background: Fructose providing excess calories in the form of sugar sweetened beverages (SSBs) increases markers of non-alcoholic fatty liver disease (NAFLD). Whether this effect holds for other important food sources of fructose-containing sugars is unclear. To investigate the role of food source and energy, we conducted a systematic review and meta-analysis of controlled trials of the effect of fructose-containing sugars by food source at different levels of energy control on non-alcoholic fatty liver disease (NAFLD) markers. Methods and Findings: MEDLINE, Embase, and the Cochrane Library were searched through 7 January 2022 for controlled trials ≥7-days. Four trial designs were prespecified: substitution (energy-matched substitution of sugars for other macronutrients); addition (excess energy from sugars added to diets); subtraction (excess energy from sugars subtracted from diets); and ad libitum (energy from sugars freely replaced by other macronutrients). The primary outcome was intrahepatocellular lipid (IHCL). Secondary outcomes were alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Independent reviewers extracted data and assessed risk of bias. The certainty of evidence was assessed using GRADE. We included 51 trials (75 trial comparisons, n = 2059) of 10 food sources (sugar-sweetened beverages (SSBs); sweetened dairy alternative; 100% fruit juice; fruit; dried fruit; mixed fruit sources; sweets and desserts; added nutritive sweetener; honey; and mixed sources (with SSBs)) in predominantly healthy mixed weight or overweight/obese younger adults. Total fructose-containing sugars increased IHCL (standardized mean difference = 1.72 [95% CI, 1.08 to 2.36], p < 0.001) in addition trials and decreased AST in subtraction trials with no effect on any outcome in substitution or ad libitum trials. There was evidence of influence by food source with SSBs increasing IHCL and ALT in addition trials and mixed sources (with SSBs) decreasing AST in subtraction trials. The certainty of evidence was high for the effect on IHCL and moderate for the effect on ALT for SSBs in addition trials, low for the effect on AST for the removal of energy from mixed sources (with SSBs) in subtraction trials, and generally low to moderate for all other comparisons. Conclusions: Energy control and food source appear to mediate the effect of fructose-containing sugars on NAFLD markers. The evidence provides a good indication that the addition of excess energy from SSBs leads to large increases in liver fat and small important increases in ALT while there is less of an indication that the removal of energy from mixed sources (with SSBs) leads to moderate reductions in AST. Varying uncertainty remains for the lack of effect of other important food sources of fructose-containing sugars at different levels of energy control.

Keywords: alanine aminotransferase; aspartate aminotransferase; intrahepatocellular lipid; non-alcoholic fatty liver disease; sugar-sweetened beverages; sugars.

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Conflict of interest statement

Declaration of interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf. DL reports receiving a stipend from University of Toronto Department of Nutritional Sciences Graduate Student Fellowship, University of Toronto Fellowship in Nutritional Sciences, University of Toronto Supervisor’s Research Grant—Early Researcher Awards, and Dairy Farmers of Canada Graduate Student Fellowships; a scholarship from St. Michael’s Hospital Research Training Centre, and a University of Toronto School of Graduate Studies Conference Grant. LC was a Mitacs-Elevate post-doctoral fellow jointly funded by the Government of Canada and the Canadian Sugar Institute. She was previously employed as a casual clinical coordinator at INQUIS Clinical Research, Ltd. (formerly Glycemic Index Laboratories, Inc.), a contract research organization. SA-C has received funding from CIHR Canadian Graduate Scholarship-Master’s and Doctoral, the Loblaw Food as Medicine Award, and the Ontario Graduate Scholarship. TAK has received research support from the Canadian Institutes of Health Research (CIHR), the International Life Science Institute (ILSI), and National Honey Board. He has been an invited speaker at the Calorie Control Council Annual meeting for which he has received an honorarium. He was funded by a Toronto 3D Postdoctoral Fellowship Award. AZ is a part-time Research Associate at INQUIS Clinical Research, Ltd., a contract research organization, and has received funding from a BBDC Postdoctoral Fellowship. AC and AA have received funding from a Toronto 3D MSc Scholarship award. FA-Y is a part-time Research Assistant at INQUIS Clinical Research, Ltd., a contract research organization. VSM has received funding from the Canada Research Chairs Program; Connaught New Researcher Award, University of Toronto; The Joannah & Brian Lawson Centre for Child Nutrition, University of Toronto; Temerty Faculty of Medicine Pathway Grant, University of Toronto; Canada Foundation for Innovation; Ontario Research Fund, and reports personal fees from the City and County of San Francisco and from Kaplan Fox & Kilsheimer, LLP, outside the submitted work. RJdS has served as an external resource person to the World Health Organization’s Nutrition Guidelines Advisory Group on trans fats, saturated fats, and polyunsaturated fats. The WHO paid for his travel and accommodation to attend meetings from 2012–2017 to present and discuss this work. He has presented updates of this work to the WHO in 2022. He has also done contract research for the Canadian Institutes of Health Research’s Institute of Nutrition, Metabolism, and Diabetes, Health Canada, and the World Health Organization for which he received remuneration. He has received speaker’s fees from the University of Toronto, and McMaster Children’s Hospital. He has held grants from the Canadian Institutes of Health Research, Canadian Foundation for Dietetic Research, Population Health Research Institute, and Hamilton Health Sciences Corporation as a principal investigator, and is a co-investigator on several funded team grants from the Canadian Institutes of Health Research. He has served as an independent director of the Helderleigh Foundation (Canada). He serves as a member of the Nutrition Science Advisory Committee to Health Canada (Government of Canada), and a co-opted member of the Scientific Advisory Committee on Nutrition (SACN) Subgroup on the Framework for the Evaluation of Evidence (Public Health England).TMSW was previously part owner, and now is an employee of INQUIS and received an honorarium from Springer/Nature for being an Associate Editor of the European Journal of Clinical Nutrition. CWCK has received grants or research support from the Advanced Food Materials Network, Agriculture and Agri-Foods Canada, Almond Board of California, American Pistachio Growers, Barilla, Calorie Control Council, Canadian Institutes of Health Research, Canola Council of Canada, International Nut and Dried Fruit Council, International Tree Nut Council Research and Education Foundation, Loblaw Brands, Pulse Canada, Saskatchewan Pulse Growers and Unilever; has received in-kind research support from the Almond Board of California, American Peanut Council, Barilla, California Walnut Commission, Kellogg Canada, Loblaw Companies, Quaker (PepsiCo), Primo, Unico, Unilever, WhiteWave Foods; has received travel support or honorariums from the American Peanut Council, American Pistachio Growers, Barilla, California Walnut Commission, Canola Council of Canada, General Mills, International Nut and Dried Fruit Council, International Pasta Organization, Loblaw Brands Ltd., Nutrition Foundation of Italy, Oldways Preservation Trust, Paramount Farms, Peanut Institute, Pulse Canada, Sabra Dipping, Saskatchewan Pulse Growers, Sun-Maid, Tate & Lyle, Unilever and White Wave Foods; has served on the scientific advisory board for the International Tree Nut Council, International Pasta Organization, Lantmannen, McCormick Science Institute, Oldways Preservation Trust, Paramount Farms and Pulse Canada; is a member of the International Carbohydrate Quality Consortium, executive board member of the Diabetes and Nutrition Study Group of the European Association for the Study of Diabetes; is on the Clinical Practice Guidelines Expert Committee for Nutrition Therapy of the European Association for the Study of Diabetes; and is a director of the Toronto 3D Knowledge Synthesis and Clinical Trials Foundation. DJAJ has received research grants from Saskatchewan & Alberta Pulse Growers Associations, the Agricultural Bioproducts Innovation Program through the Pulse Research Network, the Advanced Foods and Material Network, Loblaw Companies Ltd., Unilever Canada and Netherlands, Barilla, the Almond Board of California, Agriculture and Agri-food Canada, Pulse Canada, Kellogg’s Company, Canada, Quaker Oats, Canada, Procter & Gamble Technical Centre Ltd., Bayer Consumer Care, Springfield, NJ, Pepsi/Quaker, International Nut & Dried Fruit Council (INC), Soy Foods Association of North America, the Coca-Cola Company (investigator initiated, unrestricted grant), Solae, Haine Celestial, the Sanitarium Company, Orafti, the International Tree Nut Council Nutrition Research and Education Foundation, the Peanut Institute, Soy Nutrition Institute (SNI), the Canola and Flax Councils of Canada, the Calorie Control Council, the Canadian Institutes of Health Research (CIHR), the Canada Foundation for Innovation (CFI)and the Ontario Research Fund (ORF). He has received in-kind supplies for trials as a research support from the Almond board of California, Walnut Council of California, American Peanut Council, Barilla, Unilever, Unico, Primo, Loblaw Companies, Quaker (Pepsico), Pristine Gourmet, Bunge Limited, Kellogg Canada, WhiteWave Foods. He has been on the speaker’s panel, served on the scientific advisory board and/or received travel support and/or honoraria from Nutritional Fundamentals for Health (NFH)-Nutramedica, Saint Barnabas Medical Center, The University of Chicago, 2020 China Glycemic Index (GI) International Conference, Atlantic Pain Conference, Academy of Life Long Learning, the Almond Board of California, Canadian Agriculture Policy Institute, Loblaw Companies Ltd., the Griffin Hospital (for the development of the NuVal scoring system), the Coca-Cola Company, Epicure, Danone, Diet Quality Photo Navigation (DQPN), Better Therapeutics (FareWell), Verywell, True Health Initiative (THI), Heali AI Corp, Institute of Food Technologists (IFT), Soy Nutrition Institute (SNI), Herbalife Nutrition Institute (HNI), Saskatchewan & Alberta Pulse Growers Associations, Sanitarium Company, Orafti, the American Peanut Council, the International Tree Nut Council Nutrition Research and Education Foundation, the Peanut Institute, Herbalife International, Pacific Health Laboratories, Barilla, Metagenics, Bayer Consumer Care, Unilever Canada and Netherlands, Solae, Kellogg, Quaker Oats, Procter & Gamble, Abbott Laboratories, Dean Foods, the California Strawberry Commission, Haine Celestial, PepsiCo, the Alpro Foundation, Pioneer Hi-Bred International, DuPont Nutrition and Health, Spherix Consulting and WhiteWave Foods, the Advanced Foods and Material Network, the Canola and Flax Councils of Canada, Agri-Culture and Agri-Food Canada, the Canadian Agri-Food Policy Institute, Pulse Canada, the Soy Foods Association of North America, the Nutrition Foundation of Italy (NFI), Nutra-Source Diagnostics, the McDougall Program, the Toronto Knowledge Translation Group (St. Michael’s Hospital), the Canadian College of Naturopathic Medicine, The Hospital for Sick Children, the Canadian Nutrition Society (CNS), the American Society of Nutrition (ASN), Arizona State University, Paolo Sorbini Foundation and the Institute of Nutrition, Metabolism and Diabetes. He received an honorarium from the United States Department of Agriculture to present the 2013 W.O. Atwater Memorial Lecture. He received the 2013 Award for Excellence in Research from the International Nut and Dried Fruit Council. He received funding and travel support from the Canadian Society of Endocrinology and Metabolism to produce mini cases for the Canadian Diabetes Association (CDA). He is a member of the International Carbohydrate Quality Consortium (ICQC). His wife, Alexandra L Jenkins, is a director and partner of INQUIS Clinical Research for the Food Industry, his 2 daughters, Wendy Jenkins and Amy Jenkins, have published a vegetarian book that promotes the use of the foods described here, The Portfolio Diet for Cardiovascular Risk Reduction (Academic Press/Elsevier 2020 ISBN:978-0-12-810510-8)and his sister, Caroline Brydson, received funding through a grant from the St. Michael’s Hospital Foundation to develop a cookbook for one of his studies. JLS has received research support from the Canadian Foundation for Innovation, Ontario Research Fund, Province of Ontario Ministry of Research and Innovation and Science, Canadian Institutes of health Research (CIHR), Diabetes Canada, American Society for Nutrition (ASN), International Nut and Dried Fruit Council (INC) Foundation, National Honey Board (the U.S. Department of Agriculture [USDA] honey “Checkoff” program), Institute for the Advancement of Food and Nutrition Sciences (IAFNS), Pulse Canada, Quaker Oats Center of Excellence, The United Soybean Board (the USDA soy “Checkoff” program), The Tate and Lyle Nutritional Research Fund at the University of Toronto, The Glycemic Control and Cardiovascular Disease in Type 2 Diabetes Fund at the University of Toronto (a fund established by the Alberta Pulse Growers), The Plant Protein Fund at the University of Toronto (a fund which has received contributions from IFF), and The Nutrition Trialists Fund at the University of Toronto (a fund established by an inaugural donation from the Calorie Control Council). He has received food donations to support randomized controlled trials from the Almond Board of California, California Walnut Commission, Peanut Institute, Barilla, Unilever/Upfield, Unico/Primo, Loblaw Companies, Quaker, Kellogg Canada, WhiteWave Foods/Danone, Nutrartis, and Dairy Farmers of Canada. He has received travel support, speaker fees and/or honoraria from ASN, Danone, Dairy Farmers of Canada, FoodMinds LLC, Nestlé, Abbott, General Mills, Nutrition Communications, International Food Information Council (IFIC), Calorie Control Council, International Sweeteners Association, and International Glutamate Technical Committee. He has or has had ad hoc consulting arrangements with Perkins Coie LLP, Tate & Lyle, Phynova, and INQUIS Clinical Research. He is a former member of the European Fruit Juice Association Scientific Expert Panel and former member of the Soy Nutrition Institute (SNI) Scientific Advisory Committee. He is on the Clinical Practice Guidelines Expert Committees of Diabetes Canada, European Association for the study of Diabetes (EASD), Canadian Cardiovascular Society (CCS), and Obesity Canada/Canadian Association of Bariatric Physicians and Surgeons. He serves or has served as an unpaid member of the Board of Trustees and an unpaid scientific advisor for the Carbohydrates Committee of IAFNS. He is a member of the International Carbohydrate Quality Consortium (ICQC), Executive Board Member of the Diabetes and Nutrition Study Group (DNSG) of the EASD, and Director of the Toronto 3D Knowledge Synthesis and Clinical Trials foundation. His spouse is an employee of AB InBev. QL, XQ, SBM, VLC, AE-S, and LAL declare no competing interests. There are no products in development or marketed products to declare.

Figures

Figure 1
Figure 1
Flow of the literature for the effect of different food sources of fructose-containing sugars and NAFLD risk markers. ALT = alanine aminotransferase; AST = aspartate aminotransferase; IHCL = intrahepatocellular lipid.
Figure 2
Figure 2
Summary plot for the effect of important food sources of fructose-containing sugars on intrahepatocellular lipid (IHCL). Data are weighted standardized mean differences (95% confidence intervals) for summary effects of individual food sources and total food sources on IHCL. Analyses conducted by generic, inverse variance random effects models (at least five trials available) or fixed effects models (fewer than five trials available). Between-study heterogeneity was assessed by the Cochrane Q statistic, where PQ < 0.100 is considered statistically significant, and quantified by the I2 statistic, where I2 ≥ 50% is considered evidence of substantial heterogeneity. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) of randomized controlled trials are rated as “High” certainty of evidence and can be downgraded by five domains and upgraded by one domain. The white squares represent no downgrades, while filled black squares indicate a single downgrade or upgrades for each outcome, and the black square with a white “2” indicates a double downgrade for each outcome. CI = confidence interval; GRADE = Grading of Recommendations, Assessment, Development and Evaluation; IHCL = intrahepatocellular lipid; N = number; SMD = standardized mean difference; SSB = sugar-sweetened beverage. a For the interpretation of the magnitude, we used the MIDs to assess the importance of magnitude of our point estimate using the effect size categories according to new GRADE guidance. * Where there was a significant interaction by food source in substitution and addition trials and SSBs and mixed sources were the sole food sources in subtraction and ad libitum trials, we performed the GRADE analysis for each individual food source. To convert SMD to % liver fat, multiply the SMD by the baseline pooled standard deviation, 0.71%.
Figure 3
Figure 3
Summary plot for the effect of important food sources of fructose-containing sugars on alanine aminotransferase (ALT). Data are weighted mean differences (95% confidence intervals) for summary effects of individual food sources and total food sources on ALT. Analyses conducted by generic, inverse variance random effects models (at least five trials available) or fixed effects models (fewer than five trials available). Between-study heterogeneity was assessed by the Cochrane Q statistic, where PQ < 0.100 is considered statistically significant, and quantified by the I2 statistic, where I2 ≥ 50% is considered evidence of substantial heterogeneity. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) of randomized controlled trials are rated as “High” certainty of evidence and can be downgraded by five domains and upgraded by one domain. The white squares represent no downgrades, while filled black squares indicate a single downgrade or upgrades for each outcome, and the black square with a white “2” indicates a double downgrade for each outcome. ALT = alanine aminotransferase; CI = confidence interval; GRADE = Grading of Recommendations, Assessment, Development and Evaluation; MD = mean difference; N = number; SMD = standardized mean difference; SSB = sugar-sweetened beverage. a For the interpretation of the magnitude, we used the MIDs to assess the importance of magnitude of our point estimate using the effect size categories according to new GRADE guidance. † Not upgraded for dose–response (see Table S7 for details). * Where there was a significant interaction by food source in substitution and addition trials and SSBs and mixed sources were the sole food sources in subtraction and ad libitum trials, we performed the GRADE analysis for each individual food source. To convert U/L to ukat/L, multiply U/L by 0.0167.
Figure 4
Figure 4
Summary plot for the effect of important food sources of fructose-containing sugars on aspartate aminotransferase (AST). Data are weighted mean differences (95% confidence intervals) for summary effects of individual food sources and total food sources on ALT. Analyses conducted by generic, inverse variance random effects models (at least five trials available) or fixed effects models (fewer than five trials available). Between-study heterogeneity was assessed by the Cochrane Q statistic, where PQ < 0.100 is considered statistically significant, and quantified by the I2 statistic, where I2 ≥ 50% is considered evidence of substantial heterogeneity. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) of randomized controlled trials are rated as “High” certainty of evidence and can be downgraded by five domains and upgraded by one domain. The white squares represent no downgrades, while filled black squares indicate a single downgrade or upgrades for each outcome, and the black square with a white “2” indicates a double downgrade for each outcome. AST = aspartate aminotransferase; CI = confidence interval; GRADE = Grading of Recommendations, Assessment, Development and Evaluation; MD = mean difference; N = number; SMD = standardized mean difference; SSB = sugar-sweetened beverage. a For the interpretation of the magnitude, we used the MIDs to assess the importance of magnitude of our point estimate using the effect size categories according to new GRADE guidance. * Where there was a significant interaction by food source in substitution and addition trials and SSBs and mixed sources were the sole food sources in subtraction and ad libitum trials, we performed the GRADE analysis for each individual food source. To convert U/L to ukat/L, multiply U/L by 0.0167.
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