Personalised Nutrition in Non-Alcoholic Fatty Liver Disease: Feasibility of a Nutrigenetic Therapeutic Approach

Abstract

Background: This multi-phased project investigates diet lifestyle care for patients with non-alcoholic fatty liver disease (NAFLD) and explores the feasibility of a genotype driven randomised controlled trial (RCT) investigating the differential response to a Mediterranean diet (MD) intervention of patients according to genotype for the rs738409 (I148M) variant of PNPLA3. Methods: Clinicians completed an e-survey to assess current practice and perceived barriers to the effective delivery of lifestyle interventions. In a meta-analysis, data from randomised and clinical controlled trials describing the effects of MD and calorie-restricted interventions (CRI) in NAFLD were synthesised. A randomised, crossover feasibility trial was undertaken. Participants were randomised to Diet 1 (MD) or Diet 2 (control i.e., habitual diet) for 4-weeks, separated by a 4-weeks washout period. The primary outcome was the feasibility, acceptability and effectiveness of the protocol. Secondary outcomes included assessment of liver fibrosis biomarkers and the influence of PNPLA3 genotype. Results: A cross-sectional survey revealed that provision of diet lifestyle care differs across centres and professional roles, and deviates from standard of care guidance. A meta-analysis found that dietary interventions (MD and CRI) improved NAFLD surrogate markers in as little as two weeks and improvements were sustained for up to two years. There was a dose-response relationship between degree of calorie restriction and beneficial effects on liver function and weight loss. The MD may be an effective diet therapy. Experimental data established the feasibility of a genotype-driven RCT and the effectiveness of a MD intervention, which rapidly improved cardiovascular risk (CVR) with evidence of early benefits on hepatic fibrosis. Carriers of the I148M variant appear to benefit less in terms of CVR factors when prescribed a MD intervention. Conclusion: There is considerable variability in diet lifestyle care for patients with NAFLD. The effectiveness of calorie restriction and diet modification, observed in the meta-analysis, suggests this strategy should remain the cornerstone of NAFLD management. The findings of the feasibility study lay the foundation for a future definitive RCT, by informing trial design and optimising the dietary treatments, instruments and procedures