Association between lactate-to-albumin ratio and 28-days all-cause mortality in patients with sepsis-associated liver injury: a retrospective cohort study

Sepsis is a global public health challenge characterized by a dysregulated host response to infection, resulting in life-threatening organ dysfunction [1, 2]. It affects millions of individuals worldwide annually, with septic shock and sepsis-related mortality rates of one in three and one in six, respectively [3, 4]. Sepsis represents an intricate and dysregulated host reaction to infection, potentially culminating in multiple organ dysfunction syndrome (MODS) [5]. Due to its critical involvement in metabolism, synthesis, and immune pathways, the liver plays a key role in sepsis-associated liver injury (SALI), which assumes a crucial role in the complications of sepsis. In the context of sepsis, the liver experiences multifaceted alterations, encompassing changes in immune responses, metabolic processes, microvascular dynamics, and coagulation, ultimately resulting in hepatic dysfunction [6]. We recognize that the severity of SALI is significant. As a result, guidelines and studies have emerged, diagnosing SALI in patients based on total bilirubin and INR [7]. However, alternative literature defines this condition using higher levels of total bilirubin and alanine transaminase [8]. Early recognition and appropriate management of SALI are crucial for preventing associated mortality. Thus, a comprehensive understanding of the involvement of the liver in sepsis can help mitigate SALI and improve patient outcomes.

Lactate is produced by anaerobic glycolysis. It is well known that hyperlactatemia is an established indicator of tissue and organ hypoxia [9]. Elevated lactate levels have been associated with higher mortality rates in ICU patients [10]. The liver plays a vital role in lactic acid metabolism. Therefore, abnormal liver function affects lactic acid levels, such as acid–base imbalance and lactic acidosis in liver cirrhosis. In patients with chronic liver diseases (e.g., cirrhosis), lactic acid levels do not accurately reflect tissue hypoxia [11]. Similarly, metformin may also affect the body's lactic acid level [12]. A single lactic acid level cannot fully reflect liver function. Albumin is synthesized in the liver and is correlated with the inflammatory state. With decreasing serum albumin, the mortality of critically ill patients increases substantially [13]. However, malnutrition and chronic inflammation may also affect patient albumin levels. In this regard, predictions based solely on albumin levels are also subject to limitations [14]. Recent research has demonstrated the predictive value of Lactate-to-Albumin Ratio (LAR) in sepsis [15] and septic shock [16]. However, its association with the 28-day mortality in patients with SALI remains unclear.

This study aimed to investigate the relationship between LAR and all-cause mortality within 28 days after admission in patients with SALI.

In this retrospective cohort analysis of large public datasets, we found a significant correlation between LAR and 28-day all-cause mortality in the SALI population. The Kaplan–Meier survival curve analysis indicated a higher 28-day mortality rate in the Q4 group of the LAR quartile compared to the other quartiles. Furthermore, the COX multivariate regression analysis, following adjustment for confounding factors, consistently revealed a significant rise in the risk of 28-day mortality among SALI patients with an increased LAR.

Our research finds a noteworthy association between LAR and mortality of SALI. Recent investigations have demonstrated the predictive utility of LAR in mortality prediction across diverse conditions, including Heart Failure [22], Sepsis [23], and Acute Respiratory Failure [24]. Consistent with these insights, our study highlights a distinct association between heightened LAR and mortality. Our study found a 28-day all-cause mortality rate of 29.3% in patients with SALI, consistent with other literature [25, 26] supporting the high mortality associated with SALI. Therefore, SALI is a health area that merits attention from numerous scholars. Notably, prior studies have not delved into the role of LAR in the context of SALI. Our research expands the applicability of LAR to the cohort of patients afflicted with SALI, contributing novel insights to this specific medical context.

Our investigation includes the evaluation of both lactate and albumin in the context of SALI. The results reveal that heightened lactate levels, reduced albumin levels, and an increased LAR are correlated with heightened mortality risk in individuals with SALI. This observation aligns with the emerging recognition of lactate and albumin as potential biomarkers for diverse pathological conditions. Lactate serves as an indicator of tissue hypoxia, while albumin plays a role in the redox processes associated with various diseases [27]. Notably, existing research proves a robust correlation between lactate levels and mortality in patients with suspected infections and sepsis [28]. In a study on the mortality rate of COVID-19 concerning albumin, the findings revealed a negative correlation, with an increase in mortality rate as albumin levels decrease [29]. Notably, in a cohort study, albumin emerged as an independent predictor of mortality in elderly sepsis cases [30]. Serum albumin levels can increase following the infusion of human albumin, especially when left untreated. As albumin contributes to the increase in colloid osmotic pressure, several studies have confirmed its potential therapeutic use in diseases such as sepsis and other conditions [31‐33]. Consequently, our study exclusively incorporated laboratory indicators from the first day of patient admission, minimizing the potential impact of treatment and ensuring the reliability of our results. The Multivariable Cox regression analysis provided evidence of a significant correlation between LAR and the 28-day all-cause mortality rate in patients with SALI. Therefore, LAR may be an independent risk factor for all-cause mortality in SALI patients.

Through separate multivariable regression analyses for LAR, lactate, and albumin, we observed that SALI patients have a higher risk of mortality with increasing LAR (Supplementary Table 4). Studies have shown that the LAR exhibits enhanced predictive accuracy for sepsis prognosis compared to individual assessments of lactate and albumin. A prospective study found that LAR was better than lactic acid in predicting in-hospital mortality in patients with sepsis [34]. Kamran Shadvar et al. [35] conducted a study involving 151 patients with septic shock. Utilizing ROC curve analysis and logistic multivariate regression, they discovered that the LAR outperformed both lactate levels and lactate clearance rate in predicting the prognosis of septic shock patients. In a separate investigation by Cakir et al. [23], encompassing 1136 sepsis patients admitted to the ICU, the LAR emerged as a more reliable predictor of clinical outcomes in sepsis patients, as determined by the area under the ROC curve, compared to individual assessments of lactate and albumin. While these findings contribute to our understanding of the prognostic implications of LAR in sepsis treatment, they do not offer insights into SALI. Our study, however, establishes a significant correlation between LAR and the 28-day mortality rate in the context of SALI. Meanwhile, K-M survival curve analysis showed that the mortality rate in the highest quartile group was higher than that in other groups. These findings offer valuable insights into prognostic indicators for SALI, particularly the association between LAR and adverse outcomes in SALI patients.

We conducted a sensitivity analysis using diagnostic criteria for SALI from the literature that differed from those used in our study. The hazard ratio (HR) in the sensitivity analysis was 1.49 (1.13–1.96), in contrast to the main study where the HR stood at 1.21 (1.11–1.31). Consistent results confirmed a significant association between LAR and SALI. In a study investigating AST/platelet ratio and SALI, the criteria were set at total bilirubin equal to or greater than 4 mg/dl and ALT exceeding 2 times the upper limit of normal [8]. Our sensitivity analysis employed the diagnostic criteria outlined in the referenced literature. In our study, we adhered to the diagnostic standards outlined in the Surviving Sepsis Campaign guidelines [20], a criterion aligned with multiple literature on SALI. In Dou's study, although there were no indicators for coagulation function, the diagnostic criteria included higher bilirubin concentrations. Moreover, a cohort study revealed an association between elevated total bilirubin levels and adverse outcomes in patients with SALI [36]. Hence, we speculate that elevated bilirubin levels may be one of the reasons for the increased risk of SALI mortality identified in our sensitivity analysis. Through sensitivity analysis, the significant correlation between LAR and mortality in SALI patients was once again validated. Therefore, LAR can be extended as an indicator of adverse outcomes in SALI patients admitted to the ICU, offering clinicians new perspectives for consideration.

LAR emerges as a potential independent risk factor for the 28-day mortality rate in SALI patients. Through factor regression analysis and sensitivity analyses based on varying diagnostic criteria, a significant correlation between the two has been established. Subgroup analyses in our study also indicate no interaction effects when stratifying by age, gender, race, BMI, CRRT, vasoactive agent exposure, and comorbidities. Interaction effects were observed only in the subgroup using mechanical ventilation. However, due to limitations in our sample size, especially with reduced numbers after stratification, the results may exhibit bias, warranting further validation through large-scale prospective studies.

In conclusion, LAR can be used as an independent risk factor for all-cause mortality in patients of SALI within 28-d of admission. As LAR increases, there is a corresponding rise in the 28-day mortality rate. However, further validation through a large-scale multicenter prospective study is required to establish its widespread applicability and objectivity.