Original PNPLA3 genotypes modify the adverse effect of the total energy intake on high-risk nonalcoholic steatohepatitis development

Background: The relationship between diet and risk genotypes in nonalcoholic steatohepatitis (NASH) development and fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD) remains unclear.Objective: We aimed to investigate the effects of diet on NASH development and fibrosis progression in patients with NAFLD stratified by the PNPLA3 genotype.Methods: We performed a prospective study in a cohort of patients with biopsy-confirmed NAFLD. Histologic deterioration was obtained using serial transient elastography at every 1 or 2 y. The primary outcome was fibrosis progression, and the secondary outcome was development of high-risk NASH, defined as FibroScan-aspartate aminotransferase score >= 0.67 during the follow-up of patients with nonalcoholic fatty liver at the baseline. Dietary intake was evaluated using a semiquantitative food frequency questionnaire.Results: The primary outcome was observed in 42 (29.0%) of the 145 patients during a median follow-up of 49 mo; neither the total energy intake nor each macronutrient intake significantly affected the primary outcome occurrence. Conversely, the total energy intake (HR per 1-SD: 3.03; 95% CI: 1.31, 7.01) and the PNPLA3 rs738409 genotype [HR per 1 risk allele (G): 2.06; 95% CI: 1.11, 3.83)] were independent risk factors for high-risk NASH. The significant interaction between the total energy intake and PNPLA3 genotype was noted in developing high-risk NASH (P = 0.044). As the number of PNPLA3 risk alleles decreased, the effect of the total energy intake on high-risk NASH increased; the HR per 1-SD increment in total energy intake was 1.52 (95% CI: 0.42, 5.42), 3.54 (95% CI: 1.23, 10.18), and 8.27 (95% CI: 1.20, 57.23) for the GG, CG, and CC genotypes, respectively.Conclusions: The total energy intake adversely affected the development of high-risk NASH in patients with biopsy-confirmed NAFLD. The effect was more prominent in patients without the PNPLA3 risk allele, highlighting the importance of personalized dietary interventions in NAFLD treatment.

Automated summary

This study aimed to investigate the effects of diet on the development of nonalcoholic steatohepatitis (NASH) and fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD). The total energy intake had no impact on fibrosis progression but was associated with high-risk NASH. The effect of total energy intake on high-risk NASH was more pronounced in patients without the PNPLA3 risk allele.