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Van Nynatten LR, Patel MA, Daley M, Miller MR, Cepinskas G, Slessarev M, Russell JA, Fraser DD. Putative biomarkers of hepatic dysfunction in critically ill sepsis patients. Clin Exp Med 2025; 25:28. [PMID: 39751971 PMCID: PMC11698781 DOI: 10.1007/s10238-024-01545-3] [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] [Received: 08/29/2024] [Accepted: 12/23/2024] [Indexed: 01/04/2025]
Abstract
Sepsis is a major cause of morbidity and mortality worldwide. Among the various types of end-organ damage associated with sepsis, hepatic injury is linked to significantly higher mortality rates compared to dysfunction in other organ systems. This study aimed to investigate potential biomarkers of hepatic injury in sepsis patients through a multi-center, case-control approach. We enrolled three matched cohorts: 37 sepsis patients with hepatic dysfunction (S-HD), 37 sepsis patients without hepatic dysfunction (S-CON), and 18 healthy controls (HC). We measured five proposed biomarkers of hepatic dysfunction-ARG1, MDH1, GSTα, 5-NT, and SDH-using multiplex immunoassays. These biomarkers were compared to traditional markers of hepatic dysfunction, including albumin, bilirubin, ALT, AST, and GGT, across the cohorts using both conventional statistical methods and machine learning techniques. The median age of participants was comparable across cohorts: S-HD (65.0 years, IQR 49.5-82.5), S-CON (65.0 years, IQR 48.0-81.5), and HC (62.5 years, IQR 53.0-65.0; P = 0.794). Patients with hepatic dysfunction (S-HD) exhibited higher illness severity scores compared to those without hepatic dysfunction (S-CON): MODS scores were median 7.0 (IQR 4.0-10.0) in S-HD versus median 4.0 (IQR 2.0-7.0) in S-CON (P = 0.005), and SOFA scores were median 7.0 (IQR 4.0-11.0) in S-HD versus median 3.0 (IQR 2.0-6.0) in S-CON (P < 0.001). Hemoglobin and platelet counts were lower, while creatinine levels were higher in S-HD compared to S-CON (P < 0.05). On ICU Day 1, bilirubin, ALT, AST, GGT, and INR were significantly elevated in S-HD relative to S-CON (P ≤ 0.001), and albumin levels were lower (P < 0.05). Additionally, ARG1, GSTα, 5-NT, and SDH were significantly higher in S-HD patients on ICU Day 1 compared to S-CON (P < 0.05). ARG1, MDH1, and SDH showed positive correlations with AST, ALT, and MODS (P < 0.01). From ICU Day 1 to Day 7, ARG1, GSTα, SDH, and AST levels significantly decreased in S-HD patients (P < 0.05), whereas MDH1 and 5-NT levels did not. Among the proposed biomarkers, GSTα and 5-NT did not correlate with traditional hepatic dysfunction markers but were significant in identifying S-HD patients (feature importance 0.131 and 0.097, respectively) in a random forest classification model. This comprehensive model demonstrated excellent performance in distinguishing sepsis patients with hepatic injury, with sensitivity 0.93, specificity 0.94, NPV 0.94, PPV 0.94, and AUC 0.94. The biomarkers ARG1, MDH1, GSTα, 5-NT, and SDH show promise as novel indicators of hepatic dysfunction associated with sepsis. This study provides a foundational basis for subsequent research aimed at characterizing and clinically validating these markers. Future investigations should focus on integrating these potential biomarkers into routine laboratory assessments for sepsis and related hepatic injury.
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Affiliation(s)
| | - Maitray A Patel
- Epidemiology and Biostatistics, Western University, London, ON, Canada
| | - Mark Daley
- Epidemiology and Biostatistics, Western University, London, ON, Canada
| | - Michael R Miller
- London Health Sciences Centre Research Institute, London, ON, Canada
| | - Gediminas Cepinskas
- London Health Sciences Centre Research Institute, London, ON, Canada
- Medical Biophysics, Western University, London, ON, Canada
- Anatomy and Cell Biology, Western University, London, ON, Canada
| | - Marat Slessarev
- Medicine, Western University, London, ON, Canada
- London Health Sciences Centre Research Institute, London, ON, Canada
| | - James A Russell
- University of British Columbia, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.
| | - Douglas D Fraser
- Pediatrics, Western University, London, ON, Canada.
- London Health Sciences Centre Research Institute, London, ON, Canada.
- Physiology and Pharmacology, Western University, London, ON, Canada.
- Clinical Neurological Sciences, Western University, London, ON, Canada.
- London Health Sciences Centre, 800 Commissioners Road East, London, ON, N6A 5W9, Canada.
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2
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Hassan HM, Liang X, Xin J, Lu Y, Cai Q, Shi D, Ren K, Li J, Chen Q, Li J, Li P, Guo B, Yang H, Luo J, Yao H, Zhou X, Hu W, Jiang J, Li J. Thrombospondin 1 enhances systemic inflammation and disease severity in acute-on-chronic liver failure. BMC Med 2024; 22:95. [PMID: 38439091 PMCID: PMC10913480 DOI: 10.1186/s12916-024-03318-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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 02/23/2024] [Indexed: 03/06/2024] Open
Abstract
BACKGROUND The key role of thrombospondin 1 (THBS1) in the pathogenesis of acute-on-chronic liver failure (ACLF) is unclear. Here, we present a transcriptome approach to evaluate THBS1 as a potential biomarker in ACLF disease pathogenesis. METHODS Biobanked peripheral blood mononuclear cells (PBMCs) from 330 subjects with hepatitis B virus (HBV)-related etiologies, including HBV-ACLF, liver cirrhosis (LC), and chronic hepatitis B (CHB), and normal controls (NC) randomly selected from the Chinese Group on the Study of Severe Hepatitis B (COSSH) prospective multicenter cohort underwent transcriptome analyses (ACLF = 20; LC = 10; CHB = 10; NC = 15); the findings were externally validated in participants from COSSH cohort, an ACLF rat model and hepatocyte-specific THBS1 knockout mice. RESULTS THBS1 was the top significantly differentially expressed gene in the PBMC transcriptome, with the most significant upregulation in ACLF, and quantitative polymerase chain reaction (ACLF = 110; LC = 60; CHB = 60; NC = 45) was used to verify that THBS1 expression corresponded to ACLF disease severity outcome, including inflammation and hepatocellular apoptosis. THBS1 showed good predictive ability for ACLF short-term mortality, with an area under the receiver operating characteristic curve (AUROC) of 0.8438 and 0.7778 at 28 and 90 days, respectively. Enzyme-linked immunosorbent assay validation of the plasma THBS1 using an expanded COSSH cohort subjects (ACLF = 198; LC = 50; CHB = 50; NC = 50) showed significant correlation between THBS1 with ALT and γ-GT (P = 0.01), and offered a similarly good prognostication predictive ability (AUROC = 0.7445 and 0.7175) at 28 and 90 days, respectively. ACLF patients with high-risk short-term mortality were identified based on plasma THBS1 optimal cut-off value (< 28 µg/ml). External validation in ACLF rat serum and livers confirmed the functional association between THBS1, the immune response and hepatocellular apoptosis. Hepatocyte-specific THBS1 knockout improved mouse survival, significantly repressed major inflammatory cytokines, enhanced the expression of several anti-inflammatory mediators and impeded hepatocellular apoptosis. CONCLUSIONS THBS1 might be an ACLF disease development-related biomarker, promoting inflammatory responses and hepatocellular apoptosis, that could provide clinicians with a new molecular target for improving diagnostic and therapeutic strategies.
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Affiliation(s)
- Hozeifa Mohamed Hassan
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, 318000, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Xi Liang
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, 318000, China
| | - Jiaojiao Xin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Yingyan Lu
- Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Qun Cai
- Department of Infectious Diseases and Liver Diseases, Ningbo Medical Center Lihuili Hospital, Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
| | - Dongyan Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Keke Ren
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Jun Li
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qi Chen
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, 318000, China
| | - Jiang Li
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Peng Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Beibei Guo
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Hui Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Jinjin Luo
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Heng Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Xingping Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Wen Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Jing Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China.
| | - Jun Li
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, 318000, China.
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China.
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Gong JL, Yu J, Wang TL, He XS, Tang YH, Zhu XF. Application of extended criteria donor grafts in liver transplantation for acute-on-chronic liver failure: A retrospective cohort study. World J Gastroenterol 2023; 29:5630-5640. [PMID: 38077155 PMCID: PMC10701327 DOI: 10.3748/wjg.v29.i41.5630] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 09/24/2023] [Accepted: 10/23/2023] [Indexed: 11/07/2023] Open
Abstract
BACKGROUND There is no consensus on the usage of extended criteria donor (ECD) grafts in liver transplantation (LT) for acute-on-chronic liver failure (ACLF) patients. AIM To summarize the experience of using ECD livers in ACLF-LT. METHODS A retrospective cohort study was conducted, enrolling patients who underwent LT at the First Affiliated Hospital of Sun Yat-Sen University from January 2015 to November 2021. The patients were divided into ECD and non-ECD groups for analysis. RESULTS A total of 145 recipients were enrolled in this study, of which ECD and non-ECD recipients accounted for 53.8% and 46.2%, respectively. Donation after cardiac death (DCD) recipients accounted for the minority compared with donation after brain death (DBD) recipients (16.6% vs 83.4%). Neither overall survival nor graft survival significantly differed between ECD and non-ECD and DCD and DBD recipients. ECD grafts were associated with a significantly higher incidence of early allograft dysfunction (EAD) than non-ECD grafts (67.9% vs 41.8%, P = 0.002). Postoperative outcomes between DCD and DBD recipients were comparable (P > 0.05). ECD graft (P = 0.009), anhepatic phase (P = 0.034) and recipient gamma glutamyltransferase (P = 0.016) were independent risk factors for EAD. Recipient preoperative number of extrahepatic organ failures > 2 (P = 0.015) and intraoperative blood loss (P = 0.000) were independent predictors of poor post-LT survival. CONCLUSION Although related to a higher risk of EAD, ECD grafts can be safely used in ACLF-LT. The main factors affecting post-LT survival in ACLF patients are their own severe preoperative disease and intraoperative blood loss.
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Affiliation(s)
- Jin-Long Gong
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan Province, China
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | - Jia Yu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
- Department of Gastroenterology Surgery, The First Affiliated Hospital of University of South China, Hengyang 421005, Hunan Province, China
| | - Tie-Long Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | - Xiao-Shun He
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | - Yun-Hua Tang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | - Xiao-Feng Zhu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
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4
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Tan HQ, Zhao M, Huang Z, Liu Y, Li H, Ma LH, Liu JY. Circulating copeptin level and the clinical prognosis of patients with chronic liver disease. World J Gastroenterol 2023; 29:4797-4808. [PMID: 37664154 PMCID: PMC10473920 DOI: 10.3748/wjg.v29.i31.4797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/21/2023] [Accepted: 07/28/2023] [Indexed: 08/18/2023] Open
Abstract
BACKGROUND The relationship between copeptin and the severity of circulatory dysfunction and systemic stress response in patients with chronic liver disease (CLD) has been established. Nevertheless, the potential of serum copeptin levels to predict the prognosis of CLD patients remains unclear. AIM To conduct a systematic review and meta-analysis to investigate the correlation between serum copeptin and transplant-free survival (TFS) in this population. METHODS To achieve the objective of the meta-analysis, PubMed, Embase, the Cochrane Library, and the Web of Science were searched to identify observational studies with longitudinal follow-up. The Cochrane Q test was utilized to assess between-study heterogeneity, and the I2 statistic was estimated. Random-effects models were employed to combine the outcomes, taking into account the potential influence of heterogeneity. RESULTS Ten datasets including 3133 patients were involved. The follow-up durations were 1 to 48 mo (mean: 12.5 mo). Overall, it was shown that a high level of serum copeptin was associated with a poor TFS [risk ratio (RR): 1.82, 95% confidence interval: 1.52-2.19, P < 0.001; I2 = 0%]. In addition, sensitivity analysis by omitting one dataset at a time showed consistent results (RR: 1.73-2.00, P < 0.05). Finally, subgroup analyses according to study country, study design, patient diagnosis, cutoff of copeptin, follow-up duration, and study quality score also showed similar results (P for subgroup difference all > 0.05). CONCLUSION Patients with CLD who have high serum copeptin concentrations may be associated with a poor clinical prognosis.
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Affiliation(s)
- Hao-Qian Tan
- Department of Gastroenterology, Zhoukou Central Hospital Affiliated to Xinxiang Medical University, Zhoukou 466000, Henan Province, China
| | - Ming Zhao
- Department of Gastroenterology, Zhoukou Central Hospital, Zhoukou 466000, Henan Province, China
| | - Zan Huang
- Department of Teaching and Research, Zhoukou Central Hospital, Zhoukou 466000, Henan Province, China
| | - Yang Liu
- Department of Gastroenterology, Zhoukou Central Hospital, Zhoukou 466000, Henan Province, China
| | - Han Li
- Department of Gastroenterology, Zhoukou Central Hospital, Zhoukou 466000, Henan Province, China
| | - Long-Hui Ma
- Department of Teaching and Research, Zhoukou Central Hospital, Zhoukou 466000, Henan Province, China
| | - Jun-Ying Liu
- Department of Gastroenterology, Zhoukou Central Hospital, Zhoukou 466000, Henan Province, China
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5
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Chouhan MD, Taylor SA, Bhagwanani A, Munday C, Pinnock MA, Parry T, Hu Y, Barratt D, Yu D, Mookerjee RP, Halligan S, Mallett S. Imaging features for the prediction of clinical endpoints in chronic liver disease: a scoping review protocol. BMJ Open 2022; 12:e053204. [PMID: 35501093 PMCID: PMC9062789 DOI: 10.1136/bmjopen-2021-053204] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 04/08/2022] [Indexed: 11/04/2022] Open
Abstract
INTRODUCTION Chronic liver disease is a growing cause of morbidity and mortality in the UK. Acute presentation with advanced disease is common and prioritisation of resources to those at highest risk at earlier disease stages is essential to improving patient outcomes. Existing prognostic tools are of limited accuracy and to date no imaging-based tools are used in clinical practice, despite multiple anatomical imaging features that worsen with disease severity.In this paper, we outline our scoping review protocol that aims to provide an overview of existing prognostic factors and models that link anatomical imaging features with clinical endpoints in chronic liver disease. This will provide a summary of the number, type and methods used by existing imaging feature-based prognostic studies and indicate if there are sufficient studies to justify future systematic reviews. METHODS AND ANALYSIS The protocol was developed in accordance with existing scoping review guidelines. Searches of MEDLINE and Embase will be conducted using titles, abstracts and Medical Subject Headings restricted to publications after 1980 to ensure imaging method relevance on OvidSP. Initial screening will be undertaken by two independent reviewers. Full-text data extraction will be undertaken by three pretrained reviewers who have participated in a group data extraction session to ensure reviewer consensus and reduce inter-rater variability. Where needed, data extraction queries will be resolved by reviewer team discussion. Reporting of results will be based on grouping of related factors and their cumulative frequencies. Prognostic anatomical imaging features and clinical endpoints will be reported using descriptive statistics to summarise the number of studies, study characteristics and the statistical methods used. ETHICS AND DISSEMINATION Ethical approval is not required as this study is based on previously published work. Findings will be disseminated by peer-reviewed publication and/or conference presentations.
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Affiliation(s)
| | | | - Anisha Bhagwanani
- Imaging Department, University College London Hospitals NHS Foundation Trust, London, UK
| | - Charlotte Munday
- Department of Imaging, Royal Free London NHS Foundation Trust, London, UK
| | | | - Tom Parry
- UCL Centre for Medical Imaging, UCL, London, UK
| | - Yipeng Hu
- UCL Centre for Medical Image Computing, UCL, London, UK
| | - Dean Barratt
- UCL Centre for Medical Image Computing, UCL, London, UK
| | - Dominic Yu
- Department of Imaging, Royal Free London NHS Foundation Trust, London, UK
| | | | | | - Sue Mallett
- UCL Centre for Medical Imaging, UCL, London, UK
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Zakareya T, Akl M, Shibl S, El-Mazaly M, Abdel-Razek W. Utility of prognostic scores in predicting short-term mortality in patients with acute-on-chronic liver failure. EGYPTIAN LIVER JOURNAL 2022. [DOI: 10.1186/s43066-022-00183-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Acute-on-chronic liver failure (ACLF) is a distinct syndrome associated with high short-term mortality. Early identification of patients at high risk is essential to determine emergency for transplantation and decide and prioritize the need for intensive care unit (ICU). We aimed to evaluate the performance of the different prognostic scores in the prediction of in-hospital mortality in patients with ACLF. A total of 249 patients with ACLF were included and followed till discharge from the hospital. Univariate and Cox regression analyses were used to assess the performance of liver-specific (Child-Pugh and MELD) and ACLF prognostic scores (CLIF-C OF, CLIF-SOFA, CLIF-C AD, CLIF-C ACLF) in the prediction of in-hospital mortality.
Results
Patients were mostly males (71.1%) with a mean age of 53.9 ± 12.8 years. The etiology of pre-existing liver disease was HCV in 57.8%. Sepsis was the most common precipitating factor (49.8%) and the mortality rate was 74.3%. In univariate analysis, all scores were significantly higher in the deceased group (P<0.0001). AUROC were 0.897, 0.884, 0.870, 0.861, 0.861, and 0.850 for CLIF-C OF, CLIF-C AD, CLIF-C ACLF, Child-Pugh, CLIF-SOFA, and MELD scores, respectively. In multivariate analysis, 2 independent predictors of mortality were identified: CLIF-C ACLF score (OR 3.25, 95% CI 1.03–10.25, P<0.0001) and Child-Pugh class C (OR 1.04, 95% CI 1.02–1.06, P=0.044).
Conclusions
All the studied scores could predict in-hospital mortality of patients with ACLF. However, CLIF-C ACLF and Child-Pugh class performed better as they could significantly and independently predict mortality.
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Hassan HM, Cai Q, Liang X, Xin J, Ren K, Jiang J, Shi D, Lu Y, Li T, Shang Y, He L, Chen X, Sun S, Li P, Guo B, Chen J, Yang H, Hu W, Chen X, Li J. Transcriptomics reveals immune-metabolism disorder in acute-on-chronic liver failure in rats. Life Sci Alliance 2021; 5:5/3/e202101189. [PMID: 34853163 PMCID: PMC8645333 DOI: 10.26508/lsa.202101189] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 11/17/2021] [Accepted: 11/17/2021] [Indexed: 12/03/2022] Open
Abstract
Liver tissue transcriptomics of liver cirrhosis (LC)–based acute-on-chronic liver failure (ACLF) rats reveal immune-metabolism disorder as the core mechanism underlying ACLF development and prognosis. Acute-on-chronic liver failure (ACLF) is clinical syndrome with high mortality rate. This study aimed to perform detailed transcriptomic analysis in liver cirrhosis–based ACLF rats to elucidate ACLF pathogenesis. ACLF was induced by combined porcine serum with D-galactosamine and lipopolysaccharide. Gene expression profile of liver tissues from ACLF rats was generated by transcriptome sequencing to reveal the molecular mechanism. ACLF rats successfully developed with typical characteristics. Total of 2,354/3,576 differentially expressed genes were identified when ACLF was compared to liver cirrhosis and normal control, separately. The functional synergy analysis revealed prominent immune dysregulation at ACLF stage, whereas metabolic disruption was significantly down-regulated. Relative proportions of innate immune–related cells showed significant elevation of monocytes and macrophages, whereas adaptive immune–related cells were reduced. The seven differentially expressed genes underlying the ACLF molecular mechanisms were externally validated, among them THBS1, IL-10, and NR4A3 expressions were confirmed in rats, patient transcriptomics, and liver biopsies, verifying their potential value in the ACLF pathogenesis. This study indicates immune-metabolism disorder in ACLF rats, which may provide clinicians new targets for improving intervention strategies.
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Affiliation(s)
- Hozeifa M Hassan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qun Cai
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xi Liang
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Jiaojiao Xin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Keke Ren
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jing Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Dongyan Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Yingyan Lu
- Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Tan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuxin Shang
- Imperial College London, South Kensington Campus, London, UK
| | - Lulu He
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xi Chen
- Shanghai Pinghe School, Shanghai, China
| | - Suwan Sun
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Peng Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Beibei Guo
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiaxian Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hui Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wen Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xin Chen
- Institute of Pharmaceutical Biotechnology and The First Affiliated Hospital Department of Radiation Oncology, Zhejiang University School of Medicine, Hangzhou, China.,Joint Institute for Genetics and Genome Medicine Between Zhejiang University and University of Toronto, Zhejiang University, Hangzhou, China
| | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China .,Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
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da Silveira F, Soares PHR, Marchesan LQ, da Fonseca RSA, Nedel WL. Assessing the prognosis of cirrhotic patients in the intensive care unit: What we know and what we need to know better. World J Hepatol 2021; 13:1341-1350. [PMID: 34786170 PMCID: PMC8568574 DOI: 10.4254/wjh.v13.i10.1341] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/11/2021] [Accepted: 09/27/2021] [Indexed: 02/06/2023] Open
Abstract
Critically ill cirrhotic patients have high in-hospital mortality and utilize significant health care resources as a consequence of the need for multiorgan support. Despite this fact, their mortality has decreased in recent decades due to improved care of critically ill patients. Acute-on-chronic liver failure (ACLF), sepsis and elevated hepatic scores are associated with increased mortality in this population, especially among those not eligible for liver transplantation. No score is superior to another in the prognostic assessment of these patients, and both liver-specific and intensive care unit-specific scores have satisfactory predictive accuracy. The sequential assessment of the scores, especially the Sequential Organ Failure Assessment (SOFA) and Chronic Liver Failure Consortium (CLIF)-SOFA scores, may be useful as an auxiliary tool in the decision-making process regarding the benefits of maintaining supportive therapies in this population. A CLIF-ACLF > 70 at admission or at day 3 was associated with a poor prognosis, as well as SOFA score > 19 at baseline or increasing SOFA score > 72. Additional studies addressing the prognostic assessment of these patients are necessary.
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Affiliation(s)
- Fernando da Silveira
- Programa de Pós-Graduação em Pneumologia, Universidade Federal do Rio Grande do Sul, Porto Alegre 91430835, Brazil
- Intensive Care Unit, Grupo Hospitalar Conceição, Porto Alegre 91430835, Brazil
| | - Pedro H R Soares
- Intensive Care Unit, Grupo Hospitalar Conceição, Porto Alegre 91430835, Brazil
- Programa de Pós-Graduação em Neurociências, Universidade Federal do Rio Grande do Sul, Porto Alegre 91430835, Brazil
| | - Luana Q Marchesan
- Intensive Care Unit, Grupo Hospitalar Conceição, Porto Alegre 91430835, Brazil
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria 97105900, Brazil
| | | | - Wagner L Nedel
- Intensive Care Unit, Grupo Hospitalar Conceição, Porto Alegre 91430835, Brazil
- Programa de Pós-Graduação em Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre 91430835, Brazil.
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Islek A, Tumgor G. Acute-on-chronic liver failure in children. World J Hepatol 2021; 13:1289-1298. [PMID: 34786166 PMCID: PMC8568578 DOI: 10.4254/wjh.v13.i10.1289] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/16/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
Although various complex definitions of acute-on-chronic liver failure (ACLF) have been suggested in relation to adult patients, there is currently no universal definition of the syndrome in pediatric patients. In simplified terms, ACLF is characterized by the acute deterioration of the liver functions due to the effects of a precipitating factor on the basis of a chronic liver disease. Acute events and underlying liver diseases are very different in children from those seen in adults. Moreover, acute events and underlying chronic liver diseases vary among geographical regions, although it seems that the most common such diseases and acute events are autoimmune hepatitis, Wilson's disease, and their flares. ACLF is associated with a poor prognosis. While no scoring systems have been developed to predict the prognosis for children with ACLF, modified versions of the Asian Pacific Association for the Study of the liver's acute-on-chronic liver failure scoring system and the Chronic Liver Failure-Sequential Organ Failure Assessment criteria can be used in children until specific and validated scoring systems are available. Aside from liver transplantation, there is no proven treatment for ACLF. Thus, the early recognition of ACLF prior to the development of extrahepatic organ failure is important.
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Affiliation(s)
- Ali Islek
- Department of Pediatric Gastroenterology, Cukurova University School of Medicine, Adana 01330, Turkey
| | - Gokhan Tumgor
- Department of Pediatric Gastroenterology, Cukurova University School of Medicine, Adana 01330, Turkey.
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Zanetto A, Shalaby S, Gambato M, Germani G, Senzolo M, Bizzaro D, Russo FP, Burra P. New Indications for Liver Transplantation. J Clin Med 2021; 10:3867. [PMID: 34501314 PMCID: PMC8432035 DOI: 10.3390/jcm10173867] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/20/2021] [Accepted: 08/27/2021] [Indexed: 12/12/2022] Open
Abstract
Liver transplantation (LT) is an important therapeutic option for the treatment of several liver diseases. Modern LT is characterized by remarkable improvements in post-transplant patient survival, graft survival, and quality of life. Thanks to these great improvements, indications for LT are expanding. Nowadays, clinical conditions historically considered exclusion criteria for LT, have been considered new indications for LT, showing survival advantages for patients. In this review, we provide an updated overview of the principal newer indications for LT, with particular attention to alcoholic hepatitis, acute-on-chronic liver failure (ACLF), cholangiocarcinoma and colorectal cancer metastases.
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Affiliation(s)
| | | | | | | | | | | | | | - Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgery Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35128 Padova, Italy; (A.Z.); (S.S.); (M.G.); (G.G.); (M.S.); (D.B.); (F.P.R.)
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11
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Atkinson SR, Grove JI, Liebig S, Astbury S, Vergis N, Goldin R, Quaglia A, Bantel H, Guha IN, Thursz MR, Newcombe P, Strnad P, Aithal GP. In Severe Alcoholic Hepatitis, Serum Keratin-18 Fragments Are Diagnostic, Prognostic, and Theragnostic Biomarkers. Am J Gastroenterol 2020; 115:1857-1868. [PMID: 33156105 DOI: 10.14309/ajg.0000000000000912] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Up to 40% of patients with severe alcoholic hepatitis (AH) die within 6 months of presentation, making prompt diagnosis and appropriate treatment essential. We determined the associations between serum keratin-18 (K18) and histological features, prognosis, and differential response to prednisolone in patients with severe AH. METHODS Total (K18-M65) and caspase-cleaved K18 (K18-M30) were quantified in pretreatment sera from 824 patients enrolled in the Steroids or Pentoxifylline for Alcoholic Hepatitis trial (87 with suitable histological samples) and disease controls. RESULTS K18 fragments were markedly elevated in severe AH and strongly predicted steatohepatitis (alcoholic steatohepatitis) on biopsy (area under receiver operating characteristics: 0.787 and 0.807). Application of published thresholds to predict alcoholic steatohepatitis would have rendered biopsy unnecessary in 84% of all AH cases. K18-M30 and M65 were associated with 90-day mortality, independent of age and Model for End-stage Liver Disease score in untreated patients. The association for K18-M65 was independent of both age and Model for End-stage Liver Disease in prednisolone-treated patients. Modelling of the effect of prednisolone on 90-day mortality as a function of pretreatment serum K18 levels indicated benefit in those with high serum levels of K18-M30. At low pretreatment serum K18 levels, prednisolone was potentially harmful. A threshold of K18-M30 5 kIU/L predicted therapeutic benefit from prednisolone above this level (odds ratio: 0.433, 95% confidence interval: 0.19-0.95, P = 0.0398), but not below (odds ratio: 1.271, 95% confidence interval: 0.88-1.84, P = 0.199). Restricting prednisolone usage to the former group would have reduced exposure by 87%. DISCUSSION In a large cohort of patients with severe AH, serum K18 strongly correlated with histological severity, independently associated with 90-day mortality, and predicted response to prednisolone therapy. Quantification of serum K18 levels could assist in clinical decision-making.
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Affiliation(s)
| | - Jane I Grove
- NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - Stephanie Liebig
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Stuart Astbury
- NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - Nikhil Vergis
- Department of Hepatology, Imperial College London, London, UK
| | - Robert Goldin
- Department of Hepatology, Imperial College London, London, UK
| | - Alberto Quaglia
- Department of Cellular Pathology, Royal Free London and UCL Cancer Institute, London, UK
| | - Heike Bantel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Indra Neil Guha
- NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - Mark R Thursz
- Department of Hepatology, Imperial College London, London, UK
| | - Paul Newcombe
- MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
| | - Pavel Strnad
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, German
| | - Guruprasad P Aithal
- NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
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12
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Amin A, Mookerjee RP. Acute-on-chronic liver failure: definition, prognosis and management. Frontline Gastroenterol 2019; 11:458-467. [PMID: 33101624 PMCID: PMC7569518 DOI: 10.1136/flgastro-2018-101103] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/23/2019] [Accepted: 10/28/2019] [Indexed: 02/04/2023] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a recently described entity in chronic liver disease defined by acute hepatic decompensation, organ failure and a high risk of short-term mortality (usually less than 4 weeks). This condition is distinct from acute liver failure and stable progression of cirrhosis in numerous ways, including triggering precipitant factors, systemic inflammation, rapid progression and a potential for recovery. While a clear definition of ACLF has been forwarded from a large European Consortium study, some heterogeneity remains in how patients present and the types of organ failure, depending on whether they are described in Asian or European studies. Active alcoholism, acute alcoholic hepatitis and infections are the most frequent precipitants for ACLF. Underpinning the pathophysiology of ACLF is a state of persistent inflammation and immune dysfunction, collectively driving a systematic inflammatory response syndrome and an increased propensity to sepsis. Prevention and early treatment of organ failure are key in influencing survival. Given increasing organ shortage and more marginal grafts, liver transplantation is a limited resource and emphasises the need for new therapies to improve ACLF outcomes. Recent data indicate that liver transplantation has encouraging outcomes even in patients with advanced ACLF if patients are carefully selected during the permissive window of clinical presentation. ACLF remains a significant challenge in the field of hepatology, with considerable research and resource being channelled to improve upon the definition, prognostication, treatment and unravelling of mechanistic drivers. This Review discusses updates in ACLF definition, prognosis and management.
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Affiliation(s)
- Ahmed Amin
- Institute for Liver and Digestive Health, University College London, London, UK,Assiut University Faculty of Medicine, Assiut, Egypt
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Dynamic Prognostication in Critically Ill Cirrhotic Patients With Multiorgan Failure in ICUs in Europe and North America: A Multicenter Analysis. Crit Care Med 2019; 46:1783-1791. [PMID: 30106759 DOI: 10.1097/ccm.0000000000003369] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVES To evaluate the Chronic Liver Failure-Consortium Acute on Chronic Liver Failure score in acute on chronic liver failure patients admitted to ICUs from different global regions and compare discrimination ability with previously published scores. DESIGN Retrospective pooled analysis. SETTING Academic ICUs in Canada (Edmonton, Vancouver) and Europe (Paris, Barcelona, Chronic liver failure/Acute-on-Chronic Liver Failure in Cirrhosis [CANONIC] study). PATIENTS Sample of analysis of 867 cirrhotic patients with acute on chronic liver failure admitted to ICU. Cumulative incidence functions of death were estimated by acute on chronic liver failure grade at admission and at day 3. Survival discrimination abilities of Chronic Liver Failure-Consortium Acute on Chronic Liver Failure, Model for End-Stage Liver Disease, Acute Physiology and Chronic Health Evaluation II, and Child-Turcotte-Pugh scores were compared. INTERVENTIONS ICU admission for organ support. MEASUREMENTS AND MAIN RESULTS At admission 169 subjects (19%) had acute on chronic liver failure 1, 302 (35%) acute on chronic liver failure 2, and 396 (46%) had acute on chronic liver failure 3 with 90-mortality rates of 33%, 40%, and 74%, respectively (p < 0.001). At admission, Chronic Liver Failure-Consortium Acute on Chronic Liver Failure demonstrated superior discrimination at 90 days compared with Acute Physiology and Chronic Health Evaluation II (n = 532; concordance index 0.67 vs 0.62; p = 0.0027) and Child-Turcotte-Pugh (n = 666; 0.68 vs 0.64; p = 0.0035), but not Model for End-Stage Liver Disease (n = 845; 0.68 vs 0.67; p = 0.3). A Chronic Liver Failure-Consortium Acute on Chronic Liver Failure score greater than 70 at admission or on day 3 was associated with 90-day mortality rates of approximately 90%. Ninety-day mortality in grade 3 acute on chronic liver failure patients at admission who demonstrated improvement by day 3 was 40% (vs 79% in patients who did not). CONCLUSIONS The Chronic Liver Failure-Consortium Acute on Chronic Liver Failure demonstrated better discrimination at day 28 and day 90 compared with Acute Physiology and Chronic Health Evaluation II and Child-Turcotte-Pugh. Patients who demonstrated clinical improvement post-ICU admission (e.g., acute on chronic liver failure 3 to 1 or 2) at day 3 had better outcomes than those who did not. In high-risk ICU patients (Chronic Liver Failure-Consortium Acute on Chronic Liver Failure > 70), decisions regarding transition to palliation should be explored between patient families and the ICU providers after a short trial of therapy.
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Artru F, Samuel D. Approaches for patients with very high MELD scores. JHEP Rep 2019; 1:53-65. [PMID: 32039352 PMCID: PMC7001538 DOI: 10.1016/j.jhepr.2019.02.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 01/31/2019] [Accepted: 02/04/2019] [Indexed: 02/08/2023] Open
Abstract
In the era of the "sickest first" policy, patients with very high model for end-stage liver disease (MELD) scores have been increasingly admitted to the intensive care unit with the expectation that they will receive a liver transplant (LT) in the absence of improvement on supportive therapies. Such patients are often admitted in a context of acute-on-chronic liver failure with extrahepatic failures. Sequential assessment of scores or classification based on organ failures within the first days after admission help to stratify the risk of mortality in this population. Although the prognosis of severely ill cirrhotic patients has recently improved, transplant-free mortality remains high. LT is still the only curative treatment in this population. Yet, the increased relative scarcity of graft resource must be considered alongside the increased risk of losing a graft in the initial postoperative period when performing LT in "too sick to transplant" patients. Variables associated with poor immediate post-LT outcomes have been identified in large studies. Despite this, the performance of scores based on these variables is still insufficient. Consideration of a patient's comorbidities and frailty is an appealing predictive approach in this population that has proven of great value in many other diseases. So far, local expertise remains the last safeguard to LT. Using this expertise, data are accumulating on favourable post-LT outcomes in very high MELD populations, particularly when LT is performed in a situation of stabilization/improvement of organ failures in selected candidates. The absence of "definitive" contraindications and the control of "dynamic" contraindications allow a "transplantation window" to be defined. This window must be identified swiftly after admission given the poor short-term survival of patients with very high MELD scores. In the absence of any prospect of LT, withdrawal of care could be discussed to ensure respect of patient life, dignity and wishes.
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Affiliation(s)
- Florent Artru
- Liver Unit, CHRU Lille, France, University of Lille, LIRIC team, Inserm unit 995
| | - Didier Samuel
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, F-94800, France; Univ Paris-Sud, UMR-S 1193, Université Paris-Saclay, Villejuif, F-94800, France; Inserm, Unité 1193, Université Paris-Saclay, Villejuif, F-94800, France; Hepatinov, Villejuif, F-94800, France
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Yao J, Zhou X, Wang H, Yuan L, Chen Y, Duan Z. Persistently Increased Resting Energy Expenditure Predicts Short-Term Mortality in Patients with Acute-on-Chronic Liver Failure. ANNALS OF NUTRITION AND METABOLISM 2018; 73:2-9. [PMID: 29788014 DOI: 10.1159/000487604] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2017] [Accepted: 02/11/2018] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Hypermetabolism based on measurements of resting energy expenditure (REE) is suggested to be a potential biomarker for predicting the clinical outcomes of some diseases. We aimed to evaluate the potential value of hypermetabolism for predicting the short-term (28-day) mortality of patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). METHODS A total of 105 HBV-ACLF patients, 30 chronic hepatitis B (CHB) patients and 30 healthy controls (HCs) were included in this study. The REE was measured using indirect calorimetry in the morning after 8-10 h of fasting. The predicted REE (REEHB) was determined using Harris-Benedict equation. Persistent hypermetabolism was defined as the REE:REEHB ratio > 1.20 at day 1 and day 7 after admission. The severity of liver disease was estimated using the Model for End-Stage Liver Disease (MELD). Clinical and biochemical variables were determined using blood samples ordered upon admission. These variables were compared between nonsurviving and surviving patients who were classified according to the 28-day mortality. RESULTS The frequency of hypermetabolism at baseline was significantly higher in ACLF patients than that in HCs and CHB patients. Forty-six (43.8%) ACLF patients died within follow-up of 28 days. Persistent hypermetabolism (OR 2.10; 95% CI 1.15-3.69; p = 0.002) and MELD score (OR 1.93; 95% CI 1.47-3.51; p = 0.012) were independent predictive indicators of 28-day mortality. Furthermore, the performance of the 2 variables (persistent hypermetabolism and MELD) together with the area under the receiver operating curve (AUROC: 0.819) was significantly better than that of MELD alone -(AUROC: 0.694) for prediction of short-term mortality (p = 0.014). CONCLUSION These findings indicate that persistent hypermetabolism is predictive of short-term mortality in this small population.
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Affiliation(s)
- Jia Yao
- Department of Gastroenterology and Hepatology, Shanxi Dayi Hospital, Taiyuan, China
| | - Xiaoshuang Zhou
- Shanxi Provincial People's Hospital, Shanxi Medical University, Taiyuan, China
| | - Hui Wang
- Taiyuan Center Hospital, Taiyuan, China
| | - Lili Yuan
- Department of Gastroenterology and Hepatology, Shanxi Dayi Hospital, Taiyuan, China
| | - Yu Chen
- Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Zhongping Duan
- Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
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Remmler J, Schneider C, Treuner-Kaueroff T, Bartels M, Seehofer D, Scholz M, Berg T, Kaiser T. Increased Level of Interleukin 6 Associates With Increased 90-Day and 1-Year Mortality in Patients With End-Stage Liver Disease. Clin Gastroenterol Hepatol 2018; 16:730-737. [PMID: 28919544 DOI: 10.1016/j.cgh.2017.09.017] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 08/24/2017] [Accepted: 09/08/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Organ allocation for liver transplantation is based on prognosis, using the model for end-stage liver disease (MELD) or MELD including serum sodium (MELD-Na) score. These scores do not consider systemic inflammation and septic complications. Blood level of C-reactive protein (CRP), in addition to the MELD score, associates with mortality in patients with end-stage liver disease, whereas levels of interleukin 6 (IL6) have not been systematically studied. METHODS We performed a retrospective observational cohort study of 474 patients with end-stage liver disease (63.5% male; median age, 56.9 years), evaluated for liver transplantation in Germany, with at least 1 year of follow up. Data were collected on blood levels of CRP, IL6, and white blood cell count (WBC). Findings were analyzed in relation to mortality and compared with patients' MELD scores and MELD-Na scores. For survival analysis, the cohort was divided into quartiles of IL6, CRP, and WBC levels, as well as MELD scores. Log-rank test and the Cox proportional hazards regression model were used to compare the groups, and area under the receiver operating characteristic (AUROC) values were calculated. RESULTS Blood levels of IL6 and MELD scores associated with mortality: none of the patients with levels of IL6 below the first quartile (below 5.3 pg/mL) died within 1 year. In contrast, 67.7% of the patients in the highest quartile of IL6 level (37.0 pg/mL or more) died within 1 year. MELD score also correlated with mortality: among patients with MELD scores below 8.7, 0.9% died within 1 year, whereas in patients with MELD scores of 18.0 or more, 67.4% died within 1 year. The predictive value of level of IL6 (AUROC, 0.940) was higher than level of CRP (AUROC, 0.866) (P = .009) or WBC (AUROC, 0.773) (P < .001) for 90-day mortality. MELD scores associated with 90-day mortality (AUROC, 0.933) (P = .756) as did MELD-Na score (AUROC, 0.946) (P = .771). Level of IL6 associated with 1-year mortality (AUROC, 0.916) to a greater extent than liver synthesis or detoxification markers international normalized ratio (AUROC, 0.839) (P = .007) or bilirubin (AUROC 0.846) (P = .007). Level of IL6 was an independent, significant risk factor for mortality after adjustment for MELD score, MELD-Na score, level of CRP, or WBC. CONCLUSIONS In a retrospective analysis, we found high blood levels of IL6 to associate with 90-day and 1-year mortality in patients with end-stage liver disease; its predictive value was comparable to that of MELD or MELD-Na score, and was higher than that of level of CRP or WBC. Further studies should be performed to confirm the results in different cohorts.
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Affiliation(s)
- Johannes Remmler
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Christoph Schneider
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Theresa Treuner-Kaueroff
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Michael Bartels
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Daniel Seehofer
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Markus Scholz
- Institute for Medical Informatics, Statistics and Epidemiology, University Hospital Leipzig, Leipzig, Germany
| | - Thomas Berg
- Section of Hepatology, Department of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
| | - Thorsten Kaiser
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
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Li N, Huang C, Yu KK, Lu Q, Shi GF, Zheng JM. Validation of prognostic scores to predict short-term mortality in patients with HBV-related acute-on-chronic liver failure: The CLIF-C OF is superior to MELD, CLIF SOFA, and CLIF-C ACLF. Medicine (Baltimore) 2017; 96:e6802. [PMID: 28445322 PMCID: PMC5413287 DOI: 10.1097/md.0000000000006802] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Acute-on-chronic liver failure (ACLF) in chronic hepatitis B (CHB) patients has a high short-term mortality. Identification of effective models to predict the short-term mortality may enable early intervention and improve patients' prognosis. We aim to assess the performance of the CLIF Consortium Organ Failure score (CLIF-C OFs), CLIF sequential organ failure assessment score (CLIF-SOFAs), CLIF Consortium ACLF score (CLIF-C ACLFs), ACLF grade, and model for end-stage liver disease score (MELDs) in predicting the short-term mortality in CHB patients with ACLF.Among the 155 consecutive adult patients with liver failure as a discharge diagnosis were screened, and all the patients were treated at the Department of Infectious Diseases, Huashan Hospital, Fudan University (Shanghai, China) from January 2010 to February 2016. The diagnosis of ACLF was based on the criteria formalized by the ACLF consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL). Diagnostic accuracy for predicting short-term (28-day) mortality was calculated for CLIF-C OFs, CLIF-SOFAs, CLIF-C ACLFs, ACLF grade, and MELDs in all patients.One hundred fifty-five consecutive adult liver failure patients were screened and 85 patients including 73 males and 12 females were enrolled. Overall, the 28-day transplant-free mortality was 32% in all patients, and 100% in those with severe early course (ACLF-3). The area under the receiver operating characteristic curve (AUROC) of CLIF-C OFs (AUROC: 0.906, P = .0306, compared with MELDs) was higher than those of CLIF-SOFAs (AUROC: 0.876), CLIF-C ACLFs (AUROC: 0.858), ACLF grade (AUROC: 0.857), and MELDs (AUROC: 0.838) for predicting short-term mortality. The cut-point for baseline CLIF-C OFs in predicting death was 8.5, with 67% sensitivity, 90% specificity, and AUROC of 0.906 (95% CI: 0.8450-0.9679).The results indicate that short-term mortality is high in patients with ACLF and CLIF Consortium Organ Failure score is superior to MELD, CLIF SOFA, and CLIF-C ACLF in predicting its short-term mortality.
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