Our study explored the association of lymphocyte-to-monocyte ratio, systemic immune-inflammation index, neutrophil-percentage-to-albumin ratio, and neutrophil-to-platelet score, as the four key inflammatory markers, with the risk for both non-alcoholic fatty liver disease and cirrhosis. With the inclusion of survival analysis, trend of cumulative hazard, and baseline characteristics in this work, our results can be considered a new comprehension regarding the interaction between systemic inflammation and the progression of liver diseases.
For LMR, higher exposure categories (expo_lmr_cat=3) were associated with consistently increased risks of both NAFLD and cirrhosis. The cumulative hazard plots showed a clear dose-response relationship, with higher LMR levels associated with increased cumulative hazard for both outcomes. It suggests that the usual interpretation of LMR as a marker may indicate not reduced inflammation but the dysregulation of adaptive immunity or the prolonged activation of immune competent cells involved in hepatic inflammation and fibrotic processes. Baseline data also showed that the category of intermediate exposure was represented by more of the population, thus suggesting demographic or clinically modifiable variables that may affect the distribution of LMR and modify its association with liver disease risk.
In contrast, SII and NPAR had a protective association with both NAFLD and cirrhosis. In general, higher categories of exposure- namely expo_sii_cat = 3 and expo_npar_cat = 3-were associated with lower cumulative hazard and hazard ratios below 1 across the Cox proportional hazards models, even after adjusting for covariates. These results suggest that higher levels of SII and NPAR reflect compensatory immune mechanisms that attenuate liver injury and are opposite of their established roles as markers of systemic inflammation in other disease contexts.
Indeed, the distribution of baseline characteristics was relatively even across both SII and NPAR categories, reinforcing the stability of these associations and indicating that low levels of these markers reflect a state of increased vulnerability to metabolic stress and immune dysfunction.
In the case of NPS, a similar pattern for protection was observed for cirrhosis, where the higher categories of exposure showed reduced cumulative hazard. However, the baseline data indicated a large population imbalance, where there was an unusually high number of individuals in the low category of exposure (expo_nps_cat=1). This may be one partial explanation for the strength of the association found and points to one of the many reasons accounting for population heterogeneity in survival analyses is important.
In summary, these findings reveal the multifactorial, context-dependent function of systemic inflammation in liver disease. On one hand, inflammation has been an identified driver for NAFLD and cirrhosis; however, the protective associations that SII and NPAR point out clearly indicate the complex nonlinear relationships or threshold effects which stand in the way of any simple-minded interpretation of these markers. Furthermore, the dose-response relationship of significant p-value for trend, observed across all markers, adds to the probability of their predictive utility for the stratification of risk against liver diseases. The integration of the baseline characteristics provides a further clear suggestion as to how demographic and clinical factors can influence such associations. In fact, age, sex, socioeconomic status, and modifiable lifestyle factors might interactively relate with systemic inflammation at the determination of an individual’s risk profile. Mechanistic studies should be conducted in the future to unravel the dual role of inflammatory markers in promoting and mitigating liver disease, exploring how these markers can be integrated into personalized predictive models for improving early detection and targeted interventions in NAFLD and cirrhosis.
Although our study illuminates the role of inflammatory markers in predicting the risks of NAFLD and cirrhosis, there are some limitations that warrant mention. The first one would be that this is an observational study in which no causal inferences could be drawn. Moreover, detected associations of LMR, SII, NPAR, and NPS with liver disease outcomes may have been subjected to residual confounding. Although the multivariate models were adjusted for age, sex, socioeconomic status, and lifestyle factors, the influence of unmeasured factors, including genetic predisposition, dietary patterns, and comorbid conditions, may not be entirely eliminated.
Second, the biased distribution of participants in some categories of exposure, especially for NPS, may have biased the results. The excessively large population in the low exposure category of expo_nps_cat = 1 may have inflated the protective association observed for higher categories of exposure. Likewise, subtle differences in baseline characteristics may have influenced the risk estimates across groups, despite the adjustment.
Third, the study was based on single baseline measurements of inflammatory markers, which may not fully reflect the dynamic changes in systemic inflammation. Chronic states of inflammation, fluctuating levels of immune markers, or interventions during follow-up could alter the associations found and therefore misclassify the levels of exposure.
Last but not least, the findings hint at important biologies being involved in the role of inflammatory pathways in liver disease; no such mechanistic data is available to support the interpretation for truly causative pathways. Experimental and longitudinal studies are required that can replicate findings and further dissect whether the protective associations observed were due to a true compensatory immune path or mediated by something.
Given the limited nature of these, it increases the reliability of observed associations where consistency in results arises both from cumulative hazard plots and Cox proportional hazards models. Thus, these markers hold the potential for utility in the stratification of liver disease risk. Research in the future would also be needed to account for these limitations by way of the incorporation of repeated measures of inflammatory markers, exploration of confounding factors, and utilization of mechanistic studies in ways that would enhance this knowledge about the relationships.