|
1
|
Wang X, Yang X, Wang M, Huang X, Zhang M. The neuroprotective power of artificial liver therapy: reversing cognitive impairment in minimal hepatic encephalopathy. Brain Imaging Behav 2025; 19:497-507. [PMID: 40042700 DOI: 10.1007/s11682-024-00947-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/21/2024] [Indexed: 04/09/2025]
Abstract
Alteration of functional connectivity in brain regions is one of the potential neuropathological mechanisms underlying cognitive impairment in patients with minimal hepatic encephalopathy (MHE). Artificial liver therapy has been shown to improve cognitive impairment in patients, suggesting a potential neuroprotective effect on the brain. This study investigates the impact of artificial liver therapy (AL) on cognitive impairment in patients with minimal hepatic encephalopathy (MHE) by examining alterations in brain functional connectivity. Resting-state functional magnetic resonance imaging (fMRI) data was collected from healthy controls and MHE patients before and after therapy. The MHEpost-AL group showed improved memory, reaction time, and executive function compared to the MHEpre-AL group. Functional connectivity analysis revealed increased connectivity in specific brain regions in the MHEpre-AL group compared to healthy controls, with subsequent decreased connectivity after therapy. Lower MoCA scores, higher blood ammonia levels, and lower cholinesterase levels were associated with higher functional connectivity in the MHEpre-AL group. The study suggests that artificial liver therapy improves cognitive impairment in MHE patients, with changes in blood biochemistry mediating the link between functional connectivity and cognitive function. Correcting blood biochemistry levels may reverse abnormal brain connectivity and enhance cognitive function in MHE patients.
Collapse
Affiliation(s)
- Xiaodong Wang
- Xi'an Jiaotong University, Department of Medical Imaging, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
- Department of Radiology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China
| | - Xuhong Yang
- Jiangsu Key Laboratory of Molecular Imaging and Functional Imaging, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210009, China
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, 750004, China
| | - Minglei Wang
- Department of Radiology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China
| | - Xueying Huang
- Department of Radiology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China
| | - Ming Zhang
- Xi'an Jiaotong University, Department of Medical Imaging, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| |
Collapse
|
|
2
|
Gao S, Fan YC, Han LY, Wang K. Serum exosomal long noncoding RNA nuclear-enriched abundant transcript 1 predicts 90-day mortality in acute-on-chronic hepatitis B liver failure. Expert Rev Clin Immunol 2021; 17:789-797. [PMID: 34057878 DOI: 10.1080/1744666x.2021.1933442] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 05/19/2021] [Indexed: 01/05/2023]
Abstract
Objectives: Acute-on-chronic hepatitis B liver failure (ACHBLF) is characterized by high short-term mortality, calling for accurate prognostic biomarkers. This study aims to evaluate the predictive value of serum exosomal long noncoding RNA nuclear-enriched abundant transcript 1 (lncRNA NEAT1) for 90-day mortality of ACHBLF.Methods: This prospective study consisted of 113 ACHBLF patients from June 2013 to June 2017 as a training cohort and 72 ACHBLF patients from July 2017 to June 2020 as a validating cohort. LncRNA NEAT1 was detected using quantitative real-time polymerase chain reaction from serum exosomes.Results: LncRNA NEAT1 levels were higher in non-survivors than survivors (P< 0.01). In the training cohort, lncRNA NEAT1 (HR 1.049, 95%CI 1.023-1.075, P< 0.001) was an independent predictor for 90-day mortality of ACHBLF. Meanwhile, lncRNA NEAT1 showed significantly higher area under the curve of receiver operating characteristic (AUC) than MELD score in the training and validation cohort (P< 0.05, respectively). However, no significant difference was found in AUC between lncRNA NEAT1 and NEAT1 plus MELD score (P> 0.05). ACHBLF patients with lncRNA NEAT1 levels above 1.92 showed poorer survival condition than those below (P< 0.01).Conclusions: The serum exosomal lncRNA NEAT1 might be a better prognostic biomarker than MELD score for 90-day mortality of ACHBLF.
Collapse
Affiliation(s)
- Shuai Gao
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
- Institute of Hepatology, Shandong University, Jinan, China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
- Institute of Hepatology, Shandong University, Jinan, China
| | - Li-Yan Han
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
- Institute of Hepatology, Shandong University, Jinan, China
| | - Kai Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
- Institute of Hepatology, Shandong University, Jinan, China
| |
Collapse
|
|
3
|
Sirpal S, Yoshida EM, Chandok N. Revisiting the '6-month' liver transplant rule for alcohol-associated liver disease: It is time for a change but not without a sound policy first. CANADIAN LIVER JOURNAL 2018; 1:153-155. [PMID: 35992625 PMCID: PMC9202758 DOI: 10.3138/canlivj.2018-0002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 11/06/2018] [Indexed: 08/23/2024]
Abstract
There is historical reluctance in the medical community to offer liver transplantation to patients with alcoholic liver disease. Transplant programs broadly follow a policy that requires abstention from alcohol for a minimum of 6 months. This policy, however, is at odds with data that supports improved survival in patients with severe acute alcoholic hepatitis (SAAH). Ethicists, the public, and the transplant community must make a concerted effort to forge an updated transplant policy for SAAH that better reflects current scientific evidence for earlier transplant in well-selected recipients without unfair advantage to those of high socioeconomic status.
Collapse
Affiliation(s)
- Sanjeev Sirpal
- Department of Medicine, Centre Hospitalier de l’Université de Montréal (CHUM), University of Montréal, Montréal, Quebec
| | - Eric M Yoshida
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, British Columbia
| | - Natasha Chandok
- Division of Gastroenterology, Department of Medicine, University of Western Ontario, London, Ontario
| |
Collapse
|
|
4
|
Li M, Sun J, Li J, Shi Z, Xu J, Lu B, Cheng S, Xu Y, Wang X, Zhang X. Clinical observation on the treatment of acute liver failure by combined non-biological artificial liver. Exp Ther Med 2016; 12:3873-3876. [PMID: 28105119 PMCID: PMC5228520 DOI: 10.3892/etm.2016.3887] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 09/02/2016] [Indexed: 01/30/2023] Open
Abstract
The clinical efficacy and safety of different combinations of non-bio artificial liver in the treatment of acute liver failure was examined. A total of 61 cases were selected under blood purification treatment from the patients with severe acute liver failure admitted to the severe disease department of the hospital from December, 2010 to December, 2015. Three types of artificial liver combinations were observed, i.e., plasma exchange plus hemoperfusion plus continuous venovenous hemodiafiltration (PE+HP+CVVHDF), PE+CVVHDF and HP+CVVHDF. The heart rate (HR), mean arterial pressure (MAP), respiratory index (PaO2/FiO2), liver and kidney function indicator, as well as platelet and coagulation function were compared. A comparison before and after the treatment using the three methods, showed improvement in the HRs, MAPs, PaO2/FiO2, total bilirubins (TBIL) and alanine aminotransferases (ALT) (P<0.05), of which TBIL and ALT were decreased more significantly (P<0.01) in the PE+CVVHDF and PE+HP+CVVHDF groups. Only changes in the PE+HP+CVVHDF and PE+CVVHDF groups were statistically significant after prothrombin time and albumin treatment (P<0.05). The difference between the decrease in TBIL in the PE+HP+CVVHDF group and that in the HP+CVVHDF group was statistically significant (P<0.05). Treatment of the 61 patients using the artificial liver support system yielded a survival rate of 62.3% (38/61), and a viral survival rate of 35.0% (7/20); with the non-viral survival rate being 75.6% (31/41). In conclusion, following the treatment of three types of artificial livers, the function was improved to varying degrees, with the PE+HP+CVVHDF and the PE+CVVHDF method being better. By contrast, after the treatment of non-viral liver failure, the survival rate was significantly higher than the patients with viral liver failure.
Collapse
Affiliation(s)
- Maoqin Li
- Department of Intensive Care Unit, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou Clinical School of Xuzhou Medical College of Nanjing University of Chinese Medicine, Xuzhou, Jiangsu 221009, P.R. China
| | - Jingxi Sun
- Department of Intensive Care Unit, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou Clinical School of Xuzhou Medical College of Nanjing University of Chinese Medicine, Xuzhou, Jiangsu 221009, P.R. China
| | - Jiaqiong Li
- Department of Intensive Care Unit, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou Clinical School of Xuzhou Medical College of Nanjing University of Chinese Medicine, Xuzhou, Jiangsu 221009, P.R. China
| | - Zaixiang Shi
- Department of Intensive Care Unit, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou Clinical School of Xuzhou Medical College of Nanjing University of Chinese Medicine, Xuzhou, Jiangsu 221009, P.R. China
| | - Jiyuan Xu
- Department of Intensive Care Unit, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou Clinical School of Xuzhou Medical College of Nanjing University of Chinese Medicine, Xuzhou, Jiangsu 221009, P.R. China
| | - Bo Lu
- Department of Intensive Care Unit, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou Clinical School of Xuzhou Medical College of Nanjing University of Chinese Medicine, Xuzhou, Jiangsu 221009, P.R. China
| | - Shuli Cheng
- Department of Intensive Care Unit, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou Clinical School of Xuzhou Medical College of Nanjing University of Chinese Medicine, Xuzhou, Jiangsu 221009, P.R. China
| | - Yanjun Xu
- Department of Intensive Care Unit, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou Clinical School of Xuzhou Medical College of Nanjing University of Chinese Medicine, Xuzhou, Jiangsu 221009, P.R. China
| | - Xiaomeng Wang
- Department of Intensive Care Unit, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou Clinical School of Xuzhou Medical College of Nanjing University of Chinese Medicine, Xuzhou, Jiangsu 221009, P.R. China
| | - Xianjiang Zhang
- Department of Intensive Care Unit, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou Clinical School of Xuzhou Medical College of Nanjing University of Chinese Medicine, Xuzhou, Jiangsu 221009, P.R. China
| |
Collapse
|
|
5
|
Wang N, Fan YC, Xia HHX, Sun YY, Wang K. Plasma interleukin-10 predicts short-term mortality of acute-on-chronic hepatitis B liver failure. Aliment Pharmacol Ther 2016; 43:1208-1221. [PMID: 27038362 DOI: 10.1111/apt.13603] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Revised: 02/01/2016] [Accepted: 03/10/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND Interleukin (IL)-10 is a pleiotropic cytokine with anti-inflammatory and immunosuppressive properties in liver failure. Biomarkers are urgently needed to predict prognosis of acute-on-chronic hepatitis B liver failure (ACHBLF). AIM To investigate the potential diagnostic value of plasma IL-10 as a biomarker for predicting the mortality of ACHBLF. METHODS This prospective study consisted of 115 newly diagnosed ACHBLF patients from May 2009 to October 2013 as a training cohort and 54 ACHBLF patients from November 2013 to March 2015 as a validating cohort. Plasma IL-10 level was measured using enzyme-linked immunosorbent assay. RESULTS In the training cohort, the plasma IL-10 level of nonsurvivals [median (centile25; centile75): 12.38 (8.76; 15.52) pg/mL] was significantly higher than that in survivals [6.55 (5.43; 7.65) pg/mL, P < 0.001]. Plasma IL-10 (hazard ratio = 1.205, 95% confidence interval: 1.145-1.267, P < 0.001) was identified as an independent risk factor for mortality of ACHBLF patients. Furthermore, plasma IL-10 showed higher area under the curve of receiver operating characteristic (AUROC) than model for end-stage liver diseases (MELD) for predicting 1-month (0.887 vs. 0.779, P < 0.05), 2-month (0.878 vs. 0.779, P < 0.05) and 3-month (0.917 vs. 0.776, P < 0.001) mortality. However, we did not find significant differences in AUROC between IL-10 and IL-10 plus MELD for 1-, 2- and 3-month mortality. ACHBLF patients with plasma IL-10 > 9.6 pg/mL showed poor survival time than patients with plasma IL-10 ≤ 9.6 pg/mL at the end of 1 month in the training and validation cohorts. CONCLUSIONS Plasma IL-10 performed better than MELD in predicting the prognosis of acute-on-chronic hepatitis B liver failure. Furthermore, plasma IL-10 > 9.6 pg/mL predicts a poor 1-month mortality.
Collapse
Affiliation(s)
- N Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Y-C Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
- Institute of Hepatology, Shandong University, Jinan, China
| | - H H-X Xia
- Department of Gastroenterology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Y-Y Sun
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - K Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
- Institute of Hepatology, Shandong University, Jinan, China
| |
Collapse
|
|
6
|
Guo YM, Li FY, Gong M, Zhang L, Wang JB, Xiao XH, Li J, Zhao YL, Wang LF, Zhang XF. Short-term efficacy of treating hepatitis B virus-related acute-on-chronic liver failure based on cold pattern differentiation with hot herbs: A randomized controlled trial. Chin J Integr Med 2016; 22:573-80. [PMID: 27220737 DOI: 10.1007/s11655-016-2582-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To evaluate the clinical efficacy and safety of Yinchen Zhufu Decoction (, YCZFD) in the treatment of acute-on-chronic liver failure caused by hepatitis B virus (HBV-ACLF) with cold pattern in Chinese medicine (CM). METHODS This is a multi-center randomized controlled trial of integrative treatment of CM and Western medicine (WM) for the management of HBV-ACLF patients. A total of 200 HBV-ACLF patients with cold pattern were equally randomly assigned to receive YCZFD and WM (integrative treatment) or WM conventional therapy alone respectively for 4 weeks. The primary end point was the mortality for HBV-ACLF patients. Secondary outcome measures included Model for End-Stage Liver disease (MELD) score, liver biochemical function, coagulation function and complications. Adverse events during treatment were reported. RESULTS The mortality was decreased 14.28% in the integrative treatment group compared with WM group (χ(2) =6.156, P=0.013). The integrative treatment was found to signifificantly improve the MELD score (t=2.353, P=0.020). There were statistically signifificant differences in aspartate transaminase, total bilirubin, indirect bilirubin, direct bilirubin and prothrombin time between the two groups (P<0.05 or P<0.01). The complications of ascites (χ(2)=9.033, P=0.003) and spontaneous bacteria peritonitis (χ(2)=4.194, P=0.041) were improved signifificantly in the integrative treatment group. No serious adverse event was reported. CONCLUSIONS The integrative treatment of CM and WM was effective and safe for HBV-ACLF patients with cold pattern in CM. The Chinese therapeutic principle "treating cold pattern with hot herbs" remains valuable to the clinical therapy. (Trial registration No. ChiCTR-TRC-10000766).
Collapse
Affiliation(s)
- Yu-Ming Guo
- China Military Institute of Chinese Materia Medica, 302 Military Hospital, Beijing, 100039, China
| | - Feng-Yi Li
- Treatment and Research Center for Infectious Diseases, 302 Military Hospital, Beijing, 100039, China
| | - Man Gong
- Integrative Medical Center for Liver Diseases, 302 Military Hospital, Beijing, 100039, China
| | - Lin Zhang
- Medical Affairs, Novartis Pharma China, Beijing, 100004, China
| | - Jia-Bo Wang
- China Military Institute of Chinese Materia Medica, 302 Military Hospital, Beijing, 100039, China
| | - Xiao-He Xiao
- China Military Institute of Chinese Materia Medica, 302 Military Hospital, Beijing, 100039, China.
| | - Jun Li
- Integrative Medical Center for Liver Diseases, 302 Military Hospital, Beijing, 100039, China.
| | - Yan-Ling Zhao
- Integrative Medical Center for Liver Diseases, 302 Military Hospital, Beijing, 100039, China
| | - Li-Fu Wang
- Integrative Medical Center for Liver Diseases, 302 Military Hospital, Beijing, 100039, China
| | - Xiao-Feng Zhang
- Integrative Medical Center for Liver Diseases, 302 Military Hospital, Beijing, 100039, China
| |
Collapse
|
|
7
|
Yang J, Sun H, Liu Q. The Comparative Efficacy and Safety of Entecavir and Lamivudine in Patients with HBV-Associated Acute-on-Chronic Liver Failure: A Systematic Review and Meta-Analysis. Gastroenterol Res Pract 2016; 2016:5802674. [PMID: 27148364 PMCID: PMC4842383 DOI: 10.1155/2016/5802674] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 02/20/2016] [Accepted: 03/17/2016] [Indexed: 02/06/2023] Open
Abstract
Background. Currently, both of entecavir and lamivudine are effective for patients with HBV-associated acute-on-chronic liver failure (ACLF). However, there is no consensus on the efficacy of entecavir versus lamivudine for patients with HBV-associated ACLF. The aim of the study was to compare the efficacy and safety of entecavir with that of lamivudine for HBV-associated ACLF patients. Methods. Publications on entecavir versus lamivudine in HBV-associated ACLF patients were comprehensively identified. Odds ratio and mean difference were used to measure the effect. Results. Ten studies, totaling 1254 patients, were eligible. No significant differences between the two drugs presented in the 1-, 2-, 3-, or 6-month survival rates. However, after 12 months of treatment, patients prescribed entecavir had a statistically higher survival rate (p = 0.008) and lower total bilirubin (p < 0.0001) and alanine aminotransferase (p = 0.04) levels compared to patients prescribed lamivudine. More patients achieved HBV negative levels when taking entecavir as measured at 1-, 3-, and 12-month time points and had a lower rate of HBV recurrence. Conclusion. While entecavir and lamivudine are both relatively safe and well tolerated, entecavir was more efficacious in terms of survival rate and clinical improvement in long-term treatment. Further prospective randomized controlled trials are needed to validate these results.
Collapse
Affiliation(s)
- Jiao Yang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Chongqing 400010, China
| | - Hang Sun
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Chongqing 400010, China
| | - Qi Liu
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Chongqing 400010, China
| |
Collapse
|
|
8
|
Luo L, Zhang YZ, Yuan CL, Jiang ZL. Non-bioartificial liver support system for treating patients with severe hepatitis: Common problems and nursing countermeasures. Shijie Huaren Xiaohua Zazhi 2016; 24:873-878. [DOI: 10.11569/wcjd.v24.i6.873] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Non-bioartificial liver support system, a common and effective therapy to salvage patients with severe hepatitis and a temporary substitution of the liver function, may "bridge" patients to liver transplantation or recovery. However, nurses play a pivotal role in the process of non-bioartificial liver support system, so it is key for successful treatment that they are able to timely identify and effectively manage adverse reactions during the process. Given all this, this review discusses common problems and nursing countermeasures encountered during treatment with the non-bioartificial liver support system in patients with severe hepatitis, aiming at improving their capacity of detecting and dealing with adverse reactions, and thus increasing the efficacy.
Collapse
|
|
9
|
Blasco-Algora S, Masegosa-Ataz J, Gutiérrez-García ML, Alonso-López S, Fernández-Rodríguez CM. Acute-on-chronic liver failure: Pathogenesis, prognostic factors and management. World J Gastroenterol 2015; 21:12125-12140. [PMID: 26576097 PMCID: PMC4641130 DOI: 10.3748/wjg.v21.i42.12125] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 08/17/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
Acute-on-chronic liver failure (ACLF) is increasingly recognized as a complex syndrome that is reversible in many cases. It is characterized by an acute deterioration of liver function in the background of a pre-existing chronic liver disease often associated with a high short-term mortality rate. Organ failure (OF) is always associated, and plays a key role in determining the course, and the outcome of the disease. The definition of ACLF remains controversial due to its overall ambiguity, with several disparate criteria among various associations dedicated to the study of liver diseases. Although the precise pathogenesis needs to be clarified, it appears that an altered host response to injury might be a contributing factor caused by immune dysfunction, ultimately leading to a pro-inflammatory status, and eventually to OF. The PIRO concept (Predisposition, Insult, Response and Organ Failure) has been proposed to better approach the underlying mechanisms. It is accepted that ACLF is a different and specific form of liver failure, where a precipitating event is always involved, even though it cannot always be ascertained. According to several studies, infections and active alcoholism often trigger ACLF. Viral hepatitis, gastrointestinal haemorrhage, or drug induced liver injury, which can also provoke the syndrome. This review mainly focuses on the physiopathology and prognostic aspects. We believe these features are essential to further understanding and providing the rationale for improveddisease management strategies.
Collapse
|
|
10
|
Fan YC, Wang N, Sun YY, Xiao XY, Wang K. TIPE2 mRNA Level in PBMCs Serves as a Novel Biomarker for Predicting Short-Term Mortality of Acute-on-Chronic Hepatitis B Liver Failure: A Prospective Single-Center Study. Medicine (Baltimore) 2015; 94:e1638. [PMID: 26426653 PMCID: PMC4616875 DOI: 10.1097/md.0000000000001638] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 08/25/2015] [Accepted: 08/26/2015] [Indexed: 12/14/2022] Open
Abstract
It remains difficult to accurately predicate short-term mortality of acute-on-chronic hepatitis B liver failure (ACHBLF). Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is a novel identified negative regulator of immune response and we have previously demonstrated TIPE2 play an essential role in the pathogenesis of ACHBLF. We therefore aimed to evaluate the diagnosis value of TIPE2 mRNA in peripheral blood mononuclear cells (PBMCs) for predicting 3-month mortality of ACHBLF patients. This prospective study consisted of 108 ACHBLF patients from March 2009 to May 2013 as training cohort and 63 ACHBLF patients from June 2013 to December 2014 as validation cohort. Forty-two patients with chronic hepatitis B (CHB) and 22 healthy volunteers were also included as controls. The mRNA level of TIPE2 in PBMCs was determined using quantitative real-time polymerase chain reaction. Univariate analysis and Cox proportional hazard regression analysis were performed to identify independent risk factors to 3-month mortality. Area under the receptor operating characteristic curve (AUROC) was performed to assess diagnostic value of TIPE2 mRNA in training and validation cohort. The level of TIPE2 mRNA was significantly higher in ACHBLF patients (median (interquartile): 6.5 [3.7, 9.6]) compared with CHB (2.3 [1.6, 3.7]) and healthy controls (0.4 [0.3, 0.6]; both P < 0.05). Cox proportional hazards regression analyses showed 5 independent risk factors associated with 3-month mortality of ACHBLF: white blood cells (HR = 1.058, 95% CI: 1.023-1.095), spontaneous bacterial peritonitis (HR = 2.541, 95% CI: 1.378-4.686), hepatic encephalopathy (HR = 1.848, 95% CI: 1.028-3.321), model for end-stage liver diseases (MELD) score (HR = 1.062, 95% CI: 1.009-1.118), and TIPE2 mRNA (HR = 1.081, 95% CI: 1.009-1.159). An optimal cut-off point 6.54 of TIPE2 mRNA showed sensitivity of 74.63%, specificity of 90.24%, positive predictive value of 92.5%, and negative predictive value of 67.3% for predicting 3-month mortality in training cohort. Furthermore, TIPE2 mRNA plus MELD performed better than MELD alone for predicting 3-month mortality in training (AUROC, 0.853 vs 0.722, P < 0.05) and validation cohort (AUROC, 0.909 vs 0.717, P < 0.001). TIPE2 mRNA level might be a novel biomarker in predicting 3-month mortality of ACHBLF. Combination of TIPE2 mRNA and MELD would improve the diagnostic value of MELD alone in predicting 3-month mortality of patients with ACHBLF.
Collapse
Affiliation(s)
- Yu-Chen Fan
- From the Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China (Y-CF, NW, Y-YS, KW); Institute of Hepatology, Shandong University, Jinan, China (Y-CF, KW); and Department of Nephrology, Qilu Hospital of Shandong University, Jinan, China (X-YX)
| | | | | | | | | |
Collapse
|
|
11
|
Initial combination anti-viral therapy with lamivudine and adefovir dipivoxil decreases short-term fatality rate of hepatitis-B-virus-related acute-on-chronic liver failure. Virol J 2015; 12:97. [PMID: 26104153 PMCID: PMC4501091 DOI: 10.1186/s12985-015-0323-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Accepted: 06/10/2015] [Indexed: 12/13/2022] Open
Abstract
Background Acute-on-chronic liver failure (ACLF) is a common serious hepatitis B virus (HBV)-related disease and has a poor prognosis. Until recently, initial combination antiviral treatment in ACLF patients was rarely reported. This study evaluated the effect of initial combination treatment with lamivudine and adefovir dipivoxil on the prognosis of HBV-related ACLF. Methods In this retrospective study, 131 eligible ACLF patients, including 61 treated with 100 mg lamivudine and 10 mg adefovir dipivoxil daily and 70 not treated with any nucleoside analogs (NAs), were selected and assigned into the NA and non-NA groups. All the patients received standard medicinal therapy. At weeks 0–4 and 12, serum markers for hepatic and renal functions were measured in all patients and accumulated fatality rates were calculated. Statistical analyses, including Student’s t test, χ2 test and unconditional logistic regression analysis, were performed using SPSS version 17.0 software. Results Clinical data indicated that improvement of hepatic function was better in the NA than in the non-NA group. The accumulated fatality rate in the NA group was lower than in the non-NA group at weeks 2–4 and 12, and these differences were significant. Univariate analysis showed that age, prothrombin activity, model of end-stage liver disease (MELD) score, and treatment without NAs were risk factors for short-term survival of ACLF. Further research by unconditional logistic regression analysis identified that older age, high MELD score and treatment without NAs were independent risk factors for short-term survival of ACLF. Conclusions Initial combination antiviral treatment is effective in decreasing short-term fatality of HBV-related ACLF.
Collapse
|
|
12
|
Obed A, Stern S, Jarrad A, Lorf T. Six month abstinence rule for liver transplantation in severe alcoholic liver disease patients. World J Gastroenterol 2015; 21:4423-4426. [PMID: 25892898 PMCID: PMC4394109 DOI: 10.3748/wjg.v21.i14.4423] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2014] [Revised: 01/12/2015] [Accepted: 01/30/2015] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) is the second most common diagnosis among patients undergoing liver transplantation (LT). The recovery results of patients transplanted for ALD are often at least as good as those of patients transplanted for other diagnoses and better than those suffering from hepatitis C virus, cryptogenic cirrhosis, or hepatocellular carcinoma. In the case of medically non-responding patients with severe acute alcoholic hepatitis or acute-on chronic liver failure, the refusal of LT is often based on the lack of the required alcohol abstinence period of six months. The obligatory abidance of a period of abstinence as a transplant eligibility requirement for medically non-responding patients seems unfair and inhumane, since the majority of these patients will not survive the six-month abstinence period. Data from various studies have challenged the 6-mo rule, while excellent survival results of LT have been observed in selected patients with severe alcoholic hepatitis not responding to medical therapy. Patients with severe advanced ALD should have legal access to LT. The mere lack of pre-LT abstinence should not be an obstacle for being listed.
Collapse
|
|
13
|
Zamora Nava LE, Aguirre Valadez J, Chávez-Tapia NC, Torre A. Acute-on-chronic liver failure: a review. Ther Clin Risk Manag 2014; 10:295-303. [PMID: 24790454 PMCID: PMC4003263 DOI: 10.2147/tcrm.s59723] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
There is no universally accepted definition of acute-on-chronic liver failure; however, it is recognized as an entity characterized by decompensation from an underlying chronic liver disease associated with organ failure that conveys high short-term mortality, with alcoholism and infection being the most frequent precipitating events. The pathophysiology involves inflammatory processes associated with a trigger factor in susceptible individuals (related to altered immunity in the cirrhotic population). This review addresses the different definitions developed by leading research groups, epidemiological and pathophysiological aspects, and the latest treatments for this entity.
Collapse
Affiliation(s)
- Luis Eduardo Zamora Nava
- Department of Endoscopy, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico City, Mexico
| | - Jonathan Aguirre Valadez
- Department of Gastroenterology, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico City, Mexico
| | | | - Aldo Torre
- Department of Gastroenterology, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico City, Mexico
| |
Collapse
|
|
14
|
Wei H, Zhang J, Li H, Ren H, Hao X, Huang Y. GP73, a new marker for diagnosing HBV-ACLF in population with chronic HBV infections. Diagn Microbiol Infect Dis 2014; 79:19-24. [PMID: 24560809 DOI: 10.1016/j.diagmicrobio.2014.01.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Revised: 01/09/2014] [Accepted: 01/10/2014] [Indexed: 12/17/2022]
Abstract
Although Golgi protein 73 (GP73) has been widely evaluated for diagnosing hepatocellular carcinoma (HCC) and other liver diseases in recent decade, its serum profile of patients with hepatitis B virus (HBV)-associated acute-on-chronic liver failure (HBV-ACLF) is still unknown. This study was designed to evaluate the serum levels of GP73 in patients with HBV-ACLF. The participants included 200 apparently healthy controls; 200 patients with chronic hepatitis B (CHB); 200 patients with HCC; 210 patients with HBV-ACLF, in which 29 HBV-ACLF patients were followed up for 3 months. All patients were Hepatitis B virus surface antigen (HBsAg) positive. The concentrations of GP73 in patients with HBV-ACLF (285.3 ± 128.5 ng/mL) were markedly higher than those HCC patients (159.1 ± 105.8 ng/mL), CHB patients (64.65 ± 44.99 ng/mL), and healthy controls (35.37 ± 12.41 ng/mL). When the cut-off value was set at 182.1 ng/mL, the sensitivity and specificity of HBV-ACLF diagnosis were 77.62% (95% confidence interval [CI]: 71.37%-83.07%) and 95.50% (95% CI: 92.27%-98.26%), respectively. If serum GP73 concentration was still above 361.6 ng/mL after 14 days of follow-up, the patient's prognosis may be depressed. Serum GP73 may be used to diagnosis HBV-ACLF in population with chronic HBV infections.
Collapse
Affiliation(s)
- Hongshan Wei
- Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.
| | - Jing Zhang
- Beijing Youan Hospital, Capital Medical University, Beijing 100039, China
| | - Hongmin Li
- Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Hui Ren
- Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xiaohua Hao
- Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Yubo Huang
- Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| |
Collapse
|
|
15
|
Acute on chronic liver failure: From pathophysiology to clinical management. TRENDS IN ANAESTHESIA AND CRITICAL CARE 2013. [DOI: 10.1016/j.tacc.2013.01.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
|
|
16
|
Jalan R, Gines P, Olson JC, Mookerjee RP, Moreau R, Garcia-Tsao G, Arroyo V, Kamath PS. Acute-on chronic liver failure. J Hepatol 2012; 57:1336-48. [PMID: 22750750 DOI: 10.1016/j.jhep.2012.06.026] [Citation(s) in RCA: 441] [Impact Index Per Article: 33.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Revised: 06/19/2012] [Accepted: 06/19/2012] [Indexed: 12/12/2022]
Abstract
Acute-on-chronic liver failure (ACLF) is an increasingly recognised entity encompassing an acute deterioration of liver function in patients with cirrhosis, which is usually associated with a precipitating event and results in the failure of one or more organs and high short term mortality. Prospective data to define this is lacking but there is a large body of circumstantial evidence suggesting that this condition is a distinct clinical entity. From the pathophysiologic perspective, altered host response to injury and infection play important roles in its development. This review focuses upon the current understanding of this syndrome from the clinical, prognostic and pathophysiologic perspectives and indicates potential biomarkers and therapeutic targets for intervention.
Collapse
Affiliation(s)
- Rajiv Jalan
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, United Kingdom.
| | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Kribben A, Gerken G, Haag S, Herget-Rosenthal S, Treichel U, Betz C, Sarrazin C, Hoste E, Van Vlierberghe H, Escorsell A, Hafer C, Schreiner O, Galle PR, Mancini E, Caraceni P, Karvellas CJ, Salmhofer H, Knotek M, Ginès P, Kozik-Jaromin J, Rifai K. Effects of fractionated plasma separation and adsorption on survival in patients with acute-on-chronic liver failure. Gastroenterology 2012; 142:782-789.e3. [PMID: 22248661 DOI: 10.1053/j.gastro.2011.12.056] [Citation(s) in RCA: 268] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2010] [Revised: 12/15/2011] [Accepted: 12/29/2011] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Fractionated plasma separation and adsorption (FPSA) is an extracorporeal procedure that supports liver function by removing endogenous toxins that cause complications from acute-on-chronic liver failure (AOCLF). We performed a randomized trial to investigate survival of patients with AOCLF treated with FPSA. METHODS Patients with AOCLF were randomly assigned to groups given a combination of FPSA and standard medical therapy (SMT) (FPSA group, n = 77) or only SMT (SMT group, n = 68). The Prometheus liver support system was used to provide 8 to 11 rounds of FPSA (minimum of 4 hours each) for 3 weeks. Primary end points were survival probabilities at days 28 and 90, irrespective of liver transplantation. RESULTS Baseline clinical parameters and number of transplant patients were similar between study arms. Serum bilirubin level decreased significantly in the FPSA group but not in the SMT group. In an intention-to-treat analysis, the probabilities of survival on day 28 were 66% in the FPSA group and 63% in the SMT group (P = .70); on day 90, they were 47% and 38%, respectively (P = .35). Baseline factors independently associated with poor prognosis were high SOFA score, bleeding, female sex, spontaneous bacterial peritonitis, intermediate increases in serum creatinine concentration, and combination of alcoholic and viral etiology of liver disease. There were no differences between the 2 groups in the incidence of side effects. CONCLUSIONS Among all patients with AOCLF, extracorporeal liver support with FPSA does not increase the probability of survival. Further studies are needed to assess whether therapy might be beneficial in specific subsets of patients.
Collapse
Affiliation(s)
- Andreas Kribben
- Department of Nephrology, University Duisburg-Essen, Essen, Germany.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
18
|
Leckie P, Davies N, Jalan R. Albumin regeneration for extracorporeal liver support using prometheus: a step in the right direction. Gastroenterology 2012; 142:690-2. [PMID: 22370211 DOI: 10.1053/j.gastro.2012.02.037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
|
|
19
|
Cadena FA, Serna LFC, Quintero C. IF, Caicedo LA, Perdomo CAV, González LF. Sistemas de soporte hepático extracorpóreo. COLOMBIAN JOURNAL OF ANESTHESIOLOGY 2011. [DOI: 10.5554/rca.v39i4.133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
|
|
20
|
Wright G, Chattree A, Jalan R. Management of hepatic encephalopathy. Int J Hepatol 2011; 2011:841407. [PMID: 21994873 PMCID: PMC3177461 DOI: 10.4061/2011/841407] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2011] [Accepted: 06/08/2011] [Indexed: 12/11/2022] Open
Abstract
Hepatic encephalopathy (HE), the neuropsychiatric presentation of liver disease, is associated with high morbidity and mortality. Reduction of plasma ammonia remains the central therapeutic strategy, but there is a need for newer novel therapies. We discuss current evidence supporting the use of interventions for both the general management of chronic HE and that necessary for more acute and advanced disease.
Collapse
Affiliation(s)
- G. Wright
- University College London Institute of Hepatology, The Royal Free Hospital, Pond Street, London NW3 2PF, UK
| | - A. Chattree
- Department of Gastroenterology, King Georges Hospital, Barley Lane, Goodmayes, Ilford, Essex IG3 8YB, UK
| | - R. Jalan
- University College London Institute of Hepatology, The Royal Free Hospital, Pond Street, London NW3 2PF, UK
| |
Collapse
|
|
21
|
Krisper P, Stadlbauer V, Stauber RE. Clearing of toxic substances: are there differences between the available liver support devices? Liver Int 2011; 31 Suppl 3:5-8. [PMID: 21824275 DOI: 10.1111/j.1478-3231.2011.02588.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Toxins accumulating in liver failure split into water solved (e.g. ammonia) and albumin bound substances (e.g. bilirubin). Because the latter cannot be removed by conventional haemodialysis, special liver support systems have been developed. The majority of data concerning elimination efficiency exist for the cell-free devices Molecular Adsorbent Recirculating System (MARS) and Prometheus, as they have been commercially available in Europe since many years. Overall, Prometheus provides higher clearances for most liver toxins, especially if they are tightly albumin bound. However, for bile acids and cytokines no such differences could be found. Single pass albumin dialysis (SPAD) can be assumed to be equally effective as MARS. None of the bioartificial liver support systems being developed is on the market today and published clearance data are scarce. In general, clearance efficiency for albumin bound substances is relatively low in all systems currently available. Besides optimizing biocompatibility and selectivity, future technologies should also focus on improved detoxification efficiency of liver support devices.
Collapse
Affiliation(s)
- Peter Krisper
- Department of Internal Medicine, Division of Nephrology, Medical University Graz, Graz, Austria.
| | | | | |
Collapse
|
|
22
|
Laleman W, Verbeke L, Meersseman P, Wauters J, van Pelt J, Cassiman D, Wilmer A, Verslype C, Nevens F. Acute-on-chronic liver failure: current concepts on definition, pathogenesis, clinical manifestations and potential therapeutic interventions. Expert Rev Gastroenterol Hepatol 2011; 5:523-37; quiz 537. [PMID: 21780899 DOI: 10.1586/egh.11.47] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In recent years, acute-on-chronic liver failure has been recognized as a specific clinical form of liver failure associated with cirrhosis. The syndrome refers to an acute deterioration of liver function and subsequently of other end organs over a period of weeks following a precipitating event in a patient with previously well- or reasonably well-compensated cirrhosis. These precipitating events include either an indirect (e.g., variceal hemorrhage, sepsis) or a direct (e.g., drug-induced) hepatotoxic factor. The short-term mortality for this condition is more than 50%. At present, considerable efforts are ongoing to better characterize the syndrome, to gain further insight into its pathophysiology and to optimize therapy. This article aims to highlight the current concepts of these various aspects.
Collapse
Affiliation(s)
- Wim Laleman
- Department of Liver and Biliopancreatic disorders, University Hospital Gasthuisberg, KU Leuven, Leuven, Belgium.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Current development of bioreactors for extracorporeal bioartificial liver (Review). Biointerphases 2011; 5:FA116-31. [PMID: 21171705 DOI: 10.1116/1.3521520] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
The research and development of extracorporeal bioartificial liver is gaining pace in recent years with the introduction of a myriad of optimally designed bioreactors with the ability to maintain long-term viability and liver-specific functions of hepatocytes. The design considerations for bioartificial liver are not trivial; it needs to consider factors such as the types of cell to be cultured in the bioreactor, the bioreactor configuration, the magnitude of fluid-induced shear stress, nutrients' supply, and wastes' removal, and other relevant issues before the bioreactor is ready for testing. This review discusses the exciting development of bioartificial liver devices, particularly the various types of cell used in current reactor designs, the state-of-the-art culturing and cryopreservation techniques, and the comparison among many today's bioreactor configurations. This review will also discuss in depth the importance of maintaining optimal mass transfer of nutrients and oxygen partial pressure in the bioreactor system. Finally, this review will discuss the commercially available bioreactors that are currently undergoing preclinical and clinical trials.
Collapse
|
|
24
|
Renal failure in patients with cirrhosis: hepatorenal syndrome and renal support strategies. Curr Opin Anaesthesiol 2010; 23:139-44. [PMID: 20124895 DOI: 10.1097/aco.0b013e32833724a8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW The development of hepatorenal syndrome in liver cirrhosis leads to an increased morbidity and mortality in patients with cirrhosis. Currently, there are no proven methods for the treatment or prevention of hepatorenal syndrome except to maintain adequate hemodynamics and intravascular volume in this patient population. These patients will frequently require renal replacement therapy when presenting for hepatic transplantation. RECENT FINDINGS New consensus definitions have been published in order to create uniform standards for classifying and diagnosing acute kidney injury. Two such groups are the Acute Dialysis Quality Initiative (ADQI) and the Acute Kidney Injury Network (AKIN), which have proposed approaches to defining criteria for acute kidney injury. Recent literature supports not only the role of splanchnic vasodilation and systemic vasoconstriction but also heart failure in the pathogenesis of hepatorenal syndrome. The practice of using vasoconstrictor and intravenous albumin therapy for the treatment of hepatorenal syndrome is ongoing with a growing body of recent data supporting the use of vasopressin analogs as the first-line therapy in the ICU setting with knowledge of the possible cardiovascular side-effects. SUMMARY Hepatorenal syndrome, HRS, is a diagnosis of exclusion. There are two forms of hepatorenal syndrome: type 1 hepatorenal syndrome and type 2 hepatorenal syndrome. Type 1 HRS is rapidly progressive and portends a very poor prognosis and has a high mortality rate. Type 2 is more indolent while still associated with an overall poor prognosis. Treatment of HRS is largely still supportive. It is imperative to maintain euvolemia and hemodynamics in this patient population to optimize renal perfusion and preserve renal function. Renal replacement therapy may be necessary in this chronically ill patient population, if renal function deteriorates such that the kidneys cannot maintain metabolic and volume homeostasis. Further research is still necessary as to the prevention and effective treatment for hepatorenal syndrome.
Collapse
|
|
25
|
Leber B, Mayrhauser U, Rybczynski M, Stadlbauer V. Innate immune dysfunction in acute and chronic liver disease. Wien Klin Wochenschr 2010; 121:732-44. [PMID: 20047110 DOI: 10.1007/s00508-009-1288-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2009] [Accepted: 11/26/2009] [Indexed: 12/19/2022]
Abstract
Liver cirrhosis is a common disease causing great public-health concern because of the frequent complications requiring hospital care. Acute liver failure is also prone to several complications but is rare. One of the main complications for both acute and chronic liver diseases is infection, which regularly causes decompensation of cirrhosis, possibly leading to organ failure and death. This review focuses on innate immune function in cirrhosis, acute-on-chronic liver failure and acute liver failure. The known defects of Kupffer cells, neutrophils and monocytes are discussed, together with the pathophysiological importance of gut permeability, portal hypertension and intrinsic cellular defects, and the role of endotoxin, albumin, lipoproteins and toll-like receptors. Based on these different pathomechanisms, the available information on therapeutic strategies is presented. Antibiotic and probiotic treatment, nutritional support, artificial liver support, and experimental strategies such as inhibition of toll-like receptors and use of albumin and colony-stimulating factors are highlighted.
Collapse
Affiliation(s)
- Bettina Leber
- Division of Surgery, Medical University of Graz, Graz, Austria
| | | | | | | |
Collapse
|
|
26
|
Oppert M, Rademacher S, Petrasch K, Jörres A. Extracorporeal liver support therapy with Prometheus in patients with liver failure in the intensive care unit. Ther Apher Dial 2009; 13:426-30. [PMID: 19788460 DOI: 10.1111/j.1744-9987.2009.00761.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Acute liver failure (ALF) and acute-on-chronic liver failure (AoCLF) are associated with a high mortality. In these patients an accumulation of both water-soluble and water-insoluble, protein-bound, metabolic waste products occurs. Conventional extracorporeal blood purification techniques based on diffusion and/or convection such as hemodialysis or hemofiltration may only eliminate small molecular weight, water-soluble compounds. In recent years, fractionated plasma separation and adsorption (FPSA) with the Prometheus system has been introduced for extracorporeal liver support therapy. To date, however, only limited data is available regarding the effect of this treatment on mortality and outcome of patients with advanced liver disease. Here we report on our experience with 23 patients with severe liver failure who were treated with Prometheus in our medical intensive care unit. Fourteen patients had AoCLF, and nine patients experienced ALF. The median bilirubin level at the start of Prometheus therapy was 30.5 mg/dL and the median Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 26. During 40 individual treatment sessions lasting 5-6 h, Prometheus therapy reduced serum bilirubin levels from 23.7 mg/dL to 15.0 mg/dL (median values) (P < 0.001), and the overall survival was 26%. ALF patients had a better survival compared to AoCLF patients (44% vs. 22%; P = 0.022). Apart from one patient who developed hemodynamic instability during a treatment session, Prometheus therapy was well tolerated without relevant side-effects. In conclusion, extracorporeal liver support therapy with Prometheus is a novel and safe treatment option in patients with severe liver failure. In this series, patients with ALF showed a significantly better outcome with Prometheus therapy compared to AoCLF patients.
Collapse
Affiliation(s)
- Michael Oppert
- Department of Nephrology and Medical Intensive Care, Charité Medical University Berlin, Campus Virchow-Klinikum, Berlin, Germany
| | | | | | | |
Collapse
|
|
27
|
Laleman W. Hemodynamic effects of albumin dialysis in patients with liver failure: for better or for worse? Ther Apher Dial 2009; 13:384-92. [PMID: 19788454 DOI: 10.1111/j.1744-9987.2009.00756.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Liver failure, irrespective of is cause, is frequently associated with multi-organ dysfunction, including hemodynamic instability, and renal and cerebral insufficiency. As a result of the combined impact of these complications, liver failure carries an exceptionally high risk of mortality. A central role in the etiopathogenesis of different end-organ manifestations, as well as in the aggravation of the underlying liver failure, has been attributed to the hyperdynamic (hypotensive) state, which is characterized by a reduced systemic vascular resistance and mean arterial pressure, as well as an increased cardiac index, heart rate, and total plasma volume. Since the accumulation of toxins due to the decreased detoxification capacity by the failing liver is considered vital herein, the emergence of extracorporeal liver support has provided a rational basis for the potential reversal of these phenomena. The present article critically reviews data with regard to the hemodynamic effects of artificial liver support in the context of liver failure. Although these are scarce for acute liver failure, several uncontrolled series and small randomized trials have clearly documented that artificial liver support is able to improve both portal hypertension and the associated systemic circulatory dysfunction in patients with acute-on-chronic liver failure. The molecular basis for these effects have been related to temporary changes and/or elimination in endogenous vasoactive substances, improved albumin binding capacity, or restoration of oxidative stress-mediated damage to albumin.
Collapse
Affiliation(s)
- Wim Laleman
- Department of Hepatology, University Hospital Gasthuisberg, Catholic University Leuven, Leuven, Belgium.
| |
Collapse
|
|
28
|
Escorsell Mañosa A, Mas Ordeig A. [Acute on chronic liver failure]. GASTROENTEROLOGIA Y HEPATOLOGIA 2009; 33:126-34. [PMID: 20005602 DOI: 10.1016/j.gastrohep.2009.10.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Received: 10/07/2009] [Accepted: 10/09/2009] [Indexed: 12/30/2022]
Abstract
Acute-on-Chronic Liver Failure (ACLF) is a recently introduced term defined as severe acute deterioration of an established liver disease. This entity usually develops after an acute insult. The main clinical manifestations are hepatorenal syndrome, hepatic encephalopathy and organ failure, with a high risk of death in the short term. The true incidence of ACLF remains difficult to determine due to confusions surrounding the definition of this entity, but seems to be 40% at 5 years in patients with advanced cirrhosis, which translates into 4,000 cases in Europe within this time span. The treatment of choice is liver transplantation. However, due to the shortage of suitable organs and morbidity and mortality in these patients, other options must be used.
Collapse
Affiliation(s)
- Angels Escorsell Mañosa
- UCI-Institut de Malalties Digestives i Metabòliques, Hospital Clínic, IDIBAPS, Universitat de Barcelona, CIBERehd, Barcelona, España.
| | | |
Collapse
|
|
29
|
Abstract
Hepatorenal syndrome (HRS) is a type of renal failure that occurs in patients with advanced cirrhosis. It is a result of splanchnic arterial vasodilation, renal vasoconstriction, reduced effective arterial volume, and potentially reduced cardiac output. Often, HRS is a fatal complication, and the only definitive treatment currently available is liver or liver-kidney transplantation. A number of other treatment modalities have been tested for the management of HRS, but most evidence is derived from small noncontrolled studies. The primary role of these treatment options is to provide a bridge to liver transplantation. Treatment may also provide acute reversal of renal failure and some symptomatic relief, but relapse is a common occurrence. The best therapeutic options appear to be those that reverse portal hypertension, splanchnic vasodilation, and/or renal vasoconstriction. Vasopressin analogs, particularly terlipressin, have emerged as the preferred pharmacologic therapies for management of HRS. Albumin is an appropriate adjunctive therapy to terlipressin and can be used to prevent HRS in patients with spontaneous bacterial peritonitis. Transjugular intrahepatic portosystemic shunt may provide a surgical option for qualified patients with HRS. Octreotide is ineffective as monotherapy but may be used as adjunctive therapy to other vasoactive agents. Dopamine agonists, endothelin antagonists, natriuretic peptides, and nitric oxide synthase inhibitors have not been effective for reversing HRS. Artificial hepatic support therapies have demonstrated the ability to improve laboratory abnormalities in patients with HRS, but their effect on clinical outcomes has not been determined. The role of renal replacement therapies or the newer artificial hepatic support therapies need further evaluation before they can be routinely recommended.
Collapse
Affiliation(s)
- Tyree H Kiser
- Department of Clinical Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80045, USA.
| | | | | |
Collapse
|
|
30
|
Stauber RE, Wagner D, Stadlbauer V, Palma S, Gurakuqi G, Kniepeiss D, Iberer F, Smolle KH, Haas J, Trauner M. Evaluation of indocyanine green clearance and model for end-stage liver disease for estimation of short-term prognosis in decompensated cirrhosis. Liver Int 2009; 29:1516-20. [PMID: 19732329 DOI: 10.1111/j.1478-3231.2009.02104.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Indocyanine green (ICG) clearance has been proposed as a quantitative liver function test several decades ago. Interest in this method has been renewed following the development of finger pulse densitometry for noninvasive estimation of the ICG plasma disappearance rate (PDR). On the other hand, the model for end-stage liver disease (MELD), which is based on routine laboratory parameters, is widely used for estimation of short-term survival in cirrhosis, but its prognostic value in critically ill cirrhotic patients is unclear. AIMS The aim of the present study was to compare the diagnostic accuracy of ICG PDR vs. MELD for estimation of short-term prognosis in cirrhotic patients. METHODS Ninety consecutive cirrhotic patients who were admitted for decompensated disease or were being evaluated for liver transplantation were screened. Patients who underwent liver transplantation within the following 90 days and those with hepatocellular carcinoma were excluded. In the remaining 70 patients, routine laboratory parameters and ICG clearance were analysed. Following an injection of ICG 0.25 mg/kg, PDR was measured by finger pulse densitometry. The diagnostic accuracy of ICG PDR and MELD for prediction of 90-day survival was assessed by receiver-operating characteristic (ROC) curve analysis. RESULTS ROC curve analysis revealed superior diagnostic accuracy for MELD as compared with ICG PDR in predicting 90-day survival (area under the ROC curve 0.89 vs. 0.71). A MELD cut-off of 22 provided the best discrimination for prediction of 90-day survival. CONCLUSIONS MELD is superior to ICG PDR for estimation of short-term survival in patients with decompensated cirrhosis.
Collapse
Affiliation(s)
- Rudolf E Stauber
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
|
|
32
|
Jalan R, Schnurr K, Mookerjee RP, Sen S, Cheshire L, Hodges S, Muravsky V, Williams R, Matthes G, Davies NA. Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality. Hepatology 2009; 50:555-64. [PMID: 19642174 DOI: 10.1002/hep.22913] [Citation(s) in RCA: 175] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
UNLABELLED Albumin concentration is diminished in patients with liver failure. Albumin infusion improves survival of cirrhotic patients with spontaneous bacterial peritonitis, and it is hypothesized that this may be due in part to its detoxifying capabilities. The aim of this study was to perform detailed quantitative and qualitative assessment of albumin function in patients with cirrhosis. Healthy controls and patients with acute deterioration of cirrhosis requiring hospital admission (n = 34) were included. Albumin function was assessed using affinity of the fatty acid binding sites using a spin label (16 doxyl-stearate) titration and electron paramagnetic resonance spectroscopy and ischemia-modified albumin (IMA) was measured. Twenty-two patients developed acute-on-chronic liver failure. Twelve were treated with the Molecular Adsorbents Recirculating System (MARS) and 10 with standard medical therapy. For each parameter measured, the patients' albumin had reduced functional ability, which worsened with disease severity. Fifteen patients died, and IMA, expressed as an albumin ratio (IMAR), was significantly higher in nonsurvivors compared with survivors (P < 0.001; area under the receiver operating curve = 0.8). No change in the patients' albumin function was observed following MARS therapy. A significant negative correlation between IMAR and the fatty acid binding coefficients for sites 1 and 2 (P < 0.001 for both) was observed, indicating possible sites of association on the protein. CONCLUSION The results of this study suggests marked dysfunction of albumin function in advanced cirrhosis and provide further evidence for damage to the circulating albumin, which is not reversed by MARS therapy. IMAR correlates with disease severity and may have prognostic use in acute-on-chronic liver failure.
Collapse
Affiliation(s)
- Rajiv Jalan
- Liver Failure Group, Institute of Hepatology, University College London, London, United Kingdom
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
33
|
MacLaren R. Management of Cirrhosis and Associated Complications. J Pharm Pract 2009. [DOI: 10.1177/0897190008328693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Liver cirrhosis is the encapsulation or replacement of injured tissue by collagen, resulting in end-stage liver disease and portal hypertension. The consequences of cirrhosis are impaired hepatocyte function, increase intrahepatic circulatory resistance, portal hypertension, and the development of hepatocellular carcinoma. Complications include encephalopathy, coagulopathy, varices, ascites, spontaneous bacterial peritonitis, epatorenal syndrome, and hepatopulmonary syndrome. Managing patients with acute or chronic liver failure is challenging, and liver failure may have profound effects on other organ systems. Most therapies are directed at managing the complications and bridging patients to liver transplantation. The clinician must be aware of the pathologic presentations and the appropriate management, including pharmacologic and nonpharmacologic therapies, goals and end points of therapy, and monitoring of therapy. This review focuses on the management of the complications directly associated with liver dysfunction (encephalopathy and coagulopathy) and portal hypertension (varices, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatopulmonary syndrome).
Collapse
Affiliation(s)
- Robert MacLaren
- University of Colorado Denver, School of Pharmacy, Aurora, Colorado,
| |
Collapse
|
|
34
|
Stadlbauer V, Wright GAK, Jalan R. Role of artificial liver support in hepatic encephalopathy. Metab Brain Dis 2009; 24:15-26. [PMID: 19101787 DOI: 10.1007/s11011-008-9117-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2008] [Accepted: 10/28/2008] [Indexed: 01/21/2023]
Abstract
Hepatic encephalopathy (HE) refers to the reversible neuropsychiatric disorders observed in acute liver failure and as a complication of cirrhosis and/or portal hypertension. This review aims to describe the pathophysiology of HE, the rationale for the use of artificial liver support in the treatment of HE, the different concepts of artificial liver support and the results obtained. Ammonia has been considered central to its pathogenesis but recently an important role for its interaction with inflammatory responses and auto-regulation of cerebral hemodynamics has been suggested. Artificial liver support might be able to decrease ammonia and modulate inflammatory mediators and cerebral hemodynamics. Bioartificial liver support systems use hepatocytes in an extracorporeal device connected to the patient's circulation. Artificial liver support is intended to remove protein-bound toxins and water-soluble toxins without providing synthetic function. Both systems improve clinical and biochemical parameters and can be applied safely to patients. Clinical studies have shown that artificial liver support, especially albumin dialysis, is able to improve HE in acute and acute-on-chronic liver failure. Further studies are required to better understand the mechanism, however, artificial liver support can be added to the therapeutic bundle in treating HE.
Collapse
Affiliation(s)
- V Stadlbauer
- Institute of Hepatology, University College London Medical School, 69-75 Chenies Mews, London WC1E 6HX, UK
| | | | | |
Collapse
|
|
35
|
Gu J, Shi X, Zhang Y, Ding Y. Heterotypic interactions in the preservation of morphology and functionality of porcine hepatocytes by bone marrow mesenchymal stem cells in vitro. J Cell Physiol 2009; 219:100-8. [PMID: 19086033 DOI: 10.1002/jcp.21651] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Temporary replacement of specific liver functions with extracorporeal bioartificial liver has been hampered by rapid de-differentiation of porcine hepatocytes in vitro. Co-cultivation of hepatocytes with non-parenchymal cells may be beneficial for optimizing cell functions via mimicry of physiological microenvironment consisting of endogenous matrix proteins. However, the underlying mechanisms remain to be elucidated. A randomly distributed co-culture system composed of porcine hepatocytes and bone marrow mesenchymal stem cells was generated, and the morphological and functional changes of varying degrees of heterotypic interactions were characterized. Furthermore, contributions of extracellular matrix within this co-culture were evaluated. A rapid attachment and self-organization of three-dimensional hepatocyte spheroids were encouraged. Studies on hepatocyte viability showed a metabolically active, viable cell population in all co-culture configurations with occurrence of few dead cells. The maximal induction of albumin production, urea synthesis, and cytochrome P4503A1 activities was achieved at seeding ratio of 2:1. Immunocytochemical detection of various extracellular matrix confirmed that a high level of matrix proteins synthesis within distinct cells was involved in hepatocyte homeostasis. These results demonstrate for the first time that cell-matrix has synergic effects on the preservation of hepatic morphology and functionality in the co-culture of porcine hepatocytes with mesenchymal stem cells in vitro, which could represent a promising tool for tissue engineering, cell biology, and bioartificial liver devices.
Collapse
Affiliation(s)
- Jinyang Gu
- Department of Hepatobiliary Surgery, DrumTower Clinical Medical College of Nanjing Medical University, Nanjing, China
| | | | | | | |
Collapse
|
|
36
|
Abstract
Hepatic assist remains elusive. Bioartificial livers (BALs), consisting of liver cells or tissue in a synthetic housing, have been promising but have not proven successful in clinical trials. Artificial livers that consist of sophisticated sorbents and membranes cannot support a failing liver but may shorten episodes of acute decompensation in patients with stable cirrhosis. These artificial livers are most likely to find a place as temporary support prior to transplantation. True liver support will require a BAL. This article proposes goals for making a clinically useful BAL, with attention to systems biology and potential sources of hepatocytes.
Collapse
Affiliation(s)
- Norman L Sussman
- University of Utah, 30 North 1900 East, SOM 4R118, Salt Lake City, UT 84132-2410, USA.
| | | | | |
Collapse
|
|
37
|
Stadlbauer V, Mookerjee RP, Wright GAK, Davies NA, Jürgens G, Hallström S, Jalan R. Role of Toll-like receptors 2, 4, and 9 in mediating neutrophil dysfunction in alcoholic hepatitis. Am J Physiol Gastrointest Liver Physiol 2009. [PMID: 19033535 DOI: 10.1152/ajpqi.90512.2008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Neutrophil dysfunction in alcoholic hepatitis is associated with endotoxemia and an increased incidence of infection, but the mechanism is unclear. We aimed to investigate the role of Toll-like-receptors (TLR)2, 4, and 9 in mediating neutrophil dysfunction in alcoholic hepatitis. Neutrophils from healthy volunteers were incubated with alcoholic hepatitis patients' plasma (n = 12) with and without TLR2, 4, or 9 antagonists and with and without human albumin. TLR2, 4, and 9 expression, neutrophil oxidative burst, phagocytosis, and CXCR1+2 expression were measured by FACS analysis. Patients' plasma increased oxidative burst, decreased CXCR1+2 expression, and decreased phagocytosis of normal neutrophils in association with increased expression of TLR2, 4, and 9 and depletion of ATP. Inhibition of TLR2, 4, and 9 prevented the increase in oxidative burst and the decrease in CXCR1 and CXCR2 expression but did not prevent phagocytic dysfunction. Incubation with albumin completely prevented the patient plasma induced neutrophil dysfunction. Increased expression of TLR2, 4, and 9 is associated with neutrophil dysfunction, endotoxemia, and energy depletion. TLR2, 4, and 9 inhibition does not improve phagocytosis, indicating that TLR overexpression may be the result and not the cause of neutrophil activation. Albumin, an endotoxin scavenger, prevents the deleterious effect of patients' plasma on neutrophil phagocytosis, resting burst, and TLR expression.
Collapse
Affiliation(s)
- V Stadlbauer
- Institute of Hepatology, UCL Medical School, 68-75 Chenies Mews, London WC1E 6H, UK
| | | | | | | | | | | | | |
Collapse
|
|
38
|
Stadlbauer V, Mookerjee RP, Wright GAK, Davies NA, Jürgens G, Hallström S, Jalan R. Role of Toll-like receptors 2, 4, and 9 in mediating neutrophil dysfunction in alcoholic hepatitis. Am J Physiol Gastrointest Liver Physiol 2009; 296:G15-22. [PMID: 19033535 PMCID: PMC2636930 DOI: 10.1152/ajpgi.90512.2008] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Neutrophil dysfunction in alcoholic hepatitis is associated with endotoxemia and an increased incidence of infection, but the mechanism is unclear. We aimed to investigate the role of Toll-like-receptors (TLR)2, 4, and 9 in mediating neutrophil dysfunction in alcoholic hepatitis. Neutrophils from healthy volunteers were incubated with alcoholic hepatitis patients' plasma (n = 12) with and without TLR2, 4, or 9 antagonists and with and without human albumin. TLR2, 4, and 9 expression, neutrophil oxidative burst, phagocytosis, and CXCR1+2 expression were measured by FACS analysis. Patients' plasma increased oxidative burst, decreased CXCR1+2 expression, and decreased phagocytosis of normal neutrophils in association with increased expression of TLR2, 4, and 9 and depletion of ATP. Inhibition of TLR2, 4, and 9 prevented the increase in oxidative burst and the decrease in CXCR1 and CXCR2 expression but did not prevent phagocytic dysfunction. Incubation with albumin completely prevented the patient plasma induced neutrophil dysfunction. Increased expression of TLR2, 4, and 9 is associated with neutrophil dysfunction, endotoxemia, and energy depletion. TLR2, 4, and 9 inhibition does not improve phagocytosis, indicating that TLR overexpression may be the result and not the cause of neutrophil activation. Albumin, an endotoxin scavenger, prevents the deleterious effect of patients' plasma on neutrophil phagocytosis, resting burst, and TLR expression.
Collapse
Affiliation(s)
- V. Stadlbauer
- Institute of Hepatology, UCL Medical School, London, United Kingdom; Department of Internal Medicine and Institute of Physiological Chemistry, Center of Physiological Medicine, Medical University Graz, Graz, Austria
| | - R. P. Mookerjee
- Institute of Hepatology, UCL Medical School, London, United Kingdom; Department of Internal Medicine and Institute of Physiological Chemistry, Center of Physiological Medicine, Medical University Graz, Graz, Austria
| | - G. A. K. Wright
- Institute of Hepatology, UCL Medical School, London, United Kingdom; Department of Internal Medicine and Institute of Physiological Chemistry, Center of Physiological Medicine, Medical University Graz, Graz, Austria
| | - N. A. Davies
- Institute of Hepatology, UCL Medical School, London, United Kingdom; Department of Internal Medicine and Institute of Physiological Chemistry, Center of Physiological Medicine, Medical University Graz, Graz, Austria
| | - G. Jürgens
- Institute of Hepatology, UCL Medical School, London, United Kingdom; Department of Internal Medicine and Institute of Physiological Chemistry, Center of Physiological Medicine, Medical University Graz, Graz, Austria
| | - S. Hallström
- Institute of Hepatology, UCL Medical School, London, United Kingdom; Department of Internal Medicine and Institute of Physiological Chemistry, Center of Physiological Medicine, Medical University Graz, Graz, Austria
| | - R. Jalan
- Institute of Hepatology, UCL Medical School, London, United Kingdom; Department of Internal Medicine and Institute of Physiological Chemistry, Center of Physiological Medicine, Medical University Graz, Graz, Austria
| |
Collapse
|
|
39
|
|