Plasma Calprotectin Levels Associate with Suspected Metabolic-Associated Fatty Liver Disease and All-Cause Mortality in the General Population

Abstract

Metabolic-associated fatty liver disease (MAFLD) is characterized by hepatic steatosis, metabolic dysregulation, and neutrophilic inflammation. In this study, we hypothesized that systemic levels of plasma calprotectin, as a biomarker of neutrophilic inflammation, may be associated with suspected MAFLD. Plasma calprotectin levels were measured in subjects (n = 5446) participating in the Prevention of Renal and Vascular ENd-stage Disease (PREVEND) cohort study. Suspected MAFLD was defined by the fatty liver index (FLI ≥ 60) and hepatic steatosis index (HSI ≥ 36) as proxies. Plasma calprotectin levels were significantly higher in subjects with FLI ≥ 60 (0.57 [IQR: 0.42−0.79] mg/L, n = 1592) (p < 0.001) compared to subjects with FLI < 60 (0.46 [0.34−0.65] mg/L, n = 3854). Multivariable logistic regression analyses revealed that plasma calprotectin levels were significantly associated with suspected MAFLD (FLI ≥ 60), even after adjustment for potential confounding factors, including current smoking, alcohol consumption, hypertension, diabetes, cardiovascular diseases, insulin resistance (HOMA-IR), hs-CRP, eGFR, and total cholesterol levels (OR 1.19 [95% CI: 1.06−1.33], p = 0.003). Interaction analyses revealed significant effect modifications for the association between plasma calprotectin and suspected MAFLD by BMI (p < 0.001) and hypertension (p = 0.003), with the strongest associations in subjects with normal BMI and without hypertension. Prospectively, plasma calprotectin levels were significantly associated with all-cause mortality after adjustment for potential confounding factors, particularly in subjects without suspected MAFLD (FLI < 60) (hazard ratio (HR) per doubling: 1.34 (1.05−1.72), p < 0.05). In conclusion, higher plasma calprotectin levels are associated with suspected MAFLD and with the risk of all-cause mortality, the latter especially in subjects without suspected MAFLD.

Keywords: calprotectin; fatty liver index; hepatic steatosis index; inflammation; metabolic-associated fatty liver disease (MAFLD).

Figure 1

Stratified analyses for the association between plasma calprotectin levels and suspected MALFD (FLI ≥ 60) across various subgroups. Odds ratios (ORs) with corresponding 95% confidence intervals derived from multivariable logistic regression analyses are shown. p-values indicate p-values for interaction terms. First, we tested for potential effect modification for the variables shown, and subsequently performed stratified analyses. ORs demonstrate almost consistently positive associations between plasma calprotectin levels and the risk of all-cause mortality in all analyzed subgroups. ORs were adjusted for potential confounding factors, including all factors incorporated in Model 4 (Table 2). Abbreviations: CI, confidence interval; BMI, body mass index; CVD, cardiovascular disease; HR, hazard ratio; UAE, urinary albumin excretion.

Figure 2

Plasma calprotectin levels are associated with the risk of all-cause mortality in the general population. (A) Kaplan–Meier survival curves for tertiles of plasma calprotectin levels, showing survival distributions with 95% confidence intervals based on the outcome of all-cause mortality. The highest rate of all-cause mortality was observed in the highest tertile of plasma calprotectin levels (log-rank test, p < 0.001). (B) Restricted cubic spline (RCS) regression demonstrating the relationship between plasma calprotectin levels and the risk of all-cause mortality. Estimates were derived from the Cox proportional hazards regression model, while RCS was based on three knots set at the 10th, 50th, and 90th percentiles. A likelihood ratio test for nonlinearity was not statistically significant (p = 0.519). The dark-red-shaded area represents the 95% confidence interval. Abbreviations: HR, hazards ratio.