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Miah MK, Bickel U, Mehvar R. Bile duct ligation-induced cirrhosis does not alter the blood-brain barrier permeability to sucrose in rats. Metab Brain Dis 2024; 40:53. [PMID: 39636464 PMCID: PMC11621172 DOI: 10.1007/s11011-024-01486-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024]
Abstract
Contradictory results have been reported about the effects of liver diseases on the blood-brain barrier (BBB) permeability to markers. For instance, both an increase and no change in the BBB permeability to BBB markers sodium fluorescein and Evans blue have been reported in experimental cholestasis induced by bile duct ligation (BDL) in rats. These contradictory effects might be due to inherent limitations of these markers and/or methodological issues. Here, we investigated the time course of the impact of BDL in rats on BBB permeability using a recently developed stable isotope labeled marker [13C]sucrose, which is expected to be devoid of limitations of other markers, such as sodium fluorescein. At various times (five days, two weeks, and four weeks) after BDL or sham surgery, the brain uptake clearance (Kin) of [13C]sucrose was estimated using quantitation of the marker in plasma, blood, and brain by a specific LC-MS/MS analytical method. BDL caused substantial increases in the plasma concentrations of liver biochemical markers (bilirubin, total bile acids, ammonia, and cholesterol) and reduced liver cytochrome P450 content and metabolic activities. However, compared with the sham group, the plasma or blood AUC, brain concentrations, and Kin of [13C]sucrose in BDL animals remained unchanged at all the studied times. Additionally, we observed a negative correlation between the sucrose Kin and plasma total bile acids concentrations in the BDL animals. It is concluded that cholestatic liver disease, induced by BDL surgery in rats, does not significantly affect the BBB permeability to sucrose up to 4 weeks after the surgery.
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Affiliation(s)
- Mohammad K Miah
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas, USA
- Clinical Pharmacology & Quantitative Pharmacology, CPSS, AstraZeneca, Boston, Massachusetts, USA
| | - Ulrich Bickel
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas, USA
- Center for Blood-Brain Barrier Research, Texas Tech University Health Sciences Center, Amarillo, Texas, USA
| | - Reza Mehvar
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
- Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, 9401 Jeronimo Road, Irvine, California, USA.
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2
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Kulkarni AV, Venishetty S, Vora M, Naik P, Chouhan D, Iyengar S, Karandikar P, Gupta A, Gahra A, Rakam K, Parthasarthy K, Alla M, Sharma M, Ramachandra S, Menon B, Gupta R, Padaki NR, Reddy DN. Standard-Volume Is As Effective As High-Volume Plasma Exchange for Patients With Acute Liver Failure. J Clin Exp Hepatol 2024; 14:101354. [PMID: 38406612 PMCID: PMC10885581 DOI: 10.1016/j.jceh.2024.101354] [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] [Received: 10/24/2023] [Accepted: 01/26/2024] [Indexed: 02/27/2024] Open
Abstract
Background/Aims Acute liver failure (ALF) is associated with fatal outcomes without liver transplantation. Two randomized studies reported standard volume (SV) and high volume (HV) plasma exchange (PLEX) as effective therapeutic modalities for patients with ALF. However, no studies have compared the safety and efficacy of SV with HV PLEX, which we aimed to assess. Methods This retrospective study included patients with ALF admitted between March 2021 and March 2023 who underwent PLEX. All patients underwent HV PLEX until May 2022, and then thereafter, SV PLEX was performed. The objectives of the study were to compare transplant-free survival (TFS) at 30 days, efficacy in reducing severity scores, biochemical variables, and adverse events between SV (total plasma volume x 1) and HV (total plasma volume x 1.5-2) PLEX. Results Forty two ALF patients (median age: 23.5 years; females: 57.1%; MELD Na: 34.67 ± 6.07; SOFA score- 5.24 ± 1.42) underwent PLEX. Of these, 22 patients underwent SV-PLEX, and 20 underwent HV-PLEX. The mean age, sex, etiology distribution, and severity scores were similar between the groups. The median number of PLEX sessions (2) was similar in both groups. On Kaplan-Meier analysis, TFS was 45.5% in SV group and 45% in HV group (P = 0.76). A comparable decline in total bilirubin, PT/INR, ammonia, and MELD Na scores was noted in both groups. The cumulative number of adverse events was similar between the HV group (77.3%) and SV group (54.5%; P = 0.12). Conclusions SV PLEX is safe and as effective as HV PLEX in patients with ALF. Further randomized controlled trials with a larger sample size are needed to validate these findings.
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Affiliation(s)
| | | | - Moiz Vora
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | - Pragati Naik
- Department of Transfusion Medicine, AIG Hospitals, Hyderabad, India
| | | | - Sowmya Iyengar
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | - Puja Karandikar
- Department of Critical Care Medicine, AIG Hospitals, Hyderabad, India
| | - Anand Gupta
- Department of Critical Care Medicine, AIG Hospitals, Hyderabad, India
| | - Amrit Gahra
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | - Kalyan Rakam
- Department of Critical Care Medicine, AIG Hospitals, Hyderabad, India
| | | | - Manasa Alla
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | - Mithun Sharma
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | - Sumana Ramachandra
- Department of Liver Transplantation Surgery, AIG Hospitals, Hyderabad, India
| | - Balachandran Menon
- Department of Liver Transplantation Surgery, AIG Hospitals, Hyderabad, India
| | - Rajesh Gupta
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | | | - Duvvu N. Reddy
- Department of Hepatology, AIG Hospitals, Hyderabad, India
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Felgendreff P, Hosseiniasl SM, Felgendreff L, Amiot BP, Minshew A, Ahmadzada B, Qu Z, Wilken S, Arribas Gomez I, Nyberg SL, Cook CN. Comprehensive analysis of brain injury parameters in a preclinical porcine model of acute liver failure. Front Med (Lausanne) 2024; 11:1363979. [PMID: 38606159 PMCID: PMC11007081 DOI: 10.3389/fmed.2024.1363979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 02/21/2024] [Indexed: 04/13/2024] Open
Abstract
Introduction Acute liver failure (ALF) is defined as acute loss of liver function leading to hepatic encephalopathy associated with a high risk of patient death. Brain injury markers in serum and tissue can help detect and monitor ALF-associated brain injury. This study compares different brain injury parameters in plasma and tissue along with the progression of ALF. Method ALF was induced by performing an 85% liver resection. Following the resection, animals were recovered and monitored for up to 48 h or until reaching the predefined endpoint of receiving standard medical therapy (SMT). Blood and serum samples were taken at Tbaseline, T24, and upon reaching the endpoint (Tend). Control animals were euthanized by exsanguination following plasma sampling. Postmortem brain tissue samples were collected from the frontal cortex (FCTx) and cerebellum (Cb) of all animals. Glial fibrillary acidic protein (GFAP) and tau protein and mRNA levels were quantified using ELISA and qRT-PCR in all plasma and brain samples. Plasma neurofilament light (NFL) was also measured using ELISA. Results All ALF animals (n = 4) were euthanized upon showing signs of brain herniation. Evaluation of brain injury biomarkers revealed that GFAP was elevated in ALF animals at T24h and Tend, while Tau and NFL concentrations were unchanged. Moreover, plasma glial fibrillary acidic protein (GFAP) levels were negatively correlated with total protein and positively correlated with both aspartate transaminase (AST) and alkaline phosphatase (AP). Additionally, lower GFAP and tau RNA expressions were observed in the FCTx of the ALF group but not in the CB tissue. Conclusion The current large animal study has identified a strong correlation between GFAP concentration in the blood and markers of ALF. Additionally, the protein and gene expression analyses in the FCTx revealed that this area appears to be susceptible, while the CB is protected from the detrimental impacts of ALF-associated brain swelling. These results warrant further studies to investigate the mechanisms behind this process.
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Affiliation(s)
- Philipp Felgendreff
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
- Department of General, Visceral, and Transplantation Surgery, Hannover Medical School, Hannover, Germany
| | | | - Lisa Felgendreff
- Department of Journalism and Communication Research, Hannover University of Music, Drama, and Media, Hanover, Germany
| | - Bruce P. Amiot
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
| | - Anna Minshew
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
| | | | - Zhi Qu
- Transplant Center, Hannover Medical School, Hannover, Germany
| | - Silvana Wilken
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
| | - Ines Arribas Gomez
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
| | - Scott L. Nyberg
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, United States
| | - Casey N. Cook
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
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Santos RPC, Toscano ECDB, Rachid MA. Anti-inflammatory strategies for hepatic encephalopathy: preclinical studies. ARQUIVOS DE NEURO-PSIQUIATRIA 2023. [PMID: 37487550 PMCID: PMC10371400 DOI: 10.1055/s-0043-1767819] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/26/2023]
Abstract
Hepatic encephalopathy (HE) is a potentially reversible neuropsychiatric syndrome. Often, HE causes cognitive and motor dysfunctions due to an acute or chronic insufficiency of the liver or a shunting between the hepatic portal vein and systemic vasculature. Liver damage induces peripheral changes, such as in the metabolism and peripheral inflammatory responses that trigger exacerbated neuroinflammation. In experimental models, anti-inflammatory strategies have demonstrated neuroprotective effects, leading to a reduction in HE-related cognitive and motor impairments. In this scenario, a growing body of evidence has shown that peripheral and central nervous system inflammation are promising preclinical targets. In this review, we performed an overview of FDA-approved drugs and natural compounds which are used in the treatment of other neurological and nonneurological diseases that have played a neuroprotective role in experimental HE, at least in part, through anti-inflammatory mechanisms. Despite the exciting results from animal models, the available data should be critically interpreted, highlighting the importance of translating the findings for clinical essays.
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Affiliation(s)
- Rafaela Pinto Coelho Santos
- Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Departamento de Patologia Geral, Laboratório de Patologia Celular e Molecular, Belo Horizonte MG, Brazil
| | - Eliana Cristina de Brito Toscano
- Universidade Federal de Juiz de Fora, Faculdade de Medicina, Departamento de Patologia, Laboratório Integrado de Pesquisa em Patologia, Juiz de Fora MG, Brazil
- Universidade Federal de Juiz e Fora, Faculdade de Medicina, Programa de Pós-Graduação em Saúde, Juiz de Fora MG, Brazil
| | - Milene Alvarenga Rachid
- Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Departamento de Patologia Geral, Laboratório de Patologia Celular e Molecular, Belo Horizonte MG, Brazil
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Bray EE, Raichlen DA, Forsyth KK, Promislow DEL, Alexander GE, MacLean EL. Associations between physical activity and cognitive dysfunction in older companion dogs: results from the Dog Aging Project. GeroScience 2023; 45:645-661. [PMID: 36129565 PMCID: PMC9886770 DOI: 10.1007/s11357-022-00655-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 09/02/2022] [Indexed: 02/03/2023] Open
Abstract
Canine cognitive dysfunction (CCD) is a form of dementia that shares many similarities with Alzheimer's disease. Given that physical activity is believed to reduce risk of Alzheimer's disease in humans, we explored the association between physical activity and cognitive health in a cohort of companion dogs, aged 6-18 years. We hypothesized that higher levels of physical activity would be associated with lower (i.e., better) scores on a cognitive dysfunction rating instrument and lower prevalence of dementia, and that this association would be robust when controlling for age, comorbidities, and other potential confounders. Our sample included 11,574 companion dogs enrolled through the Dog Aging Project, of whom 287 had scores over the clinical threshold for CCD. In this observational, cross-sectional study, we used owner-reported questionnaire data to quantify dog cognitive health (via a validated scale), physical activity levels, health conditions, training history, and dietary supplements. We fit regression models with measures of cognitive health as the outcome, and physical activity-with several important covariates-as predictors. We found a significant negative relationship between physical activity and current severity of cognitive dysfunction symptoms (estimate = - 0.10, 95% CI: - 0.11 to - 0.08, p < 0.001), extent of symptom worsening over a 6-month interval (estimate = - 0.07, 95% CI: - 0.09 to - 0.05, p < 0.001), and whether a dog reached a clinical level of CCD (odds ratio = 0.53, 95% CI: 0.45 to 0.63, p < 0.001). Physical activity was robustly associated with better cognitive outcomes in dogs. Our findings illustrate the value of companion dogs as a model for investigating relationships between physical activity and cognitive aging, including aspects of dementia that may have translational potential for Alzheimer's disease. While the current study represents an important first step in identifying a relationship between physical activity and cognitive function, it cannot determine causality. Future studies are needed to rule out reverse causation by following the same dogs prospectively over time, and to evaluate causality by administering physical activity interventions.
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Affiliation(s)
- Emily E Bray
- Arizona Canine Cognition Center, School of Anthropology, University of Arizona, Tucson, AZ, USA.
- Canine Companions for Independence, National Headquarters, Santa Rosa, CA, USA.
| | - David A Raichlen
- Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
| | - Kiersten K Forsyth
- College of Veterinary Medicine & Biomedical Sciences, M University, Texas A &, College Station, TX, USA
| | - Daniel E L Promislow
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, USA
- Department of Biology, University of Washington, Seattle, WA, USA
| | - Gene E Alexander
- Department of Psychology, University of Arizona, Tucson, AZ, USA
- Evelyn F. McKnight Brain Institute, University of Arizona, Tucson, AZ, USA
- Arizona Alzheimer's Consortium, Phoenix, AZ, USA
- Department of Psychiatry, University of Arizona, Tucson, AZ, USA
- Neuroscience Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, USA
- Physiological Sciences Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, USA
| | - Evan L MacLean
- Arizona Canine Cognition Center, School of Anthropology, University of Arizona, Tucson, AZ, USA
- Department of Psychology, University of Arizona, Tucson, AZ, USA
- Cognitive Science Program, University of Arizona, Tucson, AZ, USA
- College of Veterinary Medicine, University of Arizona, Tucson, AZ, USA
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6
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Cellular Pathogenesis of Hepatic Encephalopathy: An Update. Biomolecules 2023; 13:biom13020396. [PMID: 36830765 PMCID: PMC9953810 DOI: 10.3390/biom13020396] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/01/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome derived from metabolic disorders due to various liver failures. Clinically, HE is characterized by hyperammonemia, EEG abnormalities, and different degrees of disturbance in sensory, motor, and cognitive functions. The molecular mechanism of HE has not been fully elucidated, although it is generally accepted that HE occurs under the influence of miscellaneous factors, especially the synergistic effect of toxin accumulation and severe metabolism disturbance. This review summarizes the recently discovered cellular mechanisms involved in the pathogenesis of HE. Among the existing hypotheses, ammonia poisoning and the subsequent oxidative/nitrosative stress remain the mainstream theories, and reducing blood ammonia is thus the main strategy for the treatment of HE. Other pathological mechanisms mainly include manganese toxicity, autophagy inhibition, mitochondrial damage, inflammation, and senescence, proposing new avenues for future therapeutic interventions.
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Maiwall R, Bajpai M, Singh A, Agarwal T, Kumar G, Bharadwaj A, Nautiyal N, Tevethia H, Jagdish RK, Vijayaraghavan R, Choudhury A, Mathur RP, Hidam A, Pati NT, Sharma MK, Kumar A, Sarin SK. Standard-Volume Plasma Exchange Improves Outcomes in Patients With Acute Liver Failure: A Randomized Controlled Trial. Clin Gastroenterol Hepatol 2022; 20:e831-e854. [PMID: 33524593 DOI: 10.1016/j.cgh.2021.01.036] [Citation(s) in RCA: 85] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 12/29/2020] [Accepted: 01/24/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND High volume plasma-exchange (HVPE) improves survival in patients with acute liver failure (ALF), but apprehension regarding volume overload and worsening of cerebral edema remain. METHODS In an open-label randomized controlled trial, 40 consecutive patients of ALF were randomized 1:1 to either standard medical treatment (SMT) or SMT with standard-volume plasma-exchange (SVPE). SVPE was performed using centrifugal apheresis [target volume of 1.5 to 2.0 plasma volumes per session] until desired response was achieved. Cerebral edema was assessed by brain imaging. Results were analyzed in an intention-to-treat analysis. Primary outcome was 21-day transplant-free survival. The levels of cytokines, damage-associated molecular patterns (DAMPs) and endotoxins were analyzed at baseline and day 5. RESULTS ALF patients [aged 31.5 ± 12.2 years, 60% male, 78% viral, 83% hyperacute, 70% with SIRS were included. At day 5, SVPE [mean sessions 2.15 ± 1.42, median plasma volume replaced 5.049 L] compared to SMT alone, resulted in higher lactate clearance (p = .02), amelioration of SIRS (84% vs. 26%; P = .02), reduction in ammonia levels [(221.5 ± 96.9) vs.(439 ± 385.6) μg/dl, P = .02) and SOFA scores [9.9(±3.3) vs. 14.6(±4.8); P = .001]. There were no treatment related deaths. SVPE was associated with a higher 21-day transplant free-survival [75% vs. 45%; P = .04, HR 0.30, 95%CI 0.01-0.88]. A significant decrease in levels of pro-inflammatory cytokines and an increase in anti-inflammatory cytokines along with a decrease in endotoxin and DAMPs was seen with SVPE. CONCLUSION In ALF patients with cerebral edema, SVPE is safe and effective and improves survival possibly by a reduction in cytokine storm and ammonia. CLINICALTRIAL gov (identifier: NCT02718079).
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Affiliation(s)
- Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Meenu Bajpai
- Department of Transfusion Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Akanksha Singh
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Tanvi Agarwal
- Department of Clinical and Molecular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Guresh Kumar
- Department of Biostatistics, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ankit Bharadwaj
- Department of Biostatistics, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Nidhi Nautiyal
- Department of Clinical and Molecular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Harsh Tevethia
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rakesh Kumar Jagdish
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rajan Vijayaraghavan
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ashok Choudhury
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | | | - Ashini Hidam
- Department of Clinical and Molecular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Nirupama Trehan Pati
- Department of Clinical and Molecular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Manoj Kumar Sharma
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Anupam Kumar
- Department of Clinical and Molecular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
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Combined PEG3350 Plus Lactulose Results in Early Resolution of Hepatic Encephalopathy and Improved 28-Day Survival in Acute-on-Chronic Liver Failure. J Clin Gastroenterol 2022; 56:e11-e19. [PMID: 33060437 DOI: 10.1097/mcg.0000000000001450] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 09/12/2020] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIMS Acute-on-chronic liver failure (ACLF) is associated with high short-term mortality in those with hepatic encephalopathy (HE). Polyethylene glycol (PEG) 3350 electrolyte solution can ensure rapid gut catharsis, which may resolve HE more effectively than lactulose. In this open-label-randomized trial, we compared PEG+lactulose versus lactulose alone in ACLF with HE grade ≥2 for efficacy and outcome. PATIENTS AND METHODS Patients were randomized to receive PEG (2 L q12 h) followed by lactulose (30 mL q8 h) or standard medical treatment [SMT, lactulose (titrated 30 mL q8 h)]. Endpoints were HE grade improvement at 24 hours, 48 hours, and 7 days using hepatic encephalopathy scoring algorithm (HESA), ammonia reduction, HE resolution, and survival benefit. RESULTS Of 60 patients, 29 were randomized to PEG+lactulose arm and 31 to SMT. In the PEG arm, early reduction in HESA score was noted in more persons [18 (62.1%) vs. 10 (32.2%); P=0.021] with a shorter median time to HE resolution [4.5 (3 to 9) d vs. 9 (8 to 11) d; P=0.023]. On multivariate analysis, age [hazard ratio (HR),1.06 (1.00 to 1.13); P=0.03], HESA score [HR, 6.01 (1.27 to 28.5); P=0.024], and model for end-stage liver disease [HR, 1.26 (1.01 to 1.53); P=0.022] were predictors of mortality at 28 days. Ammonia level or reduction did not correlate with HE grades. Adverse events included excessive diarrhea (20.6% vs. 9.6%) in the PEG and SMT arms, albeit without dyselectrolytemia or worsened renal function. In the PEG versus SMT arm, survival at 28 days were 93.1% versus 67.7% (P=0.010) and at 90 days was 68.9% versus 48.3% (P=0.940), respectively, with fewer persons relapsing with HE in the PEG arm. CONCLUSIONS PEG resulted in early and sustained HE resolution with improved short-term survival making, it a suitable and safe drug in patients with acute HE in ACLF.
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9
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Abstract
Liver failure in the context of acute (ALF) and acute on chronic liver failure (ACLF) is associated with high mortality in the absence of a liver transplant. For decades, therapeutic plasma exchange (TPE) is performed for the management of immune-mediated diseases. TPE has emerged as an attractive extracorporeal blood purification technique in patients with ALF and ACLF. The basic premise of using TPE is to remove the toxic substances which would allow recovery of native liver functions by facilitating liver regeneration. In recent years, encouraging data have emerged, suggesting the benefits of TPE in patients with liver failure. TPE has emerged as an attractive liver support device for the failing liver until liver transplantation or clinical recovery. The data in patients with ALF suggest routine use of high-volume TPE, while the data for such a strategy are less robust for patients with ACLF.
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Affiliation(s)
- Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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10
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Khalil HMA, Eliwa HA, El-Shiekh RA, Al-Mokaddem AK, Hassan M, Tawfek AM, El-Maadawy WH. Ashwagandha (Withania somnifera) root extract attenuates hepatic and cognitive deficits in thioacetamide-induced rat model of hepatic encephalopathy via induction of Nrf2/HO-1 and mitigation of NF-κB/MAPK signaling pathways. JOURNAL OF ETHNOPHARMACOLOGY 2021; 277:114141. [PMID: 33905819 DOI: 10.1016/j.jep.2021.114141] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 03/05/2021] [Accepted: 04/20/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ashwagandha (ASH) is one of the medicinal plants used in traditional Indian, Ayurvedic, and Unani medicines for their broad range of pharmacological activities including, tonic, aphrodisiac, energy stimulant, and counteracting chronic fatigue. Besides, it is used in the treatment of nervous exhaustion, memory-related conditions, insomnia, as well as improving learning ability and memory capacity. ASH is preclinically proven to be efficient in hepatoprotection and improving cognitive impairment, however, its beneficial effects against hepatic encephalopathy (HE) is still unclear. Therefore, this study aimed at investigating the protective effects of ASH root extract against thioacetamide (TAA)-induced HE and delineate the underlying behavioral and pharmacological mechanisms. MATERIALS AND METHODS ASH metabolites were identified using UPLC-HRMS. Rats were pretreated with ASH (200 and 400 mg/kg) for 29 days and administrated TAA (i.p, 350 mg/kg) in a single dose. Then, behavioral (open field test, Y-maze, modified elevated plus maze and novel object recognition test), and biochemical (ammonia and hepatic toxicity indices) assessments, as well as oxidative stress markers (MDA and GSH) were evaluated. The hepatic and brain levels of glutamine synthetase (GS), nuclear factor erythroid 2-related factor 2 (Nrf2), heme-oxygenase (HO)-1, inducible nitric oxide synthase (iNOS) were detected by enzyme-linked immunosorbent assay (ELISA). The mRNA expressions of p38/ERK½ were determined using real-time polymerase chain reaction (PCR). Moreover, histopathological investigations and immunohistochemical (NF-κB and TNF-α immunohistochemical expressions) examinations were performed. RESULTS Metabolite profiling of ASH revealed more than 45 identified metabolites including phenolic acids, flavonoids and steroidal lactone triterpenoids. Compared to the TAA-intoxicated group, ASH improved the locomotor and cognitive deficits, serum hepatotoxicity indices and ammonia levels, as well as brain and hepatic histopathological alterations. ASH reduced hepatic and brain levels of MDA, GS, and iNOS, and increased their GSH, Nrf2, and HO-1 levels. Also, ASH downregulated p38 and ERK½ mRNA expressions, and NF-κB and TNF-α immunohistochemical expressions in brain and hepatic tissues. CONCLUSIONS Our results provided insights into the promising hepato- and neuroprotective effects of ASH, with superiority to 400 mg/kg ASH, to ameliorate HE with its sequential hyperammonemia and liver/brain injuries. This could be attributed to the recorded increase in the spontaneous alternation % and recognition index, antioxidant and anti-inflammatory activities, as well as upregulation of Nrf2 and downregualtion of MAPK signaling pathways.
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Affiliation(s)
- Heba M A Khalil
- Department of Veterinary Hygiene and Management, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt.
| | - Hesham A Eliwa
- Department of Pharmacology and Toxicology, College of Pharmacy and Drug Manufacturing, Misr University of Science and Technology (MUST), 6th October, Giza, 12566, Egypt.
| | - Riham A El-Shiekh
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Kasr El Aini St., Cairo, 11562, Egypt.
| | - Asmaa K Al-Mokaddem
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza Square, Giza, 12211, Egypt.
| | - Marwa Hassan
- Department of Immunology, Theodor Bilharz Research Institute, Kornaish El Nile, Warrak El-Hadar, Imbaba (P.O. 30), Giza, 12411, Egypt.
| | - Azza M Tawfek
- Department of Clinical Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt.
| | - Walaa H El-Maadawy
- Department of Pharmacology, Theodor Bilharz Research Institute, Kornaish El Nile, Warrak El-Hadar, Imbaba (P.O. 30), Giza, 12411, Egypt.
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11
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Häussinger D, Butz M, Schnitzler A, Görg B. Pathomechanisms in hepatic encephalopathy. Biol Chem 2021; 402:1087-1102. [PMID: 34049427 DOI: 10.1515/hsz-2021-0168] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 05/12/2021] [Indexed: 02/06/2023]
Abstract
Hepatic encephalopathy (HE) is a frequent neuropsychiatric complication in patients with acute or chronic liver failure. Symptoms of HE in particular include disturbances of sensory and motor functions and cognition. HE is triggered by heterogeneous factors such as ammonia being a main toxin, benzodiazepines, proinflammatory cytokines and hyponatremia. HE in patients with liver cirrhosis is triggered by a low-grade cerebral edema and cerebral oxidative/nitrosative stress which bring about a number of functionally relevant alterations including posttranslational protein modifications, oxidation of RNA, gene expression changes and senescence. These alterations are suggested to impair astrocyte/neuronal functions and communication. On the system level, a global slowing of oscillatory brain activity and networks can be observed paralleling behavioral perceptual and motor impairments. Moreover, these changes are related to increased cerebral ammonia, alterations in neurometabolite and neurotransmitter concentrations and cortical excitability in HE patients.
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Affiliation(s)
- Dieter Häussinger
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University, Moorenstr. 5, D-40225 Düsseldorf, Germany
| | - Markus Butz
- Department of Neurology/Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich Heine University, Moorenstr. 5, D-40225 Düsseldorf, Germany
| | - Alfons Schnitzler
- Department of Neurology/Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich Heine University, Moorenstr. 5, D-40225 Düsseldorf, Germany
| | - Boris Görg
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University, Moorenstr. 5, D-40225 Düsseldorf, Germany
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12
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Curcumin prevents cognitive deficits in the bile duct ligated rats. Psychopharmacology (Berl) 2020; 237:3529-3537. [PMID: 32761362 DOI: 10.1007/s00213-020-05633-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 07/29/2020] [Indexed: 12/19/2022]
Abstract
RATIONALE Bile duct ligation (BDL) in rodents can cause impaired liver function and cognition deficits. Curcumin has shown a preventive and therapeutic role in memory impairment. OBJECTIVES Therefore, this study aimed to explore the effect of curcumin on the performance of male adult Wistar rats that underwent BDL, a model of hepatic encephalopathy (HE) in the Morris water maze (MWM). METHODS Four weeks after surgery, sham (manipulation of common bile duct without ligation) and BDL rats underwent the MWM test. RESULTS The representative data showed that BDL rats exhibited impairments in spatial learning and reference memory in the MWM compared with the sham rats. Treatment of BDL rats with curcumin (40 mg/kg, i.p., for 4 weeks) prevented these impairments, while it did not affect spatial learning and memory in the sham rats, by itself. Curcumin increased expression levels of the pro-survival B cell lymphoma extra-large (Bcl-xL) gene and two genes involved in mitochondrial function, peroxisome proliferative-activated receptor-γ co-activator 1α (PGC-1α) and mitochondrial transcription factor A (TFAM), in the hippocampus of BDL rats compared with the vehicle-treated sham or BDL rats, while it decreased the pro-apoptotic Bcl-2-associated X protein (Bax) gene expression level. BDL up-regulated Bax and down-regulated TFAM, by itself. Furthermore, curcumin reduced the mRNA level of Bax, while it increased Bcl-2 and TFAM mRNA levels. CONCLUSIONS These findings demonstrate the beneficial effect of curcumin on cognitive function in BDL rats of the HE model. The curcumin effect may be related to mitochondrial function improvement in the HE.
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13
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El-Latif El-Ghazaly MA, Rashed ER, Shafey GM, Zaki HF, Attia AS. Amelioration of thioacetamide-induced hepatic encephalopathy in rats by low-dose gamma irradiation. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2020; 27:334-343. [PMID: 31786756 DOI: 10.1007/s11356-019-06934-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 10/31/2019] [Indexed: 06/10/2023]
Abstract
Brain affection is a common symptom of liver insufficiency. This study aimed to evaluate the role of low-dose γ irradiation (LDR) as a potential therapeutic agent in thioacetamide (TAA)-induced hepatic encephalopathy (HE) in rats. Effects of local and whole-body irradiation (0.5 Gy) on rat brain/liver were evaluated following the induction of HE by TAA (200 mg/kg/day/for 3 successive days). Serum activities of aspartate transaminase (AST) and alanine transaminase (ALT) and ammonia level were assessed. The effect of HE on brain was evaluated through the determination of brain contents of malondialdehyde (MDA), reduced glutathione (GSH), tumor necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1β) and glutathione peroxidase (GPx) activity. Moreover, apoptotic and inflammatory changes in brain and liver tissues were assessed together with alpha-smooth muscle actin (α-SMA); fibrosis marker. Results showed correction of the biochemical parameters which was supported by the results of the immunohistochemical examinations. LDR is a promising hepato- and neurotherapy against HE.
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Affiliation(s)
- Mona Abd El-Latif El-Ghazaly
- Drug Radiation Research Department, National Centre for Radiation Research and Technology, Atomic Energy Authority, PO box 29, Nasr City, Cairo, 11787, Egypt
| | - Engy Refaat Rashed
- Drug Radiation Research Department, National Centre for Radiation Research and Technology, Atomic Energy Authority, PO box 29, Nasr City, Cairo, 11787, Egypt
| | - Ghada Mahmoud Shafey
- Drug Radiation Research Department, National Centre for Radiation Research and Technology, Atomic Energy Authority, PO box 29, Nasr City, Cairo, 11787, Egypt.
| | - Hala Fahmy Zaki
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Amina Salem Attia
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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14
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Seetharam A. Intensive Care Management of Acute Liver Failure: Considerations While Awaiting Liver Transplantation. J Clin Transl Hepatol 2019; 7:384-391. [PMID: 31915608 PMCID: PMC6943205 DOI: 10.14218/jcth.2019.00032] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 10/06/2019] [Accepted: 10/27/2019] [Indexed: 12/15/2022] Open
Abstract
Acute liver failure is a unique clinical phenomenon characterized by abrupt deterioration in liver function and altered mentation. The development of high-grade encephalopathy and multisystem organ dysfunction herald poor prognosis. Etiologic-specific treatments and supportive measures are routinely employed; however, liver transplantation remains the only chance for cure in those who do not spontaneously recover. The utility of artificial and bioartificial assist therapies as supportive care-to allow time for hepatic recovery or as a bridge to liver transplantation-has been examined but studies have been small, with mixed results. Given the severity of derangements, intensive critical care is needed to successfully bridge patients to transplant, and evaluation of candidates occurs rapidly in parallel with serial reassessments of operative fitness. Psychosocial assessment is often suboptimal and relative contraindications to transplant, such as ventilator-dependence may be overlooked. While often employed to guide evaluation, no single prognostic model discriminates those who will spontaneously recover and those who will require transplant. The purpose of this review will be to summarize approaches in critical care, prognostic modeling, and medical evaluation of the acute liver failure transplant candidate.
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Affiliation(s)
- Anil Seetharam
- Correspondence to: Anil Seetharam, Banner Transplant and Advanced Liver Disease, University of Arizona College of Medicine, 441 N. 12th Street, 2nd Floor, Phoenix, AZ 85006, USA. Tel: +1-602-521-5800; Fax: +1-602-521-5337, E-mail:
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15
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Eid T, Lee TSW, Patrylo P, Zaveri HP. Astrocytes and Glutamine Synthetase in Epileptogenesis. J Neurosci Res 2019; 97:1345-1362. [PMID: 30022509 PMCID: PMC6338538 DOI: 10.1002/jnr.24267] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 05/15/2018] [Accepted: 05/22/2018] [Indexed: 12/31/2022]
Abstract
The cellular, molecular, and metabolic mechanisms that underlie the development of mesial temporal lobe epilepsy are incompletely understood. Here we review the role of astrocytes in epilepsy development (a.k.a. epileptogenesis), particularly astrocyte pathologies related to: aquaporin 4, the inwardly rectifying potassium channel Kir4.1, monocarboxylate transporters MCT1 and MCT2, excitatory amino acid transporters EAAT1 and EAAT2, and glutamine synthetase. We propose that inhibition, dysfunction or loss of astrocytic glutamine synthetase is an important causative factor for some epilepsies, particularly mesial temporal lobe epilepsy and glioblastoma-associated epilepsy. We postulate that the regulatory mechanisms of glutamine synthetase as well as the downstream effects of glutamine synthetase dysfunction, represent attractive, new targets for antiepileptogenic interventions. Currently, no antiepileptogenic therapies are available for human use. The discovery of such interventions is important as it will fundamentally change the way we approach epilepsy by preventing the disease from ever becoming manifest after an epileptogenic insult to the brain.
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Affiliation(s)
- Tore Eid
- Department of Laboratory Medicine, Yale School of Medicine
- Department of Molecular Medicine, University of Oslo
| | | | - Peter Patrylo
- Department of Physiology, Southern Illinois University School of Medicine
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16
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Cudalbu C, Taylor-Robinson SD. Brain Edema in Chronic Hepatic Encephalopathy. J Clin Exp Hepatol 2019; 9:362-382. [PMID: 31360029 PMCID: PMC6637228 DOI: 10.1016/j.jceh.2019.02.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 01/15/2019] [Accepted: 02/06/2019] [Indexed: 02/07/2023] Open
Abstract
Brain edema is a common feature associated with hepatic encephalopathy (HE). In patients with acute HE, brain edema has been shown to play a crucial role in the associated neurological deterioration. In chronic HE, advanced magnetic resonance imaging (MRI) techniques have demonstrated that low-grade brain edema appears also to be an important pathological feature. This review explores the different methods used to measure brain edema ex vivo and in vivo in animal models and in humans with chronic HE. In addition, an in-depth description of the main studies performed to date is provided. The role of brain edema in the neurological alterations linked to HE and whether HE and brain edema are the manifestations of the same pathophysiological mechanism or two different cerebral manifestations of brain dysfunction in liver disease are still under debate. In vivo MRI/magnetic resonance spectroscopy studies have allowed insight into the development of brain edema in chronic HE. However, additional in vivo longitudinal and multiparametric/multimodal studies are required (in humans and animal models) to elucidate the relationship between liver function, brain metabolic changes, cellular changes, cell swelling, and neurological manifestations in chronic HE.
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Key Words
- 1H MRS, proton magnetic resonance spectroscopy
- ADC, apparent diffusion coefficient
- ALF, acute liver failure
- AQP, aquaporins
- BBB, blood-brain barrier
- BDL, bile duct ligation
- CNS, central nervous system
- CSF, cerebrospinal fluid
- Cr, creatine
- DTI, diffusion tensor imaging
- DWI, diffusion-weighted imaging
- FLAIR, fluid-attenuated inversion recovery
- GM, gray matter
- Gln, glutamine
- Glx, sum of glutamine and glutamate
- HE, hepatic encephalopathy
- Ins, inositol
- LPS, lipopolysaccharide
- Lac, lactate
- MD, mean diffusivity
- MRI, magnetic resonance imaging
- MRS, magnetic resonance spectroscopy
- MT, magnetization transfer
- MTR, MT ratio
- NMR, nuclear magnetic resonance
- PCA, portocaval anastomosis
- TE, echo time
- WM, white matter
- brain edema
- chronic hepatic encephalopathy
- in vivo magnetic resonance imaging
- in vivo magnetic resonance spectroscopy
- liver cirrhosis
- mIns, myo-inositol
- tCho, total choline
- tCr, total creatine
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Affiliation(s)
- Cristina Cudalbu
- Centre d'Imagerie Biomedicale (CIBM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Simon D. Taylor-Robinson
- Division of Integrative Systems Medicine and Digestive Disease, Department of Surgery and Cancer, St Mary's Hospital Campus, Imperial College London, London, United Kingdom
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17
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Lima LCD, Miranda AS, Ferreira RN, Rachid MA, Simões E Silva AC. Hepatic encephalopathy: Lessons from preclinical studies. World J Hepatol 2019; 11:173-185. [PMID: 30820267 PMCID: PMC6393717 DOI: 10.4254/wjh.v11.i2.173] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 11/19/2018] [Accepted: 01/28/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a major complication that is closely related to the progression of end-stage liver disease. Metabolic changes in advanced liver failure can promote cognition impairment, attention deficits and motor dysfunction that may result in coma and death. HE can be subdivided according to the type of hepatic injury, namely, type A, which results from acute liver failure, type B, which is associated with a portosystemic shunting without intrinsic liver disease, and type C, which is due to chronic liver disease. Several studies have investigated the pathogenesis of the disease, and most of the mechanisms have been explored using animal models. This article aimed to review the use of preclinical models to investigate HE. The most used animal species are rats and mice. Experimental models of type A HE include surgical procedures and the administration of hepatotoxic medications, whereas models of types B and C HE are generally surgically induced lesions in liver tissue, which evolve to hepatic cirrhosis. Preclinical models have allowed the comprehension of the pathways related to HE.
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Affiliation(s)
- Luiza Cioglia Dias Lima
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais 31270-901, Brasil
| | - Aline Silva Miranda
- Departamento de Morfologia, Instituto de Ciências Biológicas, UFMG, Belo Horizonte, Minas Gerais 30130-100, Brasil
| | - Rodrigo Novaes Ferreira
- Departamento de Morfologia, Instituto de Ciências Biológicas, UFMG, Belo Horizonte, Minas Gerais 30130-100, Brasil
| | - Milene Alvarenga Rachid
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais 31270-901, Brasil
| | - Ana Cristina Simões E Silva
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, UFMG, Belo Horizonte, Minas Gerais 30130-100, Brasil.
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18
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Affiliation(s)
| | - Radha K. Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
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19
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Jayakumar A, Norenberg MD. Hyperammonemia in Hepatic Encephalopathy. J Clin Exp Hepatol 2018; 8:272-280. [PMID: 30302044 PMCID: PMC6175739 DOI: 10.1016/j.jceh.2018.06.007] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 06/10/2018] [Indexed: 12/12/2022] Open
Abstract
The precise mechanism underlying the neurotoxicity of Hepatic Encephalopathy (HE) is remains unclear. The dominant view has been that gut-derived nitrogenous toxins are not extracted by the diseased liver and thereby enter the brain. Among the various toxins proposed, the case for ammonia is most compelling. Events that lead to increased levels of blood or brain ammonia have been shown to worsen HE, whereas reducing blood ammonia levels alleviates HE. Clinical, pathological, and biochemical changes observed in HE can be reproduced by increasing blood or brain ammonia levels in experimental animals, while exposure of cultured astrocytes to ammonium salts reproduces the morphological and biochemical findings observed in HE. However, factors other than ammonia have recently been proposed to be involved in the development of HE, including cytokines and other blood and brain immune factors. Moreover, recent studies have questioned the critical role of ammonia in the pathogenesis of HE since blood ammonia levels do not always correlate with the level/severity of encephalopathy. This review summarizes the vital role of ammonia in the pathogenesis of HE in humans, as well as in experimental models of acute and chronic liver failure. It further emphasizes recent advances in the molecular mechanisms involved in the progression of neurological complications that occur in acute and chronic liver failure.
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Key Words
- AHE, Acute Hepatic Encephalopathy
- ALF, Acute Liver Failure
- CHE, Chronic Hepatic Encephalopathy
- CNS, Central Nervous System
- CSF, Cerebrospinal Fluid
- ECs, Endothelial Cells
- HE, Hepatic Encephalopathy
- IL, Interleukin
- LPS, Lipopolysaccharide
- MAPKs, Mitogen-Activated Protein Kinases
- NCX, Sodium-Calcium Exchanger
- NF-κB, Nuclear Factor-kappaB
- NHE, Sodium/Hydrogen Exchanger-1 or SLC9A1 (SoLute Carrier Family 9A1)
- SUR1, The Sulfonylurea Receptor 1
- TDP-43 and tau proteinopathies
- TDP-43, TAR DNA-Binding Protein, 43 kDa
- TLR, Toll-like Receptor
- TNF-α, Tumor Necrosis Factor-Alpha
- TSP-1, Thrombospondin-1
- ammonia
- hepatic encephalopathy
- inflammation
- matricellular proteins
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Affiliation(s)
- A.R. Jayakumar
- General Medical Research, Neuropathology Section, R&D Service, Veterans Affairs Medical Center, Miami, FL 33125, United States
- South Florida VA Foundation for Research and Education Inc., Veterans Affairs Medical Center, Miami, FL 33125, United States
| | - Michael D. Norenberg
- Department of Pathology, University of Miami School of Medicine, Miami, FL 33125, United States
- Department of Biochemistry & Molecular Biology, University of Miami School of Medicine, Miami, FL 33125, United States
- Department of Neurology and Neurological Surgery, University of Miami School of Medicine, Miami, FL 33125, United States
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20
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Mastropietro CW, Valentine KM. Medical Management of Acute Liver Failure. PEDIATRIC CRITICAL CARE 2018. [PMCID: PMC7121299 DOI: 10.1007/978-3-319-96499-7_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Pediatric acute liver failure is a rapidly progressive, life-threatening, and devastating illness in children without preexisting liver disease. Due to the rarity and heterogeneity of this syndrome, there is a significant lack of data to guide evaluation and management of this disease. Most of our practice is extrapolated from adult literature and guidelines. This leads to significant controversies in medical management of acute liver failure in children. With advances in critical care, there has been a tremendous improvement in outcomes with decreased morbidity and mortality; however, there is a dire need for more research in this field. This chapter discusses challenges as well as controversies in diagnostic evaluation and management of this rare but potentially fatal disease. Latest developments in supportive care of liver failure, including advances in the area of liver support systems, are also discussed.
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Affiliation(s)
- Christopher W. Mastropietro
- grid.257413.60000 0001 2287 3919Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN USA
| | - Kevin M. Valentine
- grid.257413.60000 0001 2287 3919Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN USA
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21
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Chong LW, Hsu CC, Lee CY, Chou RH, Lin CL, Chang KH, Hsu YC. Association of viral hepatitis and bipolar disorder: a nationwide population-based study. J Transl Med 2018; 16:173. [PMID: 29929549 PMCID: PMC6013873 DOI: 10.1186/s12967-018-1542-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 06/07/2018] [Indexed: 12/14/2022] Open
Abstract
Background Bipolar disorder (BD), a type of psychiatric mood disorder, is manifested by chronic and recurrent mood fluctuations. This study aims to determine whether hepatitis B virus (HBV) or hepatitis C virus (HCV) infection is a risk factor for BD. Methods A total of 48,215 patients with newly diagnosed viral hepatitis from 2000 to 2010 were identified and frequency-matched with 192,860 people without hepatitis. Both groups were followed until diagnosis with BD, withdrawal from the national health insurance program, or the end of 2011. Patients with viral hepatitis were grouped into 3 cohorts: HBV infection, HCV infection, and HBV/HCV coinfection. The association between viral hepatitis and BD were examined using Cox proportional hazards regression models. Results The incidence of BD was higher in HBV/HCV coinfection than in the control group, with an adjusted hazard ratio of 2.16 (95% confidence interval 1.06–4.41) when adjusted for sex, age, and comorbidity. After further adjustment, we noted that an age more than 65 years and female may be associated with an increased risk of BD in patients with chronic hepatitis B and C. Conclusion Viral hepatitis may be associated with increased risk of subsequent BD. Electronic supplementary material The online version of this article (10.1186/s12967-018-1542-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lee-Won Chong
- Division of Hepatology and Gastroenterology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.,School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
| | - Chih-Chao Hsu
- Division of Psychiatry, Taitung Branch, Taipei Veterans General Hospital, Taitung, Taiwan
| | - Chang-Yin Lee
- College of Medicine, The School of Chinese Medicine for Post Baccalaureate, I-Shou University (Yancho Campus), Kaohsiung, Taiwan.,Department of Chinese Medicine, E-DA Hospital, Kaohsiung, Taiwan.,Department of Chinese Medicine, E-DA Cancer Hospital, Kaohsiung, Taiwan
| | - Ruey-Hwang Chou
- Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.,Department of Biotechnology, Asia University, Taichung, Taiwan
| | - Cheng-Li Lin
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Kuang-Hsi Chang
- Department of Medical Research, Tungs' Taichung Metroharbor Hospital, Taichung, Taiwan. .,Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
| | - Yi-Chao Hsu
- Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan.
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22
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Abstract
Purpose of Review Pediatric acute liver failure is a rare, complex, rapidly progressing, and life-threatening illness. Majority of pediatric acute liver failures have unknown etiology. This review intends to discuss the current literature on the challenging aspects of management of acute liver failure. Recent Findings Collaborative multidisciplinary approach for management of patients with pediatric acute liver failure with upfront involvement of transplant hepatologist and critical care specialists can improve outcomes of this fatal disease. Extensive but systematic diagnostic evaluation can help to identify etiology and guide management. Early referral to a transplant center with prompt liver transplant, if indicated, can lead to improved survival in these patients. Summary Prompt identification and aggressive management of pediatric acute liver failure and related comorbidities can lead to increased transplant-free survival and improved post-transplant outcomes, thus decreasing mortality and morbidity associated with this potential fatal condition.
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Affiliation(s)
- Heli Bhatt
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Riley Hospital for Children, Indiana University School of Medicine, Indiana University, 705 Riley Hospital Drive, ROC 4210, Indianapolis, IN 46202 USA
| | - Girish S. Rao
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Riley Hospital for Children, Indiana University School of Medicine, Indiana University, 705 Riley Hospital Drive, ROC 4210, Indianapolis, IN 46202 USA
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23
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Linecker M, Krones T, Berg T, Niemann CU, Steadman RH, Dutkowski P, Clavien PA, Busuttil RW, Truog RD, Petrowsky H. Potentially inappropriate liver transplantation in the era of the "sickest first" policy - A search for the upper limits. J Hepatol 2018; 68:798-813. [PMID: 29133246 DOI: 10.1016/j.jhep.2017.11.008] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 10/11/2017] [Accepted: 11/06/2017] [Indexed: 12/11/2022]
Abstract
Liver transplantation has emerged as a highly efficient treatment for a variety of acute and chronic liver diseases. However, organ shortage is becoming an increasing problem globally, limiting the applicability of liver transplantation. In addition, potential recipients are becoming sicker, thereby increasing the risk of losing the graft during transplantation or in the initial postoperative period after liver transplantation (three months). This trend is challenging the model for end-stage liver disease allocation system, where the sickest candidates are prioritised and no delisting criteria are given. The weighting of the deontological demand for "equity", trying to save every patient, regardless of the overall utility; and "efficiency", rooted in utilitarianism, trying to save as many patients as possible and increase the overall quality of life of patients facing the same problem, has to be reconsidered. In this article we are aiming to overcome the widespread concept of futility in liver transplantation, providing a definition of potentially inappropriate liver transplantation and giving guidance on situations where it is best not to proceed with liver transplantation, to decrease the mortality rate in the first three months after transplantation. We propose "absolute" and "relative" conditions, where early post-transplant mortality is highly probable, which are not usually captured in risk scores predicting post-transplant survival. Withholding liver transplantation for listed patients in cases where liver transplant is not deemed clearly futile, but is potentially inappropriate, is a far-reaching decision. Until now, this decision had to be discussed extensively on an individual basis, applying explicit communication and conflict resolution processes, since the model for end-stage liver disease score and most international allocation systems do not include explicit delisting criteria to support a fair delisting process. More work is needed to better identify cases where transplantation is potentially inappropriate and to integrate and discuss these delisting criteria in allocation systems, following a societal debate on what we owe to all liver transplant candidates.
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Affiliation(s)
- Michael Linecker
- Swiss HPB and Transplantation Center, University Hospital Zurich, Switzerland; Department of Surgery and Transplantation, University Hospital Zurich, Switzerland
| | - Tanja Krones
- Division of Clinical Ethics, University Hospital Zurich, Switzerland; Institute of Biomedical Ethics and History of Medicine, University of Zurich, Switzerland
| | - Thomas Berg
- Division of Hepatology, University of Leipzig, Germany
| | - Claus U Niemann
- Department of Anesthesiology, University of California, San Francisco, USA; Department of Surgery, University of California San Francisco, USA
| | - Randolph H Steadman
- Department of Anesthesiology and Perioperative Medicine, Ronald Reagan Medical Center, University of California Los Angeles, Los Angeles, USA
| | - Philipp Dutkowski
- Swiss HPB and Transplantation Center, University Hospital Zurich, Switzerland; Department of Surgery and Transplantation, University Hospital Zurich, Switzerland
| | - Pierre-Alain Clavien
- Swiss HPB and Transplantation Center, University Hospital Zurich, Switzerland; Department of Surgery and Transplantation, University Hospital Zurich, Switzerland
| | - Ronald W Busuttil
- Dumont-UCLA Transplant Center, Ronald Reagan Medical Center, University of California Los Angeles, USA
| | - Robert D Truog
- Center for Bioethics, Harvard Medical School, Boston, USA; Department of Anesthesia, Perioperative and Pain Medicine, Boston Children's Hospital, USA
| | - Henrik Petrowsky
- Swiss HPB and Transplantation Center, University Hospital Zurich, Switzerland; Department of Surgery and Transplantation, University Hospital Zurich, Switzerland.
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24
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Miah MK, Bickel U, Mehvar R. Effects of hepatic ischemia-reperfusion injury on the blood-brain barrier permeability to [ 14C] and [ 13C]sucrose. Metab Brain Dis 2017; 32:1903-1912. [PMID: 28779418 DOI: 10.1007/s11011-017-0069-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 07/11/2017] [Indexed: 01/28/2023]
Abstract
Hepatic encephalopathy that is associated with severe liver failure may compromise the blood-brain barrier (BBB) integrity. However, the effects of less severe liver diseases, in the absence of overt encephalopathy, on the BBB are not well understood. The goal of the current study was to investigate the effects of hepatic ischemia-reperfusion (IR) injury on the BBB tight junction permeability to small, hydrophilic molecules using the widely used [14C]sucrose and recently-proposed alternative [13C]sucrose as markers. Rats were subjected to 20 min of hepatic ischemia or sham surgery, followed by 8 h of reperfusion before administration of a single bolus dose of [14C] or [13C]sucrose and collection of serial (0-30 min) blood and plasma and terminal brain samples. The concentrations of [14C] and [13C]sucrose in the samples were determined by measurement of total radioactivity (nonspecific) and LC-MS/MS (specific), respectively. IR injury significantly increased the blood, plasma, and brain concentrations of both [14C] and [13C]sucrose. However, when the brain concentrations were corrected for their respective area under the blood concentration-time curve, only [14C]sucrose showed significantly higher (30%) BBB permeability values in the IR animals. Because [13C]sucrose is a more specific BBB permeability marker, these data indicate that our animal model of hepatic IR injury does not affect the BBB tight junction permeability to small, hydrophilic molecules. Methodological differences among studies of the effects of liver diseases on the BBB permeability may confound the conclusions of such studies.
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Affiliation(s)
- Mohammad K Miah
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
- School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ulrich Bickel
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
- Center for Blood-Brain Barrier Research, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
| | - Reza Mehvar
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
- Center for Blood-Brain Barrier Research, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
- Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, 9401 Jeronimo Road, Irvine, CA, USA.
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Silva VR, Secolin R, Vemuganti R, Lopes-Cendes I, Hazell AS. Acute liver failure is associated with altered cerebral expression profiles of long non-coding RNAs. Neurosci Lett 2017. [PMID: 28648459 DOI: 10.1016/j.neulet.2017.06.038] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Hepatic encephalopathy (HE) represents a serious complication of acute liver failure (ALF) in which cerebral edema leading to brainstem herniation as a result of increased intracranial hypertension is a major consequence. Long non-coding RNAs (lncRNAs) play a significant role in coordinating gene expression, with recent studies indicating an influence in the pathogenesis of several diseases. To investigate their involvement in the cerebral pathophysiology of ALF, we profiled the expression of lncRNAs in the frontal cortex of mice at coma stage following treatment with the hepatotoxin azoxymethane. Of the 35,923 lncRNAs profiled using microarrays, 868 transcripts were found to be differentially expressed in the ALF-treated group compared to the sham control group. Of these, 382 lncRNAs were upregulated and 486 lncRNAs downregulated. Pathway analysis revealed these lncRNAs target a number of biological and molecular pathways that include cytokine-cytokine receptor interaction, the mitogen activated protein kinase signaling pathway, the insulin signaling pathway, and the nuclear factor-κB signaling pathway. False discovery rate adjustment identified 9 upregulated lncRNAs, 2 of which are associated with neuroepithelial transforming gene 1 (NET1) and the monocarboxylate transporter 2 (Slc16a7), potential contributors to astrocyte cytoskeletal disruption/swelling and lactate production, respectively. Our findings suggest an important role for lncRNAs in the brain in ALF in relation to inflammation, neuropathology, and in terms of the functional basis of HE. Further work on these non-coding RNAs may lead to new therapeutic approaches for the treatment and management of cerebral dysfunction resulting from this potentially life-threatening disorder.
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Affiliation(s)
- Vinícius R Silva
- Programa de Postgrado en Fisiopatología Médica, University of Campinas-UNICAMP, Campinas, SP, Brazil
| | - Rodrigo Secolin
- Programa de Postgrado en Fisiopatología Médica, University of Campinas-UNICAMP, Campinas, SP, Brazil; Department of Medical Genetics, University of Campinas-UNICAMP, Campinas, SP, Brazil
| | - Raghu Vemuganti
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA
| | - Iscia Lopes-Cendes
- Programa de Postgrado en Fisiopatología Médica, University of Campinas-UNICAMP, Campinas, SP, Brazil; Department of Medical Genetics, University of Campinas-UNICAMP, Campinas, SP, Brazil
| | - Alan S Hazell
- Programa de Postgrado en Fisiopatología Médica, University of Campinas-UNICAMP, Campinas, SP, Brazil; Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
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Abstract
Pediatric acute liver failure is rare but life-threatening illness that occurs in children without preexisting liver disease. The rarity of the disease, along with its severity and heterogeneity, presents unique clinical challenges to the physicians providing care for pediatric patients with acute liver failure. In this review, practical clinical approaches to the care of critically ill children with acute liver failure are discussed with an organ system-specific approach. The underlying pathophysiological processes, major areas of uncertainty, and approaches to the critical care management of pediatric acute liver failure are also reviewed.
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Donnelly MC, Hayes PC, Simpson KJ. Role of inflammation and infection in the pathogenesis of human acute liver failure: Clinical implications for monitoring and therapy. World J Gastroenterol 2016; 22:5958-5970. [PMID: 27468190 PMCID: PMC4948263 DOI: 10.3748/wjg.v22.i26.5958] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 05/25/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Acute liver failure is a rare and devastating clinical condition. At present, emergency liver transplantation is the only life-saving therapy in advanced cases, yet the feasibility of transplantation is affected by the presence of systemic inflammation, infection and resultant multi-organ failure. The importance of immune dysregulation and acquisition of infection in the pathogenesis of acute liver failure and its associated complications is now recognised. In this review we discuss current thinking regarding the role of infection and inflammation in the pathogenesis of and outcome in human acute liver failure, the implications for the management of such patients and suggest directions for future research.
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