Effects of fructose restriction on liver steatosis (FRUITLESS); a double-blind randomized controlled trial

Nynke Simons, Pandichelvam Veeraiah, Pomme I H G Simons, Nicolaas C Schaper, M Eline Kooi, Vera B Schrauwen-Hinderling, Edith J M Feskens, E M C Liesbeth van der Ploeg, Mathias D G Van den Eynde, Casper G Schalkwijk, Coen D A Stehouwer, Martijn C G J Brouwers, Nynke Simons, Pandichelvam Veeraiah, Pomme I H G Simons, Nicolaas C Schaper, M Eline Kooi, Vera B Schrauwen-Hinderling, Edith J M Feskens, E M C Liesbeth van der Ploeg, Mathias D G Van den Eynde, Casper G Schalkwijk, Coen D A Stehouwer, Martijn C G J Brouwers

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.

Keywords: dietary intervention; fructose; glucose metabolism; hepatic steatosis; intrahepatic lipid; nonalcoholic fatty liver disease; nutrition; randomized controlled trial.

© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.

Figures

FIGURE 1
FIGURE 1
Flowchart of study. Seventy-one individuals were assessed for eligibility. Forty-four participants were randomly assigned to the intervention group (fructose-restricted diet plus glucose supplementation) or control group (fructose-restricted diet plus fructose supplementation), of whom 19 were assigned before and 25 after the protocol amendment (i.e., abandonment of the fructose intake ≥ 45 g/d inclusion criterion). Six participants discontinued participation because of various reasons. At completion of the study, 1 participant did not appear to meet the inclusion criteria (i.e., FLI ≥ 60) and was therefore excluded. Per-protocol analyses were carried out with 16 and 21 participants in the intervention and the control group, respectively. FLI, fatty liver index; RCT, randomized controlled trial.
FIGURE 2
FIGURE 2
Adherence to the intervention. (A) Daily fructose intake, (B) daily fructose intake including supplementation, (C) 24-h urinary fructose concentration, (D) daily caloric intake, and (E) BMI in Ctrl (white bars, n = 21) and Int (grey bars, n = 16) at baseline (pre) and after completion of the study (post). Data are expressed as median ± IQR. Differences within groups are analyzed with Wilcoxon's Signed Rank test. Differences between groups are analyzed with a Mann–Whitney U test. Ctrl, control group; IHL, intrahepatic lipid; Int, intervention group.
FIGURE 3
FIGURE 3
IHL content, glucose tolerance, and serum lipid concentrations. (A) IHL content, (B) glucose AUC during an OGTT, (C) serum total cholesterol, (D) serum HDL cholesterol, (E) serum LDL cholesterol, and (F) serum triglycerides in Ctrl (white bars, n = 21) and Int (grey bars, n = 16) at baseline (pre) and after completion of the study (post). Data are expressed as median ± IQR. Differences within groups are analyzed with Wilcoxon's Signed Rank test. Differences between groups are analyzed with a Mann–Whitney U test. Ctrl, control group; IHL, intrahepatic lipid; Int, intervention group; OGTT, oral-glucose-tolerance test.

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