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1
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Amaris NR, Marenco-Flores A, Barba R, Rubio-Cruz D, Medina-Morales E, Goyes D, Saberi B, Patwardhan V, Bonder A. Acute Liver Failure Etiology Determines Long-Term Outcomes in Patients Undergoing Liver Transplantation: An Analysis of the UNOS Database. J Clin Med 2024; 13:6642. [PMID: 39597786 PMCID: PMC11594988 DOI: 10.3390/jcm13226642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/01/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024] Open
Abstract
Background: Acute liver failure (ALF) involves rapid liver injury, often leading to multi-organ failure. Liver transplantation (LT) has improved survival rates, with U.S. rates reaching 92%. This study analyzes UNOS data (2002-2020) to evaluate long-term survival and identify risk factors affecting waitlist and post-LT outcomes in ALF patients. Methods: A retrospective analysis was performed on adult ALF patients waitlisted for LT (Status 1/1A). ALF etiologies, including viral infections, drug-induced liver injury (DILI), acetaminophen (APAP) overdose, autoimmune hepatitis (AIH), Wilson disease (WD), and unknown causes, were assessed with patient and donor characteristics. Kaplan-Meier and Cox regression analyses identified predictors of patient and graft survival. Sensitivity analysis confirmed the model's robustness. Results: We identified 2759 ALF patients. APAP (HR 1.7; p < 0.001) and unknown etiology (HR 1.3; p = 0.037) were linked to higher waitlist removal risk, while WD (HR 0.36; p < 0.001) increased LT probability. Among 2014 LT recipients, WD showed improved survival (HR 0.53; p = 0.002). Black/African American race (HR 1.47; p < 0.001), diabetes (HR 1.81; p < 0.001), and encephalopathy (HR 1.27; p < 0.001) predicted higher mortality. AIH had the lowest 1- and 10-year survival (83% and 62%), while APAP had the lowest 5-year survival (76%). WD had the highest graft survival at 1, 5, and 10 years (93%, 88%, and 80%). Conclusions: ALF etiology significantly affects survival outcomes. AIH and APAP are associated with worse survival, while WD shows favorable outcomes. Tailored post-LT management is essential to improve survival in ALF patients.
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Affiliation(s)
- Natalia Rojas Amaris
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (N.R.A.); (A.M.-F.); (D.R.-C.); (B.S.); (V.P.)
| | - Ana Marenco-Flores
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (N.R.A.); (A.M.-F.); (D.R.-C.); (B.S.); (V.P.)
| | - Romelia Barba
- Department of Internal Medicine, Texas Tech University System, Lubbock, TX 79430, USA;
| | - Denisse Rubio-Cruz
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (N.R.A.); (A.M.-F.); (D.R.-C.); (B.S.); (V.P.)
| | - Esli Medina-Morales
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA;
| | - Daniela Goyes
- Division of Digestive Diseases, Yale School of Medicine, New Haven, CT 06520, USA;
| | - Behnam Saberi
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (N.R.A.); (A.M.-F.); (D.R.-C.); (B.S.); (V.P.)
| | - Vilas Patwardhan
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (N.R.A.); (A.M.-F.); (D.R.-C.); (B.S.); (V.P.)
| | - Alan Bonder
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (N.R.A.); (A.M.-F.); (D.R.-C.); (B.S.); (V.P.)
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2
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Shi S, Zhang M, Chen X, Wang Z, Ding S, Chen Z, Yang Y, Zheng S. Liver transplantation for hepatitis B virus-related cirrhosis with acute-on-chronic liver failure and grade 3-4 hepatic encephalopathy: Survival and quality of life. Chin Med J (Engl) 2024; 137:2119-2121. [PMID: 38630917 PMCID: PMC11374271 DOI: 10.1097/cm9.0000000000003037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Indexed: 04/19/2024] Open
Affiliation(s)
- Shaohua Shi
- Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, Zhejiang 310003, China
| | - Minghui Zhang
- Department of General Surgery, The Sixth People's Hospital of Zhengzhou City, Zhengzhou, Henan 450015, China
| | - Xuliang Chen
- Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, Zhejiang 310003, China
| | - Zhuoyi Wang
- Department of Intensive Care Unit, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, Zhejiang 310003, China
| | - Songming Ding
- Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, Zhejiang 310003, China
| | - Zhitao Chen
- Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, Zhejiang 310003, China
| | - Yu Yang
- Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, Zhejiang 310003, China
| | - Shusen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, Zhejiang 310003, China
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3
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Buckholz AP, Brown RS. Future Therapies of Hepatic Encephalopathy. Clin Liver Dis 2024; 28:331-344. [PMID: 38548443 PMCID: PMC10987054 DOI: 10.1016/j.cld.2024.02.002] [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] [Indexed: 04/02/2024]
Abstract
Hepatic encephalopathy, either covert or overt, affects more than half of patients with cirrhosis and has lasting effects even after portal hypertension is corrected. Unfortunately, the current therapeutic options still result in high rates of relapse and progression, in part owing to cost barriers and side effects, leading to poor adherence. This review summarizes emerging treatment options, which could take advantage of alternative disease pathways to improve future care of those with hepatic encephalopathy.
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Affiliation(s)
- Adam P Buckholz
- Division of Gastroenterology and Hepatology, New York/Presbyterian-Weill Cornell Medical College, 1305 York Avenue, 4th Floor, New York, NY 10021, USA
| | - Robert S Brown
- Division of Gastroenterology and Hepatology, New York/Presbyterian-Weill Cornell Medical College, 1305 York Avenue, 4th Floor, New York, NY 10021, USA.
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4
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Singh SA, Pampaniya H, Mehtani R, Jadaun SS, Kumar M, Khurana S, Das DJ, Gupta S, Saigal S. Living donor liver transplant in acute on chronic liver failure grade 3: Who not to transplant. Dig Liver Dis 2024; 56:152-158. [PMID: 37550101 DOI: 10.1016/j.dld.2023.07.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 07/05/2023] [Accepted: 07/23/2023] [Indexed: 08/09/2023]
Abstract
BACKGROUND AND AIM Liver transplantation(LT)offers definitive treatment for acute on chronic liver failure(ACLF) patients. This study was done to analyze and compare the outcomes of living donor LT(LDLT) in patients with ACLF versus Chronic liver disease(CLD) and within the grades of ACLF. Factors affecting mortality in patients with ACLF and ACLF grade3 (ACLF3) following LDLT were also derived. METHODS Records of adult LDLT between 1/2/2017 and 30/9/2021 were analyzed. ACLF was classified based on EASL-CLIF definition. Post-transplant outcomes of ACLF were compared with CLD and within ACLF grades. Post LDLT mortality predictors were identified in ACLF and ACLF3 patients. RESULTS Out of 853 patients who had LT in that period; 704 patients with CLD and 103 with ACLF [of which 54 (52.42%) had ACLF3] underwent LDLT. The one month and one-year post LDLT mortality was 8.81% and 9.80% in CLD; 19.42% and 31.06% in ACLF; and 25.92% and 38.89% in ACLF3 respectively. On log regression analysis, use of grafts from older donors and pre-operative respiratory failure in recipients was associated with poor survival in ACLF, while respiratory failure was a predictor of poor survival in ACLF3 following LDLT. CONCLUSION Outcomes following LDLT are poorer in ACLF as compared to after CLD. Higher donor age and preoperative respiratory failure with PF Ratio<200 were associated with poor survival post LDLT in ACLF and ACLF3.
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Affiliation(s)
- Shweta A Singh
- Department of Anaesthesiology and Critical Care, Center for Liver and Biliary Sciences, Max Super Speciality Hospital, Saket, New Delhi, 110017, India.
| | - Hetal Pampaniya
- Department of Anaesthesiology and Critical Care, Center for Liver and Biliary Sciences, Max Super Speciality Hospital, Saket, New Delhi, 110017, India
| | - Rohit Mehtani
- Department of Gastroenterology and Hepatology, Center for Liver and Biliary Sciences, Max Super Speciality Hospital, Saket, New Delhi, 110017, India
| | - Shekhar Singh Jadaun
- Department of Gastroenterology and Hepatology, Center for Liver and Biliary Sciences, Max Super Speciality Hospital, Saket, New Delhi, 110017, India
| | - Mukesh Kumar
- Department of Surgical Gastroenterology and LT, Center for Liver and Biliary Sciences, Max Super Speciality Hospital, New Delhi, 11001, India
| | - Saurabh Khurana
- Department of Anaesthesiology and Critical Care, Center for Liver and Biliary Sciences, Max Super Speciality Hospital, Saket, New Delhi, 110017, India
| | - Dibya Jyoti Das
- Department of Surgical Gastroenterology and LT, Center for Liver and Biliary Sciences, Max Super Speciality Hospital, New Delhi, 11001, India
| | - Subhash Gupta
- Department of Surgical Gastroenterology and LT, Center for Liver and Biliary Sciences, Max Super Speciality Hospital, New Delhi, 11001, India
| | - Sanjiv Saigal
- Department of Gastroenterology and Hepatology, Center for Liver and Biliary Sciences, Max Super Speciality Hospital, Saket, New Delhi, 110017, India
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5
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Min EK, Yim SH, Choi MC, Lee JG, Joo DJ, Kim MS, Kim DG. Incidence, mortality, and risk factors associated with carbapenem-resistant Acinetobacter baumannii bacteremia within 30 days after liver transplantation. Clin Transplant 2023; 37:e14956. [PMID: 36860160 DOI: 10.1111/ctr.14956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/10/2023] [Accepted: 02/26/2023] [Indexed: 03/03/2023]
Abstract
Carbapenem-resistant Acinetobacter baumannii bacteremia (CRAB-B) is a fatal infectious complication of liver transplantation (LT). This study investigated the incidence, effects, and risk factors associated with CRAB-B during the early post-LT period. Among 1051 eligible LT recipients, 29 patients experienced CRAB-B within 30 days of LT with a cumulative incidence of 2.7%. In the patients with CRAB-B (n = 29) and matched controls (n = 145) by nested-case control design, the cumulative incidence of death on days 5, 10, and 30 from the index date was 58.6%, 65.5%, and 65.5%, and 2.1%, 2.8%, and 4.2%, respectively (p < .001). Pre-transplant MELD (OR 1.11, 95% confidence interval [CI] 1.04-1.19, p = .002), severe encephalopathy (OR 4.62, 95% CI 1.24-18.61, p = .025), donor body mass index (OR .57, 95% CI .41-.75, p < .001), and reoperation (OR 6.40, 95% CI 1.19-36.82, p = .032) were independent risk factors for 30-day CRAB-B. CRAB-B showed extremely high mortality within 30 days after LT, especially within 5 days after its occurrence. Therefore, assessment of risk factors and early detection of CRAB, followed by proper treatment, are necessary to control CRAB-B after LT.
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Affiliation(s)
- Eun-Ki Min
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Seung Hyuk Yim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Mun Chae Choi
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Jae Geun Lee
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Dong Jin Joo
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Myoung Soo Kim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Deok-Gie Kim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
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6
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Chen YQ, Liu JL. Advances in research of microbiome regulation as a therapy for liver failure. Shijie Huaren Xiaohua Zazhi 2022; 30:971-977. [DOI: 10.11569/wcjd.v30.i22.971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
The intestinal flora of the human body is complex and diverse, and the structure and composition of the intestinal micro-ecosystem formed by the intestinal flora are complicated. Studies have shown that the imbalance of the intestinal micro-ecosystem is closely related to the occurrence and development of liver failure, and the degree of intestinal microecological imbalance is significantly correlated with the severity of liver failure. Therefore, the role of intestinal microbiome regulation in the treatment of liver failure and the improvement of prognosis has increasingly attracting the attention of scholars. However, due to the complexity of the composition and structure of the intestinal flora and its mechanism of action involved in the development of liver failure, the application of intestinal microbiome regulation in the clinic is limited to a certain extent. In this paper, we review the research progress of microbiome regulation as a therapy for liver failure.
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Affiliation(s)
- Yue-Qiao Chen
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine, Nanning 530200, Guangxi Zhuang Autonomous Region, China
| | - Jia-Ling Liu
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine, Nanning 530200, Guangxi Zhuang Autonomous Region, China
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7
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Cheng Y, Li JL, Zhou JM, Zhang GY, Shen W, Zhang XD. Renormalization of Thalamic Sub-Regional Functional Connectivity Contributes to Improvement of Cognitive Function after Liver Transplantation in Cirrhotic Patients with Overt Hepatic Encephalopathy. Korean J Radiol 2021; 22:2052-2061. [PMID: 34564958 PMCID: PMC8628146 DOI: 10.3348/kjr.2020.1432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 06/15/2021] [Accepted: 07/07/2021] [Indexed: 11/18/2022] Open
Abstract
Objective The role of preoperative overt hepatic encephalopathy (OHE) in the neurophysiological mechanism of cognitive improvement after liver transplantation (LT) remains elusive. This study aimed to explore changes in sub-regional thalamic functional connectivity (FC) after LT and their relationship with neuropsychological improvement using resting-state functional MRI (rs-fMRI) data in cirrhotic patients with and without a history of OHE. Materials and Methods A total of 51 cirrhotic patients, divided into the OHE group (n = 21) and no-OHE group (n = 30), and 30 healthy controls were enrolled in this prospective study. Each patient underwent rs-fMRI before and 1 month after LT. Using 16 bilateral thalamic subregions as seeds, we conducted a seed-to-voxel FC analysis to compare the thalamic FC alterations before and after LT between the OHE and no-OHE groups, as well as differences in FC between the two groups of cirrhotic patients and the control group. Correction for multiple comparisons was conducted using the false discovery rate (p < 0.05). Results We found abnormally increased FC between the thalamic sub-region and prefrontal cortex, as well as an abnormally decreased FC between the bilateral thalamus in both OHE and no-OHE cirrhotic patients before LT, which returned to normal levels after LT. Compared with the no-OHE group, the OHE group exhibited more extensive abnormalities prior to LT, and the increased FC between the right thalamic subregions and right inferior parietal lobe was markedly reduced to normal levels after LT. Conclusion The renormalization of FC in the cortico-thalamic loop might be a neuro-substrate for the recovery of cognitive function after LT in cirrhotic patients. In addition, hyperconnectivity between thalamic subregions and the inferior parietal lobe might be an important feature of OHE. Changes in FC in the thalamus might be used as potential biomarkers for recovery of cognitive function after LT in cirrhotic patients.
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Affiliation(s)
- Yue Cheng
- Department of Radiology, Tianjin First Central Hospital, Tianjin, China
| | - Jing-Li Li
- Department of Radiology, Tianjin First Central Hospital, Tianjin, China
| | - Jia-Min Zhou
- Department of Radiology, Tianjin First Central Hospital, Tianjin, China
| | - Gao-Yan Zhang
- Tianjin Key Lab of Cognitive Computing and Application, College of Intelligence and Computing, Tianjin University, Tianjin, China
| | - Wen Shen
- Department of Radiology, Tianjin First Central Hospital, Tianjin, China
| | - Xiao-Dong Zhang
- Department of Radiology, Tianjin First Central Hospital, Tianjin, China.
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8
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Kwak JH, Shavelle R, Brooks J. Life Expectancy After Liver Transplantation for Hepatocellular Carcinoma With Cirrhosis. Prog Transplant 2021; 31:62-71. [PMID: 33686888 DOI: 10.1177/1526924820978603] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatocelluar carcinoma, the most common primary liver cancer, has a historically dire prognosis. For hepatic cancer patients with cirrhosis who underwent liver transplantation, we sought to calculate life expectancies both at time of transplant and several years later, stratified by some key variables, and to determine if survival has improved in recent years. METHODS Data on 13,797 hepatic cancer patients with cirrhosis who underwent liver transplantation in the MELD era (2002-2018) from the US Organ Procurement and Transplantation Network database were analyzed using the Cox proportional hazards regression model and life table methods. RESULTS The major factors related to survival were age, donor age, transplant year, diabetes, functional status, and the presence of severe hepatic encephalopathy. Survival was significantly worse with increasing age and decreasing functional status level. There was no significant difference in survival between males and females. Survival improved over the study period, at 5% per calendar year during the first 5 years post transplant, and 1% per year thereafter. CONCLUSIONS Life expectancies were markedly reduced from normal, even among 5-year survivors with the most favorable characteristics. Survival improved modestly over the years 2002-2018.
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Affiliation(s)
- Ji Hun Kwak
- Life Expectancy Project, San Francisco, CA, USA
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9
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Fallahzadeh MA, Rahimi RS. Hepatic Encephalopathy and Nutrition Influences: A Narrative Review. Nutr Clin Pract 2019; 35:36-48. [PMID: 31872484 DOI: 10.1002/ncp.10458] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Hepatic encephalopathy (HE) is a potentially reversible neurocognitive condition seen in patients with advanced liver disease. The overt form of HE has been reported in up to 45% of patients with cirrhosis. This debilitating condition is associated with increased morbidity and mortality and imposes a significant burden on the caregivers and healthcare system. After providing an overview of HE epidemiology and pathophysiology, this review focuses on the interaction of HE and frailty, nutrition requirements and recommendations in cirrhotic patients with HE, and current dietary and pharmacologic options for HE treatment.
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Affiliation(s)
- Mohammad Amin Fallahzadeh
- Division of Hepatology, Baylor University Medical Center, Baylor Scott & White Health, Dallas, Texas, USA
| | - Robert S Rahimi
- Division of Hepatology, Baylor University Medical Center, Baylor Scott & White Health, Dallas, Texas, USA
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10
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Ito T, Nakamura K, Kageyama S, Korayem IM, Hirao H, Kadono K, Aziz J, Younan S, DiNorcia J, Agopian VG, Yersiz H, Farmer DG, Busuttil RW, Kupiec-Weglinski JW, Kaldas FM. Impact of Rifaximin Therapy on Ischemia/Reperfusion Injury in Liver Transplantation: A Propensity Score-Matched Analysis. Liver Transpl 2019; 25:1778-1789. [PMID: 31509643 PMCID: PMC6887108 DOI: 10.1002/lt.25633] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 08/13/2019] [Indexed: 12/22/2022]
Abstract
Intestinal microbiota is thought to play an important role in hepatic ischemia/reperfusion injury (IRI) after liver transplantation (LT). Rifaximin, a nonabsorbable antibiotic used to treat encephalopathy, exhibits antibacterial activity within the gut. We report the first study examining the impact of pre-LT rifaximin use on reducing hepatic IRI and inflammatory cell infiltration after LT. This retrospective single-center study included adult LT recipients from January 2013 through June 2016. Patients were divided into 2 groups based on duration of rifaximin use before LT: rifaximin group (≥28 days) and control group (none or <28 days). Patients receiving other antibiotics within 28 days of LT and re-LTs were excluded. Outcomes and messenger RNA (mRNA) expression in the graft were compared by 1:1 propensity score-matching and multivariate analyses. On 1:1 matching (n = 39/group), rifaximin patients had lower postoperative serum transaminase levels and lower early allograft dysfunction (EAD; 10.3% versus 33.3%; P = 0.014). Of the matched patients, 8 patients (n = 4/group) had postreperfusion liver biopsies (approximately 2 hours after reperfusion) available for mRNA analysis. Hepatic expression of CD86 (macrophage marker) and cathepsin G (neutrophil marker) was significantly lower in rifaximin patients than controls (P < 0.05). The multivariate analysis included 458 patients. Rifaximin treatment <28 days was identified as an independent risk factor EAD in all patients and those with high Model for End-Stage Liver Disease (MELD) score (MELD ≥35; n = 230). In conclusion, the propensity score-matched and multivariate analyses suggest a therapeutic role of rifaximin in reducing EAD. Pre-LT rifaximin administration exerted a protective function against early liver injury, potentially by suppressing inflammatory cell activation in the graft.
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Affiliation(s)
- Takahiro Ito
- The Dumont-UCLA Transplantation Center, Division of Liver
and Pancreas Transplantation, Department of Surgery, David Geffen School of
Medicine, University of California, Los Angeles, CA
| | - Kojiro Nakamura
- The Dumont-UCLA Transplantation Center, Division of Liver
and Pancreas Transplantation, Department of Surgery, David Geffen School of
Medicine, University of California, Los Angeles, CA,Department of Surgery, Kyoto University, Kyoto,
Japan
| | - Shoichi Kageyama
- The Dumont-UCLA Transplantation Center, Division of Liver
and Pancreas Transplantation, Department of Surgery, David Geffen School of
Medicine, University of California, Los Angeles, CA
| | - Islam M. Korayem
- The Dumont-UCLA Transplantation Center, Division of Liver
and Pancreas Transplantation, Department of Surgery, David Geffen School of
Medicine, University of California, Los Angeles, CA,Hepato-Pancreato-Biliary Surgery Unit, Department of
Surgery, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
| | - Hirofumi Hirao
- The Dumont-UCLA Transplantation Center, Division of Liver
and Pancreas Transplantation, Department of Surgery, David Geffen School of
Medicine, University of California, Los Angeles, CA
| | - Kentaro Kadono
- The Dumont-UCLA Transplantation Center, Division of Liver
and Pancreas Transplantation, Department of Surgery, David Geffen School of
Medicine, University of California, Los Angeles, CA
| | - Justine Aziz
- The Dumont-UCLA Transplantation Center, Division of Liver
and Pancreas Transplantation, Department of Surgery, David Geffen School of
Medicine, University of California, Los Angeles, CA
| | - Stephanie Younan
- The Dumont-UCLA Transplantation Center, Division of Liver
and Pancreas Transplantation, Department of Surgery, David Geffen School of
Medicine, University of California, Los Angeles, CA
| | - Joseph DiNorcia
- The Dumont-UCLA Transplantation Center, Division of Liver
and Pancreas Transplantation, Department of Surgery, David Geffen School of
Medicine, University of California, Los Angeles, CA
| | - Vatche G. Agopian
- The Dumont-UCLA Transplantation Center, Division of Liver
and Pancreas Transplantation, Department of Surgery, David Geffen School of
Medicine, University of California, Los Angeles, CA
| | - Hasan Yersiz
- The Dumont-UCLA Transplantation Center, Division of Liver
and Pancreas Transplantation, Department of Surgery, David Geffen School of
Medicine, University of California, Los Angeles, CA
| | - Douglas G. Farmer
- The Dumont-UCLA Transplantation Center, Division of Liver
and Pancreas Transplantation, Department of Surgery, David Geffen School of
Medicine, University of California, Los Angeles, CA
| | - Ronald W. Busuttil
- The Dumont-UCLA Transplantation Center, Division of Liver
and Pancreas Transplantation, Department of Surgery, David Geffen School of
Medicine, University of California, Los Angeles, CA
| | - Jerzy W. Kupiec-Weglinski
- The Dumont-UCLA Transplantation Center, Division of Liver
and Pancreas Transplantation, Department of Surgery, David Geffen School of
Medicine, University of California, Los Angeles, CA
| | - Fady M. Kaldas
- The Dumont-UCLA Transplantation Center, Division of Liver
and Pancreas Transplantation, Department of Surgery, David Geffen School of
Medicine, University of California, Los Angeles, CA
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11
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Nakamura K, Kageyama S, Ito T, Hirao H, Kadono K, Aziz A, Dery KJ, Everly MJ, Taura K, Uemoto S, Farmer DG, Kaldas FM, Busuttil RW, Kupiec-Weglinski JW. Antibiotic pretreatment alleviates liver transplant damage in mice and humans. J Clin Invest 2019; 129:3420-3434. [PMID: 31329160 PMCID: PMC6668671 DOI: 10.1172/jci127550] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Accepted: 05/21/2019] [Indexed: 12/13/2022] Open
Abstract
Although modifications of gut microbiota with antibiotics (Abx) influence mouse skin and cardiac allografts, its role in orthotopic liver transplantation (OLT) remains unknown. We aimed to determine whether and how recipient Abx pretreatment may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. Mice (C57BL/6) with or without Abx treatment (10 days) were transplanted with allogeneic (BALB/c) cold-stored (18 hours) livers, followed by liver and blood sampling (6 hours). We divided 264 human OLT recipients on the basis of duration of pre-OLT Abx treatment into control (Abx-free/Abx <10 days; n = 108) and Abx treatment (Abx ≥10days; n = 156) groups; OLT biopsy (Bx) samples were collected 2 hours after OLT (n = 52). Abx in mice mitigated IRI-stressed OLT (IRI-OLT), decreased CCAAT/enhancer-binding protein homologous protein (CHOP) (endoplasmic reticulum [ER] stress), enhanced LC3B (autophagy), and inhibited inflammation, whereas it increased serum prostaglandin E2 (PGE2) and hepatic PGE2 receptor 4 (EP4) expression. PGE2 increased EP4, suppressed CHOP, and induced autophagosome formation in hepatocyte cultures in an EP4-dependent manner. An EP4 antagonist restored CHOP, suppressed LC3B, and recreated IRI-OLT. Remarkably, human recipients of Abx treatment plus OLT (Abx-OLT), despite severe pretransplantation clinical acuity, had higher EP4 and LC3B levels but lower CHOP levels, which coincided with improved hepatocellular function (serum aspartate aminotransferase/serum aspartate aminotransferase [sALT/sAST]) and a decreased incidence of early allograft dysfunction (EAD). Multivariate analysis identified "Abx-free/Abx <10 days" as a predictive factor of EAD. This study documents the benefits of Abx pretreatment in liver transplant recipients, identifies ER stress and autophagy regulation by the PGE2/EP4 axis as a homeostatic underpinning, and points to the microbiome as a therapeutic target in OLT.
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Affiliation(s)
- Kojiro Nakamura
- Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Shoichi Kageyama
- Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Takahiro Ito
- Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Hirofumi Hirao
- Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Kentaro Kadono
- Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Antony Aziz
- Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Kenneth J. Dery
- Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | | | - Kojiro Taura
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Douglas G. Farmer
- Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Fady M. Kaldas
- Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Ronald W. Busuttil
- Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Jerzy W. Kupiec-Weglinski
- Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
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Sarin SK, Choudhury A, Sharma MK, Maiwall R, Al Mahtab M, Rahman S, Saigal S, Saraf N, Soin AS, Devarbhavi H, Kim DJ, Dhiman RK, Duseja A, Taneja S, Eapen CE, Goel A, Ning Q, Chen T, Ma K, Duan Z, Yu C, Treeprasertsuk S, Hamid SS, Butt AS, Jafri W, Shukla A, Saraswat V, Tan SS, Sood A, Midha V, Goyal O, Ghazinyan H, Arora A, Hu J, Sahu M, Rao PN, Lee GH, Lim SG, Lesmana LA, Lesmana CR, Shah S, Prasad VGM, Payawal DA, Abbas Z, Dokmeci AK, Sollano JD, Carpio G, Shresta A, Lau GK, Fazal Karim M, Shiha G, Gani R, Kalista KF, Yuen MF, Alam S, Khanna R, Sood V, Lal BB, Pamecha V, Jindal A, Rajan V, Arora V, Yokosuka O, Niriella MA, Li H, Qi X, Tanaka A, Mochida S, Chaudhuri DR, Gane E, Win KM, Chen WT, Rela M, Kapoor D, Rastogi A, Kale P, Rastogi A, Sharma CB, Bajpai M, Singh V, Premkumar M, Maharashi S, Olithselvan A, Philips CA, Srivastava A, Yachha SK, Wani ZA, Thapa BR, Saraya A, Shalimar, Kumar A, Wadhawan M, Gupta S, Madan K, Sakhuja P, Vij V, Sharma BC, Garg H, Garg V, Kalal C, et alSarin SK, Choudhury A, Sharma MK, Maiwall R, Al Mahtab M, Rahman S, Saigal S, Saraf N, Soin AS, Devarbhavi H, Kim DJ, Dhiman RK, Duseja A, Taneja S, Eapen CE, Goel A, Ning Q, Chen T, Ma K, Duan Z, Yu C, Treeprasertsuk S, Hamid SS, Butt AS, Jafri W, Shukla A, Saraswat V, Tan SS, Sood A, Midha V, Goyal O, Ghazinyan H, Arora A, Hu J, Sahu M, Rao PN, Lee GH, Lim SG, Lesmana LA, Lesmana CR, Shah S, Prasad VGM, Payawal DA, Abbas Z, Dokmeci AK, Sollano JD, Carpio G, Shresta A, Lau GK, Fazal Karim M, Shiha G, Gani R, Kalista KF, Yuen MF, Alam S, Khanna R, Sood V, Lal BB, Pamecha V, Jindal A, Rajan V, Arora V, Yokosuka O, Niriella MA, Li H, Qi X, Tanaka A, Mochida S, Chaudhuri DR, Gane E, Win KM, Chen WT, Rela M, Kapoor D, Rastogi A, Kale P, Rastogi A, Sharma CB, Bajpai M, Singh V, Premkumar M, Maharashi S, Olithselvan A, Philips CA, Srivastava A, Yachha SK, Wani ZA, Thapa BR, Saraya A, Shalimar, Kumar A, Wadhawan M, Gupta S, Madan K, Sakhuja P, Vij V, Sharma BC, Garg H, Garg V, Kalal C, Anand L, Vyas T, Mathur RP, Kumar G, Jain P, Pasupuleti SSR, Chawla YK, Chowdhury A, Alam S, Song DS, Yang JM, Yoon EL. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update. Hepatol Int 2019; 13:353-390. [PMID: 31172417 PMCID: PMC6728300 DOI: 10.1007/s12072-019-09946-3] [Show More Authors] [Citation(s) in RCA: 546] [Impact Index Per Article: 91.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 04/03/2019] [Indexed: 02/07/2023]
Abstract
The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set up in 2004 on acute-on-chronic liver failure (ACLF) was published in 2009. With international groups volunteering to join, the "APASL ACLF Research Consortium (AARC)" was formed in 2012, which continued to collect prospective ACLF patient data. Based on the prospective data analysis of nearly 1400 patients, the AARC consensus was published in 2014. In the past nearly four-and-a-half years, the AARC database has been enriched to about 5200 cases by major hepatology centers across Asia. The data published during the interim period were carefully analyzed and areas of contention and new developments in the field of ACLF were prioritized in a systematic manner. The AARC database was also approached for answering some of the issues where published data were limited, such as liver failure grading, its impact on the 'Golden Therapeutic Window', extrahepatic organ dysfunction and failure, development of sepsis, distinctive features of acute decompensation from ACLF and pediatric ACLF and the issues were analyzed. These initiatives concluded in a two-day meeting in October 2018 at New Delhi with finalization of the new AARC consensus. Only those statements, which were based on evidence using the Grade System and were unanimously recommended, were accepted. Finalized statements were again circulated to all the experts and subsequently presented at the AARC investigators meeting at the AASLD in November 2018. The suggestions from the experts were used to revise and finalize the consensus. After detailed deliberations and data analysis, the original definition of ACLF was found to withstand the test of time and be able to identify a homogenous group of patients presenting with liver failure. New management options including the algorithms for the management of coagulation disorders, renal replacement therapy, sepsis, variceal bleed, antivirals and criteria for liver transplantation for ACLF patients were proposed. The final consensus statements along with the relevant background information and areas requiring future studies are presented here.
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Affiliation(s)
- Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India.
| | - Ashok Choudhury
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Manoj K Sharma
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Salimur Rahman
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Sanjiv Saigal
- Department of Hepatology, Medanta The Medicity, Gurgaon, India
| | - Neeraj Saraf
- Department of Hepatology, Medanta The Medicity, Gurgaon, India
| | - A S Soin
- Department of Hepatology, Medanta The Medicity, Gurgaon, India
| | | | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Seoul, South Korea
| | - R K Dhiman
- Department of Hepatology, PGIMER, Chandigarh, India
| | - Ajay Duseja
- Department of Hepatology, PGIMER, Chandigarh, India
| | - Sunil Taneja
- Department of Hepatology, PGIMER, Chandigarh, India
| | - C E Eapen
- Department of Hepatology, CMC, Vellore, India
| | - Ashish Goel
- Department of Hepatology, CMC, Vellore, India
| | - Q Ning
- Institute and Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Chen
- Translational Hepatology Institute Capital Medical University, Beijing You'an Hospital, Beijing, China
| | - Ke Ma
- Institute and Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Z Duan
- Translational Hepatology Institute Capital Medical University, Beijing You'an Hospital, Beijing, China
| | - Chen Yu
- Translational Hepatology Institute Capital Medical University, Beijing You'an Hospital, Beijing, China
| | | | - S S Hamid
- Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan
| | - Amna S Butt
- Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan
| | - Wasim Jafri
- Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan
| | - Akash Shukla
- Department of Gastroenterology, Lokmanya Tilak Municipal General Hospital and Lokmanya Tilak Municipal Medical College, Sion, Mumbai, India
| | | | - Soek Siam Tan
- Department of Medicine, Hospital Selayang, Bata Caves, Selangor, Malaysia
| | - Ajit Sood
- Department of Gastroenterology, DMC, Ludhiana, India
| | - Vandana Midha
- Department of Gastroenterology, DMC, Ludhiana, India
| | - Omesh Goyal
- Department of Gastroenterology, DMC, Ludhiana, India
| | - Hasmik Ghazinyan
- Department of Hepatology, Nork Clinical Hospital of Infectious Disease, Yerevan, Armenia
| | - Anil Arora
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital and GRIPMER, New Delhi, Delhi, India
| | - Jinhua Hu
- Department of Medicine, 302 Millitary Hospital, Beijing, China
| | - Manoj Sahu
- Department of Gastroenterology and Hepatology Sciences, IMS & SUM Hospital, Bhubaneswar, Odisha, India
| | - P N Rao
- Asian Institute of Gastroenterology, Hyderabad, India
| | - Guan H Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| | - Seng G Lim
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| | | | | | - Samir Shah
- Department of Hepatology, Global Hospitals, Mumbai, India
| | | | - Diana A Payawal
- Fatima University Medical Center Manila, Manila, Philippines
| | - Zaigham Abbas
- Department of Medicine, Ziauddin University Hospital, Karachi, Pakistan
| | - A Kadir Dokmeci
- Department of Medicine, Ankara University School of Medicine, Ankara, Turkey
| | - Jose D Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - Gian Carpio
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - Ananta Shresta
- Department of Hepatology, Foundation Nepal Sitapaila Height, Kathmandu, Nepal
| | - G K Lau
- Department of Medicine, Humanity and Health Medical Group, New Kowloon, Hong Kong, China
| | - Md Fazal Karim
- Department of Hepatology, Sir Salimullah Medical College, Dhaka, Bangladesh
| | - Gamal Shiha
- Egyptian Liver Research Institute And Hospital, Cairo, Egypt
| | - Rino Gani
- Division of Hepatobiliary, Department of Internal Medicine, Faculty of Medicine, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia
| | - Kemal Fariz Kalista
- Division of Hepatobiliary, Department of Internal Medicine, Faculty of Medicine, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia
| | - Man-Fung Yuen
- Department of Medicine, Queen Mary Hospital Hong Kong, The University of Hong Kong, Hong Kong, China
| | - Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Rajeev Khanna
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Vikrant Sood
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Bikrant Bihari Lal
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Viniyendra Pamecha
- Department of Hepatobilliary Pancreatic Surgery and Liver Transplant, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - V Rajan
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Vinod Arora
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | | | - Hai Li
- Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaolong Qi
- CHESS Frontier Center, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, China
| | - Atsushi Tanaka
- Department of Medicine, Tokyo University School of Medicine, Tokyo, Japan
| | - Satoshi Mochida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | | | - Ed Gane
- New Zealand Liver Transplant Unit, Auckland Hospital, Auckland, New Zealand
| | | | - Wei Ting Chen
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Medical Foundation, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Mohd Rela
- Department of Liver Transplant Surgery, Dr. Rela Institute and Medical Centre, Chennai, India
| | | | - Amit Rastogi
- Department of Hepatology, Medanta The Medicity, Gurgaon, India
| | - Pratibha Kale
- Department of Microbiology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Chhagan Bihari Sharma
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Meenu Bajpai
- Department of Immunohematology and Transfusion Medicine, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | | | | | | | - A Olithselvan
- Division of Liver Transplantation and Hepatology, Manipal Hospitals, Bangalore, India
| | - Cyriac Abby Philips
- The Liver Unit, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, India
| | - Anshu Srivastava
- Department of Pediatric Gastroenterology, SGPGIMS, Lucknow, India
| | | | | | - B R Thapa
- Department of Gastroenterology and Pediatric Gastroenterology, PGIMER, Chandigarh, India
| | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition, AIIMS, New Delhi, India
| | - Shalimar
- Department of Gastroenterology and Human Nutrition, AIIMS, New Delhi, India
| | - Ashish Kumar
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital and GRIPMER, New Delhi, Delhi, India
| | - Manav Wadhawan
- Department of Gastroenterology, Hepatology and Liver Transplant, B L K Hospital, New Delhi, India
| | - Subash Gupta
- Centre for Liver and Biliary Science, Max Hospital, New Delhi, India
| | - Kaushal Madan
- Department of Gastroenterology, Hepatology and Liver Transplant, Max Hospital, New Delhi, India
| | - Puja Sakhuja
- Department of Pathology, GB Pant Hospital, New Delhi, India
| | - Vivek Vij
- Department of Liver Transplant and Hepatobilliary Surgery, Fortis Hospital, New Delhi, India
| | - Barjesh C Sharma
- Department of Gastroenterology, GB Pant Hospital, New Delhi, India
| | - Hitendra Garg
- Department of Gastroenterology, Hepatology and Liver Transplant, Apollo Hospital, New Delhi, India
| | - Vishal Garg
- Department of Gastroenterology, Hepatology and Liver Transplant, Apollo Hospital, New Delhi, India
| | - Chetan Kalal
- Department of Hepatology, Sir H N Reliance Hospital and Research Centre, Mumbai, India
| | - Lovkesh Anand
- Department of Gastroenterology and Hepatology, Narayana Hospital, Gurugram, India
| | - Tanmay Vyas
- Department of Hepatology, Parimal Multi-Speciality Hospital, Ahmedabad, India
| | - Rajan P Mathur
- Department of Nephrology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Guresh Kumar
- Department of Statistics and Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Priyanka Jain
- Department of Statistics and Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Samba Siva Rao Pasupuleti
- Department of Statistics and Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Yogesh K Chawla
- Department of Hepatology and Gastroenterology, Kalinga Institute of Med Sciences, KIIT University, Bhubaneswar, India
| | - Abhijit Chowdhury
- Department of Hepatology, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Shahinul Alam
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Do Seon Song
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jin Mo Yang
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Eileen L Yoon
- Department Of Internal Medicine, Inje University College of Medicine, Busan, South Korea
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Abstract
PURPOSE OF REVIEW Hepatic encephalopathy is one of the most debilitating clinical manifestations of cirrhosis and associated with increased morbidity and mortality. Treatment modalities available include the nonabsorbable disaccharides (lactulose) and the nonabsorbable antibiotics (rifaximin). RECENT FINDINGS Newer therapeutic targets under evaluation include ammonia scavengers (ornithine phenylacetate) and modulation of gut microbiota (fecal microbiota transplantation). SUMMARY This review will focus on the pathophysiology of hepatic encephalopathy along with an update on therapeutic targets under investigation.
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Artzner T, Michard B, Besch C, Levesque E, Faitot F. Liver transplantation for critically ill cirrhotic patients: Overview and pragmatic proposals. World J Gastroenterol 2018; 24:5203-5214. [PMID: 30581269 PMCID: PMC6295835 DOI: 10.3748/wjg.v24.i46.5203] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 11/12/2018] [Accepted: 11/13/2018] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation for critically ill cirrhotic patients with acute deterioration of liver function associated with extrahepatic organ failures is controversial. While transplantation has been shown to be beneficial on an individual basis, the potentially poorer post-transplant outcome of these patients taken as a group can be held as an argument against allocating livers to them. Although this issue concerns only a minority of liver transplants, it calls into question the very heart of the allocation paradigms in place. Indeed, most allocation algorithms have been centered on prioritizing the sickest patients by using the model for end-stage liver disease score. This has led to allocating increasing numbers of livers to increasingly critically ill patients without setting objective or consensual limits on how sick patients can be when they receive an organ. Today, finding robust criteria to deem certain cirrhotic patients too sick to be transplanted seems urgent in order to ensure the fairness of our organ allocation protocols. This review starts by fleshing out the argument that finding such criteria is essential. It examines five types of difficulties that have hindered the progress of recent literature on this issue and identifies various strategies that could be followed to move forward on this topic, taking into account the recent discussion on acute on chronic liver failure. We move on to review the literature along four axes that could guide clinicians in their decision-making process regarding transplantation of critically ill cirrhotic patients.
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Affiliation(s)
- Thierry Artzner
- Service de Réanimation Médicale, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg 67000, France
| | - Baptiste Michard
- Service de Réanimation Médicale, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg 67000, France
- Service de Chirurgie Hépatobiliaire et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg 67000, France
| | - Camille Besch
- Service de Chirurgie Hépatobiliaire et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg 67000, France
| | - Eric Levesque
- Service d’Anesthésie et Réanimation Chirurgicale, Hôpital Henri Mondor, Créteil 94000, France
| | - François Faitot
- Service de Chirurgie Hépatobiliaire et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg 67000, France
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15
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Chang KV, Chen JD, Wu WT, Huang KC, Lin HY, Han DS. Is sarcopenia associated with hepatic encephalopathy in liver cirrhosis? A systematic review and meta-analysis. J Formos Med Assoc 2018; 118:833-842. [PMID: 30279030 DOI: 10.1016/j.jfma.2018.09.011] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 07/17/2018] [Accepted: 09/12/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND/PURPOSE Hepatic encephalopathy (HE), a major neuropsychiatric complication in advanced liver disease, is associated with poor prognosis. Sarcopenia, characterized by a decline in muscle mass, strength, and physical performance, is prevalent in liver cirrhosis. This study aims to explore whether sarcopenia is associated with HE in cirrhotic patients. METHODS PubMed and EMBASE were searched for relevant cohort and case-control studies investigating the association between sarcopenia and HE up to July 2018. Data of patients' characteristics, definition of low muscle mass, and protocols of grading/diagnosing HE were retrieved. The primary outcome was estimated by a pooled odds ratio (OR) and its 95% confidence interval (CI), using a random effect model. RESULTS The meta-analysis enrolled 6 studies, comprising 1795 patients. Sarcopenia was positively associated with the presence of HE (OR 2.74 with a 95% CI, 1.87 to 4.01). The association was less likely to be influenced by differences in research designs, focused study outcomes, muscle mass measurements, and protocols of grading/diagnosing HE. There was lack of evidence supporting higher serum ammonia levels in patients with sarcopenia. CONCLUSION In patients with liver cirrhosis, there is a significant association between sarcopenia and HE. A greater number of prospective studies are necessary to clarify whether the association remains even after adjusting relevant confounders and to suggest effective prevention of HE in patients with coexisting sarcopenia.
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Affiliation(s)
- Ke-Vin Chang
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taiwan; Community and Geriatric Medicine Research Center, National Taiwan University Hospital, Bei-Hu Branch, Taiwan; Department of Physical Medicine and Rehabilitation, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jin-De Chen
- Community and Geriatric Medicine Research Center, National Taiwan University Hospital, Bei-Hu Branch, Taiwan; Department of Gastroenterology, National Taiwan University Hospital, Bei-Hu Branch, Taiwan
| | - Wei-Ting Wu
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taiwan
| | - Kuo-Chin Huang
- Community and Geriatric Medicine Research Center, National Taiwan University Hospital, Bei-Hu Branch, Taiwan; Department of Family Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hong-Yi Lin
- Department of Physical Medicine and Rehabilitation, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Der-Sheng Han
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taiwan; Community and Geriatric Medicine Research Center, National Taiwan University Hospital, Bei-Hu Branch, Taiwan; Department of Physical Medicine and Rehabilitation, National Taiwan University College of Medicine, Taipei, Taiwan; Health Science and Wellness Center, National Taiwan University, Taipei, Taiwan.
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Sarin SK, Choudhury A. Management of acute-on-chronic liver failure: an algorithmic approach. Hepatol Int 2018; 12:402-416. [PMID: 30116993 DOI: 10.1007/s12072-018-9887-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 07/13/2018] [Indexed: 02/07/2023]
Abstract
Acute-on-chronic liver failure (ACLF) is a distinct syndrome of liver failure in a patient with chronic liver disease presenting with jaundice, coagulopathy and ascites and/or hepatic encephalopathy, developing following an acute hepatic insult and associated with high 28-day mortality. The definition though lacks global consensus, excludes patients with known distinct entities such as acute liver failure and those with end-stage liver disease. The initial Systemic Inflammatory Response Syndrome (SIRS) because of cytokine storm in relation to acute insult and/or subsequent development of sepsis due to immunoparalysis leads to extrahepatic organ failure. These cascades of events progress through a 'Golden Window' period of about 7 days, subsequent to which majority of the patients develop complications, such as sepsis and extrahepatic organ failure. Prevention of sepsis, support of organs and management of organ failure (commonly hepatic, renal, cerebral, coagulation) and early referral for transplant is crucial. The APASL ACLF research consortium (AARC) liver failure score is a dynamic prognostic model for management decisions and is superior to existing models. Aggressive multidisciplinary approach can lead to a transplant-free survival in nearly half of the cases. The present review provides an algorithmic approach to management of organ failure, sepsis prevention, use of dynamic prognostic models for management decision and is aimed to improve the skills for managing and improving the outcomes of such critically ill patients.
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Affiliation(s)
- Shiv Kumar Sarin
- Department of Hepatology and Liver Transplant, Institute of Liver and Biliary Sciences, D-1, VasantKunj, New Delhi, 110070, India.
| | - Ashok Choudhury
- Department of Hepatology and Liver Transplant, Institute of Liver and Biliary Sciences, D-1, VasantKunj, New Delhi, 110070, India
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17
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Waitlist Outcomes in Liver Transplant Candidates with High MELD and Severe Hepatic Encephalopathy. Dig Dis Sci 2018; 63:1647-1653. [PMID: 29611079 DOI: 10.1007/s10620-018-5032-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 03/15/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Organ Procurement and Transplantation Network and United Network for Organ Sharing (OPTN/UNOS) implemented the Share 35 policy in June 2013 to prioritize the sickest patients awaiting liver transplantation (LT). However, Model for End-Stage Liver Disease (MELD) score does not incorporate hepatic encephalopathy (HE), an independent predictor of waitlist mortality. AIM To evaluate the impact of severe HE (grade 3-4) on waitlist outcomes in MELD ≥ 30 patients. METHODS Using the OPTN/UNOS database, we evaluated LT waitlist registrants from 2005-2014. Demographics, comorbidities, and waitlist survival were compared between four cohorts: MELD 30-34 with severe HE, MELD 30-34 without severe HE, MELD ≥ 35 with severe HE, and MELD ≥ 35 without severe HE. RESULTS Among 10,003 waitlist registrants studied, 41.6% had MELD score 30-34 and 58.4% had MELD ≥ 35. Patients with severe HE had a higher 90-day waitlist mortality in both MELD 30-34 (severe HE 71.1% vs. no HE 56.6%; p < 0.001) and MELD ≥ 35 subgroups (severe HE 85% versus no HE 74.2%; p < 0.001). MELD 30-34 patients with severe HE had similar 90-day waitlist mortality as MELD ≥ 35 patients without severe HE (71.1 vs. 74.2%, respectively; p = 0.35). On multivariate Cox proportional hazards modeling, MELD ≥ 30 patients had 58% greater risk of 90-day waitlist mortality than those without severe HE (HR 1.58, 95% CI 1.53-1.62; p < 0.001). CONCLUSION Patients awaiting LT with MELD score of 30-34 and severe HE should receive priority status for organ allocation with exception MELD ≥ 35.
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18
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19
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Bernal W. Improving outcomes for transplantation of critically ill patients with cirrhosis? Clin Liver Dis (Hoboken) 2017; 10:25-28. [PMID: 30992754 PMCID: PMC6467230 DOI: 10.1002/cld.646] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 05/14/2017] [Accepted: 05/20/2017] [Indexed: 02/04/2023] Open
Affiliation(s)
- William Bernal
- Liver Intensive Therapy Unit, Institute of Liver StudiesKings College HospitalLondonUnited Kingdom
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20
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Jeyaraj R, Morgan MY, Gluud LL. Aminoglycosides and metronidazole for people with cirrhosis and hepatic encephalopathy. Hippokratia 2017. [DOI: 10.1002/14651858.cd012734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Rebecca Jeyaraj
- Division of Medicine, Royal Free Campus, University College London; UCL Institute for Liver & Digestive Health; Rowland Hill Street Hampstead London UK NW3 2PF
| | - Marsha Y Morgan
- Division of Medicine, Royal Free Campus, University College London; UCL Institute for Liver & Digestive Health; Rowland Hill Street Hampstead London UK NW3 2PF
| | - Lise Lotte Gluud
- Copenhagen University Hospital Hvidovre; Gastrounit, Medical Division; Kettegaards Alle Hvidovre Denmark 2650
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21
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Elwir S, Rahimi RS. Hepatic Encephalopathy: An Update on the Pathophysiology and Therapeutic Options. J Clin Transl Hepatol 2017; 5:142-151. [PMID: 28660152 PMCID: PMC5472935 DOI: 10.14218/jcth.2016.00069] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 02/11/2017] [Accepted: 03/24/2017] [Indexed: 12/11/2022] Open
Abstract
Hepatic encephalopathy is a spectrum of reversible neuropsychiatric abnormalities, seen in patients with liver dysfunction and/or portosystemic shunting. One of the most debilitating complications of cirrhosis, encephalopathy affects 30-45% of cirrhotics. In addition to significantly affecting the lives of patients and their caregivers, it is also associated with increased morbidity and mortality as well as significant utilization of health care resources. In this paper, we provide an overview on the pathophysiology, diagnosis, management and newer therapies of hepatic encephalopathy.
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Affiliation(s)
- Saleh Elwir
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX, USA
| | - Robert S. Rahimi
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX, USA
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22
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Levesque E, Winter A, Noorah Z, Daurès JP, Landais P, Feray C, Azoulay D. Impact of acute-on-chronic liver failure on 90-day mortality following a first liver transplantation. Liver Int 2017; 37:684-693. [PMID: 28052486 DOI: 10.1111/liv.13355] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Accepted: 12/10/2016] [Indexed: 02/13/2023]
Abstract
BACKGROUND Acute-on-chronic liver failure (ACLF) is associated with a significant short-term mortality rate (23%-74%), depending on the number of organ failures. Some patients present with ACLF at the time of liver transplantation (LT). The aim of this study was to assess whether ACLF was also a prognostic factor after LT and, if applicable, to construct a score that could predict 90-day mortality. METHODS Three hundred and fifty cirrhotic patients, who underwent LT between January 2008 and December 2013, were enrolled. We used ACLF grades according to EASL-CLIF consortium criteria to categorize the cirrhotic patients. A propensity score was applied with an Inverse Probability Treatment Weighting in a Cox model. A predictive score of early mortality after LT was generated. RESULTS One hundred and forty patients (40%) met the criteria for ACLF. The overall mortality rate at 90 days post-transplant was 10.6% (37/350 patients). ACLF at the time of LT (HR: 5.78 [3.42-9.77], P<.001) was an independent predictor of 90-day mortality. Infection occurring during the month before LT, high recipient age and male recipient, the reason for LT and a female donor were also independent risk factors for early mortality. Using these factors, we have proposed a model to predict 90-day mortality after LT. CONCLUSIONS LT is feasible in cirrhotic patients with ACLF. However, we have shown that ACLF is a significant and independent predictor of 90-day mortality. We propose a score that can identify candidate cirrhotic patients in whom LT might be associated with futile LT.
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Affiliation(s)
- Eric Levesque
- Department of Anaesthesia and Surgical Intensive Care - Liver ICU, AP-HP Henri Mondor Hospital, Créteil, France.,INSERM, Unité U955, Créteil, France
| | - Audrey Winter
- UPRES EA 2415 Department of Biostatistics, Clinical Research University Institute, Montpellier University, Montpellier, France.,Beau Soleil Clinic, Languedoc Mutualité, Montpellier, France
| | - Zaid Noorah
- Department of Anaesthesia and Surgical Intensive Care - Liver ICU, AP-HP Henri Mondor Hospital, Créteil, France
| | - Jean-Pierre Daurès
- UPRES EA 2415 Department of Biostatistics, Clinical Research University Institute, Montpellier University, Montpellier, France.,Beau Soleil Clinic, Languedoc Mutualité, Montpellier, France
| | - Paul Landais
- UPRES EA 2415 Department of Biostatistics, Clinical Research University Institute, Montpellier University, Montpellier, France.,Department of Biostatistics, Epidemiology, Public Health and Medical Information, University Hospital, Nîmes, France
| | - Cyrille Feray
- Department of Hepatology, AP-HP Henri Mondor Hospital, Créteil, France
| | - Daniel Azoulay
- INSERM, Unité U955, Créteil, France.,Digestive Surgery and Liver Transplant Unit, AP-HP Henri Mondor Hospital, Créteil, France
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23
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Bajaj JS, O'Leary JG, Tandon P, Wong F, Garcia-Tsao G, Kamath PS, Maliakkal B, Biggins SW, Thuluvath PJ, Fallon MB, Subramanian RM, Vargas HE, Lai J, Thacker LR, Reddy KR. Hepatic Encephalopathy Is Associated With Mortality in Patients With Cirrhosis Independent of Other Extrahepatic Organ Failures. Clin Gastroenterol Hepatol 2017; 15:565-574.e4. [PMID: 27720916 DOI: 10.1016/j.cgh.2016.09.157] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Revised: 09/09/2016] [Accepted: 09/16/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Although survival times have increased for patients with cirrhosis, hepatic encephalopathy (HE) remains a major complication and its relative contribution toward mortality in North America is unclear. We investigated whether HE is associated with mortality independent of extrahepatic organ failures (EHOFs). METHODS We collected data from the North American Consortium for Study of End-stage Liver Disease database of hospitalized patients with cirrhosis at tertiary-care centers. EHOFs were defined as need for ventilation (respiratory failure), dialysis (renal failure), or shock (circulatory failure). We analyzed in-hospital and 30-day mortality for patients with varying HE grades and EHOF using adjusted models. RESULTS We analyzed data from 1560 patients, 516 with HE (371 grade 1-2 and 145 grade 3-4). Patients with maximum HE grade 3-4 HE during hospitalization had a higher median model for end-stage liver disease (MELD) score (22) than patients with HE grade 1-2 (MELD score, 19) or no HE (MELD score, 18) (P < .0001). Thirty-day mortality for patients with HE grade 3-4 was significantly higher (38%) than for patients with HE grade 1-2 (8%) or no HE (7%). A total of 107 patients had 2 or more EHOFs, with or without HE; 151 had 1 EHOF and 1302 had no organ failure. Unadjusted mortality was highest for patients with HE of grade 3-4 with 2 EHOFs (n = 44). On regression analysis, HE severity was significantly associated with in-hospital and 30-day mortality, independent of any EHOF, white blood cell count, systemic inflammatory response syndrome, or MELD score (odds ratio, 3.3; P < .0001). CONCLUSIONS In an analysis of more than 1500 patients hospitalized for cirrhosis, HE of grade 3 or 4 was associated with higher in-hospital and 30-day mortality, independently of failure of other organs.
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Affiliation(s)
- Jasmohan S Bajaj
- Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia.
| | | | | | | | | | | | | | | | | | | | | | | | - Jennifer Lai
- University of California, San Francisco, California
| | - Leroy R Thacker
- Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia
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24
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Liu A, Yoo ER, Siddique O, Perumpail RB, Cholankeril G, Ahmed A. Hepatic encephalopathy: what the multidisciplinary team can do. J Multidiscip Healthc 2017; 10:113-119. [PMID: 28392702 PMCID: PMC5373836 DOI: 10.2147/jmdh.s118963] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatic encephalopathy (HE) is a complex disease requiring a multidisciplinary approach among specialists, primary care team, family, and caregivers. HE is currently a diagnosis of exclusion, requiring an extensive workup to exclude other possible etiologies, including mental status changes, metabolic, infectious, traumatic, and iatrogenic causes. The categorization of HE encompasses a continuum, varying from the clinically silent minimal HE (MHE), which is only detectable using psychometric tests, to overt HE, which is further divided into four grades of severity. While there has been an increased effort to create fast and reliable methods for the detection of MHE, screening is still underperformed due to the lack of standardization and efficient methods of diagnosis. The management of HE requires consultation from various disciplines, including hepatology, primary care physicians, neurology, psychiatry, dietician/nutritionist, social workers, and other medical and surgical subspecialties based on clinical presentation and clear communication among these disciplines to best manage patients with HE throughout their course. The first-line therapy for HE is lactulose with or without rifaximin. Following the initial episode of overt HE, secondary prophylaxis with lactulose and/or rifaximin is indicated with the goal to prevent recurrent episodes and improve quality of life. Recent studies have demonstrated the negative impact of MHE on quality of life and clinical outcomes. In light of all this, we emphasize the importance of screening and treating MHE in patients with liver cirrhosis, particularly through a multidisciplinary team approach.
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Affiliation(s)
- Andy Liu
- Department of Medicine, California Pacific Medical Center, San Francisco, CA
| | - Eric R Yoo
- Department of Medicine, University of Illinois College of Medicine, Chicago, IL
| | - Osama Siddique
- Department of Medicine, Brown University, Providence, RI
| | - Ryan B Perumpail
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA
| | - George Cholankeril
- Division of Gastroenterology and Hepatology, University of Tennessee Health Sciences Center, Memphis, TN, USA
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA
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25
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Rana A, Kueht M, Desai M, Lam F, Miloh T, Moffett J, Galvan NTN, Cotton R, O'Mahony C, Goss J. No Child Left Behind: Liver Transplantation in Critically Ill Children. J Am Coll Surg 2017; 224:671-677. [PMID: 28167225 DOI: 10.1016/j.jamcollsurg.2016.12.025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 12/14/2016] [Indexed: 12/24/2022]
Abstract
BACKGROUND Advances in critical care prolong survival in children with liver failure, allowing more critically ill children to undergo orthotopic liver transplantation (OLT). In order to justify the use of a scarce donor resource and avoid futile transplants, we sought to determine survival in children who undergo OLT while receiving pre-OLT critical care. STUDY DESIGN We analyzed 13,723 pediatric OLTs using the United Network for Organ Sharing (UNOS) database from 1987 to 2015, including 6,746 recipients in the Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease (MELD/PELD) era (2002 to 2015). There were 1,816 recipients (26.9%) admitted to the ICU at the time of transplantation. We also analyzed 354 pediatric OLT recipients at our center from 2002 to 2015, one of the largest institutional experiences. Sixty-five recipients (18.3%) were admitted to the ICU at the time of transplantation. Kaplan-Meier, volume threshold, and multivariable analyses were performed. RESULTS Patient survival improved steadily over the study period, (66% 1-year survival in 1987 vs 92% in 2015; p < 0.001). Our institutional experience of ICU recipients in the MELD/PELD era had acceptable outcomes (87% 1-year survival), even among our sickest recipients with vasoactive medications, mechanical ventilation, dialysis, and molecular adsorbent recirculating system requirements. Volume analysis revealed inferior outcomes (hazard ratio [HR] 1.68; 95% CI 1.11 to 2.51) in low-volume centers (<5 annual cases). Identifiable risk factors (previous transplantation, elevated serum sodium, hemodialysis, mechanical ventilation, body weight < 6 kg, and low center volume) increased risk of mortality. CONCLUSIONS This analysis demonstrates that the use of advanced critical care in children and infants with liver failure is justified because OLT can be performed on the sickest children and acceptable outcomes achieved. It is an appropriate use of a scarce donor allograft in a child who would otherwise succumb to a terminal liver disease.
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Affiliation(s)
- Abbas Rana
- Michael E DeBakey Department of Surgery, Division of Abdominal Transplantation and Hepatobiliary Surgery, Baylor College of Medicine, Houston, TX.
| | - Michael Kueht
- Michael E DeBakey Department of Surgery, Division of Abdominal Transplantation and Hepatobiliary Surgery, Baylor College of Medicine, Houston, TX
| | - Moreshwar Desai
- Department of Pediatrics, Division of Critical Care, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | - Fong Lam
- Department of Pediatrics, Division of Critical Care, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | - Tamir Miloh
- Department of Pediatrics, Division of Hepatology/Gastroenterology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
| | - Jennifer Moffett
- Michael E DeBakey Department of Surgery, Division of Abdominal Transplantation and Hepatobiliary Surgery, Baylor College of Medicine, Houston, TX
| | - N Thao N Galvan
- Michael E DeBakey Department of Surgery, Division of Abdominal Transplantation and Hepatobiliary Surgery, Baylor College of Medicine, Houston, TX
| | - Ronald Cotton
- Michael E DeBakey Department of Surgery, Division of Abdominal Transplantation and Hepatobiliary Surgery, Baylor College of Medicine, Houston, TX
| | - Christine O'Mahony
- Michael E DeBakey Department of Surgery, Division of Abdominal Transplantation and Hepatobiliary Surgery, Baylor College of Medicine, Houston, TX
| | - John Goss
- Michael E DeBakey Department of Surgery, Division of Abdominal Transplantation and Hepatobiliary Surgery, Baylor College of Medicine, Houston, TX
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26
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Bajaj JS, Kamath PS. The brain gets its say: Hepatic encephalopathy and its evolving role in transplant priority. Liver Transpl 2016; 22:1319-20. [PMID: 27509240 DOI: 10.1002/lt.24521] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 07/25/2016] [Indexed: 01/13/2023]
Affiliation(s)
- Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA.
| | - Patrick S Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic School of Medicine, Rochester, MN
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27
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Kinny-Köster B, Bartels M, Becker S, Scholz M, Thiery J, Ceglarek U, Kaiser T. Plasma Amino Acid Concentrations Predict Mortality in Patients with End-Stage Liver Disease. PLoS One 2016; 11:e0159205. [PMID: 27410482 PMCID: PMC4943589 DOI: 10.1371/journal.pone.0159205] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 06/28/2016] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND The liver plays a key role in amino acid metabolism. In former studies, a ratio between branched-chain and aromatic amino acids (Fischer's ratio) revealed associations with hepatic encephalopathy. Furthermore, low concentrations of branched-chain amino acids were linked to sarcopenia in literature. Encephalopathy and sarcopenia are known to dramatically worsen the prognosis. Aim of this study was to investigate a complex panel of plasma amino acids in the context of mortality in patients with end-stage liver disease. METHODS 166 patients evaluated for orthotopic liver transplantation were included. 19 amino acids were measured from citrated plasma samples using mass spectrometry. We performed survival analysis for plasma amino acid constellations and examined the relationship to established mortality predictors. RESULTS 33/166 (19.9%) patients died during follow-up. Lower values of valine (p<0.001), Fischer's ratio (p<0.001) and valine to phenylalanine ratio (p<0.001) and higher values of phenylalanine (p<0.05) and tyrosine (p<0.05) were significantly associated with mortality. When divided in three groups, the tertiles discriminated cumulative survival for valine (p = 0.016), phenylalanine (p = 0.024) and in particular for valine to phenylalanine ratio (p = 0.003) and Fischer's ratio (p = 0.005). Parameters were also significantly correlated with MELD and MELD-Na score. CONCLUSIONS Amino acids in plasma are valuable biomarkers to determine increased risk of mortality in patients with end-stage liver disease. In particular, valine concentrations and constellations composed of branched-chain and aromatic amino acids were strongly associated with prognosis. Due to their pathophysiological importance, the identified amino acids could be used to examine individual dietary recommendations to serve as potential therapeutic targets.
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Affiliation(s)
- Benedict Kinny-Köster
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Michael Bartels
- Department of Visceral, Vascular, Thoracic and Transplant Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Susen Becker
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
- LIFE – Leipzig Research Center for Civilization Diseases, University Hospital Leipzig, Leipzig, Germany
| | - Markus Scholz
- LIFE – Leipzig Research Center for Civilization Diseases, University Hospital Leipzig, Leipzig, Germany
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
| | - Joachim Thiery
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
- LIFE – Leipzig Research Center for Civilization Diseases, University Hospital Leipzig, Leipzig, Germany
| | - Uta Ceglarek
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
- LIFE – Leipzig Research Center for Civilization Diseases, University Hospital Leipzig, Leipzig, Germany
| | - Thorsten Kaiser
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
- * E-mail:
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28
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Saab S, Suraweera D, Au J, Saab EG, Alper TS, Tong MJ. Probiotics are helpful in hepatic encephalopathy: a meta-analysis of randomized trials. Liver Int 2016; 36:986-93. [PMID: 26561214 DOI: 10.1111/liv.13005] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 11/02/2015] [Indexed: 12/27/2022]
Abstract
BACKGROUND Hepatic encephalopathy (HE) is a major complication of cirrhosis and is associated with decreased survival and increased health care utilization. AIM The aim of this study was to evaluate the efficacy of probiotics in the management minimal hepatic encephalopathy HE (MHE) and overt HE (OHE) in comparison to no treatment/placebo and lactulose. METHODS The main outcomes measured were mortality, improvement in MHE, progression to OHE in patients with MHE and hospitalization. We calculated odds ratios (OR) with 95% confidence intervals (CI). Study heterogeneity was assessed using the I(2) statistic. RESULTS Fourteen studies totalling 1152 patients were included in the analysis. The use of probiotics had no impact on the overall mortality when compared to either lactulose (OR: 1.07, 95% CI: 0.47-2.44, P = 0.88) or no treatment/placebo (OR: 0.69, 95% CI: 0.42-1.14, P = 0.15). When probiotics was compared to no treatment/placebo, it was associated with a significant improvement in MHE (OR: 3.91, 95% CI: 2.25-6.80, P < 0.00001), decreased hospitalization rates (OR: 0.53, 95% CI: 0.33-0.86, P = 0.01) and decreased progression to overt hepatic encephalopathy (OR: 0.40, 95% CI: 0.26-0.60, P < 0.0001). However when compared to lactulose, probiotics did not show a significant difference in improvement of MHE (OR: 0.81, 95% CI: 0.52-1.27, P = 0.35), hospitalization rates (OR: 1.02, 95% CI: 0.52-1.99, P = 0.96) or progression to overt hepatic encephalopathy (OR: 1.24, 95% CI 0.73-2.10, P = 0.42). CONCLUSIONS Overall the use of probiotics was more effective in decreasing hospitalization rates, improving MHE and preventing progression to OHE in patients with underlying MHE than placebo, but similar to that seen with lactulose. The use of probiotics did not affect mortality rates.
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Affiliation(s)
- Sammy Saab
- Department of Surgery, University of California at Los Angeles, Los Angeles, CA, USA.,Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
| | | | - Jennifer Au
- Department of Medicine, Albert Einstein Medical Center, Philadelphia, PA, USA
| | - Elena G Saab
- Department of Surgery, University of California at Los Angeles, Los Angeles, CA, USA
| | - Tori S Alper
- Department of Surgery, University of California at Los Angeles, Los Angeles, CA, USA
| | - Myron J Tong
- Department of Surgery, University of California at Los Angeles, Los Angeles, CA, USA.,Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.,Liver Center, Huntington Medical Research Institutes, Pasadena, CA, USA
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29
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Liu FC, Lin JR, Chen HP, Tsai YF, Yu HP. Prevalence, predictive factors, and survival outcome of new-onset diabetes after liver transplantation: A population-based cohort study. Medicine (Baltimore) 2016; 95:e3829. [PMID: 27336869 PMCID: PMC4998307 DOI: 10.1097/md.0000000000003829] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
The aim of the present nationwide population-based cohort study was to explore the prevalence, risk factors, and survival outcome of new-onset diabetes (NOD) in recipients after liver transplantation.The National Health Insurance Research Database of Taiwan was searched for ICD-9-codes, 2248 patients who had received liver transplant without pretransplant diabetes from July 1, 1998 to December 31, 2012 were included in the study. The preoperative risks factors were considered and analyzed using logistic regression analysis, following adjustments for age and sex. All patients were followed up until the end of the study or death.The final dataset included 189 patients with NOD and 2059 without diabetes after liver transplantation. The prevalence of NOD was 8.4% and in 64% NOD appeared in the first year after liver transplantation. Preoperative clinical events, alcoholic liver cirrhosis, and hepatic encephalopathy were the most important risk factors for NOD after liver transplantation. The mortality rate was lower in NOD recipients than in non-NOD recipients within 5 years.In this study, we provide evidence that NOD recipients had better 5-year survival outcomes in this clinical population. The most important identifiable predictive factors for NOD after liver transplantation were alcoholic hepatitis, ascites, hepatic coma, and esophageal varices.
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Affiliation(s)
- Fu-Chao Liu
- Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jr-Rung Lin
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Clinical Informatics and Medical Statistics Research Center and Graduate Institute of Clinical Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Hsiu-Pin Chen
- Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yung-Fong Tsai
- Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Huang-Ping Yu
- Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
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30
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Jackson CD, Gram M, Halliday E, Olesen SS, Sandberg TH, Drewes AM, Morgan MY. New spectral thresholds improve the utility of the electroencephalogram for the diagnosis of hepatic encephalopathy. Clin Neurophysiol 2016; 127:2933-2941. [PMID: 27236607 DOI: 10.1016/j.clinph.2016.03.027] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Revised: 02/19/2016] [Accepted: 03/14/2016] [Indexed: 01/06/2023]
Abstract
OBJECTIVE The utility of the electroencephalogram (EEG) for the diagnosis of hepatic encephalopathy, using conventional spectral thresholds, is open to question. The aim of this study was to optimise its diagnostic performance by defining new spectral thresholds. METHODS EEGs were recorded in 69 healthy controls and 113 patients with cirrhosis whose neuropsychiatric status was classified using clinical and psychometric criteria. New EEG spectral thresholds were calculated, on the parietal P3-P4 lead derivation, using an extended multivariable receiver operating characteristic curve analysis. Thresholds were validated in a separate cohort of 68 healthy controls and 113 patients with cirrhosis. The diagnostic performance of the newly derived spectral thresholds was further validated using a machine learning technique. RESULTS The diagnostic performance of the new thresholds (sensitivity 75.0%; specificity 77.4%) was better balanced than that of the conventional thresholds (58.3%; 93.2%) and comparable to the performance of a machine learning technique (72.9%; 76.8%). The diagnostic utility of the new thresholds was confirmed in the validation cohort. CONCLUSIONS Adoption of the new spectral thresholds would significantly improve the utility of the EEG for the diagnosis of hepatic encephalopathy. SIGNIFICANCE These new spectral EEG thresholds optimise the performance of the EEG for the diagnosis of hepatic encephalopathy and can be adopted without the need to alter data recording or the initial processing of traces.
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Affiliation(s)
- Clive D Jackson
- Department of Neurophysiology, Royal Free Hospital, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, UK.
| | - Mikkel Gram
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark.
| | - Edwin Halliday
- Department of Neurophysiology, Royal Free Hospital, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, UK.
| | - Søren Schou Olesen
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark.
| | - Thomas Holm Sandberg
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark
| | - Asbjørn Mohr Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
| | - Marsha Y Morgan
- UCL Institute for Liver and Digestive Health, Department of Medicine, Royal Free Campus, University College London, Hampstead, London NW3 2PF, UK.
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31
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Okafor PN, Chiejina M, de Pretis N, Talwalkar JA. Secondary analysis of large databases for hepatology research. J Hepatol 2016; 64:946-56. [PMID: 26739689 DOI: 10.1016/j.jhep.2015.12.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2015] [Revised: 12/15/2015] [Accepted: 12/21/2015] [Indexed: 12/15/2022]
Abstract
Secondary analysis of large datasets involves the utilization of existing data that has typically been collected for other purposes to advance scientific knowledge. This is an established methodology applied in health services research with the unique advantage of efficiently identifying relationships between predictor and outcome variables but which has been underutilized for hepatology research. Our review of 1431 abstracts published in the 2013 European Association for the Study of Liver (EASL) abstract book showed that less than 0.5% of published abstracts utilized secondary analysis of large database methodologies. This review paper describes existing large datasets that can be exploited for secondary analyses in liver disease research. It also suggests potential questions that could be addressed using these data warehouses and highlights the strengths and limitations of each dataset as described by authors that have previously used them. The overall goal is to bring these datasets to the attention of readers and ultimately encourage the consideration of secondary analysis of large database methodologies for the advancement of hepatology.
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Affiliation(s)
- Philip N Okafor
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, United States.
| | - Maria Chiejina
- Department of Internal Medicine, Good Shepard Medical Center, Longview, TX 75601, United States
| | - Nicolo de Pretis
- Division of Gastroenterology and Gastrointestinal Endoscopy, Department of Medicine, University of Verona, Piazzale L.A. Scuro, 10, 37134 Verona, Italy
| | - Jayant A Talwalkar
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, United States; Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, United States
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