The Role of the Liver in Sepsis

Despite some advances that have been made in the clinical management of sepsis, its morbidity and mortality rates remain high. The pathogenesis of systemic inflammation and organ damage leading to septic mortality is not fully understood. Interleukin-33 (IL-33), a new member of the IL-1 superfamily, can be a traditional cytokine and a nuclear factor regulating gene transcription. Due to its biological characteristics, IL-33 can act as a double-edged sword in sepsis: It not only contributes to clear bacteria and improves survival but also causes inflammation, immunosuppression, and organ damage via modulating immune response. In this review, we will summarize updated information on the dual functions of IL-33 in the host immune response to sepsis.

Imatinib 400 mg daily is the standard treatment for patients with chronic myelogenous leukemia (CML). The safety and efficacy of imatinib in CML patients with pre-existing liver and/or renal dysfunction has not been analyzed. The authors analyzed the outcome of 259 patients with early chronic phase CML treated with imatinib (starting dose 400 mg in 50, 800 mg in 209). Pre-existing liver and/or renal dysfunction was seen in 38 (15%) and 11 (4%) patients, respectively. Dose reductions were required in 91 (43%) of 210 patients with normal organ function, compared with 8 (73%) of 11 (P = .065) with renal dysfunction, and 19 (50%) of 38 (P = .271) with liver dysfunction. Grade 3-4 hematologic toxicities including anemia (29%, 10%, and 7% of patients with renal dysfunction, liver dysfunction, and normal organ function, respectively), neutropenia (57%, 30%, and 30%), and thrombocytopenia (43%, 30%, and 26%) were more frequent in patients with pre-existing renal dysfunction treated with high-dose imatinib. Grade 3-4 nonhematologic toxicities were observed at similar frequencies. Complete cytogenetic response rates, event-free survival, and overall survival were similar in all groups. Although patients with pre-existing liver and/or renal dysfunction might have a higher rate of hematologic toxicity and require more frequent dose reductions, most patients can be adequately managed, resulting in response rates and survival similar to those without pre-existing organ dysfunction.

Purpose: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a life-saving intervention for refractory cardiopulmonary failure. Identifying factors associated with survival is essential for optimizing patient selection and management. In this study, we aimed to identify VA-ECMO survival predictors and evaluate the associated complications, costs, and outcomes.Methods: A retrospective analysis was conducted on data from 123 adult patients who underwent VA-ECMO at the Songklanagarind Hospital between 2017 and 2023. Clinical characteristics, ECMO-related complications, hospital expenses, and survival outcomes were analyzed. Univariate and multivariate logistic regression analyses were used to determine independent predictors of survival.Results: Fifty (40.7%) patients survived until hospital discharge. Compared to central VA-ECMO, peripheral VA-ECMO was significantly associated with improved survival (adjusted OR: 26.44, 95% CI: 1.95–358.7, p = 0.014). Preexisting liver dysfunction (adjusted OR: 0.27, 95% CI: 0.09–0.79, p = 0.016) and renal dysfunction (adjusted OR: 0.29, 95% CI: 0.1–0.85, p = 0.023) were independent mortality predictors. Survival odds were significantly lower in patients with American Society of Anesthesiologists (ASA) Class 5 (adjusted OR: 0.07, 95% CI: 0.01–0.67, p = 0.022). Neurological complications were more common in nonsurvivors than in survivors (41.1% vs. 18%, p = 0.012). Survivors had significantly higher total hospital costs (997,563.5 vs. 696,191 THB, p = 0.004) and longer hospital stays (28.5 vs. 3 days, p < 0.001). The multivariate model demonstrated strong predictive performance, with an area under the curve of 0.85.Conclusions: ECMO cannulation strategy, preexisting liver and renal dysfunction, and ASA classification were key factors associated with survival. Peripheral VA-ECMO was associated with better outcomes, and organ dysfunction significantly increased the mortality risk.

The safety and efficacy of front-line nilotinib and dasatinib in patients with newly diagnosed chronic-phase chronic myelogenous leukemia (CML-CP) with pre-existing liver and/or renal dysfunction are unknown. We analyzed the adverse event rates, response rates, and survival rates of 215 patients with CML-CP with or without renal and/or liver dysfunction who had been treated with front-line nilotinib (n = 108) or dasatinib (n = 107). The overall median follow-up period was 49 months. At baseline, 6 dasatinib-treated patients (6%) had mild renal dysfunction and 13 (12%) had mild liver dysfunction. Also, 8 nilotinib-treated patients (7%) had mild renal dysfunction, 1 (1%) moderate renal dysfunction, and 9 (8%) mild liver dysfunction. No significant differences were found in the rate of complete cytogenetic response, major molecular response, or molecular response by a 4.5 log reduction on the international scale between the organ function cohorts. Dasatinib- or nilotinib-treated patients with baseline renal dysfunction had a greater incidence of transient reversible acute kidney injury (P = .011 and P < .001), and nilotinib-treated patients with renal dysfunction had a greater incidence of bleeding (P < .001). Patients with CML-CP and mild to moderate renal or liver dysfunction can be safely treated with front-line dasatinib or nilotinib and can achieve response rates similar to those of patients with CML-CP without organ dysfunction.

Sectm1a Facilitates Protection against Inflammation-Induced Organ Damage through Promoting TRM Self-Renewal

Clinical Safety and Efficacy Of Nilotinib Or Dasatinib In Patients (Pts) With Newly Diagnosed Chronic-Phase Chronic Myelogenous Leukemia (CML-CP) With Pre-Existing Liver and/Or Renal Dysfunction

IL-1R1 blockade attenuates liver injury through inhibiting the recruitment of myeloid-derived suppressor cells in sepsis

Sepsis, a syndrome characterized by systemic inflammation during infection, continues to be one of the most common causes of patient mortality in hospitals across the United States. While standardized treatment protocols have been implemented, a wide variability in clinical outcomes persists across racial groups. Specifically, black and Hispanic populations are frequently associated with higher rates of morbidity and mortality in sepsis compared to the white population. While this is often attributed to systemic bias against minority groups, a growing body of literature has found patient, community, and hospital-based factors to be driving racial differences. In this article, we provide a focused review on some of the factors driving racial disparities in sepsis. We also suggest potential interventions aimed at reducing health disparities in the prevention, early identification, and clinical management of sepsis.

G-Protein-Coupled Receptor 30 Mediates Estrogen's Nongenomic Effects after Hemorrhagic Shock and Trauma

Liver dysfunction is a common problem in BMT recipients and it is important to determine the etiology in order to institute appropriate therapy. The purpose of this study was to evaluate the possible causes of liver dysfunction during the first post-transplant year in BMT recipients and to identify a possible relationship between pre-existing liver dysfunction and viral hepatitis with prognosis after BMT. We reviewed liver status before and after BMT in 130 consecutive patients at the Catholic Hematopoietic Stem Cell Transplantation Center. Liver dysfunction during the first post-transplant year occurred in 85 out of 101 (84. 2%) allogeneic BMT recipients and 13 out of 29 (44.8%) autologous BMT recipients. In allogeneic BMT, GVHD and drug hepatotoxicity were major causes. In autologous BMT, drug hepatotoxicity was the most common cause. Eighteen out of 130 patients (13.8%) had abnormal liver function tests before BMT. These patients did not have an increased risk of post-transplant liver dysfunction, GVHD, and death compared to patients who had normal liver function tests prior to BMT. Nine patients were hepatitis B antigen positive and three patients were anti-HCV positive prior to BMT. There was no significant increase in the incidence of post-transplant liver dysfunction, GVHD, and death in these patients.

The clinical management of sepsis has benefited from breakthroughs in antimicrobial chemotherapy as well as other pharmacologic and technologic means of critical care support. Despite such advances, the course of patients suffering sepsis remains unpredictable and often protracted [1]. Disruptions of immunologic and metabolic homeostasis are well recognized sequelae of sepsis that contribute to the morbidity and mortality of chronic sepsis. In addition, variables related to the clinical status of patients prior to the onset of sepsis also appear to impact on the acute manifestations of sepsis.

During sepsis, the liver plays a key role. It is implicated in the host response, participating in the clearance of the infectious agents/products. Sepsis also induces liver damage through hemodynamic alterations or through direct or indirect assault on the hepatocytes or through both. Accordingly, liver dysfunction induced by sepsis is recognized as one of the components that contribute to the severity of the disease. Nevertheless, the incidence of liver dysfunction remains imprecise, probably because current diagnostic tools are lacking, notably those that can detect the early liver insult. In this review, we discuss the epidemiology, diagnostic tools, and impact on outcome as well as the pathophysiological aspects, including the cellular events and clinical picture leading to liver dysfunction. Finally, therapeutic considerations with regard to the weakness of the pertinent specific approach are examined.

The Liver in Sepsis.

Part II: Liver function in oncology: towards safer chemotherapy use

Liver dysfunction is believed to contribute to the metabolic derangements of critical illness. The cellular basis of liver dysfunction is poorly understood and its consequences largely unknown. Recent work by Gonnert and colleagues sheds additional light. Using two imaging techniques to track the clearance of biotransformed dyes by the liver in a rat model of intra-abdominal infection, the authors show that the predominant defect in sepsis lies in the excretion of biotransformed molecules from the hepatocyte into the bile canaliculi. Their work both points to a new aspect of hepatic dysfunction through focus on a role in the metabolic derangements of sepsis and suggests a possible strategy to diagnose and monitor this process in critically ill patients.