Wang TW, Zhou LL, Yuan J, Zhou WX, Wang HR, Yu TT, Zhai JC, Tang CB, Jiang W, Yu JQ, Zheng RQ, Yu HL, Shao J. Study of the relationship between iron metabolism disorders and sepsis-associated liver injury: A prospective observational study. World J Gastroenterol 2025; 31(14): 104584 [DOI: 10.3748/wjg.v31.i14.104584]
Corresponding Author of This Article
Jun Shao, Associate Chief Physician, Department of Center for Cardiac Macrovascular Disease, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, No. 98 Nantong Road West, Guangling District, Yangzhou 225001, Jiangsu Province, China. sjun1982@163.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Observational Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Tian-Wei Wang, Lu-Lu Zhou, Hao-Ran Wang, Ting-Ting Yu, Ji-Chao Zhai, Wei Jiang, Jiang-Quan Yu, Rui-Qiang Zheng, Department of Intensive Care Unit, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou 225001, Jiangsu Province, China
Jing Yuan, Department of Functional Examination, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou 225001, Jiangsu Province, China
Wen-Xin Zhou, Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu Province, China
Cheng-Bin Tang, Jun Shao, Department of Center for Cardiac Macrovascular Disease, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou 225001, Jiangsu Province, China
Hai-Long Yu, Department of Neuro Intensive Care Unit, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou 225001, Jiangsu Province, China
Hai-Long Yu, Department of Neurology, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou 225001, Jiangsu Province, China
Co-corresponding authors: Hai-Long Yu and Jun Shao.
Author contributions: Yu HL and Shao J contributed equally to this study as co-corresponding authors; Yu HL and Shao J conceived and planned this study; Wang TW and Zhou LL contributed equally to this study as co-first authors; Wang TW and Zhou LL performed the vast majority of the data acquisition and analysis for this experiment; Yuan J, Zhou WX, Wang HR, Yu TT, Zhai JC, and Jiang W performed the remaining data collection and analysis; Wang TW wrote the first draft of the manuscript; Tang CB, Yu JQ, and Zheng RQ were responsible for the execution and supervision of the entire project.
Supported by the National Science Foundation of Jiangsu Province, No. BK20221280; the National Natural Science Foundation of China, No. 82371336; the Chinese Postdoctoral Science Foundation, No. 2022M711426; the Special Fund for Social Key Research and Development Plan of Yangzhou City, No. YZ2022097; Yangzhou Municipal Science and Technology Bureau, No. YZ2024091 and No. YZ2022098.
Institutional review board statement: The medical research ethics committee of the Northern Jiangsu People’s Hospital provided approval for this study (ethics number: 2023ky297).
Informed consent statement: All patients were informed about the process and purpose of this study, voluntarily participated, and signed an informed consent form.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Data sharing statement: The data are available from the corresponding author upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jun Shao, Associate Chief Physician, Department of Center for Cardiac Macrovascular Disease, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, No. 98 Nantong Road West, Guangling District, Yangzhou 225001, Jiangsu Province, China. sjun1982@163.com
Received: December 25, 2024 Revised: February 17, 2025 Accepted: March 25, 2025 Published online: April 14, 2025 Processing time: 107 Days and 10.4 Hours
Abstract
BACKGROUND
Sepsis-associated liver injury (SALI) refers to secondary liver function impairment caused by sepsis, patients with SALI often have worse clinical outcomes. The early identification and assessment of the occurrence and progression of SALI are pressing issues that urgently need to be resolved.
AIM
To investigate the relationship between iron metabolism and SALI.
METHODS
In this prospective study, 139 patients were recruited, with 53 assigned to the SALI group. The relationships between SALI and various iron metabolism-related biomarkers were examined. These biomarkers included serum iron (SI), total iron-binding capacity (TIBC), serum ferritin, transferrin, and transferrin saturation. To identify independent risk factors for SALI, both univariate and multivariate logistic regression analyses were performed. Additionally, receiver operating characteristic curve analysis was utilized to assess the predictive value of these biomarkers for the occurrence of SALI.
RESULTS
There were no statistically significant differences in age, sex, body mass index, Sequential Organ Failure Assessment scores (excluding liver function), or APACHE II scores between the two groups of patients. Compared with the sepsis group, the SALI group presented significantly higher SI (P < 0.001), TIBC (P < 0.001), serum ferritin (P = 0.001), transferrin (P = 0.005), and transferrin saturation levels (P < 0.001). Multivariate logistic regression analysis revealed that SI (odds ratio = 1.24, 95% confidence interval: 1.11-1.40, P < 0.001) and TIBC levels (odds ratio = 1.13, 95% confidence interval: 1.05-1.21, P < 0.001) were independent predictors of SALI. Receiver operating characteristic curve analysis revealed that SI and TIBC had areas under the curve of 0.816 and 0.757, respectively, indicating moderate predictive accuracy for SALI.
CONCLUSION
Iron metabolism disorders are closely associated with the development of SALI, and SI and TIBC may serve as potential predictive biomarkers. The combined use of SI and TIBC has superior diagnostic efficacy for SALI. These findings provide valuable insights for the early identification and management of SALI among patients with sepsis.
Core Tip: Sepsis-associated liver injury (SALI) refers to secondary liver function impairment caused by sepsis, the SALI patients often have worse clinical outcomes. Recent evidence has suggested that iron metabolism plays a significant role in the adverse processes of sepsis and sepsis-induced organ damage. Our research indicates that iron metabolism disorders are closely related to the occurrence and development of SALI and that serum iron and total iron-binding capacity can serve as potential predictive indicators for SALI. These findings provide valuable information for further exploration of the mechanisms underlying the occurrence of SALI and the development of new treatment strategies.
Citation: Wang TW, Zhou LL, Yuan J, Zhou WX, Wang HR, Yu TT, Zhai JC, Tang CB, Jiang W, Yu JQ, Zheng RQ, Yu HL, Shao J. Study of the relationship between iron metabolism disorders and sepsis-associated liver injury: A prospective observational study. World J Gastroenterol 2025; 31(14): 104584
Sepsis-associated liver injury (SALI) is defined as liver dysfunction that arises secondary to sepsis. Its primary clinical features encompass hypoxic hepatitis, cholestasis, and elevated bilirubin levels[1]. The mechanisms underlying the incidence of SALI have not been fully elucidated but may involve inflammation, oxidative stress, autophagy, and apoptosis[2,3]. Previous clinical evidence has shown that liver dysfunction is an early event during sepsis and has been employed as a powerful predictor of high mortality and poor outcomes in patients[4,5]. Therefore, the early identification and assessment of the occurrence and progression of SALI are pressing issues that urgently need to be resolved.
In these years, more and more evidence has suggested that the dysregulation of trace element metabolism plays a significant role in the pathophysiological mechanisms of sepsis[6]. Iron is an essential trace element that is required in many fundamental processes[7,8]. Recent evidence has showed that iron metabolism plays a significant role in the adverse processes of sepsis and sepsis-induced organ damage, both as something that starts oxidative stress and mitochondrial problems, and as something that controls the chain of inflammation. Iron plays a key role in microbial metabolism; indeed, the virulence of numerous pathogens is contingent upon the availability of iron. An abundance of unbound iron within the cytoplasm can intensify inflammatory responses, precipitate cellular demise, and ultimately lead to extensive multiorgan impairment or, in severe cases, fatalities.
Recently, Wang et al[9] examined an animal model and found that the serum iron (SI), total iron-binding capacity (TIBC), and transferrin saturation (TSAT) were significantly reduced 2 hours after lipopolysaccharide treatment. Similar findings were reported in clinical trials, including decreased SI concentrations, reduced transferrin (TRF) levels, increased ferritin, and elevated hepcidin levels in patients with sepsis[10]. Furthermore, McCullough and Bolisetty[11] demonstrated that hepcidin has significant predictive value for sepsis-associated kidney injury. Overall, research from both human and animal studies shows that iron metabolism problems might be very important in the development of sepsis.
The liver plays a vital role in maintaining iron homeostasis, primarily through the regulation of hepcidin levels, taking in non-transferrin-bound iron, and absorbing ferritin. Iron metabolism also exerts significant regulatory effects on the main mechanisms of SALI[12], and animal studies have pointed out that increased free iron in the liver exacerbates liver injury after the occurrence of sepsis[13]. This evidence indicates that iron metabolism disorders play an important role in the pathophysiology of SALI. However, it remains unclear whether there is a strong association between iron metabolism and SALI. The objective of this study was to elucidate the link between iron metabolism and the onset of SALI by examining the differences in iron metabolic profiles between patient groups. The findings of this investigation will provide novel perspectives for the early identification and therapeutic intervention of SALI.
MATERIALS AND METHODS
Patients
This prospective study was a prospective observational study, which included sepsis patients admitted to the Northern Jiangsu People’s Hospital from January 2024 to December 2024. Patients were categorized into a group without liver injury (the sepsis group) and a SALI group based on the presence or absence of SALI at the time of their first intensive care unit (ICU) admission.
Inclusion and exclusion criteria
The inclusion criteria were as follows: (1) Patients diagnosed with sepsis on the basis of the Third International Consensus Definitions for Sepsis (Sepsis-3), i.e., a Sequential Organ Failure Assessment score ≥ 2 and suspected or confirmed infection[14]; (2) Age ≥ 18 years old; and (3) Patients who were informed about the process and purpose of this study, voluntarily participated, and signed an informed consent form.
The exclusion criteria for the study were as follows: (1) Patients with chronic liver diseases or acute exacerbations of chronic hepatic dysfunction; (2) Patients with drug-induced liver injury; (3) Patients with a history of liver transplantation; (4) Patients diagnosed with sepsis more than 24 hours prior to enrolment; (5) Patients with a history of blood transfusion; and (6) Patients with an expected survival time of less than 24 hours.
SALI
In accordance with previous studies, the diagnostic criteria for SALI were as follows: Serum total bilirubin > 34.1 μmol/L or alanine aminotransferase (ALT) > 80 U/L[15-17].
Data collection
The clinical data of all sepsis patients were collected as follows: (1) The baseline characteristics included sex, age, underlying comorbidities, site of infection, duration of hospital stay, length of ICU stay, APACHE II score, and Sequential Organ Failure Assessment score; and (2) The laboratory parameters included total bilirubin, indirect bilirubin, direct bilirubin, ALT, aspartate aminotransferase, SI, serum ferritin (SF), TRF, TSAT, TIBC, and soluble TRF receptor. All the results were obtained by the laboratory department of our hospital.
Statistical analysis
The Shapiro-Wilk test was used to determine if the variables had a normal distribution. Continuous variables that were normally distributed are presented as the mean ± SD. In contrast, variables that did not follow a normal distribution are shown as the median (interquartile range, IQR). Categorical variables are reported as frequencies and percentages. The nonparametric Mann-Whitney U test was used to analyse data that did not follow a normal distribution or data that exhibited heterogeneity of variance, while the Pearson χ2 test was used to analyse categorical variables. Univariate and multivariate logistic regression analyses were conducted to identify risk factors for the occurrence of SALI. A receiver operating characteristic (ROC) curve was constructed to evaluate the predictive value of SI metabolism-related indicators for the occurrence of SALI. All the statistical analyses were performed using R-Project 4.2, and a P value of less than 0.05 was considered statistically significant.
RESULTS
Baseline characteristics of the sepsis and SALI groups
As shown in Figure 1, in this study, a total of 154 patients were diagnosed with sepsis. Among them, 10 patients were excluded due to chronic liver diseases or acute exacerbations of chronic hepatic dysfunction; 3 patients were excluded due to a history of blood transfusion; and 2 patients were excluded due to an expected survival time of less than 24 hours. Ultimately, 139 patients were included in the study, comprising 86 patients in the sepsis group and 53 patients in the SALI group. As shown in Table 1, a total of 139 patients admitted to the ICU of Northern Jiangsu People’s Hospital from September 2023 to September 2024 were included in this study. The patients were divided into two groups on the basis of the diagnostic criteria for SALI, with 53 patients included in the SALI group. Table 1 summarizes the baseline characteristics of the included patients. The average age of these patients was 67.74 ± 12.78 years, and there were 50 females (35.97%). Additionally, there were significant differences between the two groups in terms of the duration of ICU stay (P = 0.034), the duration of hospital stay (P = 0.037), history of alcohol consumption (20.93% vs 50.94%, respectively; P < 0.001), the presence of pulmonary infection (65.12% vs 37.74%, respectively; P = 0.002), the presence of abdominal infection (24.42% vs 50%, respectively; P = 0.002), and the case fatality rate (9.30% vs 22.64%, respectively; P = 0.030). These data indicate that patients in the SALI group had longer ICU and hospital stays than did those in the sepsis group did, and the early mortality rate of SALI patients was also significantly greater than that of sepsis group. Furthermore, alcohol consumption, pulmonary infection, and abdominal infection were more likely to lead to the occurrence of SALI. There were no statistically significant differences in any other parameters examined herein between the two groups.
Comparison of iron metabolism levels between the two groups of patients
As shown in Table 2, patients in the SALI group had significantly higher levels of SI (IQR: 3.50-8.04 vs IQR: 29.08-38.58, P < 0.001), TIBC (IQR: 20.44-32.80 vs IQR: 29.08-38.58, P < 0.001), SF (IQR: 277.25-985.75 vs IQR: 479.00-6387.00, P = 0.001), TRF (IQR: 16.23-24.45 vs IQR: 18.92-27.01, P = 0.005), and TSAT (IQR: 0.13-0.26 vs IQR: 0.17-0.67, P < 0.001) than did those in the sepsis group. However, there was no statistically significant difference in soluble TRF receptor levels between the two groups.
Table 2 Comparison of iron metabolism levels between the two groups of patients.
Logistic regression analysis of various indicators of SALI
We initially performed univariate logistic regression analysis, as shown in Table 3. The indicators that were found to be statistically significant in univariate logistic regression analysis were platelet (PLT) (P = 0.028), albumin (P = 0.002), Lac (P < 0.001), SI (P < 0.001), TIBC (P < 0.001), SF (P = 0.002), TSAT (P < 0.001), drinking (P < 0.001), and abdominal infection (P = 0.003). We further included the factors that were significant in the univariate analysis into multivariate logistic regression model. As shown in Table 4, the PLT (P = 0.048), Lac (P = 0.011), SI (P < 0.001), TIBC (P < 0.001), drinking (P = 0.007), and abdominal infection (P = 0.002) were found to be independent risk factors for SALI.
Table 3 Univariate logistic regression analysis of risk factors for sepsis-associated liver injury among patients with sepsis.
ROC curve analysis of the predictive value of SI and TIBC for SALI
We selected significant iron metabolism-related parameters (i.e., SI and TIBC) from multifactorial logistic regression analysis and assessed their predictive value for the occurrence of SALI via ROC curve analysis. As shown in Table 5 and Figure 2, the area under the curve (AUC) for SI was 0.816, and the optimal cut-off value was 7.745. For TIBC, the AUC was 0.757, and the optimal cut-off value was 26.3. When these two parameters are combined, they exhibit superior diagnostic performance, with an AUC of 0.865.
Figure 2 Receiver operating characteristic curves of serum iron and total iron-binding capacity for predicting sepsis-associated liver injury.
SI: Serum iron; TIBC: Total iron-binding capacity.
Table 5 Receiver operating characteristic curve analysis of the predictive value of serum iron and total iron-binding capacity for sepsis-associated liver injury.
This study demonstrated that compared with the sepsis group, the SALI group presented significantly higher levels of SI (P < 0.001), TIBC (P < 0.001), SF (P = 0.001), TRF (P = 0.005), and TSAT (P < 0.001). High levels of SI and TIBC are risk factors for SALI, and the combination of SI and TIBC can be used as an effective predictive marker of the occurrence of SALI.
An increasing amount of evidence has demonstrated that the liver is one of the organs frequently involved in sepsis and that liver injury is an independent risk factor for the development of multiple organ dysfunction and high mortality in sepsis patients[18]. However, there is currently a lack of reliable methods for predicting the occurrence of SALI. Therefore, there is an urgent need to identify reliable biological markers to predict the occurrence of SALI in order to guide clinicians in early intervention, reduce the mortality rate of SALI and improve its prognosis. Recently, abnormal changes in trace elements within the body have been widely examined. Iron is a crucial trace element within cells, and it plays a role in a variety of biochemical processes. In sepsis, iron homeostasis is disrupted, leading to iron metabolism disorders. Excessive iron can promote oxidative stress, exacerbate inflammatory responses, and subsequently lead to hepatocyte injury[19].
Consistent with the findings of a previous study, the baseline data revealed that patients in the SALI group had longer ICU stays and hospitalizations. Interestingly, although there was no significant difference in 28-day mortality rates between the two groups, the 14-day mortality rate in the SALI group was significantly greater than that in the sepsis group. This finding suggests that the deterioration of SALI patients’ conditions could occur mainly in the early stages of the disease course, thus indicating the need for clinicians to detect and intervene in SALI as early as possible.
Previous studies have examined iron metabolism disorders in sepsis patients[19]. Iron is an essential nutrient for bacterial survival, and higher iron levels are more likely to lead to bacterial infections. A large cohort study of patients with sepsis revealed that higher SI levels are independently associated with increased 90-day mortality[20]. Previous studies have indicated that iron metabolism plays a crucial role in sepsis-induced cardiomyopathy, and genes related to iron metabolism are expected to improve the diagnosis of septic cardiomyopathy[21,22]. Iron metabolism plays a significant role in sepsis-associated kidney injury[23]. Ferritin light chains and SF can modulate inflammatory responses, thereby mitigating renal injury during sepsis[11]. Furthermore, studies utilizing experimental models have demonstrated that sepsis can trigger acute lung injury (ALI) due to increased iron concentrations within the lungs. In this context, higher iron levels in lung epithelial cells are associated with the promotion of lipid peroxidation, and within macrophages, these elevated iron levels contribute to the increased migration of neutrophils, which in turn intensifies inflammatory reactions[24].
The liver plays an important role in the regulation of iron homeostasis and, therefore, there is a strong association between disorders of iron metabolism and liver disease[25]. Corradini et al[26] showed that elevated SF levels are frequently detected in patients with non-alcoholic fatty liver disease (NAFLD) and are associated with an altered iron metabolism and a worse prognosis of the patients. Moreover, in a group of NAFLD patients in Italy, genetic variants associated with iron metabolism, particularly plasma copper blue protein, were associated with high ferritin levels, hepatic iron deposition and more severe liver disease[26]. Another study showed that disorders of iron metabolism in the liver as well as systemically can promote hepatocyte apoptosis and hepatic fibrosis, thereby exacerbating liver injury[27]. Mayneris-Perxachs et al[28] demonstrated that the state of iron metabolism can influence the development of NAFLD by influencing the state of the intestinal flora.
However, the involvement of iron metabolism disorders in SALI is not clear. Our findings revealed that patients with SALI presented markedly lower levels of SI, TIBC, SF, TRF, and TSAT than did those with sepsis alone. These results are consistent with those of a previous study on the associations between iron metabolism parameters and the prognosis of sepsis[29]. These significant discrepancies suggest that disorders in iron metabolism could be instrumental in the complex pathophysiology of SALI.
Furthermore, we initially conducted univariate logistic regression analysis on the collected data, and then, we included the factors that were significant in the univariate analysis in a subsequent stepwise multivariate logistic regression analysis. The results revealed that PTL (P = 0.048), Lac (P = 0.011), SI (P < 0.001), TIBC (P < 0.001), drinking (P = 0.007), and abdominal infection (P = 0.002) were statistically significant. Patients in the SALI group had lower PLT levels, which may be due to the fact that when liver function is impaired, the synthesis of thrombopoietin may decrease, potentially leading to a reduction in platelet count. These results suggest that the aforementioned factors may be independent risk factors for SALI. In acute liver injury, the level of SI may increase due to the release of ferritin from damaged hepatocytes. Moreover, the TIBC may also increase due to the release of TRF.
Duvigneau et al[30] demonstrated that the administration of lipopolysaccharide resulted in oxidative liver damage. They reported a marked elevation in the hepatic levels of labile iron, which was significantly associated with the deterioration of mitochondrial functionality and a decrease in tissue adenosine triphosphate levels[30]. Furthermore, during sepsis, impaired intestinal barrier function and increased intestinal permeability can lead to increased translocation of iron and intestinal bacteria to the portal vein, which in turn exacerbates systemic inflammation, oxidative stress, and bacterial proliferation, thereby increasing iron deposition and promoting liver injury[31].
To further investigate the predictive efficacy of iron metabolism-related parameters for the occurrence of SALI, we conducted a thorough evaluation of the predictive value of SI and TIBC for SALI via ROC curve analysis. The findings demonstrated that both SI and TIBC have substantial predictive accuracy for SALI. Notably, TIBC exhibited lower sensitivity but superior specificity, whereas SI displayed acceptable sensitivity and specificity. These indicators are valuable predictive factors for SALI, with SI being particularly useful for confirming the presence of SALI because of its high sensitivity and specificity and TIBC being more useful for excluding SALI due to its high specificity. The combined predictive power of the SI and TIBC was also assessed, and the results were promising, as the AUC improved when both factors were considered together. This finding suggests that the combination of SI and TIBC can serve as a biomarker for the early detection of SALI. Iron is an essential metal, and liver cells are its primary storage site[25]. Iron is believed to be associated with the promotion of liver inflammation. Research indicates that iron may regulate inflammation in various forms of liver injury[32]. Research by Cheng et al[33] indicated that during the storage and transport of iron, the disruption of iron homeostasis leads to excessive lipid peroxidation, which may induce liver injury through ferroptosis. A separate study revealed that increased levels of SF were strongly correlated with the presence of hepatic steatosis and elevated ALT levels among the general Korean population[34]. A recent study indicated that there is a positive correlation between SI levels and liver transaminases. A previous study revealed that the SI concentration was independently and positively correlated with ALT and aspartate aminotransferase levels, which are key indicators of liver function[35]. These findings underscore the potential of SI as a biomarker for assessing liver health.
Disorders of iron metabolism can lead to SALI through multiple pathways. In sepsis, inflammatory factors such as interleukin-6 are released in large quantities, which induces an increase in the expression of hepcidin (iron modulator)[36,37]. Iron modulators inhibit ferritin degradation and iron release, leading to the accumulation of intracellular iron ions[38]. Iron ions catalyse the generation of hydroxyl radicals from intracellular hydrogen peroxide, triggering lipid peroxidation and damaging cell membrane structure and function[12]. In addition, iron ions bind to intracellular divalent iron-dependent enzymes, further promoting oxidative stress[19]. In sepsis, intracellular accumulation of iron ions in hepatocytes activates iron-death-related pathways, such as the nuclear factor E2-related factor 2/glutathione peroxidase 4 (GPX4) pathway[39]. Decreased expression of nuclear factor E2-related factor 2, a key regulator of antioxidant responses, leads to reduced activity of antioxidant enzymes such as GPX4. Reduced GPX4 activity weakens cellular defense against lipid peroxidation, leading to lipid accumulation of peroxidation products, which ultimately induces iron death in hepatocytes.
Disturbed iron metabolism can also affect the inflammatory response and thus aggravate liver injury through multiple pathways. On the one hand, iron ions can promote the production and release of inflammatory factors, such as inducing Kupffer cells to secrete more inflammatory factors such as tumor necrosis factor-α and interleukin-1β[40]. On the other hand, iron ions also activate inflammatory signalling pathways such as nuclear factor-kappaB, further exacerbating the inflammatory response. The massive release of inflammatory factors not only directly damages hepatocytes, but also leads to hepatic microcirculation disorders, further aggravating liver injury[41]. Iron metabolism disorders can lead to hepatic microcirculation disorders, which in turn aggravate liver injury[42]. Iron ions can induce swelling, destruction and dysfunction of hepatic sinusoidal endothelial cells, leading to obstruction of blood flow within the hepatic sinusoids. In addition, ferric ions can activate platelets, causing them to aggregate within the hepatic sinusoids and form microthrombi, further reducing blood circulation within the hepatic sinusoids. Impaired hepatic microcirculation leads to hepatic ischemia and hypoxia, aggravating hepatocellular injury[43]. In summary, disorders of iron metabolism contribute to the development and progression of septic liver injury through a variety of mechanisms, including triggering oxidative stress, inducing iron death, influencing inflammatory responses, and leading to hepatic microcirculatory disorders. Therefore, modulation of iron metabolism may be a potential strategy for the treatment of septic liver injury.
Iron in the labile iron pool is considered a core component of the mitochondrial respiratory chain complexes. When the intracellular storage capacity of ferritin is insufficient or non-selective autophagy is activated by stress, the level of labile iron pool further increases[44]. Mitochondria are the primary site of iron metabolism, and most cytosolic iron must enter the mitochondria to participate in physiological activities[45]. An increase in cytosolic iron levels enhances the expression of mitochondrial iron transport, leading to mitochondrial iron overload[44]. Elevated mitochondrial iron levels can also disrupt the synthesis of iron-containing proteins, resulting in mitochondrial dysfunction and excessive production of oxidative stress. The increase in reactive oxygen species (ROS) and other sepsis-related factors may further damage mitochondria and significantly reduce iron metabolism capacity. Animal experimental models have shown that intracellular iron increases the production of mitochondrial ROS and is associated with an increased inflammatory response[46].
In addition to participating in the synthesis of mitochondrial proteins, iron is also involved in the regulation of enzyme activity. Lipoxygenases (LOXs) and cyclooxygenases (COXs) are key enzymes that catalyze the specific regions of oxygenation of polyunsaturated fatty acids and require iron as a cofactor. Moreover, LOX and COX products derived from arachidonic acid, such as prostaglandins and leukotrienes, are responsible for the failure of the microvascular system and the progression of sepsis[47,48]. Elevated iron levels enhance the expression of LOXs and COXs, leading to increased production of lipid ROS and cytokines, which may result in a vicious cycle of iron metabolism disorders[49].
In summary, iron metabolism disorders promote the occurrence and progression of sepsis-induced liver injury through various mechanisms, including causing oxidative stress, inducing ferroptosis, influencing inflammatory responses, and leading to hepatic microcirculatory disturbances. Therefore, modulating iron metabolism may be a potential therapeutic strategy for sepsis-induced liver injury.
CONCLUSION
In summary, our research indicates that iron metabolism disorders are closely related to the occurrence and development of SALI and that SI and TIBC can serve as potential predictive indicators for SALI. These findings provide valuable information for further exploration of the mechanisms underlying the occurrence of SALI and the development of new treatment strategies.
This study also has several limitations. First, the sample size was relatively small, which may affect the generalizability of the results. Second, as a single-centre study, there may be selection bias. Future studies should validate these findings with a larger sample size and a multi-centre design. Additionally, this study only collected relevant indicators on the first day of enrolment and did not conduct continuous observations.
ACKNOWLEDGEMENTS
The authors would like to express their sincere gratitude to Dr. Guang-Yu Lu from the School of Public Health, Yangzhou University, for her expert assistance with the data analysis of this study.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B, Grade B, Grade B
Novelty: Grade B, Grade B, Grade C
Creativity or Innovation: Grade B, Grade C, Grade C
Scientific Significance: Grade B, Grade C, Grade C
P-Reviewer: Hu ZY; Yan J S-Editor: Wang JJ L-Editor: A P-Editor: Zheng XM
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