The neutrophil-to-lymphocyte ratio predicts all-cause and cardiovascular mortality in patients with nonalcoholic fatty liver disease: Evidence from the National Health and Nutrition Examination Survey 1999 to 2018

Systemic inflammation, metabolic dysregulation, and thrombotic activity may all contribute to disease progression and prognosis in nonalcoholic fatty liver disease (NAFLD). However, the relative prognostic performance of biomarkers reflecting these pathways remains unclear. This study aimed to compare 3 biologically distinct indices - neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-HDL cholesterol ratio (NHR), and platelet-to-lymphocyte ratio (PLR) - and to investigate the association between the optimal marker and the risk of all-cause and cardiovascular mortality among American adults with NAFLD. This study included 5830 adults with NAFLD from the National Health and Nutrition Examination Survey (1999-2018). Time-dependent receiver operating characteristic (ROC) analyses were performed to compare the discriminative performance of NLR, NHR, and PLR at multiple follow-up time points. Based on comparative results, NLR was selected for subsequent analyses. Cox proportional hazards regression models were used to elucidate the relationship between NLR levels and mortality in NAFLD patients, and stratified analyses were performed to identify patients with higher mortality risk. Restricted cubic spline, Kaplan-Meier curves, Time-dependent receiver operating characteristic curve (ROC) analysis, and sensitivity analyses were also conducted to visualize the association of the NLR with mortality risk. During a median follow-up of 110 months, 1087 all-cause deaths occurred. In time-dependent ROC analysis, NLR consistently demonstrated superior discriminative performance compared with NHR and PLR across all evaluated time points. After adjusting for covariates, compared to participants with lower NLR (≤2.88) levels, those with higher NLR (>2.88) levels had a 56% increased risk for all-cause mortality (hazard ratio 1.56, 95% confidence interval: 1.29-1.89, P < .0001) and 89% higher risk for cardiovascular disease (CVD) mortality (hazard ratio 1.89, 95% confidence interval: 1.39-2.58, P < .0001). The results were robust in subgroup and sensitivity analyses. Kaplan-Meier analysis showed that the survival was significantly worse in the high NLRs group than in the low NLRs group for both total and CVD (both P < .0001). Furthermore, the Restricted cubic spline curve showed a positive linear and reverse L-shaped relationship between NLR and overall mortality and cardiovascular mortality, respectively. This research suggests that NLR is independently associated with all-cause and CVD mortality, and NLR > 2.88 may be a risk factor for mortality.