Effects of n-3 fish oil on metabolic and histological parameters in NASH: A double-blind, randomized, placebo-controlled trial

Abstract

This study’s aim was to assess the histological and metabolic effects of N-3 polyunsaturated fatty acids (PUFA) versus placebo while adjusting for the impact of age and weight change in NASH patients. (ClinicalTrials.gov: NCT00681408). Methods Forty-one subjects with non-cirrhotic NASH were enrolled, and 34 completed the study. 17 received N-3 fish oil 3000 mg/day and 17 received placebo daily for 1 year with typical counseling on caloric intake and physical activity for all subjects. Results N-3- and placebo-treated groups showed no significant difference for the primary endpoint of NAS reduction ≥ 2 points without fibrosis progression after adjustment for known covariates (N-3, 4/17 (23.5%); placebo, 3/17, (17.6%), p=0.99). Among subjects with increased or stable weight, N-3 subjects showed a larger decrease in liver fat content by MRI than placebo-treated subjects (p=0.014 for 2nd quartile, p=0.003 for 3rd quartile of weight change). N-3 treatment showed significant fat reduction on paired analysis of image-assisted fat morphometry regardless of weight loss or gain. Exercise capacity remained markedly reduced in all subjects. No independent effects on markers of hepatocyte injury or insulin sensitivity indices were observed. Conclusion N-3 PUFA at 3000 mg/day for one year did not lead to improvement in the primary outcome of histological activity in NASH patients (≥ 2 point NAS reduction). N-3 led to reduced liver fat by multiple measures. Other metabolic effects were not seen, although no detrimental effects were apparent. Whether longer duration, higher dose, or different composition of N-3 therapy would lead to additional benefit is uncertain.

EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease

“…Preliminary data from small or uncontrolled studies suggested that n-3 polyunsaturated fatty acids (PUFA) might reduce liver fat [136], but two trials testing PUFA on histological outcomes were negative [102,104]. Available data on pentoxifylline and orlistat are limited or inconclusive [86,91,97].…”

Non-alcoholic fatty liver disease: an emerging driving force in chronic kidney disease

“…In a phase 2 double-blind, randomized, placebo-controlled trial, treatment with low-dosage (1800 mg/day) or high-dosage (2700 mg/day) ethyl-eicosapentanoic acid for 12 months had no significant effects on the histologic features of NASH 137 . In contrast, others have shown a benefit of n-3 PUFA treatment on liver fat assessed by magnetic resonance imaging (and have suggested that a greater benefit in NAFLD was associated with docosahexanoic acid treatment) [138][139][140] . Additionally, it has been suggested that the PNPLA3 148MM may attenuate any beneficial effect conferred by n-3 PUFA treatment in NAFLD 141 , emphasizing that future clinical trials testing new potential treatments for NAFLD should also perhaps consider the influence of different genotypes to modify any treatment effect.…”

Time to Replace Assessment of Liver Histology With MR-Based Imaging Tests to Assess Efficacy of Interventions for Nonalcoholic Fatty Liver Disease

“…Improving intra-hepatic triglyceride content assessed non-invasively by either the magnetic resonance spectroscopy-proton density fat fraction or the magnetic resonance imagingproton density fat fraction 16,17 , would allow a focus on the early stages of disease in NAFLD. Such an approach has been used recently by us 18 and by other investigators 19,20 , and the use of magnetic resonance-based techniques would also consistently improve retention of participants within clinical trials. In our experience, many patients recruited to clinical trials that test interventions for NAFLD are reluctant to undergo potentially risky liver biopsies where there is no direct benefit for their own clinical care.…”