Abstract
BACKGROUND: Despite the clear link between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus, little is understood about how glycemic control impacts histological severity. We aimed to investigate the deeper association between hemoglobin A1c (HbA1c) and the histologic severity of liver fibrosis. METHODS: A total of 568 adults with biopsy-proven NAFLD from the PERSONS cohort in Wenzhou were enrolled. The association between mean HbA1c and hepatic histological features was investigated with ordinal logistic regression. Generalized additive models were used to identify the non-linear relationship between HbA1c and increased fibrosis stage (stage F ≥ 3). Causal mediation analysis was performed to calculate the indirect effect of the relationship between HbA1c and hepatic fibrosis mediated by cytokines. RESULTS: Every 1% increase in mean HbA1c was associated with 16% higher odds of increased fibrosis stage (odds ratio 1.16, 95%CI 1.04-1.30), even after adjustment for confounding factors. There was a non-linear association between HbA1c and increased fibrosis stage (stage F ≥ 3), and the HbA1c inflection point was 9.2%. In particular, the ORs on the left and right sides of this inflection point were 2.1 (95%CI 1.4-3.3) and 0.1 (95%CI 0-4.8), respectively. 7% of the association (OR 1.07, 95%CI 1.01-1.12) between HbA1c and liver fibrosis was mediated by leukemia inhibitory factor. CONCLUSIONS: Glycemic control predicts severity of hepatic fibrosis and leukemia inhibitory factor plays an intermediary role between them, and thus optimizing glycemic control may be a means of modifying the risk of fibrosis progression in NAFLD.