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Effects of fructose restriction on liver steatosis (FRUITLESS); a double-blind randomized controlled trial.
Simons, N, Veeraiah, P, Simons, PIHG, Schaper, NC, Kooi, ME, Schrauwen-Hinderling, VB, Feskens, EJM, van der Ploeg, EMCL, Van den Eynde, MDG, Schalkwijk, CG, et al
The American journal of clinical nutrition. 2021;113(2):391-400
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The use of fructose in the food industry may have contributed to the increase in non-alcoholic fatty liver disease (NAFLD) in the general population. Consequently, obesity and associated comorbidities like type 2 diabetes, dyslipidaemia, NAFLD, and cardiovascular disease have increased. Although glucose and fructose are both sugars, they are metabolised differently by the body. The overfeeding of fructose may contribute to steatosis or accumulation of fat in the liver than glucose. The aim of this randomised, double-blind trial was to measure intrahepatic lipid content in 44 overweight subjects with high fatty liver index following fructose restriction for six weeks. In this study, fructose restriction resulted in a small but significant reduction in intrahepatic lipid content with a small effect size of 0.7% point. Fructose restriction did not seem to affect glucose tolerance, serum lipid concentration or HOMA-IR, variables related to intrahepatic lipid content. As a supplement, fructose may have a different metabolic profile than when taken as a food component. The study found no effect on glucose tolerance or serum lipid levels. The results of this study may help healthcare professionals to comprehend the role of fructose in steatosis and NAFLD.
Abstract
BACKGROUND There is an ongoing debate on whether fructose plays a role in the development of nonalcoholic fatty liver disease. OBJECTIVES The aim of this study was to investigate the effects of fructose restriction on intrahepatic lipid (IHL) content in a double-blind randomized controlled trial using an isocaloric comparator. METHODS Between March 2017 and October 2019, 44 adult overweight individuals with a fatty liver index ≥ 60 consumed a 6-wk fructose-restricted diet (<7.5 g/meal and <10 g/d) and were randomly assigned to supplementation with sachets of glucose (= intervention group) or fructose (= control group) 3 times daily. Participants and assessors were blinded to the allocation. IHL content, assessed by proton magnetic resonance spectroscopy, was the primary outcome and glucose tolerance and serum lipids were the secondary outcomes. All measurements were conducted in Maastricht University Medical Center. RESULTS Thirty-seven participants completed the study protocol. After 6 wk of fructose restriction, dietary fructose intake and urinary fructose excretion were significantly lower in the intervention group (difference: -57.0 g/d; 95% CI: -77.9, -39.5 g/d; and -38.8 μmol/d; 95% CI: -91.2, -10.7 μmol/d, respectively). Although IHL content decreased in both the intervention and control groups (P < 0.001 and P = 0.003, respectively), the change in IHL content was more pronounced in the intervention group (difference: -0.7% point, 95% CI: -2.0, -0.03% point). The changes in glucose tolerance and serum lipids were not significantly different between groups. CONCLUSIONS Six weeks of fructose restriction per se led to a small, but statistically significant, decrease in IHL content in comparison with an isocaloric control group.This trial was registered at clinicaltrials.gov as NCT03067428.
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Acute responses of hepatic fat content to consuming fat, glucose and fructose alone and in combination in non-obese non-diabetic individuals with non-alcoholic fatty liver disease.
Kovar, J, Dusilova, T, Sedivy, P, Bruha, R, Gottfriedova, H, Pavlikova, P, Pitha, J, Smid, V, Drobny, M, Dezortova, M, et al
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society. 2021;72(1)
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Non-alcoholic fatty liver disease (NAFLD) is often associated with obesity or conditions related to obesity, such as type 2 diabetes. Steatosis is one of the four stages of NAFLD, where there is a small layer of fat build-up on the liver. Currently, one in three people in the UK has simple fatty liver or steatosis. A fascinating aspect of this study is exploring the long-term cumulative effects of daily fat intake when consumed with glucose or fructose and in the pathogenesis of steatosis. In this randomised controlled study, the researchers examined the immediate impact of high-fat loads on hepatic fat content (HFC) when administered with glucose or fructose in eight healthy overweight males with NFALD. The experiments lasted only eight hours. HFC was only transiently elevated by co-administration of glucose and high-fat loading. However, fructose co-administration with multiple high-fat loads promoted HFC. Small sample size and short duration are the limitations of this study. Long-term robust studies are needed to confirm the findings. Yet, healthcare professionals can use this study to distinguish between the immediate effects of fructose or glucose when combined with multiple doses of high fat on HFC in healthy and NAFLD subjects.
Abstract
We have recently demonstrated that a high-fat load can induce immediate increase in hepatic fat content (HFC) and that such an effect can be modified differently by co-administration of fructose or glucose in healthy subjects. Therefore, we addressed the question how consumption of these nutrients affects changes in HFC in subjects with non-alcoholic fatty liver disease (NAFLD). Eight male non-obese non-diabetic patients with NAFLD underwent 6 experiments each lasting 8 hours: 1. fasting, 2. high-fat load (150 g of fat (dairy cream) at time 0), 3. glucose (three doses of 50 g at 0, 2, and 4 hours), 4. high-fat load with three doses of 50 g of glucose, 5. fructose (three doses of 50 g at 0, 2, and 4 hours), 6. high-fat load with three doses of 50 g of fructose. HFC was measured using magnetic resonance spectroscopy prior to meal administration and 3 and 6 hours later. Plasma triglycerides, non-esterified fatty acids, glucose and insulin were monitored throughout each experiment. HFC increased by 10.4 ± 6.9% six hours after a high-fat load and by 15.2 ± 12.5% after high-fat load with fructose. When co-administering glucose with fat, HFC rose only transiently to return to baseline at 6 hours. Importantly, NAFLD subjects accumulated almost five times more fat in their livers than healthy subjects with normal HFC. Consumption of a high-fat load results in fat accumulation in the liver of NAFLD patients. Fat accumulation after a fat load is diminished by glucose but not fructose co-administration.
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Association of Major Food Sources of Fructose-Containing Sugars With Incident Metabolic Syndrome: A Systematic Review and Meta-analysis.
Semnani-Azad, Z, Khan, TA, Blanco Mejia, S, de Souza, RJ, Leiter, LA, Kendall, CWC, Hanley, AJ, Sievenpiper, JL
JAMA network open. 2020;3(7):e209993
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Fructose is a type of sugar that has been implicated as a contributor to the development of metabolic syndrome (MetS), which is a condition where large waist circumference, high blood pressure and elevated blood lipid levels may all coexist. However, it remains unclear as to the role of fructose containing foods in the development of MetS. This systematic review and meta-analysis of 13 prospective cohort studies aimed to determine the association of several fructose containing foods and drinks with MetS. The results showed that sugary drinks containing fructose increased the risk of MetS, whereas no associations were found with mixed fruit juice, 100% fruit juice, honey, ice cream or confectionary. Interestingly fruit and yoghurt containing fructose decreased the risk of developing MetS. It was concluded that fructose containing food and drinks are not all equal in their biological effects. Sugary drinks increased the risk of developing MetS but yoghurt and fruit had a protective effect against development. Reasons for this could be due to a generally unhealthier lifestyle in those who consume sugary drinks or may be due to the increased protective effects associated with the vitamins and minerals in fruit and yoghurt. This study could be used by healthcare professionals to recommend a diet eliminating sugary drinks and containing regular fruit and yoghurt intake.
Abstract
Importance: Sugar-sweetened beverages (SSBs) are associated with increased risk of metabolic syndrome (MetS). However, the role of other important food sources of fructose-containing sugars in the development of MetS remains unclear. Objective: To examine the association of major food sources of fructose-containing sugars with incident MetS. Data Sources: MEDLINE, Embase, and Cochrane Library were searched from database inception to March 24, 2020, in addition to manual searches of reference lists from included studies using the following search terms: sugar-sweetened beverages, fruit drink, yogurt, metabolic syndrome, and prospective study. Study Selection: Inclusion criteria included prospective cohort studies of 1 year or longer that investigated the association of important food sources of fructose-containing sugars with incident MetS in participants free of MetS at the start of the study. Data Extraction and Synthesis: Study quality was assessed using the Newcastle-Ottawa Scale. Extreme quantile risk estimates for each food source with MetS incidence were pooled using a random-effects meta-analysis. Interstudy heterogeneity was assessed (Cochran Q statistic) and quantified (I2 statistic). Dose-response analyses were performed using a 1-stage linear mixed-effects model. The certainty of the evidence was assessed using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Results were reported according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Main Outcomes and Measures: Pooled risk ratio (RR) of incident MetS (pairwise and dose response). Results: Thirteen prospective cohort studies (49 591 participants [median age, 51 years; range, 6-90 years]; 14 205 with MetS) that assessed 8 fructose-containing foods and MetS were included. An adverse linear dose-response association for SSBs (RR for 355 mL/d, 1.14; 95% CI, 1.05-1.23) and an L-shaped protective dose-response association for yogurt (RR for 85 g/d, 0.66; 95% CI, 0.58-0.76) and fruit (RR for 80 g/d, 0.82; 95% CI, 0.78-0.86) was found. Fruit juices (mixed and 100%) had a U-shaped dose-response association with protection at moderate doses (mixed fruit juice: RR for 125 mL/d, 0.58; 95% CI, 0.42-0.79; 100% fruit juice: RR for 125 mL/d, 0.77; 95% CI, 0.61-0.97). Honey, ice cream, and confectionary had no association with MetS incidence. The certainty of the evidence was moderate for SSBs, yogurt, fruit, mixed fruit juice, and 100% fruit juice and very low for all other food sources. Conclusions and Relevance: The findings of this meta-analysis suggest that the adverse association of SSBs with MetS does not extend to other food sources of fructose-containing sugars, with a protective association for yogurt and fruit throughout the dose range and for 100% fruit juice and mixed fruit juices at moderate doses. Therefore, current policies and guidelines on the need to limit sources of free sugars may need to be reexamined.
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Dietary Fructose and the Metabolic Syndrome.
Taskinen, MR, Packard, CJ, Borén, J
Nutrients. 2019;11(9)
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Fructose is a naturally occurring sugar in carbohydrate foods and is often used as an ingredient in foods and sugar sweetened beverages (SSB) such as sport and energy drinks. The consumption of these drinks accounts for up to 15-17% of calorie intake in the modern western diet. Excessive sugar consumption is becoming a major public health issue with high sugar intake linked to Metabolic Syndrome (MetS), cardiovascular disease, type II diabetes and non-alcoholic fatty liver disease. Fructose is largely absorbed in the small intestines however the liver is considered the major organ for fructose metabolism. Too much fructose in the diet appears to stimulate the liver to produce more sugars and triglyceride fats which can raise cholesterol levels and promote insulin resistance. This partially explains the role of fructose in promoting a build-up of fat around the liver leading to non-alcoholic fatty liver disease and central obesity. Too much fructose is also linked to unfavourable changes in gut bacteria which may contribute to obesity and MetS. Overall the study concludes that too much fructose contributes to an unhealthy lifestyle and is a risk factor for metabolic disturbances.
Abstract
Abstract: Consumption of fructose, the sweetest of all naturally occurring carbohydrates, has increased dramatically in the last 40 years and is today commonly used commercially in soft drinks, juice, and baked goods. These products comprise a large proportion of the modern diet, in particular in children, adolescents, and young adults. A large body of evidence associate consumption of fructose and other sugar-sweetened beverages with insulin resistance, intrahepatic lipid accumulation, and hypertriglyceridemia. In the long term, these risk factors may contribute to the development of type 2 diabetes and cardiovascular diseases. Fructose is absorbed in the small intestine and metabolized in the liver where it stimulates fructolysis, glycolysis, lipogenesis, and glucose production. This may result in hypertriglyceridemia and fatty liver. Therefore, understanding the mechanisms underlying intestinal and hepatic fructose metabolism is important. Here we review recent evidence linking excessive fructose consumption to health risk markers and development of components of the Metabolic Syndrome.
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Relation of Total Sugars, Sucrose, Fructose, and Added Sugars With the Risk of Cardiovascular Disease: A Systematic Review and Dose-Response Meta-analysis of Prospective Cohort Studies.
Khan, TA, Tayyiba, M, Agarwal, A, Mejia, SB, de Souza, RJ, Wolever, TMS, Leiter, LA, Kendall, CWC, Jenkins, DJA, Sievenpiper, JL
Mayo Clinic proceedings. 2019;94(12):2399-2414
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Sugar-sweetened beverages have been associated with a risk for poor health outcomes, however risk for poor health outcomes with the fructose sugar they contain remains unclear. This systematic review and meta-analysis of 24 prospective cohort studies aimed to determine the role of total added fructose in the development of heart disease. Total sugars, sucrose and fructose were not associated with the incidence of heart disease, however total sugars and fructose increased the risk of death due to heart disease, the extent of which was dependent upon the amount consumed. Interestingly sucrose had a protective effect against death due to heart disease. It was concluded that consumption of fructose, total sugars and added sugars is associated with death due to heart disease, whereas sucrose is not. Although not all food stuffs containing fructose and added sugars were analysed, it is still indicative that healthcare professionals could recommend a low sugar and fructose diet to lower the risk of death due to heart disease.
Abstract
OBJECTIVE To determine the association of total and added fructose-containing sugars on cardiovascular (CVD) incidence and mortality. METHODS MEDLINE, EMBASE and Cochrane Library were searched from January 1, 1980, to July 31, 2018. Prospective cohort studies assessing the association of reported intakes of total, sucrose, fructose and added sugars with CVD incidence and mortality in individuals free from disease at baseline were included. Risk estimates were pooled using the inverse variance method, and dose-response analysis was modeled. RESULTS Eligibility criteria were met by 24 prospective cohort comparisons (624,128 unique individuals; 11,856 CVD incidence cases and 12,224 CVD mortality cases). Total sugars, sucrose, and fructose were not associated with CVD incidence. Total sugars (risk ratio, 1.09 [95% confidence interval, 1.02 to 1.17]) and fructose (1.08 [1.01 to 1.15]) showed a harmful association for CVD mortality, there was no association for added sugars and a beneficial association for sucrose (0.94 [0.89 to 0.99]). Dose-response analyses showed a beneficial linear dose-response gradient for sucrose and nonlinear dose-response thresholds for harm for total sugars (133 grams, 26% energy), fructose (58 grams, 11% energy) and added sugars (65 grams, 13% energy) in relation to CVD mortality (P<.05). The certainty of the evidence using GRADE was very low for CVD incidence and low for CVD mortality for all sugar types. CONCLUSION Current evidence supports a threshold of harm for intakes of total sugars, added sugars, and fructose at higher exposures and lack of harm for sucrose independent of food form for CVD mortality. Further research of different food sources of sugars is needed to define better the relationship between sugars and CVD. REGISTRATION clinicaltrials.gov, NCT01608620.
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Relation of total sugars, fructose and sucrose with incident type 2 diabetes: a systematic review and meta-analysis of prospective cohort studies.
Tsilas, CS, de Souza, RJ, Mejia, SB, Mirrahimi, A, Cozma, AI, Jayalath, VH, Ha, V, Tawfik, R, Di Buono, M, Jenkins, AL, et al
CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2017;189(20):E711-E720
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Sugars, particularly fructose-containing sugars, have been implicated as an important driver in the rise in incidence of type 2 diabetes. The aim of this study was to determine the role of fructose-containing sugars independent of food form in the development of type 2 diabetes. This study is a systemic review and meta-analysis of prospective cohort studies. The study included 15 cohorts from 9 studies. Results indicate that intakes of total sugars and fructose were not associated with type 2 diabetes, whereas intake of sucrose was associated with an 11% decrease in type 2 diabetes. Authors conclude that in the absence of a clear signal for harm, sugars alone do not appear to explain the relation between sugar-sweetened beverages and type 2 diabetes.
Abstract
BACKGROUND Sugar-sweetened beverages are associated with type 2 diabetes. To assess whether this association holds for the fructose-containing sugars they contain, we conducted a systematic review and meta-analysis of prospective cohort studies. METHODS We searched MEDLINE, Embase, CINAHL and the Cochrane Library (through June 2016). We included prospective cohort studies that assessed the relation of fructose-containing sugars with incident type 2 diabetes. Two independent reviewers extracted relevant data and assessed risk of bias. We pooled risk ratios (RRs) using random effects meta-analyses. The overall quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS Fiffeen prospective cohort studies (251 261 unique participants, 16 416 cases) met the eligibility criteria, comparing the highest intake (median 137, 35.2 and 78 g/d) with the lowest intake (median 65, 9.7 and 25.8 g/d) of total sugars, fructose and sucrose, respectively. Although there was no association of total sugars (RR 0.91, 95% confidence interval [CI] 0.76-1.09) or fructose (RR 1.04, 95% CI 0.84-1.29) with type 2 diabetes, sucrose was associated with a decreased risk of type 2 diabetes (RR 0.89, 95% CI 0.80-0.98). Our confidence in the estimates was limited by evidence of serious inconsistency between studies for total sugars and fructose, and serious imprecision in the pooled estimates for all 3 sugar categories. INTERPRETATION Current evidence does not allow us to conclude that fructose-containing sugars independent of food form are associated with increased risk of type 2 diabetes. Further research is likely to affect our estimates. TRIAL REGISTRATION ClinicalTrials.gov, no. NCT01608620.
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Fructose and Sucrose Intake Increase Exogenous Carbohydrate Oxidation during Exercise.
Trommelen, J, Fuchs, CJ, Beelen, M, Lenaerts, K, Jeukendrup, AE, Cermak, NM, van Loon, LJ
Nutrients. 2017;9(2)
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During prolonged exercise, the metabolic rate and energy requirement increase severalfold. Carbohydrate oxidation provides energy to muscles during exercise. In this randomised cross-over, double-blind study, researchers examined the effects of fructose or sucrose co-ingestion with glucose on exogenous carbohydrate oxidation rates during prolonged exercise in ten trained male cyclists. The administration of glucose with fructose or sucrose resulted in fewer gastrointestinal complaints than the administration of glucose alone. Co-ingestion of fructose or sucrose with glucose may enhance gastric absorption of carbohydrates and decrease the accumulation of carbohydrates in the gastrointestinal tract, which may explain lower gastrointestinal complaints among participants. Fructose co-ingestion increased exogenous carbohydrate oxidation rate during prolonged exercise by 35-55% more than glucose. Compared to glucose administration alone, fructose or sucrose co-administration also increased plasma lactate production and oxidation. The study concludes that fructose and sucrose can serve as functional ingredients in sports drinks to provide energy during prolonged exercise. As this study only focused on whole-body exogenous oxidation rates, more research is still needed to identify specific oxidation sites. Nevertheless, this study's findings can help healthcare professionals understand how different types of sugar can provide energy during prolonged exercise.
Abstract
Peak exogenous carbohydrate oxidation rates typically reach ~1 g∙min-1 during exercise when ample glucose or glucose polymers are ingested. Fructose co-ingestion has been shown to further increase exogenous carbohydrate oxidation rates. The purpose of this study was to assess the impact of fructose co-ingestion provided either as a monosaccharide or as part of the disaccharide sucrose on exogenous carbohydrate oxidation rates during prolonged exercise in trained cyclists. Ten trained male cyclists (VO2peak: 65 ± 2 mL∙kg-1∙min-1) cycled on four different occasions for 180 min at 50% Wmax during which they consumed a carbohydrate solution providing 1.8 g∙min-1 of glucose (GLU), 1.2 g∙min-1 glucose + 0.6 g∙min-1 fructose (GLU + FRU), 0.6 g∙min-1 glucose + 1.2 g∙min-1 sucrose (GLU + SUC), or water (WAT). Peak exogenous carbohydrate oxidation rates did not differ between GLU + FRU and GLU + SUC (1.40 ± 0.06 vs. 1.29 ± 0.07 g∙min-1, respectively, p = 0.999), but were 46% ± 8% higher when compared to GLU (0.96 ± 0.06 g∙min-1: p < 0.05). In line, exogenous carbohydrate oxidation rates during the latter 120 min of exercise were 46% ± 8% higher in GLU + FRU or GLU + SUC compared with GLU (1.19 ± 0.12, 1.13 ± 0.21, and 0.82 ± 0.16 g∙min-1, respectively, p < 0.05). We conclude that fructose co-ingestion (0.6 g∙min-1) with glucose (1.2 g∙min-1) provided either as a monosaccharide or as sucrose strongly increases exogenous carbohydrate oxidation rates during prolonged exercise in trained cyclists.
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Fructose, high-fructose corn syrup, sucrose, and nonalcoholic fatty liver disease or indexes of liver health: a systematic review and meta-analysis.
Chung, M, Ma, J, Patel, K, Berger, S, Lau, J, Lichtenstein, AH
The American journal of clinical nutrition. 2014;100(3):833-49
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There have been increasing concerns on the relationship between non-alcoholic fatty liver disease (NAFLD) and fructose or high-fructose corn syrup (HFCS). The objective of this systematic review was to assess the effect of dietary fructose in different forms on NAFLD and various biomarkers of liver health. This review included 21 published intervention studies and found a diet supplemented with fructose or glucose increases liver fat and aspartate aminotransferase (AST) concentrations when compared with a maintenance diet in healthy adults. Based on the available research, the authors point out the relationship between liver health markers and fructose, but also recognise this association may be confounded by excess energy intake. Due to the lack of robust findings, they conclude there is insufficient evidence on HFCS and NAFLD.
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. DESIGN 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.