The association of systemic inflammatory biomarkers with non-alcoholic fatty liver disease: a large population-based cross-sectional study

Purpose The aim of this study was to explore the relationship between non-alcoholic fatty liver disease (NAFLD) and the two blood inflammatory markers including the systemic immune-inflammation (SII) index, and the system inflammation response index (SIRI). Methods The National Health and Nutrition Examination Survey data between the year of 2017–2018 was used for this cross-sectional study. In order to analyze the association of SII index, and SIRI and risk of NAFLD, we used multivariable logistic regression models, restricted cubic spline (RCS) plot, and subgroup analysis to analyze the data. Results In total, there were 1,199 individuals who participated in the survey. As shown by the RCS plot, SII index, and SIRI were linked with NAFLD risk in a U-shaped pattern. With regard to known confounding variables, when comparing the lowest quartile, the odds ratio with 95 % confidence interval for prevalence of NAFLD across the quartiles of SII index and SIRI were (0.89 (0.57, 1.41), 0.56 (0.35, 0.89) and 1.01 (0.64, 1.59)), and (0.77 (0.48, 1.23), 0.79 (0.50, 1.24) and 0.94 (0.60, 1.47)), respectively. Additionally, SII index, and SIRI and NAFLD risk also were U-curve correlated among the participants in age ≥60 years, female, without hypertension, and BMI of ≥30 kg/m2. Conclusions There was a U-shaped association of SII index and SIRI with prevalence of NAFLD, indicating that SII index and SIRI should be monitored dynamically.


Introduction
Non-alcoholic fatty liver disease (NAFLD) still occupies an important place in adult chronic liver diseases, with a global prevalence estimated at 32.4 % and rising (Riazi et al., 2022).NAFLD refers to liver fat deposition and hepatocyte steatosis caused by metabolic disorders in addition to alcohol, immunity, infection and other factors, and thus develops into liver inflammation, fibrosis, cirrhosis and even liver cancer (Zafrani, 2004).Although its mechanism has not been clearly explained, it is associated with lipid metabolism disorder, insulin resistance decline, type 2 diabetes and so on (Yan et al., 2022).
The blood inflammatory index is an inexpensive and easily accessible biomarker.As an indicator of both local immune response and systemic inflammation, the SII index, integrating three of inflammatory cells (lymphocyte, neutrophil, and platelet), is considered to be a good and stable index (Hu et al., 2014;Tong et al., 2017).Several studies have shown that SII index can predict the outcome of patients with multiple cancers, acute ischemic stroke, heart failure, and acute kidney injuries (Jiang et al., 2022;Tang et al., 2021;Xie et al., 2021;Yang et al., 2018;Zhou et al., 2022).Additionally, SIRI, which is composed of lymphocyte, monocyte, and neutrophil counts, is a more comprehensive indicator of chronic low-grade inflammation (Jia et al., 2019).The previous studies suggested that SIRI has been widely recognized as the potential indicators for early diagnosis and prognosis monitoring in stroke, inflammatory diseases and cancers (Li et al., 2017;Ma et al., 2022;Qi et al., 2016;Zhang et al., 2021).The consideration of the harmful effects of NAFLD, the identification of risk factors, and the taking of measures to prevent or control the consequences, as soon as possible, is very helpful in reducing or preventing the consequences of NAFLD.There has been no evidence that the SII index and SIRI are associated with NAFLD risk in the general American population based on the epidemiological research to date.By analysing the data from the Nutrition and Health Examination Survey (NHANES) between the year of 2017-2018, we tried to examine the association of the SII index and SIRI with the prevalence of NAFLD.

Study population
For the purpose of collecting information about the general population's health and nutrition, the National Health and Nutrition Examination Survey (NHANES) database (https://www.cdc.gov/nchs/nhanes/) uses a multistage stratified random sampling method (Xiao et al., 2023a).For the purpose of this study, we analysed the data from the NHANES data from the 2017 and 2018 years.In total, 8,897 participants in total sample were included in the study, however we excluded 2,949 participants without NAFLD data, and 257 participants without SII index and SIRI data.Further, participants who did not have data on missing covariate data (n = 4,492) were also excluded from the analysis.Finally, the research included 1,199 individuals (Fig. 1).Every participant was required to provide informed consent prior to participating in the study.In addition, the National Center for Health Statistics obtained institutional review board approval prior to data collection (Zipf et al., 2013).

Statistical analysis
In this study, we conducted all analyses by using the SPSS version   stroke, angina pectoris, and heart attack, ALT, TG, hs CRP, GGT, mean energy intake, UA, BUN, AST, waist circumference, FBG, Scr, Hb, eGFR, TC, and HDL-C.

Baseline characteristics
Table 1 provides an overview of the laboratory examinations and basic clinical characteristics.There was a prevalence of 28.0 % of NAFLD in this study.We computed that the number of participants in this study is likely representative of the total U.S. population of 64,397,408.There was a statistically significant difference in age, sex Marital status, hypertension, DM, alcohol user, CHF, angina pectoris, BMI, Neu, mean energy intake, GGT, Lym, waist circumference, Ast, platelet, Hb, Alt, hs CRP, and eGFR between non-NAFLD and NAFLD.

Association of SII index and SIRI with NAFLD
Based on the restricted cubic spline plot (RCS), we can notice that there is a U-shaped association between SII index and SIRI coexisting with NAFLD prevalence (P for nonlinearity < 0.05, Fig. 2A and B).With the increase of SII index and SIRI, NAFLD risk was significantly reduced.The prevalence of NAFLD was lowest when the SII index and SIRI reached 565.438 and 1.668, respectively, and then the curve showed an upward trend.The association of SII index and SIRI with prevalence of NAFLD was investigated employing three multivariate logistic regression models (Models 1, 2, and 3) (Table 2 and 3).With regard to known confounding variables, when comparing the lowest quartile, the odds ratio with 95 % confidence interval for prevalence of NAFLD across the quartiles of SII index and SIRI were (0.89 (0.57, 1.41), 0.56 (0.35, 0.89) and 1.01 (0.64, 1.59)), and (0.77 (0.48, 1.23), 0.79 (0.50, 1.24) and 0.94 (0.60, 1.47)), respectively.
W. Sun et al. that SII index, and SIRI and NAFLD risk also were U-curve correlated among participants in age ≥ 60 years, female, without hypertension, and BMI of ≥30 kg/m 2 .

Discussion
In the study, firstly, we found that a U-shaped correlation between the SII index and prevalence of NAFLD in the RCS plot.The SII index is a marker of the comprehensive evaluation system and is derives from peripheral neutrophils, lymphocytes, and platelets counts, which probably indicate three pathways, such as the formation of inflammation, thrombus formation, and adaptive immunity, that contribute to the disease process (Azab et al., 2010;Kurtul and Ornek, 2019).It is well known that inflammation plays an important role in the occurrence and progression of NAFLD, which can lead to a change in the levels of peripheral blood leukocytes as a result of such a process (Tilg et al., 2021).Additionally, it is important to point out that the presence of the neutrophils in the liver is a hallmark of inflammation that can occur in the several different types of liver disease.A common feature of NAFLD is the presence of neutrophil infiltration, which results in the recruitment of macrophages and cell damage resulting from the release of inflammatory mediators or reactive oxygen species (Rensen et al., 2009).A systemic inflammatory condition will result in an increase in the total circulating neutrophils and platelets, but a decrease in lymphocytes.Previous studies have shown that hepatic stellate cells were shown to increase the survival of neutrophils, which, in turn, contributes to the formation of reactive oxygen species in the liver, which will lead to liver fibrosis (Zhou et al., 2018).The platelets interplay with inflammatory cells, which results in the release of chemokines, which promotes the accumulation of immune mediators, which plays a crucial role in promoting the formation of NAFLD (Ye et al., 2023).Song et al. found that a positive correlation was found between SII index and the hepatic steatosis among U.S. adults.Thus, the SII index may be an effective and affordable tool for detecting hepatic steatosis in a simple and straightforward manner (Song et al., 2022).This is a good explanation for the increased risk of NAFLD as SII increases.Zhao et al. also showed that in population with NAFLD identified by ultrasound, SII index had a Jshaped curve associated with all-cause deaths and higher SII levels were associated with increased mortality.Despite the fact that multiple confounding variables were adjusted for, this association still persisted (Zhao et al., 2023).This conclusion is consistent with the findings of the study.Additionally, this study is the first to find a correlation between SIRI and NAFLD.We also found a U-shaped correlation between the SIRI and prevalence of NAFLD.As mentioned above, inflammation plays a crucial role in the development and progression of NAFLD.Zhao et al. revealed that as the level of continuous SIRI increases by a unit, there is a 30 % increase in the hazard of mortality due to all causes as well as cardiovascular disease among hypertensive patients (Zhao et al., 2022).Additionally, a few studies have shown that in certain types of inflammation-related disorders like acne vulgaris, and chronic spontaneous urticaria, SIRI is with the potential to reliably predict the effectiveness of anti-inflammatory therapies (Cos ¸ansu et al., 2022;Cosansu et al., 2022).However, broader investigations are necessary to explore the relationship between SIRI and prevalence of NAFLD.
This study has strong strengths in terms of its large sample size and representative sample selection.As a result, the findings are generalizable.It is important to note, however, that our study has several limitations that should be taken into account.Firstly, due to year limitations, we only included general population data from NHANES 2017-2018.Secondly, the determination of some covariates was derived from selfreport questionnaires, so self-reported confounders would emerge.Thirdly, we could not rule out the possibility that NAFLD may be caused by drug-induced hepatotoxicity.Due to this, we cannot determine a causal relationship between a history of drug use and NAFLD.Finally, due to the fact that this was a cross-sectional study, it was limited to identifying the associations rather than causal relationships.

Conclusion
To conclude, there is a U-shaped curve in the American population when it comes to the SII index, and SIRI in relation to the prevalence of NAFLD.The SII index or SIRI can serve as a biomarker for NAFLD and a diagnostic or therapeutic target for the systemic inflammation.The potential mechanisms underlying the systemic inflammatory biomarkers (SII index and SIRI), in relation to NAFLD need to be further explored.

Fig. 2 .
Fig. 2. The restricted cubic spline curve for the association of (a) SII index and (b) SIRI with the prevalence of NAFLD in adults in the United States from NHANES 2017-2018.Abbreviations: OR, odd ratio; CI, confidence interval; SII index, systemic immune-inflammation index; NAFLD, non-alcoholic fatty liver disease; SIRI, system inflammation response index.
Demographic characteristics of the study adults in the United States from NHANES2017-2018 (n = 1,199).
Study flow chart.Abbreviations: NAFLD, non-alcoholic fatty liver disease; SII index, systemic immune-inflammation index; NHANES, National Health and Nutrition Examination Surveys; SIRI, system inflammation response index;W.Sun et al.23.0 (SPSS Inc., Chicago, IL, USA) and R version 4.3.2(RFoundation for Statistical Computing, Vienna, Austria).The estimates were based on the weighted NHANES sample.The statistical significance of the study was determined by P-value < 0.05.The two systemic inflammatory biomarkers were all divided into quartiles, including SII index (uous are expressed as means (standard deviations, SDs), while variables that are categorical are expressed as percentages (%).We used weighted Student's t-test for continuous variables and weighted chi-square tests for categorical variables to calculate differences between groups.The association of SIRI, and SII index with prevalence of NAFLD were investigated using weighted multivariate logistic regression analysis.Firstly, model 1 was adjusted for sex, race/ethnicity, and age.Secondly, model 2 was adjusted for model 1 variables plus the complication of hypertension, smoke status, marital status, drink status, education level, the complication of DM, family PIR, and BMI.Finally, model 3 was adjusted for model 2 variables plus the complication of CHF, CHD, Table1

Table 2
The adjusted ORs for the association of SII index with the prevalence of NAFLD in adults in the United States from NHANES 2017-2018.

Table 3
The adjusted ORs for the association of SIRI with the prevalence of NAFLD in adults in the United States from NHANES 2017-2018.