Effect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials

Abstract

Background/objectives: In the absence of consistent clinical evidence, there are concerns that fructose contributes to non-alcoholic fatty liver disease (NAFLD). To determine the effect of fructose on markers of NAFLD, we conducted a systematic review and meta-analysis of controlled feeding trials.

Subjects/methods: We searched MEDLINE, EMBASE, CINAHL and the Cochrane Library (through 3 September 2013). We included relevant trials that involved a follow-up of ≥ 7 days. Two reviewers independently extracted relevant data. Data were pooled by the generic inverse variance method using random effects models and expressed as standardized mean difference (SMD) for intrahepatocellular lipids (IHCL) and mean difference (MD) for alanine aminotransferase (ALT). Inter-study heterogeneity was assessed (Cochran Q statistic) and quantified (I(2) statistic).

Results: Eligibility criteria were met by eight reports containing 13 trials in 260 healthy participants: seven isocaloric trials, in which fructose was exchanged isocalorically for other carbohydrates, and six hypercaloric trials, in which the diet was supplemented with excess energy (+21-35% energy) from high-dose fructose (+104-220 g/day). Although there was no effect of fructose in isocaloric trials, fructose in hypercaloric trials increased both IHCL (SMD=0.45 (95% confidence interval (CI): 0.18, 0.72)) and ALT (MD=4.94 U/l (95% CI: 0.03, 9.85)).

Limitations: Few trials were available for inclusion, most of which were small, short (≤ 4 weeks), and of poor quality.

Conclusions: Isocaloric exchange of fructose for other carbohydrates does not induce NAFLD changes in healthy participants. Fructose providing excess energy at extreme doses, however, does raise IHCL and ALT, an effect that may be more attributable to excess energy than fructose. Larger, longer and higher-quality trials of the effect of fructose on histopathological NAFLD changes are required.

Figure 1

Flow of the literature.

Figure 2

Forest plots of the effect of fructose on intrahepatocellular lipid (IHCL) in healthy participants in (a) isocaloric and (b) hypercaloric feeding trials. Pooled effect estimates shown as diamonds. Data are expressed as weighted MD with 95% CI using generic inverse variance random effects models. Inter-study heterogeneity was tested by Cochrane's Q statistic (χ²-test) at a significance level of P<0.10 and quantified by I², where I²⩾50% is considered to be evidence of substantial heterogeneity and ⩾75%, considerable heterogeneity. Any CHO denotes any carbohydrate comparator; E neutral, neutral energy balance; E positive, positive energy balance; and Off-T2DM, offspring of T2DM.

Figure 3

Forest plots of the effect of fructose on ALT in healthy participants in (a) isocaloric and (b) hypercaloric feeding trials. Pooled effect estimates shown as diamonds. Data are expressed as weighted MD with 95% CI using generic inverse variance random effects models. Inter-study heterogeneity was tested by Cochrane's Q statistic (χ²-test) at a significance level of P<0.10 and quantified by I², where I²⩾50% is considered to be evidence of substantial heterogeneity and ⩾75%, considerable heterogeneity. Any CHO denotes any carbohydrate comparator; E neutral, neutral energy balance; E positive, positive energy balance; HD, high dose; LD, low dose; and Off-T2DM, offspring of T2DM.