- Email: [email protected]
Is industrial fructose just a marker of an unhealthy dietary pattern?
Letter to the Editor
Is industrial fructose just a marker of an unhealthy dietary pattern? To the Editor: We read with interest the cross-sectional study by Petta et al. [1] showing that ‘‘industrial’’ fructose and not fruit fructose intake is associated with liver fibrosis in biopsy-proven genotype 1 chronic hepatitis C (G1CHC) patients. We are concerned that important confounders were not included in their analytical models. The authors selected their multivariate models based on the significance of variables in univariate models. Taking this approach, important confounders may have been missed. One of the most important confounders in nutrition is that of energy, a factor intrinsic to all foods. Although neither ‘‘hypercaloric’’ nor ‘‘energy intake’’ were significant in univariate models, both were significantly associated with fructose intake. Excess energy has also been shown to be an important mediating factor in the effects of fructose on cardiometabolic risk. In a series of systematic reviews and meta-analyses of controlled feeding trials, we found that fructose in isocaloric exchange for other carbohydrates (energy matched conditions) showed no signal for harm in relation to markers of non-alcoholic fatty liver disease (NAFLD) [2] as well as body weight [3], glycemic control [4], insulin [4], serum fasting lipids [5], postprandial triglycerides [6], blood pressure [7], and uric acid [8]. A lack of harm is seen even under conditions of fructose overfeeding (positive energy balance) at high doses, as long as the comparison with the carbohydrate comparator remains matched for the excess calories. There may, however, be a dose threshold for some fasting lipid effects in some high dose subgroup analyses [5]. A consistent signal for harm is not seen until one examines fructose in imbalanced, hypercaloric comparisons. If fructose supplements background diets with excess energy compared with the same diets without the excess energy, then one sees adverse effects on markers of NAFLD and other cardiometabolic risk factors [2–8]. In the absence of a clear effect on markers of NAFLD and its related cardiometabolic risk factors in isocaloric comparisons (especially under conditions of positive energy balance), the effects seen in the hypercaloric comparisons appear to relate more to the excess energy than the fructose. Adjustment for total energy intake would therefore seem essential in understanding whether an association with fructose exists beyond the energy it contributes. Other lifestyle factors associated with NAFLD were also not adjusted for in their multivariate models. These include smoking, exercise, total fat, trans fat, saturated fat, cholesterol, the n-6:-3 ratio of polyunsaturated fatty acids, total carbohydrate, animal protein, dietary fibre, and an overall Western dietary pattern which embodies these variables. Even if some of these factors were not significant in univariate analyses, each has been shown to have an equal or stronger association with NAFLD [9,10] and may contribute to residual confounding. These factors individually and collectively may also contribute to important collinearity effects, as high consumers of added sugars (in the form of sugar
sweetened beverages) tend to smoke more, exercise less, and eat more calories in the form of a Western dietary pattern characterized by increased red meat, processed meat, potato products, and refined grains. The lack of adjustment for these factors greatly complicates the interpretation of the results. In the absence of adjustment for factors associated with NAFLD, one cannot conclude with confidence that ‘‘industrial’’ fructose is a risk factor for liver fibrosis in biopsy-proven G1CHC patients. Added fructose from industrial sources may simply represent a marker of an unhealthy lifestyle pattern in these patients. To understand whether fructose is an independent predictor of liver fibrosis, the authors must address these confounders in future models. There also remains an urgent need for higher quality evidence from well-conducted prospective observational studies with good measurements of exposure and the ability to adjust for known confounders as well as longer, larger, higher quality randomized controlled trials of the effect of fructose on the progression of NAFLD.
Conflict of interest LC has received research support from the Canadian Institutes of Health Research (CIHR) and is a clinical research coordinator at Glycemic Index Laboratories, Toronto, Ontario, Canada. VH has received a Province of Ontario Graduate Scholarship and research support from the Canadian Institutes of Health Research (CIHR) and World Health Organization (WHO) for work on a systematic review and meta-analysis commissioned by the WHO of the relation of saturated fatty acids with health outcomes. She also received a travel award to attend the ‘‘Journey Through Science Day’’ hosted by PepsiCo and the New York Academy of Sciences (NYAS). RJdS is funded by a CIHR Postdoctoral Fellowship Award and has received research support from the CIHR, Calorie Control Council, the Canadian Foundation for Dietetic Research (CFDR), and The Coca-Cola Company (investigator initiated, unrestricted grant). He has served as an external resource person to the World Health Organization’s (WHO) Nutrition Guidelines Advisory Group (NUGAG), and is the lead author of two systematic reviews and meta-analyses commissioned by the WHO of the relation of saturated fatty acids and trans fatty acids with health outcomes. The WHO paid for his travel and accommodation to attend NUGAG Meetings in Hangzhou, China and Copenhagen, Denmark. CWCK has received research grants, travel funding, consultant fees, honoraria, or has served on the scientific advisory board for Abbott Laboratories, Advanced Food Materials Network, Agrifoods and Agriculture Canada (AAFC), Almond Board of California, American Peanut Council, American Pistachio Growers, Barilla, California Strawberry Commission, Bayer, Calorie Control Council, Canadian Institutes of Health Research (CIHR), Canola Council of Canada, The Coca Cola Company (investigator initiated,
Journal of Hepatology 2014 vol. xxx
j
xxx–xxx
Letter to the Editor unrestricted), Danone, General Mills, Hain Celestial, International Tree Nut Council, Kellogg, Kraft, Loblaw Brands Ltd, Nutrition Foundation of Italy, Oldways Preservation Trust, Orafti, Paramount Farms, Peanut Institute, Pepsi-Co, Pulse Canada, Sabra Dipping Co., Saskatchewan Pulse Growers, Solae, Sun-Maid, Tate & Lyle and Unilever. JLS has received research support from the Canadian Institutes of Health Research (CIHR), Calorie Control Council, The Coca-Cola Company (investigator initiated, unrestricted educational grant), Dr. Pepper Snapple Group (investigator initiated, unrestricted educational grant), Pulse Canada, and The International Tree Nut Council Nutrition Research & Education Foundation. He has received travel funding, speaker fees, and/or honoraria from the American Heart Association (AHA), American College of Physicians (ACP), American Society for Nutrition (ASN), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH), Canadian Diabetes Association (CDA), Canadian Nutrition Society (CNS), University of South Carolina, University of Alabama at Birmingham, Calorie Control Council, Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD), International Life Sciences Institute (ILSI) North America, ILSI Brazil, Abbott Laboratories, Pulse Canada, Canadian Sugar Institute, Dr. Pepper Snapple Group, and The Coca-Cola Company. He is on the Clinical Practice Guidelines Expert Committee for Nutrition Therapy of both the CDA and EASD, as well as being on the ASN writing panel for a scientific statement on the metabolic and nutritional effects of fructose, sucrose and high fructose corn syrup. He is a member of the International Carbohydrate Quality Consortium (ICQC) and an unpaid scientific advisor for the ILSI North America, Food, Nutrition, and Safety Program (FNSP). His wife is an employee of Unilever Canada. References [1] Petta S, Marchesini G, Caracausi L, Macaluso FS, Camma C, Ciminnisi S, et al. Industrial, not fruit fructose intake is associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients. J Hepatol 2013;59: 1169–1176. [2] Chiu S, Sievenpiper JL,, de Souza RJ, Cozma AI, Mirrahimi A, Carleton AJ, et al. Effect of fructose on markers of Non-Alcoholic Fatty Liver Disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials. Eur J Clin Nutr 2014. http://dx.doi.org/10.1038/ejcn.2014.8, [Epub ahead of print]. [3] Sievenpiper JL, de Souza RJ, Mirrahimi A, Yu ME, Carleton AJ, Beyene J, et al. Effect of fructose on body weight in controlled feeding trials: a systematic review and meta-analysis. Ann Intern Med 2012;21:291–304. [4] Cozma AI, Sievenpiper JL, de Souza RJ, Chiavaroli L, Ha V, Wang DD, et al. Effect of fructose on glycemic control in diabetes: a systematic review and meta-analysis of controlled feeding trials. Diabetes Care 2012;35: 1611–1620.
2
[5] Sievenpiper JL, Carleton AJ, Chatha S, Jiang HY, de Souza RJ, Beyene J, et al. Heterogeneous effects of fructose on blood lipids in individuals with type 2 diabetes: systematic review and meta-analysis of experimental trials in humans. Diabetes Care 2009;32:1930–1937. [6] Wang DD, Sievenpiper JL, De Souza RJ, Cozma AI, Chiavaroli L, Ha V, et al. Effect of fructose on postprandial triglycerides: a systematic review and meta-analysis of controlled feeding trials. Atherosclerosis 2014;232: 125–133. [7] Ha V, Sievenpiper JL, de Souza RJ, Chiavaroli L, Wang DD, Cozma AI, et al. Effect of fructose on blood pressure: a systematic review and meta-analysis of controlled feeding trials. Hypertension 2012;59:787–795. [8] Wang DD, Sievenpiper JL, de Souza RJ, Chiavaroli L, Ha V, Cozma AI, et al. The effects of fructose intake on serum uric acid vary among controlled dietary trials. J Nutr 2012;142:916–923. [9] Mouzaki M, Allard JP. The role of nutrients in the development, progression, and treatment of nonalcoholic fatty liver disease. J Clin Gastroenterol 2012;46:457–467. [10] Zein CO, Unalp A, Colvin R, Liu YC, McCullough AJ. Nonalcoholic steatohepatitis clinical research network. Smoking and severity of hepatic fibrosis in nonalcoholic fatty liver disease. J Hepatol 2011;54:753–759.
Laura Chiavaroli Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON, Canada Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada Vanessa Ha Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON, Canada Cyril W.C. Kendall Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON, Canada Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada
⇑
John L. Sievenpiper Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON, Canada Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada ⇑Corresponding author. E-mail address: [email protected]
Journal of Hepatology 2014 vol. xxx j xxx–xxx
Is industrial fructose just a marker of an unhealthy dietary pattern? To the Editor: We read with interest the cross-sectional study by Petta et al. [1] showing that ‘‘industrial’’ fructose and not fruit fructose intake is associated with liver fibrosis in biopsy-proven genotype 1 chronic hepatitis C (G1CHC) patients. We are concerned that important confounders were not included in their analytical models. The authors selected their multivariate models based on the significance of variables in univariate models. Taking this approach, important confounders may have been missed. One of the most important confounders in nutrition is that of energy, a factor intrinsic to all foods. Although neither ‘‘hypercaloric’’ nor ‘‘energy intake’’ were significant in univariate models, both were significantly associated with fructose intake. Excess energy has also been shown to be an important mediating factor in the effects of fructose on cardiometabolic risk. In a series of systematic reviews and meta-analyses of controlled feeding trials, we found that fructose in isocaloric exchange for other carbohydrates (energy matched conditions) showed no signal for harm in relation to markers of non-alcoholic fatty liver disease (NAFLD) [2] as well as body weight [3], glycemic control [4], insulin [4], serum fasting lipids [5], postprandial triglycerides [6], blood pressure [7], and uric acid [8]. A lack of harm is seen even under conditions of fructose overfeeding (positive energy balance) at high doses, as long as the comparison with the carbohydrate comparator remains matched for the excess calories. There may, however, be a dose threshold for some fasting lipid effects in some high dose subgroup analyses [5]. A consistent signal for harm is not seen until one examines fructose in imbalanced, hypercaloric comparisons. If fructose supplements background diets with excess energy compared with the same diets without the excess energy, then one sees adverse effects on markers of NAFLD and other cardiometabolic risk factors [2–8]. In the absence of a clear effect on markers of NAFLD and its related cardiometabolic risk factors in isocaloric comparisons (especially under conditions of positive energy balance), the effects seen in the hypercaloric comparisons appear to relate more to the excess energy than the fructose. Adjustment for total energy intake would therefore seem essential in understanding whether an association with fructose exists beyond the energy it contributes. Other lifestyle factors associated with NAFLD were also not adjusted for in their multivariate models. These include smoking, exercise, total fat, trans fat, saturated fat, cholesterol, the n-6:-3 ratio of polyunsaturated fatty acids, total carbohydrate, animal protein, dietary fibre, and an overall Western dietary pattern which embodies these variables. Even if some of these factors were not significant in univariate analyses, each has been shown to have an equal or stronger association with NAFLD [9,10] and may contribute to residual confounding. These factors individually and collectively may also contribute to important collinearity effects, as high consumers of added sugars (in the form of sugar
sweetened beverages) tend to smoke more, exercise less, and eat more calories in the form of a Western dietary pattern characterized by increased red meat, processed meat, potato products, and refined grains. The lack of adjustment for these factors greatly complicates the interpretation of the results. In the absence of adjustment for factors associated with NAFLD, one cannot conclude with confidence that ‘‘industrial’’ fructose is a risk factor for liver fibrosis in biopsy-proven G1CHC patients. Added fructose from industrial sources may simply represent a marker of an unhealthy lifestyle pattern in these patients. To understand whether fructose is an independent predictor of liver fibrosis, the authors must address these confounders in future models. There also remains an urgent need for higher quality evidence from well-conducted prospective observational studies with good measurements of exposure and the ability to adjust for known confounders as well as longer, larger, higher quality randomized controlled trials of the effect of fructose on the progression of NAFLD.
Conflict of interest LC has received research support from the Canadian Institutes of Health Research (CIHR) and is a clinical research coordinator at Glycemic Index Laboratories, Toronto, Ontario, Canada. VH has received a Province of Ontario Graduate Scholarship and research support from the Canadian Institutes of Health Research (CIHR) and World Health Organization (WHO) for work on a systematic review and meta-analysis commissioned by the WHO of the relation of saturated fatty acids with health outcomes. She also received a travel award to attend the ‘‘Journey Through Science Day’’ hosted by PepsiCo and the New York Academy of Sciences (NYAS). RJdS is funded by a CIHR Postdoctoral Fellowship Award and has received research support from the CIHR, Calorie Control Council, the Canadian Foundation for Dietetic Research (CFDR), and The Coca-Cola Company (investigator initiated, unrestricted grant). He has served as an external resource person to the World Health Organization’s (WHO) Nutrition Guidelines Advisory Group (NUGAG), and is the lead author of two systematic reviews and meta-analyses commissioned by the WHO of the relation of saturated fatty acids and trans fatty acids with health outcomes. The WHO paid for his travel and accommodation to attend NUGAG Meetings in Hangzhou, China and Copenhagen, Denmark. CWCK has received research grants, travel funding, consultant fees, honoraria, or has served on the scientific advisory board for Abbott Laboratories, Advanced Food Materials Network, Agrifoods and Agriculture Canada (AAFC), Almond Board of California, American Peanut Council, American Pistachio Growers, Barilla, California Strawberry Commission, Bayer, Calorie Control Council, Canadian Institutes of Health Research (CIHR), Canola Council of Canada, The Coca Cola Company (investigator initiated,
Journal of Hepatology 2014 vol. xxx
j
xxx–xxx
Letter to the Editor unrestricted), Danone, General Mills, Hain Celestial, International Tree Nut Council, Kellogg, Kraft, Loblaw Brands Ltd, Nutrition Foundation of Italy, Oldways Preservation Trust, Orafti, Paramount Farms, Peanut Institute, Pepsi-Co, Pulse Canada, Sabra Dipping Co., Saskatchewan Pulse Growers, Solae, Sun-Maid, Tate & Lyle and Unilever. JLS has received research support from the Canadian Institutes of Health Research (CIHR), Calorie Control Council, The Coca-Cola Company (investigator initiated, unrestricted educational grant), Dr. Pepper Snapple Group (investigator initiated, unrestricted educational grant), Pulse Canada, and The International Tree Nut Council Nutrition Research & Education Foundation. He has received travel funding, speaker fees, and/or honoraria from the American Heart Association (AHA), American College of Physicians (ACP), American Society for Nutrition (ASN), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH), Canadian Diabetes Association (CDA), Canadian Nutrition Society (CNS), University of South Carolina, University of Alabama at Birmingham, Calorie Control Council, Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD), International Life Sciences Institute (ILSI) North America, ILSI Brazil, Abbott Laboratories, Pulse Canada, Canadian Sugar Institute, Dr. Pepper Snapple Group, and The Coca-Cola Company. He is on the Clinical Practice Guidelines Expert Committee for Nutrition Therapy of both the CDA and EASD, as well as being on the ASN writing panel for a scientific statement on the metabolic and nutritional effects of fructose, sucrose and high fructose corn syrup. He is a member of the International Carbohydrate Quality Consortium (ICQC) and an unpaid scientific advisor for the ILSI North America, Food, Nutrition, and Safety Program (FNSP). His wife is an employee of Unilever Canada. References [1] Petta S, Marchesini G, Caracausi L, Macaluso FS, Camma C, Ciminnisi S, et al. Industrial, not fruit fructose intake is associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients. J Hepatol 2013;59: 1169–1176. [2] Chiu S, Sievenpiper JL,, de Souza RJ, Cozma AI, Mirrahimi A, Carleton AJ, et al. Effect of fructose on markers of Non-Alcoholic Fatty Liver Disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials. Eur J Clin Nutr 2014. http://dx.doi.org/10.1038/ejcn.2014.8, [Epub ahead of print]. [3] Sievenpiper JL, de Souza RJ, Mirrahimi A, Yu ME, Carleton AJ, Beyene J, et al. Effect of fructose on body weight in controlled feeding trials: a systematic review and meta-analysis. Ann Intern Med 2012;21:291–304. [4] Cozma AI, Sievenpiper JL, de Souza RJ, Chiavaroli L, Ha V, Wang DD, et al. Effect of fructose on glycemic control in diabetes: a systematic review and meta-analysis of controlled feeding trials. Diabetes Care 2012;35: 1611–1620.
2
[5] Sievenpiper JL, Carleton AJ, Chatha S, Jiang HY, de Souza RJ, Beyene J, et al. Heterogeneous effects of fructose on blood lipids in individuals with type 2 diabetes: systematic review and meta-analysis of experimental trials in humans. Diabetes Care 2009;32:1930–1937. [6] Wang DD, Sievenpiper JL, De Souza RJ, Cozma AI, Chiavaroli L, Ha V, et al. Effect of fructose on postprandial triglycerides: a systematic review and meta-analysis of controlled feeding trials. Atherosclerosis 2014;232: 125–133. [7] Ha V, Sievenpiper JL, de Souza RJ, Chiavaroli L, Wang DD, Cozma AI, et al. Effect of fructose on blood pressure: a systematic review and meta-analysis of controlled feeding trials. Hypertension 2012;59:787–795. [8] Wang DD, Sievenpiper JL, de Souza RJ, Chiavaroli L, Ha V, Cozma AI, et al. The effects of fructose intake on serum uric acid vary among controlled dietary trials. J Nutr 2012;142:916–923. [9] Mouzaki M, Allard JP. The role of nutrients in the development, progression, and treatment of nonalcoholic fatty liver disease. J Clin Gastroenterol 2012;46:457–467. [10] Zein CO, Unalp A, Colvin R, Liu YC, McCullough AJ. Nonalcoholic steatohepatitis clinical research network. Smoking and severity of hepatic fibrosis in nonalcoholic fatty liver disease. J Hepatol 2011;54:753–759.
Laura Chiavaroli Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON, Canada Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada Vanessa Ha Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON, Canada Cyril W.C. Kendall Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON, Canada Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada
⇑
John L. Sievenpiper Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON, Canada Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada ⇑Corresponding author. E-mail address: [email protected]
Journal of Hepatology 2014 vol. xxx j xxx–xxx