Systematic review and meta-analysis of controlled intervention studies on the effectiveness of long-chain omega-3 fatty acids in patients with nonalcoholic fatty liver disease

Abstract

Context: Treatment options for nonalcoholic fatty liver disease (NAFLD) are needed.

Objective: The aim of this review was to systematically assess the effects of omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs), particularly eicosapentaenoic acid and docosahexaenoic acid, on liver-related and metabolic outcomes in adult and pediatric patients with NAFLD.

Data sources: The online information service ProQuest Dialog was used to search 8 literature databases.

Study selection: Controlled intervention studies in which the independent effects of n-3 LC-PUFAs could be isolated were eligible for inclusion.

Data extraction: The 18 unique studies that met the criteria for inclusion were divided into 2 sets, and data transcriptions and study quality assessments were conducted in duplicate. Each effect size was expressed as the weighted mean difference and 95%CI, using a random-effects model and the inverse of the variance as a weighting factor.

Results: Based on the meta-analyses, supplementation with n-3 LC-PUFAs resulted in statistically significant improvements in 6 of 13 metabolic risk factors, in levels of 2 of 3 liver enzymes, in liver fat content (assessed via magnetic resonance imaging/spectroscopy), and in steatosis score (assessed via ultrasonography). Histological measures of disease [which were assessed only in patients with nonalcoholic steatohepatitis (NASH)] were unaffected by n-3 LC-PUFA supplementation.

Conclusions: Omega-3 LC-PUFAs are useful in the dietary management of patients with NAFLD. Additional trials are needed to better understand the effects of n-3 LC-PUFAs on histological outcomes in patients with NASH.

Systematic review registration: PROSPERO CRD42017055951.

Figure 1

Flow diagram of the literature search process. Abbreviations: NAFLD, nonalcoholic fatty liver disease; LC-PUFAS, long-chain polyunsaturated fatty acids.

Figure 2

Effects of n-3 LC-PUFAs vs a control on AST levels in patients with NAFLD. A random-effects model was used to calculate the pooled estimate of the differences in means and the accompanying 95%CI. Studies were weighted by the inverse of their variance; the area of each symbol is proportional to the weight of the study. The diamond represents the pooled effect. The pooled change from baseline in serum AST levels with intake of n-3 LC-PUFAs, corrected for changes from baseline in the control group, is −2.41 IU/L (95%CI, −7.35 to 2.52 IU/L; P=0.338). Using the trim and fill method of Duval and Tweedie, 1 study was found to be missing to the right of the mean effect. With this study imputed, the pooled effect is −1.56 IU/L (95%CI, −6.47 to 3.35 IU/L). Abbreviations: AST, aspartate aminotransferase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HyperL, hyperlipidemia/dyslipidemia; n-3 LC-PUFAs, omega-3 long-chain polyunsaturated fatty acids; MetSyn, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NR, not reported; T2DM, type 2 diabetes mellitus.

Figure 3

Effects of n-3 LC-PUFAs vs a control on ALT levels in patients with NAFLD. A random-effects model was used to calculate the pooled estimate of the differences in means and the accompanying 95%CI. Studies were weighted by the inverse of their variance; the area of each symbol is proportional to the weight of the study. The diamond represents the pooled effect. The pooled change from baseline in serum ALT levels with intake of n-3 LC-PUFAs, corrected for changes from baseline in the control group, is −4.63 IU/L (95%CI, −9.18 to −0.08 IU/L; P=0.046). Using the trim and fill method of Duval and Tweedie, no studies were found to be missing to the right of the mean effect. Abbreviations: ALT, alanine aminotransferase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HyperL, hyperlipidemia/dyslipidemia; n-3 LC-PUFAs, omega-3 long-chain polyunsaturated fatty acids; MetSyn, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NR, not reported; PCOS, polycystic ovarian syndrome; T2DM, type 2 diabetes mellitus.

Figure 4

Effects of n-3 LC-PUFAs vs a control on GGT levels in patients with NAFLD. A random-effects model was used to calculate the pooled estimate of the differences in means and the accompanying 95%CI. Studies were weighted by the inverse of their variance; the area of each symbol is proportional to the weight of the study. The diamond represents the pooled effect. The pooled change from baseline in serum GGT with intake of n-3 LC-PUFAs, corrected for changes from baseline in the control group, is −5.56 IU/L (95%CI, −9.61 to −1.50 IU/L; P=0.007). Using the trim and fill method of Duval and Tweedie, 1 study was found to be missing to the right of the mean effect. With this study imputed, the pooled reduction in serum GGT levels with n-3 LC-PUFAs vs a control is −5.16 IU/L (95%CI, −8.92 to −1.40 IU/L). Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; GGT, γ-glutamyl transferase; HyperL, hyperlipidemia/dyslipidemia; n-3 LC-PUFAs, omega-3 long-chain polyunsaturated fatty acids; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NR, not reported.

Figure 5

Effects of n-3 LC-PUFAs vs a control on liver fat content, assessed using magnetic resonance imaging or magnetic resonance spectroscopy, in patients with NAFLD. A random-effects model was used to calculate the pooled estimate of the differences in means and the accompanying 95%CI. Studies were weighted by the inverse of their variance; the area of each symbol is proportional to the weight of the study. The diamond represents the pooled effect. The pooled change from baseline in liver fat content with intake of n-3 LC-PUFAs, corrected for changes from baseline in the control group, is −5.19% (95%CI, −9.58 to −0.79%; P=0.021). Using the trim and fill method of Duval and Tweedie, no studies were found to be missing to the right of the mean effect. Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; n-3 LC-PUFAs, omega-3 long-chain polyunsaturated fatty acids; LFC, liver fat content; MetSyn, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PCOS, polycystic ovarian syndrome.

Figure 6

Effects of n-3 LC-PUFAs vs a control on the grade of steatosis, assessed using ultrasonography, in patients with NAFLD. A random-effects model was used to calculate the pooled estimate of the differences in means and the accompanying 95%CI. Studies were weighted by the inverse of their variance; the area of each symbol is proportional to the weight of the study. The diamond represents the pooled effect. The pooled change from baseline in the grade of steatosis with intake of n-3 LC-PUFAs, corrected for changes from baseline in the control group, is −0.71 (95%CI, −0.99 to −0.42; P<0.001). Using the trim and fill method of Duval and Tweedie, no studies were found to be missing to the right of the pooled effect. Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HyperL, hyperlipidemia/dyslipidemia; n-3 LC-PUFAs, omega-3 long-chain polyunsaturated fatty acids; NAFLD, nonalcoholic fatty liver disease; NR, not reported; SG, steatosis grade.

Figure 7

Effects of n-3 LC-PUFAs vs a control on the fibrosis score, assessed histologically, in patients with NASH. A random-effects model was used to calculate the pooled estimate of the differences in means and the accompanying 95%CI. Studies were weighted by the inverse of their variance; the area of each symbol is proportional to the weight of the study. The diamond represents the pooled effect. The pooled change from baseline in the fibrosis score with intake of n-3 LC-PUFAs, corrected for changes from baseline in the control group, is −0.23 (95%CI, −0.56 to 0.093; P=0.162). Using the trim and fill method of Duval and Tweedie, no studies were found to be missing to the right of the mean effect. Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; n-3 LC-PUFAs, omega-3 long-chain polyunsaturated fatty acids; NASH, nonalcoholic steatohepatitis; NR, not reported; T2DM, type 2 diabetes mellitus.

Figure 8

Effects of n-3 LC-PUFAs vs a control on the hepatocellular ballooning score, assessed histologically, in patients with NASH. A random-effects model was used to calculate the pooled estimate of the differences in means and the accompanying 95%CI. Studies were weighted by the inverse of their variance; the area of each symbol is proportional to the weight of the study. The diamond represents the pooled effect. The pooled change from baseline in the hepatocellular ballooning score with intake of n-3 LC-PUFAs, corrected for changes from baseline in the control group, is −0.18 (95%CI, −0.62 to 0.27; P=0.443). Using the trim and fill method of Duval and Tweedie, no studies were found to be missing to the right of the mean effect. Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; n-3 LC-PUFAs, omega-3 long-chain polyunsaturated fatty acids; NASH, nonalcoholic steatohepatitis; NR, not reported; T2DM, type 2 diabetes mellitus.

Figure 9

Effects of n-3 LC-PUFAs vs a control on the steatosis score, assessed histologically, in patients with NASH. A random-effects model was used to calculate the pooled estimate of the differences in means and the accompanying 95%CI. Studies were weighted by the inverse of their variance; the area of each symbol is proportional to the weight of the study. The diamond represents the pooled effect. The pooled change from baseline in the steatosis score with intake of n-3 LC-PUFAs, corrected for changes from baseline in the control group, is −0.09 (95%CI, −0.60 to 0.41; P=0.717). Using the trim and fill method of Duval and Tweedie, no studies were found to be missing to the right of the mean effect. Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; n-3 LC-PUFAs, omega-3 long-chain polyunsaturated fatty acids; NASH, nonalcoholic steatohepatitis; SS, steatosis score; T2DM, type 2 diabetes mellitus.

Figure 10

Effects of n-3 LC-PUFAs vs a control on the lobular inflammation score, assessed histologically, in patients with NASH. A random-effects model was used to calculate the pooled estimate of the differences in means and the accompanying 95%CI. Studies were weighted by the inverse of their variance; the area of each symbol is proportional to the weight of the study. The diamond represents the pooled effect. The pooled change from baseline in the lobular inflammation score with intake of n-3 LC-PUFAs, corrected for changes from baseline in the control group, is −0.03 (95%CI, −0.58 to 0.52; P=0.911). Using the trim and fill method of Duval and Tweedie, no studies were found to be missing to the right of the mean effect. Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; n-3 LC-PUFAs, omega-3 long-chain polyunsaturated fatty acids; LI, lobular inflammation; NASH, nonalcoholic steatohepatitis; T2DM, type 2 diabetes mellitus.

Figure 11

Effects of n-3 LC-PUFAs vs a control on NAS, assessed histologically, in patients with NASH. A random-effects model was used to calculate the pooled estimate of the differences in means and the accompanying 95%CI. Studies were weighted by the inverse of their variance; the area of each symbol is proportional to the weight of the study. The diamond represents the pooled effect. The pooled change from baseline in NAS with intake of n-3 LC-PUFAs, corrected for changes from baseline in the control group, is 0.56 (95%CI, −0.12 to 1.23; P=0.105). Using the trim and fill method of Duval and Tweedie, no studies were found to be missing to the right of the mean effect. Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; n-3 LC-PUFAs, omega-3 long-chain polyunsaturated fatty acids; NAS, nonalcoholic fatty liver disease activity score; NASH, nonalcoholic steatohepatitis; T2DM, type 2 diabetes mellitus.