Association of Systemic Inflammation Response Index with Short-Term All-Cause Mortality in Decompensated Liver Cirrhosis Patients

Introduction

Cirrhosis, a chronic liver condition, arises from persistent inflammation and fibrosis, marking the advanced stage of liver damage.^1,2 This disease stands as the 11th leading cause of global mortality and is notably the third most common cause of death among individuals between the ages of 45 and 64.^3,4 With an annual death toll of approximately 2 million, cirrhosis poses a significant health challenge worldwide.^3,4 Decompensated liver cirrhosis (DLC) signifies a pivotal and critical phase in the progression of liver cirrhosis. It is characterized by a decline in liver function and the emergence of severe, life-threatening complications. DLC is often associated with a grim prognosis and imposes a substantial burden on healthcare systems.^5,6 The short-term mortality rate among patients with DLC can soar to 15%.^7,8 underscoring the imperative need for early detection of high-risk individuals and the swift implementation of therapeutic interventions to ameliorate patient outcomes.

Inflammation is a pivotal factor in the prognosis of liver cirrhosis. It can trigger a cascade of complications, such as ascites and hepatic encephalopathy, which in turn accelerate the progression of the disease.⁹ Furthermore, inflammation contributes to the development of portal hypertension, a condition that can lead to devastating cirrhosis-related complications like variceal bleeding.¹⁰ The onset of these complications is often a harbinger of poor short-term survival rates for patients. Systemic inflammation also heightens the risk of infections, which can intensify organ damage, playing a critical role in the outcomes of patients with DLC.¹¹

The Systemic Inflammation Response Index (SIRI) serves as a comprehensive indicator of inflammation, based on the counts of monocytes, neutrophils, and lymphocytes.¹² Recent research has revealed that SIRI is independently correlated with the prognosis of patients suffering from a variety of conditions, including different types of tumors, autoimmune rheumatic diseases, cardiovascular diseases, cerebral hemorrhage, and pneumonia.^12–19 However, the relationship between SIRI and the short-term prognosis in patients with decompensated cirrhosis (DLC) remains unexplored. Our research aims to elucidate this connection, potentially offering new insights for the management of DLC.

Materials and Methods

Patients

Patients diagnosed with DLC and admitted to the Second Affiliated Hospital of Wannan Medical College between March 2016 and March 2023 were retrospectively assembled to form the initial cohort for this investigation. DLC was characterized by biochemical, clinical, endoscopic manifestations, imaging indicators, and complications such as ascites, gastrointestinal bleeding, hepatorenal syndrome, or hepatic encephalopathy.²⁰ Exclusion criteria encompassed: (1) non-initial admissions, (2) malignancies, (3) autoimmune disorders, (4) primary renal diseases, (5) cardio-cerebrovascular diseases, (6) infectious diseases, (7) incomplete data, and (8) loss to follow-up. Utilizing identical exclusion criteria, patients with DLC admitted to the Yijishan Hospital of Wannan Medical College from January 2018 to March 2023 constituted the validation cohort. A detailed patient selection process is depicted in Figure 1.

Figure 1 Flowchart of the patients selection process.

Data Collection

Patient outcomes at 3 and 6 months post-admission were evaluated through review of medical records or via direct communication with patients or their relatives. Data collected at the time of admission included gender, age, etiology of cirrhosis, presence of ascites (yes/no), variceal bleeding (yes/no), hepatorenal syndrome (yes/no), hepatic encephalopathy (yes/no), and laboratory findings. The SIRI was calculated using the formula: neutrophil count (×10⁹/L) × monocyte count (×10⁹/L) / lymphocyte count (×10⁹/L).¹⁷ The neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR) and platelet-to-lymphocyte ratio (PLR) were calculated as neutrophil count (×10⁹/L) / lymphocyte count (×10⁹/L), monocyte count (×10⁹/L) / lymphocyte count (×10⁹/L), and platelet count (×10⁹/L) / lymphocyte count (×10⁹/L), respectively.

Statistical Analysis

Continuous variables were presented as mean ± standard deviation or median (first quartile, third quartile), while categorical variables were expressed as counts (percentages). Independent sample t-tests or Mann–Whitney U-tests were employed to compare continuous variables that were normally distributed or not, respectively. Categorical data were compared using chi-square tests. Receiver operating characteristic (ROC) curves were generated to ascertain the area under the curve (AUC), and patients were stratified into high and low SIRI groups based on the Youden index derived from the ROC curve. The Delong test was used to compare the AUC values.²¹ Univariate analysis was conducted to assess the correlation between various variables and all-cause mortality, with variables yielding a p-value less than 0.05 being selected for inclusion in the multivariable analysis. Multivariable logistic regression analysis was then performed to ascertain the independent relationship between SIRI and all-cause mortality. Based on multivariable analysis, restricted cubic splines (RCS) analysis was utilized to graphically represent the association between SIRI (as a continuous variable) and the risk of all-cause mortality. All statistical procedures were carried out using SPSS (version 27.0), R (version 4.0.2), and MedCalc (Version 15.2). All statistical tests were two-tailed, with a p-value of less than 0.05 considered indicative of statistical significance.

Results

Baseline Characteristics

The present study enrolled a total of 926 patients with DLC who met the inclusion criteria. Within the initial cohort, the mean age of the patients was 64 years, comprising 82 females (45.3%) and 99 males (54.7%). Chronic hepatitis B virus (HBV) infection was identified as the predominant cause of cirrhosis in 119 cases (65.7%). Complications included ascites in 135 cases (74.6%), esophagogastric variceal bleeding in 35 cases (19.3%), hepatic encephalopathy in 11 cases (6.1%), and hepatorenal syndrome in 4 cases (2.2%). The all-cause mortality rates at the 3- and 6-month endpoints were 8.8% and 11.6%, respectively. Detailed characteristics of the initial and validation cohorts are summarized in Table 1.

Table 1 Clinical and Laboratory Characteristics of Patients with Decompensated Liver Cirrhosis in the Initial and Validation Cohort at the 3-Month, and 6-Month Follow-Ups

Clinical Features and Laboratory Results Between Survival and Deceased Groups

In the initial cohort, values of neutrophils (Neut), monocytes (Mono), total bilirubin (Tbil), creatinine (Cr), prothrombin time (PT), and SIRI were markedly elevated in the deceased group compared to the survival group at both the 3- and 6-month follow-up endpoints. At the 6-month mark, lymphocyte (LYM) counts were significantly reduced in the deceased group relative to the survival group; no significant inter-group differences were observed at the 3-month mark. Hemoglobin (HGB), platelet (PLT) counts, albumin (Alb), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), and gender remained consistent between the two groups across both follow-up endpoints. Comprehensive details for the survival and deceased groups in the initial and validation cohorts are delineated in Table 1.

Clinical Characteristics and Laboratory Results Between High and Low SIRI Groups

In the initial cohort, ROC analysis revealed AUC values for SIRI at 3 and 6 months to be 0.841 and 0.807, respectively (Figure 2A and B). Participants were categorized into high and low SIRI groups based on the Youden index from the ROC curve. The optimal cutoff points for 3 and 6 months were established at 2.227 and 0.961, respectively. Within the high SIRI group, elevated values of Neut, Mono, Tbil, PT, and SIRI, alongside a higher all-cause mortality rate, were observed, with a concurrent significant decrease in Alb compared to the low SIRI group. At the 3-month mark, HGB values were notably lower in the high SIRI group; this difference was not apparent at the 6-month mark. Further details regarding the high and low SIRI groups in the validation cohort are presented in Table 2.

Table 2 Comparison of Clinical and Laboratory Characteristics Between Low and High SIRI Groups in the Initial and Validation Cohort in Patients with Decompensated Liver Cirrhosis

Figure 2 Receiver operating characteristic curve for the prognosis prediction of patients with decompensated cirrhosis by SIRI. (A) 3 months of initial cohort; (B) 6 months of initial cohort; (C) 3 months of validation cohort; (D) 6 months of validation cohort.

High SIRI Levels are Independently Associated with All-Cause Mortality in Patients with DLC

Univariate analysis was conducted to identify variables significantly linked to patient outcomes (P < 0.05), which were subsequently included in the multivariable analysis. The findings from the multivariable analysis indicated that elevated SIRI levels are independently correlated with all-cause mortality at both 3- and 6-month follow-up endpoints (Table 3). The RCS analysis, based on multivariable analysis, demonstrated a positive correlation between SIRI values and the risk of all-cause mortality. There was a general trend of increasing all-cause mortality risk with rising SIRI values, although the risk appeared to plateau when SIRI values approached 2.7 (Figure 3A and B).

Table 3 SIRI is Independently Associated with the All-Cause Mortality of Patients with Decompensated Liver Cirrhosis in the Initial Cohort and Validation Cohort

Figure 3 Association between SIRI and the prognosis of patients with decompensated liver cirrhosis. (A) 3 months of initial cohort; (B) 6 months of initial cohort; (C) 3 months of validation cohort; (D) 6 months of validation cohort.

Verified of Results in the Validation Cohort

In the validation cohort, the AUC values for SIRI at 3 and 6 months were 0.773 and 0.747, respectively, suggesting promising predictive capabilities (Figure 2C and D). Furthermore, although the AUC value of SIRI was higher than that of the NLR, MLR, and PLR at 3 and 6 months in the initial cohort, it did not reach statistical significance. In the validation cohort, the SIRI demonstrated significantly better predictive ability than MLR and PLR at 3 months, and significantly better predictive ability than NLR, MLR, and PLR at 6 months (Supplementary Figure 1). Our findings confirmed that high SIRI levels are independently associated with all-cause mortality at both 3- and 6-month endpoints (Table 3). The RCS analysis corroborated results akin to those of the initial cohort (Figure 3C and D).

Discussion

This study evaluated the relationship between the SIRI and short-term prognosis in patients with DLC. Our findings indicate that SIRI levels were significantly elevated in deceased patients compared to survivors across both cohorts. A higher SIRI is independently associated with adverse short-term outcomes in DLC, suggesting that SIRI could serve as a potential new prognostic predictor for patients with DLC. Furthermore, we observed a positive correlation between SIRI values and the risk of all-cause mortality across two cohorts. As SIRI values increased, there was an overall trend of rising risk for all-cause mortality.

Inflammation plays a crucial role in the prognosis of DLC; It not only speeds up the progression of cirrhosis but also significantly increases the risk of complications.²² Inflammatory cells trigger a series of complications, including infections and organ failure, by releasing inflammatory factors; these complications exacerbate the condition, leading to a poorer prognosis.^23,24 Neutrophils trigger a systemic inflammatory response by producing a large number of pro-inflammatory factors, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6).²⁵ Transforming growth factor-β1 (TGF-β1), released by neutrophils, activates hepatic stellate cells, leading to the secretion of fibrogenic factors, which accelerates the process of liver fibrosis.²⁶ Moreover, impaired chemotaxis, phagocytosis, and bactericidal capacity of neutrophils increase the risk of infection, organ failure, and death.^27,28 Numerous studies indicate that monocytes can accelerate the progression of cirrhosis, leading to poor patient outcomes.^29–31 Xu et al observed a significant increase in the number of CD169+ monocytes in the blood and liver of patients with cirrhosis, leading to elevated levels of pro-inflammatory factors (including IL-6, IL-1β, TNF-α, and IL-10); Additionally, CD169+ monocytes prolong the lifespan of neutrophils, further exacerbating the inflammatory response.³⁰ Wu et al reported that the HBV enhances the expression of Triggering Receptor Expressed on Myeloid cells-1 on monocytes, leading to elevated levels of inflammatory cytokines such as TNF-α, IL-1β, and IL-6; This process contributes to liver damage, inflammation, and fibrosis in patients with liver cirrhosis.³¹ The reduction in lymphocyte count and function is associated with the occurrence of DLC complications and is linked to adverse outcomes in patients. In patients with alcoholic cirrhosis, the absolute numbers of circulating mucosal-associated invariant T cells, NKT cells, and NK cells are lower than those in healthy individuals; This reduction is associated with the occurrence of complications, leading to poorer outcomes.³² HBV impairs lymphocyte function by interfering with their activation and differentiation processes, increasing the risk of infection and adversely affecting patient prognosis.³³ In hepatitis C virus (HCV), the reduction of T and B cells, along with a decrease in NK cell activity, is associated with adverse outcomes in DLC.³⁴ Therefore, the combined profile of neutrophils, monocytes and lymphocytes primarily reflects the inflammatory state in patients with DLC, potentially predicting their prognosis.

Previous studies have found that the SIRI is independently associated with the prognosis of various diseases. A retrospective study by Wang et al showed that the SIRI is independently associated with both 5-year and 10-year survival rates in breast cancer patients.¹⁴ Jiang et al reported that SIRI serves as an independent prognostic factor for patients with advanced EGFR-mutant lung adenocarcinoma.¹⁸ Zhang et al observed SIRI as a promising inflammatory marker for predicting the prognosis of stroke.¹² Similarly, SIRI is independently associated with the short-term prognosis of patients with DLC in our study. Interestingly, there was a difference in the optimal cutoff values between 3 months (2.23) and 6 months (0.96) in the initial cohort. The number of deaths within 6 months was higher by five patients compared to the number of deaths within 3 months. These five patients had SIRI values of 0.736, 0.980, 1.320, 1.499, and 9.391, with 4 patients having SIRI values exceeding 0.96. Therefore, by lowering the cutoff points from 2.23 to 0.96, it was statistically ensured that the high SIRI group (> 0.96) included more deceased patients, leading to the highest AUC value and supporting the concept that patients in the high SIRI group have an increased risk of mortality. As a predictive indicator, SIRI may offer the following advantages: (1) Non-invasive: SIRI is a non-invasive indicator that assesses a patients systemic inflammatory status by analyzing neutrophil, monocyte, and lymphocyte counts in peripheral blood. (2) Cost-effective: SIRI is cost-effective to measure since it is based on standard blood tests, making it highly feasible for clinical application.

This study has certain limitations. First, this study is retrospective and may be subject to selection bias and unidentified biases, necessitating further prospective research. Second, the potential mechanisms and clinical applications of SIRI in patients with DLC have not been extensively studied. While this study found higher levels of SIRI in patients with poorer prognosis of DLC, the underlying mechanisms of SIRI in DLC patients require further investigation. Third, there is an imbalance in sample sizes between the death group and the survivor group, which may lower the predictive accuracy of the minority class and weaken the power of statistical tests, thereby increasing bias in the analysis. Fourth, it is important to consider that decompensated cirrhosis patients may exhibit differing inflammatory statuses depending on the underlying etiology. Therefore, additional research is necessary to explore the influence of inflammatory status on the prognosis of patients with varying etiologies. Fifth, the amount of missing data (cases with incomplete data and with lost to follow-up) was relatively low in this study. We chose to directly deleted these cases; however, it is important to note that this approach may introduce selection bias.

Conclusion

Our research has established the SIRI as a clinically relevant biomarker for predicting short-term all-cause mortality in patients with DLC. The findings underscore the significance of systemic inflammation in the prognosis of liver cirrhosis, suggesting SIRI as a simple yet effective tool for risk stratification and clinical decision-making in this patient population. The independent association of SIRI with the risk of death in DLC highlights its potential utility in clinical practice. Identifying high-risk patients allows clinicians to prioritize resources and tailor treatment strategies more effectively, potentially improving patient outcomes.