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Project: Fructose Consumption and Non-alcoholic Fatty Liver Disease (NAFLD)

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Project Summary

Title and Description

Title Fructose Consumption and Non-alcoholic Fatty Liver Disease (NAFLD)
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Description Background: There are growing concerns about the effects of dietary fructose on health outcomes because the intakes appear to have parallel trends in non-alcoholic fatty liver disease (NAFLD) and obesity prevalence in the United States. Purpose: To examine the effect of different levels and sources of dietary fructose on the incidence or prevalence of NAFLD and on indices of liver health in humans. Data Sources: English-language studies identified from MEDLINE, Cochrane Central Register of Controlled Trials, CAB Abstracts, and Global Health databases up to September 2012. Study Selection: Human studies of any design in children and adults with low to no alcohol intake and reporting at least one predetermined measure of liver health. Data Extraction: Study data was extracted by one investigator and corroborated by a second investigator. Differences were resolved by consensus. Data Synthesis: Twenty-two studies met the inclusion criteria, 3 reported NAFLD outcomes and 19 reported indices of liver health. Of these, all but 1 study were rated at medium or high risk of bias. The overall strength of evidence for an association between fructose intake and incidence of NAFLD was rated insufficient because of the biases and confounding in the study results. The 19 studies reporting indices of liver health were synthesized separately by each outcome: liver fat outcomes (7 studies), liver enzymes (11 studies), hepatic de novo lipogenesis rates (2 studies), and plasma bilirubin concentrations (2 studies). The overall strength of evidence was rated insufficient for all outcomes, except for some plasma liver enzymes. Our random-effects meta-analysis of 3 short-term RCTs (6 to 7 days) showed a significant increase in alanine aminotransferase (ALT) concentrations (+4.32 IU/L, 95% CI 0.20, 8.43, P=0.04) when a free fructose enriched excess energy diet was compared to a habitual weight maintenance diet. Limitations: Most studies were rated at medium or high risk of bias, were small in sample size, included healthy adult men only, and were highly heterogeneous in study design and intervention, and thus limiting comparability. Conclusions: Due to scarce, poor-quality, and heterogeneous data, we concluded that evidence is insufficient to draw conclusions regarding the effect of fructose consumption on NAFLD, while there is low level of evidence for a relationship between high free fructose intake in excess of energy needs and elevated liver enzyme concentrations. Large prospective cohort studies using standard NAFLD diagnosis are needed to examine the complex relationships between dietary factors and the risk of NAFLD.
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Contributor(s) Mei Chung, PhD, MPH Jiantao Ma, MD, MS Kamal Patel, MPH, MBA Samantha Berger, BS Joseph Lau, MD Alice H. Lichtenstein, ScD
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Methodology See Chung M, Ma J, Patel K, Berger S, Lau J, Lichtenstein AH. Fructose, high-fructose corn syrup, sucrose, and nonalcoholic fatty liver disease or indexes of liver health: a systematic review and meta-analysis. Am J Clin Nutr. 2014 Sep;100(3):833-49. doi: 10.3945/ajcn.114.086314. Epub 2014 Aug 6. PubMed PMID: 25099546; PubMed Central PMCID: PMC4135494.
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DOI https://dx.doi.org/10.7301/Z04Q7RWZ
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Funding Source The International Life Sciences Institute (ILSI) North American Branch
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Notes We created a standardized extraction form for all qualifying studies in this systematic review (Key questions 1 and 2). We used different risk of bias tools for different study designs, and for each risk of bias tool, we created a stand alone Risk-of-Bias form (Key questions 3, 4, and 5). There are a few glitches in the SRDR system causing missing data in the study preview. These glitches are being resolved, and the complete extraction forms can be viewed to see what data was collected from each study. Funding for this systematic review was provided by the Technical Committee on Carbohydrates of the International Life Sciences Institute (ILSI) North American Branch. ILSI North America’s participation was limited to discussion with the team about the initial formulation of Key Questions (during one kick-off teleconference). The sponsor had no role in study selection, quality assessment, or synthesis.
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Key Questions

1 What is the effect of fructose consumption on the risk of NAFLD? a) Is there a dose-response relationship between fructose intake and NAFLD? b) Does the relationship between fructose intake and NAFLD exhibit a threshold effect within or beyond the range of typical fructose intakes? c) What factors modify the effect of fructose consumption on NAFLD?
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2 What are the relationships between fructose consumption and indices of liver health?
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3 Risk of Bias - RCTs and non-RCT
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4 Risk of Bias - Cohort, Case-Control, and Single Arm Studies
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5 Risk of Bias - Cross-Sectional Studies
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Associated Extraction Forms

Title Created by Key Questions Addressed Form Notes
Fructose and NAFLD SRDR Administrator 1, 2
Intervention Studies Quality SRDR Administrator 3
Cohort, Case Control, Single Arm Quality SRDR Administrator 4
Case Control & Cross Sectional Quality SRDR Administrator 5


Associated Studies (each link opens a new tab)

Title Author Year
Volynets et al. 2012
Sucrose-sweetened beverages increase fat storage in the liver, muscle, and visceral fat depot: a 6-mo randomized intervention study. Maersk M., Belza A., Stødkilde-Jørgensen H., Ringgaard S., Chabanova E., Thomsen H., Pedersen SB., Astrup A., Richelsen B. 2012
Cholesterol synthesis is associated with hepatic lipid content and dependent on fructose/glucose intake in healthy humans Silbernagel et al. 2012
Low to moderate sugar-sweetened beverage consumption impairs glucose and lipid metabolism and promotes inflammation in healthy young men: a randomized controlled trial Aeberli et al. 2011
Increased hepatic fat in overweight Hispanic youth influenced by interaction between genetic variation in PNPLA3 and high dietary carbohydrate and sugar consumption Davis et al. 2010
Effects of short-term overfeeding with fructose, fat and fructose plus fat on plasma and hepatic lipids in healthy men Sobrecases et al. 2010
Dietary and physical activity patterns in children with fatty liver Mager et al. 2010
Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response Perez-Polo et al. 2010
Effects of a short-term overfeeding with fructose or glucose in healthy young males Ngo Sock et al. 2010
Fructose and oxidized low-density lipoprotein in pediatric nonalcoholic fatty liver disease: a pilot study Vos et al. 2009
Fructose overconsumption causes dyslipidemia and ectopic lipid deposition in healthy subjects with and without a family history of type 2 diabetes. Lê KA., Ith M., Kreis R., Faeh D., Bortolotti M., Tran C., Boesch C., Tappy L. 2009
Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. Stanhope KL., Schwarz JM., Keim NL., Griffen SC., Bremer AA., Graham JL., Hatcher B., Cox CL., Dyachenko A., Zhang W., McGahan JP., Seibert A., Krauss RM., Chiu S., Schaefer EJ., Ai M., Otokozawa S., Nakajima K., Nakano T., Beysen C., Hellerstein MK., Berglund L., Havel PJ. 2009
Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake. Thuy S., Ladurner R., Volynets V., Wagner S., Strahl S., Königsrainer A., Maier KP., Bischoff SC., Bergheim I. 2008
Fructose consumption as a risk factor for non-alcoholic fatty liver disease. Ouyang X., Cirillo P., Sautin Y., McCall S., Bruchette JL., Diehl AM., Johnson RJ., Abdelmalek MF. 2008
Markedly blunted metabolic effects of fructose in healthy young female subjects compared with male subjects. Couchepin C., Lê KA., Bortolotti M., da Encarnaçao JA., Oboni JB., Tran C., Schneiter P., Tappy L. 2008
A 4-wk high-fructose diet alters lipid metabolism without affecting insulin sensitivity or ectopic lipids in healthy humans. Lê KA., Faeh D., Stettler R., Ith M., Kreis R., Vermathen P., Boesch C., Ravussin E., Tappy L. 2006
Effect of fructose overfeeding and fish oil administration on hepatic de novo lipogenesis and insulin sensitivity in healthy men. Faeh D., Minehira K., Schwarz JM., Periasamy R., Periasami R., Park S., Seongsu P., Tappy L. 2005
The influence of diet upon liver function tests and serum lipids in healthy male volunteers resident in a Phase I unit. Purkins L., Love ER., Eve MD., Wooldridge CL., Cowan C., Smart TS., Johnson PJ., Rapeport WG. 2004
Effects of daily consumption of honey solution on hematological indices and blood levels of minerals and enzymes in normal individuals. Al-Waili NS. 2003
Effects of fructose feeding on blood parameters and blood pressure in impaired glucose-tolerant subjects. Koh ET., Ard NF., Mendoza F. 1988
Diet-induced changes in serum transaminase and triglyceride levels in healthy adult men. Role of sucrose and excess calories. Porikos KP., Van Itallie TB. 1983
Diets high in glucose or sucrose and young women. Kelsay JL., Behall KM., Holden JM., Prather ES. 1974
Effects of supplementation with essential amino acids on intrahepatic lipid concentrations during fructose overfeeding in humans. Theytaz F., Noguchi Y., Egli L., Campos V., Buehler T., Hodson L., Patterson BW., Nishikata N., Kreis R., Mittendorfer B., Fielding B., Boesch C., Tappy L. 2012




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The data contained in this project are distributed under the terms of the Creative Commons Attribution-NonCommerical license, which permits the use, dissemination, and reproduction in any medium, provided the original work is properly cited, and that the use is non-commercial and otherwise in compliance with the license. See: https://creativecommons.org/licenses/by-nc/3.0/