Several recently completed clinical trials in NASH patients have included fibrosis stage reductions in 20 30 of the patients in placebo cohorts¹,²,³. The mechanisms driving these reductions have not yet been identified. Reductions of alcohol (EtOH) intake could be influential, as moderate EtOH intake has been shown to enhance hepatic de novo lipogenesis⁴. Moreover, EtOH consumption is common in populations worldwide and has increased in some populations during the COVID-19 pandemic⁵,⁶. NASH clinical trial protocols do not exclude moderate EtOH consumers (20-30 g/d, equivalent to 1.5-2 standard drinks/d). A quantitative systems pharmacology (QSP) model, NAFLDsym⁷ (Figure 1), was employed to test the hypothesis that reductions in daily moderate EtOH intake could reduce liver lipid burden, lipotoxicity, and fibrosis stage in NASH patients (Figure 2).
NASH SimCohorts (Table 1) regularly consuming 30 or 15 g/d EtOH were used to simulate reductions in daily EtOH intake. Baseline EtOH administration was simulated as one or two 15 g drinks over one hour (Figure 3), coincident with the dinner meal. EtOH consumption at these levels were simulated for 1 year in the SimCohorts before subsequent reductions in intake were simulated. GastroPlus was used to simulate the rate of hepatic EtOH metabolism. Consistent with previous reports, 20% of the metabolized EtOH was able to contribute to hepatic de novo lipogenesis in the simulations⁴-⁸. Reductions of EtOH intake to 15 g/d or 0 g/d were simulated for 52 weeks in the 30 g/d SimCohorts (Figure 4). Similarly, the 15 g/d SimCohorts were used to simulate 0 g/d of EtOH intake (Figure 5). Changes in de novo lipogenesis, liver fat, plasma ALT, NAS, and fibrosis stage were predicted. Body weight did not change.
Decreased EtOH intake elicited fibrosis stage and NAS reductions in the SimCohorts originally consuming 30 g/d, with a greater proportion of patients with an improved fibrosis stage in the 0 g/d vs. 15 g/d simulations (Figure 4). Twenty-four-hour average de novo lipogenesis was predicted to decline in the 0 g/d or 15 g/d simulations. Modest reductions in liver fat and ALT were predicted when EtOH intake was reduced to 0 or 15 g/d. Similar changes were predicted as SimCohorts transitioned from consuming 15 g/d to 0 g/d (Figure 5).
Reductions in moderate EtOH intake for NASH patients who are regular consumers may lead to improvements in fibrosis stage due to decreased de novo lipogenesis. This behavioral adjustment may influence the frequency of observed fibrosis
stage reductions in clinical trials whether on placebo or treatment, particularly in studies conducted in regions with a higher prevalence of moderate EtOH consumption.
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Christina Battista, James J. Beaudoin, Kyunghee Yang, Scott Q. Siler
American Association for the Study of Liver Diseases (AASLD) Liver Meeting, November 4-8, 2022, Washington, DC