Sepsis-associated Liver Dysfunction Research Articles

Acute gastrointestinal injury and altered gut microbiota are related to sepsis-induced cholestasis in patients with intra-abdominal infection: a retrospective and prospective observational study.

Sepsis-associated liver dysfunction (SALD) has high incidence and mortality in patients with intra-abdominal infection (IAI). The associations between acute gastrointestinal injury (AGI), gut microbiota, and SALD were evaluated in patients with IAI. A retrospective study was conducted to assess the relationship between AGI and SALD in patients with IAI. Patients were divided into non-SALD and sepsis-induced cholestasis (SIC) groups, which is a subtype of SALD. SIC was defined as total bilirubin >2 mg/dL. AGI incidences between the two groups were compared using Chi-square test. Subsequently, a prospective study was conducted to investigate the gut microbiota differences between patients without SALD and those with SIC. Fecal samples were collected on days 1, 3, and 7 after admission to analyze changes in gut microbiota using 16S ribosomal ribonucleic acid sequencing. One hundred thirty-four patients with IAI were included retrospectively, with 77 SALD and 57 non-SALD cases. Among patients with SALD, 71 were diagnosed with SIC. Patients with SIC had a higher incidence of AGI compared to those without SALD (28.07% vs. 56.34%, p < 0.05), and a severity-dependent relationship was found between AGI grade and SIC occurrence. Subsequently, 20 patients with IAI were recruited prospectively, with 10 patients each assigned to the non-SALD and SIC groups. Patients with SIC had a more severe gut microbiota disorder on day 7 than those without SALD, including lower microbiota diversities, decreased abundance of Firmicutes and Bacteroidetes, and increased abundance of Proteobacteria and Actinobacteria at the phylum level. Furthermore, Burkholderia - Caballeronia - Paraburkholderia and Delftia, the two most abundant genera, were significantly higher in the SIC group than in the non-SALD group. Functional prediction analysis showed that the top three KEGG pathways were ribosome, pyrimidine metabolism, and the two-component system. During the first week, the abundance of Proteobacteria decreased significantly, whereas Cyanobacteria increased in the non-SALD group; however, the phyla taxa did not change significantly in the SIC group. There exists a severity-dependent relationship between AGI grade and SIC occurrence in adult patients with IAI. A severe gut microbiota disorder was discovered in SIC during the first week of the intensive care unit stay.

Novel Time-dependent Multi-omics Integration in Sepsis-associated Liver Dysfunction

The recently developed technologies that allow the analysis of each single omics have provided an unbiased insight into ongoing disease processes. However, it remains challenging to specify the study design for the subsequent integration strategies that can associate sepsis pathophysiology and clinical outcomes. Here, we conducted a time-dependent multi-omics integration (TDMI) in a sepsis-associated liver dysfunction (SALD) model. We successfully deduced the relation of the Toll-like receptor 4 (TLR4) pathway with SALD. Although TLR4 is a critical factor in sepsis progression, it is not specified in single-omics analyses but only in the TDMI analysis. This finding indicates that the TDMI-based approach is more advantageous than single-omics analyses in terms of exploring the underlying pathophysiological mechanism of SALD. Furthermore, TDMI-based approach can be an ideal paradigm for insightful biological interpretations of multi-omics datasets that will potentially reveal novel insights into basic biology, health, and diseases, thus allowing the identification of promising candidates for therapeutic strategies.

Relationship between liver dysfunction, lipoprotein concentration and mortality during sepsis.

High-density lipoproteins (HDLs) are synthesized by the liver and display endothelioprotective properties, including anti-inflammatory, antiapoptotic, antithrombotic and antioxidant effects. In both septic and chronic liver failure patients, a low HDL cholesterol (HDL-C) concentration is associated with overmortality. Whereas sepsis-associated liver dysfunction is poorly defined, the aim of this study was to characterize the relationship between liver dysfunction, lipoprotein concentrations and mortality in septic patients in the intensive care unit (ICU). A prospective observational study was conducted in a university hospital ICU. All consecutive patients admitted for septic shock or sepsis were included. Total cholesterol, HDL-C, low-density lipoprotein-cholesterol (LDL-C), and triglyceride levels were assessed at admission. Sepsis-associated liver dysfunction was defined as a serum bilirubin≥ 2N or aspartate aminotransferase/alanine aminotransferase concentrations ≥ 2N. Short-term and one-year prognostic outcomes were prospectively assessed. A total of 219 septic patients were included, and 15% of them presented with sepsis-associated liver dysfunction at admission. Low concentrations of lipoproteins were associated with mortality at Day 28 in the overall population. Sepsis-associated liver dysfunction at admission was associated with overmortality. In this subgroup, patients had a lower HDL-C concentration than patients without hepatic dysfunction (HDL-C = 0.31 [0.25, 0.55] mmol/L vs. 0.48 [0.29, 0.73] mmol/L, p = 0.0079) but there was no relationship with the outcome. Interestingly, no correlation was observed between lipoprotein concentrations and liver dysfunction markers. Sepsis-associated liver dysfunction at ICU admission is strongly associated with overmortality and is associated with a lower HDL-C concentration. However, in this subgroup of patients, HDL-C concentration had no relationship with mortality. Further exploratory studies are needed to better understand the interaction between lipoproteins and liver dysfunction during sepsis.

6-Shogaol Mitigates Sepsis-Associated Hepatic Injury through Transcriptional Regulation.

Sepsis-associated liver dysfunction presents a significant public health problem. 6-Shogaol is the key bioactive component in dry ginger, which has antioxidant and anti-inflammation capacity. The present study aims to investigate the preventive effect of 6-shogaol on sepsis-induced liver injury. 6-Shogaol was administered to mice for 7 consecutive days before being intraperitoneally injected with lipopolysaccharide (LPS). After 24 h, mice were sacrificed, and biochemical and transcriptomic analyses were performed. Our results demonstrated that 6-shogaol prevented LPS-induced impairment in antioxidant enzymes and elevation in malondialdehyde level in the liver. The hepatic inflammatory response was significantly suppressed by 6-shogaol through suppressing the MAPK/NFκB pathway. RNA-sequencing data analysis revealed that 41 overlapped genes between the LPS vs. control group and 6-shogaol vs. LPS group were identified, among which 36 genes were upregulated, and 5 genes were downregulated for the LPS vs. control group. These overlapped genes are enriched in inflammation-related pathways, e.g., TNF and NFκB. The mRNA expression of the overlapped genes was also verified in the LPS-induced BRL-3A cell model. In summary, 6-shogaol shows great potential as a natural chemopreventive agent to treat sepsis-associated hepatic disorders.

Estrogen-Related Receptor γ Agonist DY131 Ameliorates Lipopolysaccharide-Induced Acute Liver Injury.

Sepsis-associated liver dysfunction remains a challenge in clinical practice with high mortality and limited specific therapies. DY131 is a pharmacological agonist of the orphan receptor estrogen-related receptor (ERR) γ which plays a crucial role in regulating energy generation, oxidative metabolism, cell apoptosis, inflammatory responses, etc. However, its role in acute liver injury is unknown. In this study, we evaluated the effect of DY131 on lipopolysaccharide (LPS)-induced liver injury. Mice were pretreated with DY131 through intraperitoneal injection at a dose of 5 mg/kg/day for 3 days prior to LPS challenge (10 mg/kg). 24 h later, they were anesthetized and sacrificed. Blood and liver tissues were collected for further studies. In a separate experiment, mice were treated with saline (vehicle) or DY131 for 3 days to evaluate the toxicity of DY131. We found that ERRγ was downregulated in the liver tissues from LPS-treated mice. Pretreatment with DY131 ameliorated LPS-induced liver injury as demonstrated by reduced liver enzyme release (ALT, AST, and LDH), improved liver morphological damage, and attenuated oxidative stress, inflammation and apoptosis. Meanwhile, DY131 had no significant side effects on hepatic and renal functions in mice. Finally, transcriptomics analysis revealed that the dysregulated pathways associated with inflammation and metabolism were significantly reversed by DY131 in LPS-treated mice, providing more evidence in favor of the protective effect of DY131 against LPS-induced liver injury. Altogether, these findings highlighted the protective effect of DY131 on LPS-induced hepatotoxicity possibly via suppressing oxidative stress, inflammation, and apoptosis.

Sites and Causes of Infection in Patients with Sepsis-Associated Liver Dysfunction: A Population Study from the Medical Information Mart for Intensive Care III.

BackgroundLittle is known about the relationship between the site of infection, type of pathogen, and the occurrence of sepsis-associated liver dysfunction (SALD). This population study aimed to identify the sites and types of infection in SALD patients.Material/MethodsWe conducted a retrospective observational study using the Medical Information Mart for Intensive Care III. Patients with sepsis were divided into a SALD group and a control group. We evaluated the effect of the location of culture-positive specimens and the distribution of pathogens on the occurrence of SALD and then compared the clinical outcomes.ResultsA total of 14 596 admissions were included, and the incidence of SALD was 11.96%. Positive bile culture (odds ratio [OR] 7.450, P<0.001), peritoneal fluid culture (OR 3.616, P<0.001), and blood culture (OR 1.957, P<0.001) were correlated with the occurrence of SALD. Infection with Enterococcus faecium (OR 3.065, P<0.001), Bacteroides fragilis (OR 2.061, P<0.001), Klebsiella oxytoca (OR 2.066, P<0.001), Enterobacter aerogenes (OR 1.92, P=0.001), and Aspergillus fumigatus (OR 2.144, P=0.001) were correlated with the occurrence of SALD. The Intensive Care Unit mortality and hospital mortality were higher in the SALD group than in the control group (24.7% vs 9.0%, P<0.001; 34.2% vs 13.8%, P<0.001, respectively).ConclusionsSALD should be considered for patients with sepsis whose infection site is the biliary system, abdominal cavity, or blood and the pathogen is Enterococcus faecium, B. fragilis, K. oxytoca, Enterobacter aerogenes, or A. fumigatus. When SALD occurs in patients with sepsis, the above infection sites and pathogens should be considered first.

Reduced Mrp2 surface availability as PI3K\u03b3-mediated hepatocytic dysfunction reflecting a hallmark of cholestasis in sepsis

Sepsis-associated liver dysfunction manifesting as cholestasis is common during multiple organ failure. Three hepatocytic dysfunctions are considered as major hallmarks of cholestasis in sepsis: impairments of microvilli covering canalicular membranes, disruptions of tight junctions sealing bile-collecting canaliculae and disruptions of Mrp2-mediated hepatobiliary transport. PI3Kγ loss-of-function was suggested as beneficial in early sepsis. Yet, the PI3Kγ-regulated cellular processes in hepatocytes remained largely unclear. We analysed all three sepsis hallmarks for responsiveness to massive PI3K/Akt signalling and PI3Kγ loss-of-function, respectively. Surprisingly, neither microvilli nor tight junctions were strongly modulated, as shown by electron microscopical studies of mouse liver samples. Instead, quantitative electron microscopy proved that solely Mrp2 surface availability, i.e. the third hallmark, responded strongly to PI3K/Akt signalling. Mrp2 plasma membrane levels were massively reduced upon PI3K/Akt signalling. Importantly, Mrp2 levels at the plasma membrane of PI3Kγ KO hepatocytes remained unaffected upon PI3K/Akt signalling stimulation. The effect explicitly relied on PI3Kγ’s enzymatic ability, as shown by PI3Kγ kinase-dead mice. Keeping the surface availability of the biliary transporter Mrp2 therefore is a cell biological process that may underlie the observation that PI3Kγ loss-of-function protects from hepatic excretory dysfunction during early sepsis and Mrp2 should thus take center stage in pharmacological interventions.

Liver dysfunction in sepsis.

Despite continuous progress in medicine, sepsis remains the main cause of deaths in the intensive care unit. Liver failure complicating sepsis/septic shock has a significant impact on mortality in this group of patients. The pathophysiology of sepsis-associated liver dysfunction is very complicated and still not well understood. According to the Surviving Sepsis Campaign (SSC) Guidelines, the diagnosis of liver dysfunction during sepsis is based on the increase in bilirubin concentration >2 mg/dL and the occurrence of coagulation disorders with INR > 1.5. The lack of specificity and ability to distinguish acute liver failure from previous liver dysfunction disqualifies bilirubin as a single parameter reflecting the complex liver function. Clinical manifestations of sepsis-associated liver dysfunction include hypoxic hepatitis, sepsis-induced cholestasis and dysfunction of protein synthesis manifesting with, e.g., coagulopathies. Detoxifying liver dysfunction, which is associated with an increase in serum ammonia concentration, manifesting with e.g., confusion, loss of consciousness and hepatic encephalopathy, may be disguised by analgosedation used in the intensive care unit. To determine a liver dysfunction in a critically ill patient, the concept of shock liver may be used. It is a complex syndrome of hemodynamic, cellular, molecular and immunologic changes leading to severe liver hypoxia. In clinical practice, there is no standardized diagnostic panel that would allow for an early, clear diagnosis of acute liver dysfunction, and there is no therapeutic panel enabling the full restoration of damaged liver function. The aim of the article is to present the pathophysiology and clinical manifestations of sepsis-associated liver dysfunction.

Clinical characteristics and prognosis of sepsis-associated liver injure in pediatric intensive care unit

Objective To discuss the incidence, clinical characteristics of sepsis-associated liver injure in pediatric patients and risk factors that may affect the prognosis. Methods A retrospective analysis was made on the data of patients with sepsis-associated liver injure that had been hospitalized in Shanghai Children′s Hospital from January 2011 to December 2015.The cases were divided into the survival group and the death group.Logistic regression analysis was made to screen out risk factors of patients with sepsis-associated liver injure that influence the prognosis. Results The incidence of sepsis associated liver dysfunction was 9.7%(120/1 242), the mortality rate was 35.8%(43/120). The most common focus of infection was respiratory tract infection(50.0%), followed by abdominal cavity infection(33.3%) and central nervous system infection(6.7%). The pathogenic microorganisms were mainly gram-negative bacilli(51.3%), followed by virus(26.5%) and gram-positive bacterium(17.7%). The main manifestations of the liver injure were elevated glutamic-pyruvic transaminase(117 cases, 97.5%), prolonged prothrombin time(PT)(93 cases, 77.5%), hypoproteinemia(83 cases, 69.2%) and hyperbilirubinemia(70 cases, 58.3%). The total bilirubin(TBIL), PT, activated partial thromboplastin time and total bile acid of the death group were higher than thoes of the survival group.Logistic regression analysis indicated that elevated TBIL(OR=2.937, 95%CI 1.179-7.315, P=0.021) was the independent risk factor for death.The area under receiver operating characteristic curve for TBIL(cut off was 64.5 μmol/L)was 0.736 with sensitivity 57.7% and specificity 84.8%. Conclusion The incidence rate of sepsis-associated liver injure among pediatric patient is high.Gram-negative bacilli are the main pathogenic microorganisms.This disease is manifested as the elevated glutamic-pyruvic transaminase, hypoproteinemia, prolonged PT and hyperbilirubinemia.Hyperbilirubinemia is the independent risk factor that influences the prognosis. Key words: Sepsis; Total Bilirubin; Sepsis-associated liver injure; Pediatric intensive care unit; Children,

Advances in sepsis-associated liver dysfunction.

Recent studies have revealed liver dysfunction as an early event in sepsis. Sepsis-associated liver dysfunction is mainly resulted from systemic or microcirculatory disturbances, spillovers of bacteria and endotoxin (lipopolysaccharide, LPS), and subsequent activation of inflammatory cytokines as well as mediators. Three main cell types of the liver which contribute to the hepatic response in sepsis are Kupffer cells (KCs), hepatocytes and liver sinusoidal endothelial cells (LSECs). In addition, activated neutrophils, which are also recruited to the liver and produce potentially destructive enzymes and oxygen-free radicals, may further enhance acute liver injury. The clinical manifestations of sepsis-associated liver dysfunction can roughly be divided into two categories: Hypoxic hepatitis and jaundice. The latter is much more frequent in the context of sepsis. Hepatic failure is traditionally considered as a late manifestation of sepsis-induced multiple organ dysfunction syndrome. To date, no specific therapeutics for sepsis-associated liver dysfunction are available. Treatment measure is mainly focused on eradication of the underlying infection and management for severe sepsis. A better understanding of the pathophysiology of liver response in sepsis may lead to further increase in survival rates.

Septic liver: clinical relevance of early inhomogeneous enhancement of the liver in patients with acute pyelonephritis

CT scans of patients with febrile illness occasionally show hepatobiliary changes, although infection does not originate in the hepatobiliary system. These findings may cause radiologists and clinicians to misrecognize hepatobiliary diseases and initiate an inappropriate treatment. Thus, it is important to recognize hepatobiliary CT findings in cases of extrahepatobiliary infectious disease. To evaluate extrarenal CT manifestations in patients with acute pyelonephritis and to determine the correlation between these extrarenal CT findings and septic liver based on laboratory parameters of sepsis. This study included 157 retrospectively identified patients with confirmed acute pyelonephritis based on CT imaging and urine test, and who had also undergone multi-phase dynamic contrast-enhanced CT scan. Two radiologists reviewed CT findings including early inhomogeneous enhancement of the liver, periportal low density and gallbladder edema, which were correlated with laboratory data including liver function enzymes, albumin, C-reactive protein, white blood cell count, and results of a blood culture by using the Fisher's exact test and Mann-Whitney U test. Forty-six patients (29.3%) showed early inhomogeneous enhancement of the liver, which was associated with increased C-reactive protein (P < 0.001), a positive blood culture (P < 0.005), and decreased albumin level (P < 0.002). The periportal low density and gallbladder wall edema were noted in 15 patients (9.6%) and six patients (3.8%), respectively. These two CT findings were significantly associated with only decreased albumin level (P < 0.001 and P < 0.040). Early inhomogeneous enhancement of the liver in patients with acute pyelonephritis was significantly associated with increased CRP level, a positive blood culture and decreased albumin level, reflecting sepsis and sepsis-associated liver dysfunction, requiring rapid and appropriate intensive treatment.

Immunostimulatory CpG-oligodeoxynucleotides (CpG-ODN) induce early hepatic injury, but provide a late window for protection against endotoxin-mediated liver damage

An impaired immunologic response to infection has been recognized as a major defect in the pathogenesis of sepsis and multi-organ failure. Sepsis-associated liver dysfunction and damage are main determinants for the course of the disease. CpG-motif-containing DNA-sequences (CpG-ODN) were previously shown to confer protection in models of infection by stimulating both innate and specific immune responses. Herein, we studied the effect of CpG-ODN in lipopolysaccharide (LPS)-associated hepatotoxicity. Sprague Dawley rats pre-treated at day 6 with either CpG-ODN or inert DNA were challenged with E. coli LPS and subsequently studied for liver injury at 6 and 16 h using in vivo fluorescence microscopy and immunohistochemistry. Western blot protein analysis served for assessment of expression of TLR4, TNF receptor-associated factor 6 (TRAF6), NFkappaB and caspase-3. To evaluate CpG-ODN effects during non-septic conditions, additional animals were solely exposed to CpG-ODN and studied after 1 and 6 days. CpG-ODN application induced marked hepatic microcirculatory deterioration and liver dysfunction at day 1, however, with almost complete recovery to normal at day 6. Interestingly, CpG-ODN pre-treatment decreased LPS-induced leukocyte-endothelial cell interaction, sinusoidal perfusion failure and caspase-3-dependent apoptotic cell death. Although Kupffer cell phagocytic activity was not affected, CpG-ODN pre-treatment in LPS-challenged animals attenuated hepatic protein expression of TRAF6 and NFkappaB and increased TLR4 by almost 100%. CpG-containing DNA-sequences induce early hepatic injury, but mediate long-term protection against LPS hepatotoxicity. The mechanism of protection is based on the induction of cross-tolerance, probably via inhibition of the downstream TRAF6-NFkappaB signaling pathway and upregulation of the TLR4 surface receptor.

Glutamine and glutathione counteract the inhibitory effects of mediators of sepsis in neonatal hepatocytes

Background/Purpose: Surgical neonates are at risk of sepsis-associated liver dysfunction. Hydrogen peroxide (H2O2) and nitric oxide (NO) are important mediators of sepsis, which impair neonatal hepatic metabolism. Glutamine has been shown to have beneficial effects on hepatocyte metabolism during neonatal sepsis. However, the molecular basis of these effects are unknown. The aim of this study was to test the hypotheses that (1) glutamine and its dipeptides counteract the inhibitory effect of septic mediators on neonatal hepatocyte oxygen consumption and (2) the effects of glutamine are specific and not shared by other amino acids. In addition, we wished to determine the metabolic pathways and mediators involved in the action of glutamine. Methods: Hepatocytes were isolated from suckling rats, and O2 consumption measured polarographically. Study A: the ability of 10 mmol/L glutamine to reverse the inhibitory effects of 1.5 mmol/L H2O2 and 300 μmol/L S-Nitroso-N-acetylpenicillamine (SNAP; a nitric oxide donor) on O2 consumption was examined. Study B: the ability of other amino acids and dipeptides of glutamine to reverse the effects of H2O2 was examined. Study C: various concentrations of glutamine were tested for their ability to reverse the H2O2 inhibition of O2 consumption. Study D: the mechanism of action of glutamine was examined by incubating hepatocytes with either an inhibitor of entry into the Krebs cycle or an inhibitor of glutathione synthesis. Study E: the ability of glutathione to reverse the inhibitory effects of H2O2 was examined. Results: Study A: glutamine reversed the inhibition of hepatocyte O2 consumption exerted by either H2O2 or NO. Study B: glutamine dipeptides reversed the inhibition of hepatocyte O2 consumption by H2O2, but other amino acids did not. Study C: the counteracting effect of glutamine was proportional to the dose administered. Study D: blocking entry of glutamine into the Krebs cycle did not abolish the effects of glutamine, but blocking glutathione synthesis completely abolished the effect of glutamine. Study E: exogenous glutathione reversed the inhibitory effect of H2O2 on hepatocyte O2 consumption. Conclusions: This study found that glutamine and its dipeptides are unique in reversing the effects of septic mediators on neonatal rat liver oxidative metabolism. The effectiveness of glutamine appears to be mediated via glutathione synthesis. Addition of glutamine, glutamine dipeptides, or glutathione to total parenteral nutrition (TPN) may be beneficial in preventing liver damage in neonatal sepsis. J Pediatr Surg 36:282-286. Copyright © 2001 by W.B. Saunders Company.