49 results on '"Jalan R"'
Search Results
2. The "Alter Ego" of Albumin in Cirrhosis.
- Author
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Mehta G and Jalan R
- Subjects
- Albumins, Humans, Ego, Liver Cirrhosis
- Published
- 2021
- Full Text
- View/download PDF
3. A Call for Randomization in Clinical Trials of Liver Machine Perfusion Preservation.
- Author
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Martins PN, Clavien PA, Jalan R, and Ghinolfi D
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- Clinical Trials as Topic methods, Clinical Trials as Topic standards, Humans, Postoperative Complications diagnosis, Postoperative Complications etiology, Postoperative Complications prevention & control, Quality Improvement, Random Allocation, Risk Adjustment methods, Risk Adjustment organization & administration, Tissue and Organ Harvesting methods, End Stage Liver Disease surgery, Graft Survival, Liver Transplantation adverse effects, Liver Transplantation instrumentation, Liver Transplantation methods, Organ Preservation adverse effects, Organ Preservation methods, Perfusion instrumentation, Perfusion methods
- Published
- 2021
- Full Text
- View/download PDF
4. Acute on Chronic Liver Failure From Nonalcoholic Fatty Liver Disease: A Growing and Aging Cohort With Rising Mortality.
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Sundaram V, Jalan R, Shah P, Singal AK, Patel AA, Wu T, Noureddin M, Mahmud N, and Wong RJ
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- Acute-On-Chronic Liver Failure epidemiology, Acute-On-Chronic Liver Failure mortality, Adolescent, Adult, Age Factors, Aged, Female, Humans, Male, Middle Aged, Non-alcoholic Fatty Liver Disease epidemiology, Non-alcoholic Fatty Liver Disease mortality, Proportional Hazards Models, Risk Factors, United States epidemiology, Waiting Lists, Young Adult, Acute-On-Chronic Liver Failure etiology, Non-alcoholic Fatty Liver Disease complications
- Abstract
Background and Aims: We assessed the burden of nonalcoholic fatty liver disease (NAFLD)-related acute on chronic liver failure (ACLF) among transplant candidates in the United States, along with waitlist outcomes for this population., Approach and Results: We analyzed the United Network for Organ Sharing registry from 2005 to 2017. Patients with ACLF were identified using the European Association for the Study of the Liver/Chronic Liver Failure criteria and categorized into NAFLD, alcohol-associated liver disease (ALD), and hepatitis C virus (HCV) infection. We used linear regression and Chow's test to determine significance in trends and evaluated waitlist outcomes using Fine and Gray's competing risks regression and Cox proportional hazards regression. Between 2005 and 2017, waitlist registrants for NAFLD-ACLF rose by 331.6% from 134 to 574 candidates (P < 0.001), representing the largest percentage increase in the study population. ALD-ACLF also increased by 206.3% (348-1,066 registrants; P < 0.001), whereas HCV-ACLF declined by 45.2% (P < 0.001). As of 2017, the NAFLD-ACLF population consisted primarily of persons aged ≥60 years (54.1%), and linear regression demonstrated a significant rise in the proportion of patients aged ≥65 in this group (β = 0.90; P = 0.011). Since 2014, NAFLD-ACLF grade 1 was associated with a greater risk of waitlist mortality relative to ALD-ACLF (subhazard ratio [SHR] = 1.24; 95% confidence interval [CI], 1.05-1.44) and HCV-ACLF (SHR = 1.35; 95% CI, 1.08-1.71), among patients aged ≥60 years. Mortality was similar among the three groups for patients with ACLF grade 2 or 3., Conclusions: NAFLD is the fastest rising etiology of cirrhosis associated with ACLF among patients listed in the United States. As the NAFLD population continues to grow and age, patients with NAFLD-ACLF will likely have the highest risk of waitlist mortality., (© 2020 by the American Association for the Study of Liver Diseases.)
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- 2021
- Full Text
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5. Ammonia Scavenging Prevents Progression of Fibrosis in Experimental Nonalcoholic Fatty Liver Disease.
- Author
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De Chiara F, Thomsen KL, Habtesion A, Jones H, Davies N, Gracia-Sancho J, Manicardi N, Hall A, Andreola F, Paish HL, Reed LH, Watson AA, Leslie J, Oakley F, Rombouts K, Mookerjee RP, Mann J, and Jalan R
- Subjects
- Animals, Cells, Cultured, Disease Models, Animal, Disease Progression, Female, Humans, Male, Non-alcoholic Fatty Liver Disease metabolism, Rats, Rats, Sprague-Dawley, Urea Cycle Disorders, Inborn etiology, Ammonia metabolism, Liver Cirrhosis prevention & control, Non-alcoholic Fatty Liver Disease complications
- Abstract
Background and Aims: In nonalcoholic fatty liver disease (NAFLD), fibrosis is the most important factor contributing to NAFLD-associated morbidity and mortality. Prevention of progression and reduction in fibrosis are the main aims of treatment. Even in early stages of NAFLD, hepatic and systemic hyperammonemia is evident. This is due to reduced urea synthesis; and as ammonia is known to activate hepatic stellate cells, we hypothesized that ammonia may be involved in the progression of fibrosis in NAFLD., Approach and Results: In a high-fat, high-cholesterol diet-induced rodent model of NAFLD, we observed a progressive stepwise reduction in the expression and activity of urea cycle enzymes resulting in hyperammonemia, evidence of hepatic stellate cell activation, and progressive fibrosis. In primary, cultured hepatocytes and precision-cut liver slices we demonstrated increased gene expression of profibrogenic markers after lipid and/or ammonia exposure. Lowering of ammonia with the ammonia scavenger ornithine phenylacetate prevented hepatocyte cell death and significantly reduced the development of fibrosis both in vitro in the liver slices and in vivo in a rodent model. The prevention of fibrosis in the rodent model was associated with restoration of urea cycle enzyme activity and function, reduced hepatic ammonia, and markers of inflammation., Conclusions: The results of this study suggest that hepatic steatosis results in hyperammonemia, which is associated with progression of hepatic fibrosis. Reduction of ammonia levels prevented progression of fibrosis, providing a potential treatment for NAFLD., (© 2019 by the American Association for the Study of Liver Diseases.)
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- 2020
- Full Text
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6. Prognostic Role of Ammonia in Patients With Cirrhosis.
- Author
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Shalimar, Sheikh MF, Mookerjee RP, Agarwal B, Acharya SK, and Jalan R
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- Adult, Biomarkers blood, Biopsy, Needle, Case-Control Studies, Cohort Studies, Female, Hospitals, University, Humans, Immunohistochemistry, India, Kaplan-Meier Estimate, Liver Cirrhosis mortality, Liver Failure, Acute mortality, Liver Failure, Acute pathology, Male, Middle Aged, Multivariate Analysis, Prognosis, Retrospective Studies, Risk Assessment, Role, Severity of Illness Index, Statistics, Nonparametric, Survival Analysis, United Kingdom, Ammonia blood, Liver Cirrhosis blood, Liver Cirrhosis pathology, Liver Failure, Acute blood
- Abstract
Ammonia is thought to be central to the pathogenesis of hepatic encephalopathy (HE), but its prognostic role in patients with cirrhosis and acute decompensation is unknown. The aims of this study were to determine the relationship between ammonia levels and severity of HE and its association with organ dysfunction and short-term mortality. We identified 498 patients from two institutions as part of prospective observational studies in patients with cirrhosis. Plasma ammonia levels were measured on admission and Chronic Liver Failure-Sequential Organ Failure Assessment criteria were used to determine the presence of organ failures. The 28-day patient survival was determined. Receiver operating characteristic analysis was used to identify the cutoff points for ammonia values, and multivariable analysis was performed using the Cox proportional hazard regression model. The 28-day mortality was 43.4%. Plasma ammonia correlated with severity of HE (P < 0.001), was significantly higher in nonsurvivors (93 [73-121] versus 67 [55-89] µmol/L, P < 0.001), and was an independent predictor of 28-day mortality (hazard ratio, 1.009, P < 0.001). An ammonia level of 79.5 µmol/L had sensitivity of 68.1% and specificity of 67.4% for predicting 28-day mortality. An ammonia level of ≥79.5 µmol/L was associated with a higher frequency of organ failures (liver [P = 0.004], coagulation [P < 0.001], kidney [P = 0.004], and respiratory [P < 0.001]). Lack of improvement in baseline ammonia at day 5 was associated with high mortality (70.6%). Conclusion: Ammonia level correlates with not only the severity of HE but also the failure of other organs and is an independent risk factor for mortality; lack of improvement in ammonia level is associated with high risk of death, making it an important biomarker and a therapeutic target., (© 2019 by the American Association for the Study of Liver Diseases.)
- Published
- 2019
- Full Text
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7. Reply.
- Author
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Shalimar, Sheikh MF, Mookerjee RP, Agarwal B, Acharya SK, and Jalan R
- Subjects
- Humans, Prognosis, Ammonia, Liver Cirrhosis
- Published
- 2019
- Full Text
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8. Patients With Acute on Chronic Liver Failure Grade 3 Have Greater 14-Day Waitlist Mortality Than Status-1a Patients.
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Sundaram V, Shah P, Wong RJ, Karvellas CJ, Fortune BE, Mahmud N, Kuo A, and Jalan R
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Severity of Illness Index, United States epidemiology, Acute-On-Chronic Liver Failure mortality, Registries, Waiting Lists mortality
- Abstract
Patients listed for liver transplantation (LT) as status 1a currently receive the highest priority on the waiting list. The presence of acute on chronic liver failure (ACLF) with three or more organs failing (ACLF-3) portends low survival without transplantation, which may not be reflected by the Model for End-Stage Liver Disease-Sodium (MELD-Na) score. We compared short-term waitlist mortality for patients listed status 1a and those with ACLF-3 at listing. Data were analyzed from the United Network for Organ Sharing database, years 2002-2014, for 3,377 patients listed status 1a and 5,099 patients with ACLF-3. Candidates with ACLF were identified based on the European Association for the Study of the Liver Chronic Liver Failure Consortium criteria. MELD-Na score was treated as a categorical variable of scores <36, 36-40, and >40. We used competing risks regression to assess waitlist mortality risk. Evaluation of outcomes through 21 days after listing demonstrated a rising trend in mortality among ACLF-3 patients at 7 days (18.0%), 14 days (27.7%), and 21 days (32.7%) (P < 0.001) compared to a stable trend in mortality among individuals listed as status 1a at 7 days (17.9%), 14 days (19.3%), and 21 days (19.8%) (P = 0.709). Multivariable modeling with adjustment for MELD-Na category revealed that patients with ACLF-3 had significantly greater mortality (subhazard ratio, 1.45; 95% confidence interval, 1.31-1.61) within 14 days of listing compared to status-1a candidates. Analysis of the interaction between MELD-Na category and ACLF-3 showed that patients with ACLF-3 had greater risk of 14-day mortality than status-1a-listed patients, across all three MELD-Na categories. Conclusion: Patients with ACLF-3 at the time of listing have greater 14-day mortality than those listed as status 1a, independent of MELD-Na score; these findings illustrate the importance of early transplant evaluation and consideration of transplant priority for patients with ACLF-3., (© 2019 by the American Association for the Study of Liver Diseases.)
- Published
- 2019
- Full Text
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9. Orchestration of Tryptophan-Kynurenine Pathway, Acute Decompensation, and Acute-on-Chronic Liver Failure in Cirrhosis.
- Author
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Clària J, Moreau R, Fenaille F, Amorós A, Junot C, Gronbaek H, Coenraad MJ, Pruvost A, Ghettas A, Chu-Van E, López-Vicario C, Oettl K, Caraceni P, Alessandria C, Trebicka J, Pavesi M, Deulofeu C, Albillos A, Gustot T, Welzel TM, Fernández J, Stauber RE, Saliba F, Butin N, Colsch B, Moreno C, Durand F, Nevens F, Bañares R, Benten D, Ginès P, Gerbes A, Jalan R, Angeli P, Bernardi M, and Arroyo V
- Subjects
- Acute-On-Chronic Liver Failure blood, Aged, Bacterial Infections blood, Bacterial Infections complications, Case-Control Studies, Europe epidemiology, Female, Hepatic Encephalopathy blood, Hepatic Encephalopathy complications, Humans, Inflammation blood, Inflammation complications, Liver Cirrhosis blood, Liver Cirrhosis mortality, Liver Cirrhosis physiopathology, Male, Middle Aged, Prospective Studies, Renal Insufficiency blood, Renal Insufficiency complications, Acute-On-Chronic Liver Failure etiology, Kynurenine blood, Liver Cirrhosis complications, Tryptophan blood
- Abstract
Systemic inflammation (SI) is involved in the pathogenesis of acute decompensation (AD) and acute-on-chronic liver failure (ACLF) in cirrhosis. In other diseases, SI activates tryptophan (Trp) degradation through the kynurenine pathway (KP), giving rise to metabolites that contribute to multiorgan/system damage and immunosuppression. In the current study, we aimed to characterize the KP in patients with cirrhosis, in whom this pathway is poorly known. The serum levels of Trp, key KP metabolites (kynurenine and kynurenic and quinolinic acids), and cytokines (SI markers) were measured at enrollment in 40 healthy subjects, 39 patients with compensated cirrhosis, 342 with AD (no ACLF) and 180 with ACLF, and repeated in 258 patients during the 28-day follow-up. Urine KP metabolites were measured in 50 patients with ACLF. Serum KP activity was normal in compensated cirrhosis, increased in AD and further increased in ACLF, in parallel with SI; it was remarkably higher in ACLF with kidney failure than in ACLF without kidney failure in the absence of differences in urine KP activity and fractional excretion of KP metabolites. The short-term course of AD and ACLF (worsening, improvement, stable) correlated closely with follow-up changes in serum KP activity. Among patients with AD at enrollment, those with the highest baseline KP activity developed ACLF during follow-up. Among patients who had ACLF at enrollment, those with immune suppression and the highest KP activity, both at baseline, developed nosocomial infections during follow-up. Finally, higher baseline KP activity independently predicted mortality in patients with AD and ACLF. Conclusion: Features of KP activation appear in patients with AD, culminate in patients with ACLF, and may be involved in the pathogenesis of ACLF, clinical course, and mortality., (© 2018 by the American Association for the Study of Liver Diseases.)
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- 2019
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10. Cell death markers in patients with cirrhosis and acute decompensation.
- Author
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Macdonald S, Andreola F, Bachtiger P, Amoros A, Pavesi M, Mookerjee R, Zheng YB, Gronbaek H, Gerbes AL, Sola E, Caraceni P, Moreau R, Gines P, Arroyo V, and Jalan R
- Subjects
- Acute-On-Chronic Liver Failure blood, Acute-On-Chronic Liver Failure complications, Adult, Aged, Enzyme-Linked Immunosorbent Assay, Female, Humans, Liver pathology, Liver Cirrhosis blood, Liver Cirrhosis complications, Male, Middle Aged, Prospective Studies, Severity of Illness Index, Survival Analysis, Acute-On-Chronic Liver Failure physiopathology, Biomarkers blood, Cell Death, Keratin-18 blood, Liver Cirrhosis physiopathology
- Abstract
The aims of this study were to determine the role of cell death in patients with cirrhosis and acute decompensation (AD) and acute on chronic liver failure (ACLF) using plasma-based biomarkers. The patients studied were part of the CANONIC (CLIF Acute-on-Chronic Liver Failure in Cirrhosis) study (N = 337; AD, 258; ACLF, 79); additional cohorts included healthy volunteers, stable patients with cirrhosis, and a group of 16 AD patients for histological studies. Caspase-cleaved keratin 18 (cK18) and keratin 18 (K18), which reflect apoptotic and total cell death, respectively, and cK18:K18 ratio (apoptotic index) were measured in plasma by enzyme-linked immunosorbent assay. The concentrations of cK18 and K18 increased and the cK18:K18 ratio decreased with increasing severity of AD and ACLF (P < 0.001, respectively). Alcohol etiology, no previous decompensation, and alcohol abuse were associated with increased cell death markers whereas underlying infection was not. Close correlation was observed between the cell death markers and, markers of systemic inflammation, hepatic failure, alanine aminotransferase, and bilirubin, but not with markers of extrahepatic organ injury. Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining confirmed evidence of greater hepatic cell death in patients with ACLF as opposed to AD. Inclusion of cK18 and K18 improved the performance of the CLIF-C AD score in prediction of progression from AD to ACLF (P < 0.05)., Conclusion: Cell death, likely hepatic, is an important feature of AD and ACLF and its magnitude correlates with clinical severity. Nonapoptotic forms of cell death predominate with increasing severity of AD and ACLF. The data suggests that ACLF is a heterogeneous entity and shows that the importance of cell death in its pathophysiology is dependent on predisposing factors, precipitating illness, response to injury, and type of organ failure. (Hepatology 2018;67:989-1002)., (© 2017 by the American Association for the Study of Liver Diseases.)
- Published
- 2018
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11. Ammonia mediates cortical hemichannel dysfunction in rodent models of chronic liver disease.
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Hadjihambi A, De Chiara F, Hosford PS, Habtetion A, Karagiannis A, Davies N, Gourine AV, and Jalan R
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- Ammonia metabolism, Analysis of Variance, Animals, Bile Ducts surgery, Biomarkers metabolism, Blotting, Western, Chronic Disease, Disease Models, Animal, Hepatic Encephalopathy metabolism, Hyperammonemia physiopathology, Lactates metabolism, Ligation, Male, Random Allocation, Rats, Rats, Sprague-Dawley, Statistics, Nonparametric, Cerebral Cortex metabolism, Connexin 26 metabolism, Hepatic Encephalopathy physiopathology, Hyperammonemia metabolism, Liver Cirrhosis metabolism, Liver Cirrhosis physiopathology
- Abstract
The pathogenesis of hepatic encephalopathy (HE) in cirrhosis is multifactorial and ammonia is thought to play a key role. Astroglial dysfunction is known to be present in HE. Astrocytes are extensively connected by gap junctions formed of connexins, which also exist as functional hemichannels allowing exchange of molecules between the cytoplasm and the extracellular milieu. The astrocyte-neuron lactate shuttle hypothesis suggests that neuronal activity is fueled (at least in part) by lactate provided by neighboring astrocytes. We hypothesized that in HE, astroglial dysfunction could impair metabolic communication between astrocytes and neurons. In this study, we determined whether hyperammonemia leads to hemichannel dysfunction and impairs lactate transport in the cerebral cortex using rat models of HE (bile duct ligation [BDL] and induced hyperammonemia) and also evaluated the effect of ammonia-lowering treatment (ornithine phenylacetate [OP]). Plasma ammonia concentration in BDL rats was significantly reduced by OP treatment. Biosensor recordings demonstrated that HE is associated with a significant reduction in both tonic and hypoxia-induced lactate release in the cerebral cortex, which was normalized by OP treatment. Cortical dye loading experiments revealed hemichannel dysfunction in HE with improvement following OP treatment, while the expression of key connexins was unaffected., Conclusion: The results of the present study demonstrate that HE is associated with central nervous system hemichannel dysfunction, with ammonia playing a key role. The data provide evidence of a potential neuronal energy deficit due to impaired hemichannel-mediated lactate transport between astrocytes and neurons as a possible mechanism underlying pathogenesis of HE. (Hepatology 2017;65:1306-1318)., (© 2017 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)
- Published
- 2017
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12. Systemic inflammation in decompensated cirrhosis: Characterization and role in acute-on-chronic liver failure.
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Clària J, Stauber RE, Coenraad MJ, Moreau R, Jalan R, Pavesi M, Amorós À, Titos E, Alcaraz-Quiles J, Oettl K, Morales-Ruiz M, Angeli P, Domenicali M, Alessandria C, Gerbes A, Wendon J, Nevens F, Trebicka J, Laleman W, Saliba F, Welzel TM, Albillos A, Gustot T, Benten D, Durand F, Ginès P, Bernardi M, and Arroyo V
- Subjects
- Acute-On-Chronic Liver Failure blood, Biomarkers blood, Cytokines blood, Humans, Inflammation blood, Liver Cirrhosis blood, Acute-On-Chronic Liver Failure complications, Inflammation etiology, Liver Cirrhosis complications
- Abstract
Unlabelled: Acute-on-chronic liver failure (ACLF) in cirrhosis is characterized by acute decompensation (AD), organ failure(s), and high short-term mortality. Recently, we have proposed (systemic inflammation [SI] hypothesis) that ACLF is the expression of an acute exacerbation of the SI already present in decompensated cirrhosis. This study was aimed at testing this hypothesis and included 522 patients with decompensated cirrhosis (237 with ACLF) and 40 healthy subjects. SI was assessed by measuring 29 cytokines and the redox state of circulating albumin (HNA2), a marker of systemic oxidative stress. Systemic circulatory dysfunction (SCD) was estimated by plasma renin (PRC) and copeptin (PCC) concentrations. Measurements were performed at enrollment (baseline) in all patients and sequentially during hospitalization in 255. The main findings of this study were: (1) Patients with AD without ACLF showed very high baseline levels of inflammatory cytokines, HNA2, PRC, and PCC. Patients with ACLF showed significantly higher levels of these markers than those without ACLF; (2) different cytokine profiles were identified according to the type of ACLF precipitating event (active alcoholism/acute alcoholic hepatitis, bacterial infection, and others); (3) severity of SI and frequency and severity of ACLF at enrollment were strongly associated. The course of SI and the course of ACLF (improvement, no change, or worsening) during hospitalization and short-term mortality were also strongly associated; and (4) the strength of association of ACLF with SI was higher than with SCD., Conclusion: These data support SI as the primary driver of ACLF in cirrhosis. (Hepatology 2016;64:1249-1264)., (© 2016 by the American Association for the Study of Liver Diseases.)
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- 2016
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13. Not all mice are the same: Standardization of animal research data presentation.
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Omary MB, Cohen DE, El-Omar EM, Jalan R, Low MJ, Nathanson MH, Peek RM Jr, and Turner JR
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- Animals, Behavior, Animal, Disease Models, Animal, Mice, Models, Animal, Sensitivity and Specificity, Animal Experimentation standards, Mice, Inbred Strains physiology, Mice, Inbred Strains psychology, Research Design standards
- Published
- 2016
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14. Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis.
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Gustot T, Fernandez J, Garcia E, Morando F, Caraceni P, Alessandria C, Laleman W, Trebicka J, Elkrief L, Hopf C, Solís-Munoz P, Saliba F, Zeuzem S, Albillos A, Benten D, Montero-Alvarez JL, Chivas MT, Concepción M, Córdoba J, McCormick A, Stauber R, Vogel W, de Gottardi A, Welzel TM, Domenicali M, Risso A, Wendon J, Deulofeu C, Angeli P, Durand F, Pavesi M, Gerbes A, Jalan R, Moreau R, Ginés P, Bernardi M, and Arroyo V
- Subjects
- Acute-On-Chronic Liver Failure diagnosis, Acute-On-Chronic Liver Failure therapy, Adult, Aged, Europe epidemiology, Humans, Liver Transplantation, Middle Aged, Prognosis, Acute-On-Chronic Liver Failure mortality
- Abstract
Unlabelled: Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation (AD) of cirrhosis, organ failure(s), and high 28-day mortality. We investigated whether assessments of patients at specific time points predicted their need for liver transplantation (LT) or the potential futility of their care. We assessed clinical courses of 388 patients who had ACLF at enrollment, from February through September 2011, or during early (28-day) follow-up of the prospective multicenter European Chronic Liver Failure (CLIF) ACLF in Cirrhosis study. We assessed ACLF grades at different time points to define disease resolution, improvement, worsening, or steady or fluctuating course. ACLF resolved or improved in 49.2%, had a steady or fluctuating course in 30.4%, and worsened in 20.4%. The 28-day transplant-free mortality was low-to-moderate (6%-18%) in patients with nonsevere early course (final no ACLF or ACLF-1) and high-to-very high (42%-92%) in those with severe early course (final ACLF-2 or -3) independently of initial grades. Independent predictors of course severity were CLIF Consortium ACLF score (CLIF-C ACLFs) and presence of liver failure (total bilirubin ≥12 mg/dL) at ACLF diagnosis. Eighty-one percent had their final ACLF grade at 1 week, resulting in accurate prediction of short- (28-day) and mid-term (90-day) mortality by ACLF grade at 3-7 days. Among patients that underwent early LT, 75% survived for at least 1 year. Among patients with ≥4 organ failures, or CLIF-C ACLFs >64 at days 3-7 days, and did not undergo LT, mortality was 100% by 28 days., Conclusions: Assessment of ACLF patients at 3-7 days of the syndrome provides a tool to define the emergency of LT and a rational basis for intensive care discontinuation owing to futility., (© 2015 by the American Association for the Study of Liver Diseases.)
- Published
- 2015
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15. A multi-journal partnership to highlight joint first-authors of manuscripts.
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Omary MB, Wallace MB, El-Omar EM, Jalan R, and Nathanson MH
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- Manuscripts, Medical as Topic, Authorship, Gastroenterology organization & administration, Periodicals as Topic
- Published
- 2015
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16. Obeticholic acid, a Farensoid-X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats.
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Mookerjee R, Mehta G, and Jalan R
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- Animals, Male, Chenodeoxycholic Acid analogs & derivatives, Hypertension, Portal drug therapy, Signal Transduction physiology
- Published
- 2014
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17. Novel insights into ammonia-mediated neurotoxicity pointing to potential new therapeutic strategies.
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Hadjihambi A, Rose CF, and Jalan R
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- Animals, Male, Ammonia pharmacology, Astrocytes drug effects, Neural Inhibition drug effects, Neurons drug effects, Potassium metabolism, Seizures chemically induced
- Published
- 2014
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18. Albumin: pathophysiologic basis of its role in the treatment of cirrhosis and its complications.
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Garcia-Martinez R, Caraceni P, Bernardi M, Gines P, Arroyo V, and Jalan R
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- Albumins adverse effects, Albumins chemistry, Albumins physiology, Humans, Liver Cirrhosis complications, Liver Cirrhosis physiopathology, Albumins therapeutic use, Liver Cirrhosis drug therapy
- Abstract
Since the introduction of human serum albumin as a plasma expander in the 1940s, considerable research has allowed a better understanding of its biochemical properties and potential clinical benefits. Albumin has a complex structure, which is responsible for a variety of biological functions. In disease, the albumin molecule is susceptible to modifications that may alter its biological activity. During the last decades, different methods to measure albumin function have been developed. Recent studies have shown that not only albumin concentration but also albumin function is reduced in liver failure. This observation led to the concept of effective albumin concentration, which represents the fact that plasma albumin concentration does not reflect its function. Indeed, in liver disease albumin function is several times less than its concentration. In patients with cirrhosis, albumin infusion reduces mortality in patients with spontaneous bacterial peritonitis and improves outcome following large volume paracentesis. In combination with vasoconstrictors, albumin is useful in the management of patients with hepatorenal syndrome. Its role is being investigated in a large number of indications, which rely on its volume and nonvolume expansion functions such as stroke, severe sepsis, Alzheimer's disease, malaria, burns, and ovarian hyperstimulation syndrome. This review explores the above concepts, reviews the available evidence for the use of albumin in liver diseases, defines therapeutic limitations, and explores the challenges that should be addressed in future research., (Copyright © 2013 American Association for the Study of Liver Diseases.)
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- 2013
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19. Cracking the ENCODE: from transcription to therapeutics.
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Mehta G, Jalan R, and Mookerjee RP
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- Chromosome Structures, Gene Expression Profiling, Histones metabolism, Humans, Liver Diseases therapy, Proteomics, Transcription Factors genetics, Transcription, Genetic, Genome, Human, Genomics trends
- Abstract
The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.
- Published
- 2013
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20. Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: a multicenter survey on safety and efficacy.
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Laleman W, Simon-Talero M, Maleux G, Perez M, Ameloot K, Soriano G, Villalba J, Garcia-Pagan JC, Barrufet M, Jalan R, Brookes J, Thalassinos E, Burroughs AK, Cordoba J, and Nevens F
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Hepatic Encephalopathy physiopathology, Humans, Male, Middle Aged, Retrospective Studies, Treatment Outcome, Embolization, Therapeutic adverse effects, Hepatic Encephalopathy therapy
- Abstract
Unlabelled: Refractory hepatic encephalopathy (HE) remains a major cause of morbidity in cirrhosis patients. Large spontaneous portosystemic shunts (SPSSs) have been previously suggested to sustain HE in these patients. We aimed to retrospectively assess the efficacy and safety of patients treated with embolization of large SPSSs for the treatment of chronic therapy-refractory HE in a European multicentric working group and to identify patients who may benefit from this procedure. Between July 1998 and January 2012, 37 patients (Child A6-C13, MELD [Model of Endstage Liver Disease] 5-28) with refractory HE were diagnosed with single large SPSSs that were considered eligible for embolization. On a short-term basis (i.e., within 100 days after embolization), 22 out of 37 patients (59.4%) were free of HE (P < 0.001 versus before embolization) of which 18 (48.6% of patients overall) remained HE-free over a mean follow-up period of 697 ± 157 days (P < 0.001 versus before embolization). Overall, we noted improved autonomy, decreased number of hospitalizations, and severity of the worst HE episode after embolization in three-quarters of the patients. Logistic regression identified the MELD score as strongest positive predictive factor of HE recurrence with a cutoff of 11 for patient selection. As to safety, we noted one major nonlethal procedure-related complication. There was no significant increase in de novo development or aggravation of preexisting varices, portal hypertensive gastropathy, or ascites., Conclusion: This multicenter European cohort study demonstrated a role for large SPSSs in chronic protracted or recurrent HE and substantiated the effectiveness and safety of embolization of these shunts, provided there is sufficient functional liver reserve., (Copyright © 2013 American Association for the Study of Liver Diseases.)
- Published
- 2013
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21. Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial.
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Bañares R, Nevens F, Larsen FS, Jalan R, Albillos A, Dollinger M, Saliba F, Sauerbruch T, Klammt S, Ockenga J, Pares A, Wendon J, Brünnler T, Kramer L, Mathurin P, de la Mata M, Gasbarrini A, Müllhaupt B, Wilmer A, Laleman W, Eefsen M, Sen S, Zipprich A, Tenorio T, Pavesi M, Schmidt HH, Mitzner S, Williams R, and Arroyo V
- Subjects
- Adult, End Stage Liver Disease mortality, Female, Hospitalization statistics & numerical data, Humans, Liver Cirrhosis mortality, Liver Cirrhosis therapy, Liver Failure, Acute mortality, Logistic Models, Male, Middle Aged, Multiple Organ Failure mortality, Multiple Organ Failure therapy, Multivariate Analysis, Peritonitis mortality, Peritonitis therapy, Prospective Studies, Renal Dialysis adverse effects, Renal Dialysis methods, Sorption Detoxification adverse effects, Sorption Detoxification mortality, Treatment Outcome, End Stage Liver Disease therapy, Liver Failure, Acute therapy, Serum Albumin metabolism, Sorption Detoxification methods
- Abstract
Unlabelled: Acute-on-chronic liver failure (ACLF) is a frequent cause of death in cirrhosis. Albumin dialysis with the molecular adsorbent recirculating system (MARS) decreases retained substances and improves hemodynamics and hepatic encephalopathy (HE). However, its survival impact is unknown. In all, 189 patients with ACLF were randomized either to MARS (n=95) or to standard therapy (SMT) (n=94). Ten patients (five per group) were excluded due to protocol violations. In addition, 23 patients (MARS: 19; SMT: 4) were excluded from per-protocol (PP) analysis (PP population n=156). Up to 10 6-8-hour MARS sessions were scheduled. The main endpoint was 28-day ITT and PP survival. There were no significant differences at inclusion, although the proportion of patients with Model for Endstage Liver Disease (MELD) score over 20 points and with spontaneous bacterial peritonitis (SBP) as a precipitating event was almost significantly greater in the MARS group. The 28-day survival was similar in the two groups in the ITT and PP populations (60.7% versus 58.9%; 60% versus 59.2% respectively). After adjusting for confounders, a significant beneficial effect of MARS on survival was not observed (odds ratio [OR]: 0.87, 95% confidence interval [CI] 0.44-1.72). MELD score and HE at admission and the increase in serum bilirubin at day 4 were independent predictors of death. At day 4, a greater decrease in serum creatinine (P=0.02) and bilirubin (P=0.001) and a more frequent improvement in HE (from grade II-IV to grade 0-I; 62.5% versus 38.2%; P=0.07) was observed in the MARS group. Severe adverse events were similar., Conclusion: At scheduled doses, a beneficial effect on survival of MARS therapy in patients with ACLF could not be demonstrated. However, MARS has an acceptable safety profile, has significant dialysis effect, and nonsignificantly improves severe HE., (Copyright © 2012 American Association for the Study of Liver Diseases.)
- Published
- 2013
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22. Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions.
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Kremer AE, van Dijk R, Leckie P, Schaap FG, Kuiper EM, Mettang T, Reiners KS, Raap U, van Buuren HR, van Erpecum KJ, Davies NA, Rust C, Engert A, Jalan R, Oude Elferink RP, and Beuers U
- Subjects
- Allylamine analogs & derivatives, Allylamine therapeutic use, Analysis of Variance, Antipruritics therapeutic use, Biomarkers blood, Blotting, Western, Carcinoma, Hepatocellular blood, Carcinoma, Hepatocellular complications, Case-Control Studies, Cholestasis complications, Cohort Studies, Colesevelam Hydrochloride, Electrophoresis, Polyacrylamide Gel, Female, Hep G2 Cells metabolism, Humans, Liver Neoplasms blood, Liver Neoplasms complications, Lysophospholipase blood, Male, Multivariate Analysis, Phosphoric Diester Hydrolases metabolism, Polymerase Chain Reaction, Pruritus etiology, ROC Curve, Rifampin therapeutic use, Treatment Outcome, Cholestasis blood, Fibroblast Growth Factors blood, Phosphoric Diester Hydrolases blood, Pruritus blood, Pruritus drug therapy
- Abstract
Unlabelled: Pruritus is a seriously disabling symptom accompanying many cholestatic liver disorders. Recent experimental evidence implicated the lysophospholipase, autotaxin (ATX), and its product, lysophosphatidic acid (LPA), as potential mediators of cholestatic pruritus. In this study, we highlight that increased serum ATX levels are specific for pruritus of cholestasis, but not pruritus of uremia, Hodgkin's disease, or atopic dermatitis. Treatment of patients with cholestasis with the bile salt sequestrant, colesevelam, but not placebo, effectively reduced total serum bile salts and fibroblast growth factor 19 levels, but only marginally altered pruritus intensity and ATX activity. Rifampicin (RMP) significantly reduced itch intensity and ATX activity in patients with pruritus not responding to bile salt sequestrants. In vitro, RMP inhibited ATX expression in human HepG2 hepatoma cells and hepatoma cells overexpressing the pregnane X receptor (PXR), but not in hepatoma cells in which PXR was knocked down. Treatment of severe, refractory pruritus by the molecular adsorbents recirculation system or nasobiliary drainage improved itch intensity, which, again, correlated with the reduction of ATX levels. Upon reoccurrence of pruritus, ATX activity returned to pretreatment values., Conclusion: Serum ATX activity is specifically increased in patients with cholestatic, but not other forms of, systemic pruritus and closely correlates with the effectiveness of therapeutic interventions. The beneficial antipruritic action of RMP may be explained, at least partly, by the PXR-dependent transcriptional inhibition of ATX expression. Thus, ATX likely represents a novel therapeutic target for pruritus of cholestasis., (Copyright © 2012 American Association for the Study of Liver Diseases.)
- Published
- 2012
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23. Intensive care of the patient with cirrhosis.
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Olson JC, Wendon JA, Kramer DJ, Arroyo V, Jalan R, Garcia-Tsao G, and Kamath PS
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- Acute Disease, Humans, Liver Cirrhosis physiopathology, Liver Failure physiopathology, Critical Care methods, Liver Cirrhosis therapy, Liver Failure therapy
- Abstract
Acute deterioration of patients with cirrhosis manifests as multiple organ failure requiring admission to an intensive care unit. Precipitating events may be viral hepatitis, typically in Asia, and drug or alcoholic hepatitis and variceal hemorrhage in the West. Patients with cirrhosis in the intensive care unit have a high mortality, and each admission is associated with a mean charge of US $116,200. Prognosis is determined by the number of organs failing (sequential organ failure assessment [SOFA] score), the presence of infection, and the degree of liver dysfunction (Child-Turcotte-Pugh or Model for End-Stage Liver Disease scores). The most common organ failing is the kidney; sepsis is associated with further deterioration in liver function by compromise of the microcirculation. Care of these critically ill patients with impending multiple organ failure requires a team approach with expertise in both hepatology and critical care. Treatment is aimed at preventing further deterioration in liver function, reversing precipitating factors, and supporting failing organs. Liver transplantation is required in selected patients to improve survival and quality of life. Treatment is futile in some patients, but it is difficult to identify these patients a priori. Artificial and bioartificial liver support systems have thus far not demonstrated significant survival benefit in these patients., (Copyright © 2011 American Association for the Study of Liver Diseases.)
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- 2011
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24. Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality.
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Jalan R, Schnurr K, Mookerjee RP, Sen S, Cheshire L, Hodges S, Muravsky V, Williams R, Matthes G, and Davies NA
- Subjects
- Adult, Binding Sites, Case-Control Studies, Electron Spin Resonance Spectroscopy, F2-Isoprostanes blood, Female, Humans, Ischemia metabolism, Liver Cirrhosis complications, Liver Cirrhosis mortality, Liver Failure, Acute etiology, Liver Failure, Acute mortality, Liver Failure, Acute therapy, Male, Malondialdehyde blood, Middle Aged, Oxidative Stress, Renal Dialysis, Albumins metabolism, Liver Cirrhosis metabolism, Liver Failure, Acute metabolism
- Abstract
Unlabelled: Albumin concentration is diminished in patients with liver failure. Albumin infusion improves survival of cirrhotic patients with spontaneous bacterial peritonitis, and it is hypothesized that this may be due in part to its detoxifying capabilities. The aim of this study was to perform detailed quantitative and qualitative assessment of albumin function in patients with cirrhosis. Healthy controls and patients with acute deterioration of cirrhosis requiring hospital admission (n = 34) were included. Albumin function was assessed using affinity of the fatty acid binding sites using a spin label (16 doxyl-stearate) titration and electron paramagnetic resonance spectroscopy and ischemia-modified albumin (IMA) was measured. Twenty-two patients developed acute-on-chronic liver failure. Twelve were treated with the Molecular Adsorbents Recirculating System (MARS) and 10 with standard medical therapy. For each parameter measured, the patients' albumin had reduced functional ability, which worsened with disease severity. Fifteen patients died, and IMA, expressed as an albumin ratio (IMAR), was significantly higher in nonsurvivors compared with survivors (P < 0.001; area under the receiver operating curve = 0.8). No change in the patients' albumin function was observed following MARS therapy. A significant negative correlation between IMAR and the fatty acid binding coefficients for sites 1 and 2 (P < 0.001 for both) was observed, indicating possible sites of association on the protein., Conclusion: The results of this study suggests marked dysfunction of albumin function in advanced cirrhosis and provide further evidence for damage to the circulating albumin, which is not reversed by MARS therapy. IMAR correlates with disease severity and may have prognostic use in acute-on-chronic liver failure.
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- 2009
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25. L-ornithine and phenylacetate synergistically produce sustained reduction in ammonia and brain water in cirrhotic rats.
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Davies NA, Wright G, Ytrebø LM, Stadlbauer V, Fuskevåg OM, Zwingmann C, Davies DC, Habtesion A, Hodges SJ, and Jalan R
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- Animals, Drug Synergism, Male, Rats, Rats, Sprague-Dawley, Ammonia metabolism, Body Water drug effects, Body Water metabolism, Brain drug effects, Brain metabolism, Liver Cirrhosis metabolism, Ornithine pharmacology, Phenylacetates pharmacology, Phenylbutyrates pharmacology
- Abstract
Unlabelled: Treatment of hyperammonemia and hepatic encephalopathy in cirrhosis is an unmet clinical need. The aims of this study were to determine whether L-ornithine and phenylacetate/phenylbutyrate (administered as the pro-drug phenylbutyrate) (OP) combined are synergistic and produce sustained reduction in ammonia by L-ornithine acting as a substrate for glutamine synthesis, thereby detoxifying ammonia, and the phenylacetate excreting the ornithine-derived glutamine as phenylacetylglutamine in the urine. Sprague-Dawley rats were studied 4 weeks after bile duct ligation (BDL) or sham operation. Study 1: Three hours before termination, an internal carotid sampling catheter was inserted, and intraperitoneal saline (placebo), OP, phenylbutyrate, or L-ornithine were administered after randomization. BDL was associated with significantly higher arterial ammonia and brain water and lower brain myoinositol (P < 0.01, respectively), compared with sham-operated controls, which was significantly improved in the OP-treated animals; arterial ammonia (P < 0.001), brain water (P < 0.05), brain myoinositol (P < 0.001), and urinary phenylacetylglutamine (P < 0.01). Individually, L-ornithine or phenylbutyrate were similar to the BDL group. In study 2, BDL rats were randomized to saline or OP administered intraperitoneally for 6 hours or 3, 5, or 10 days and were sacrificed between 4.5 and 5 weeks. The results showed that the administration of OP was associated with sustained reduction in arterial ammonia (P < 0.01) and brain water (P < 0.01) and markedly increased arterial glutamine (P < 0.01) and urinary excretion of phenylacetylglutamine (P < 0.01) in each of the OP treated groups., Conclusion: The results of this study provide proof of the concept that L-ornithine and phenylbutyrate/phenylacetate act synergistically to produce sustained improvement in arterial ammonia, its brain metabolism, and brain water in cirrhotic rats.
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- 2009
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26. L-ornithine phenylacetate attenuates increased arterial and extracellular brain ammonia and prevents intracranial hypertension in pigs with acute liver failure.
- Author
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Ytrebø LM, Kristiansen RG, Maehre H, Fuskevåg OM, Kalstad T, Revhaug A, Cobos MJ, Jalan R, and Rose CF
- Subjects
- Ammonia blood, Animals, Arteries, Drug Combinations, Swine, Ammonia metabolism, Brain metabolism, Extracellular Space drug effects, Extracellular Space metabolism, Intracranial Hypertension etiology, Intracranial Hypertension prevention & control, Liver Failure, Acute complications, Liver Failure, Acute metabolism, Ornithine pharmacology, Ornithine therapeutic use, Phenylacetates pharmacology, Phenylacetates therapeutic use
- Abstract
Unlabelled: Hyperammonemia is a feature of acute liver failure (ALF), which is associated with increased intracranial pressure (ICP) and brain herniation. We hypothesized that a combination of L-ornithine and phenylacetate (OP) would synergistically reduce toxic levels of ammonia by (1) L-ornithine increasing glutamine production (ammonia removal) through muscle glutamine synthetase and (2) phenylacetate conjugating with the ornithine-derived glutamine to form phenylacetylglutamine, which is excreted into the urine. The aims of this study were to determine the effect of OP on arterial and extracellular brain ammonia concentrations as well as ICP in pigs with ALF (induced by liver devascularization). ALF pigs were treated with OP (L-ornithine 0.07 g/kg/hour intravenously; phenylbutyrate, prodrug for phenylacetate; 0.05 g/kg/hour intraduodenally) for 8 hours following ALF induction. ICP was monitored throughout, and arterial and extracellular brain ammonia were measured along with phenylacetylglutamine in the urine. Compared with ALF + saline pigs, treatment with OP significantly attenuated concentrations of arterial ammonia (589.6 +/- 56.7 versus 365.2 +/- 60.4 mumol/L [mean +/- SEM], P= 0.002) and extracellular brain ammonia (P= 0.01). The ALF-induced increase in ICP was prevented in ALF + OP-treated pigs (18.3 +/- 1.3 mmHg in ALF + saline versus 10.3 +/- 1.1 mmHg in ALF + OP-treated pigs;P= 0.001). The value of ICP significantly correlated with the concentration of extracellular brain ammonia (r(2) = 0.36,P< 0.001). Urine phenylacetylglutamine levels increased to 4.9 +/- 0.6 micromol/L in ALF + OP-treated pigs versus 0.5 +/- 0.04 micromol/L in ALF + saline-treated pigs (P< 0.001)., Conclusion: L-Ornithine and phenylacetate act synergistically to successfully attenuate increases in arterial ammonia, which is accompanied by a significant decrease in extracellular brain ammonia and prevention of intracranial hypertension in pigs with ALF.
- Published
- 2009
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27. High prevalence of abnormal alanine and aspartate aminotransferases in a "worried-well" population in the United Kingdom: rationale for a liver screening program?
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García-Romero D, Anastassiou J, Hart G, Mookerjee R, and Jalan R
- Subjects
- Adult, Aged, Female, Humans, Liver Diseases mortality, Male, Mass Screening, Middle Aged, Survival Analysis, United Kingdom, Alanine Transaminase blood, Aspartate Aminotransferases blood, Liver Diseases epidemiology
- Published
- 2008
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28. Ammonia impairs neutrophil phagocytic function in liver disease.
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Shawcross DL, Wright GA, Stadlbauer V, Hodges SJ, Davies NA, Wheeler-Jones C, Pitsillides AA, and Jalan R
- Subjects
- Amino Acids adverse effects, Ammonia adverse effects, Ammonia pharmacology, Animals, Cell Survival drug effects, Cell Survival physiology, Cells, Cultured, Disease Models, Animal, Double-Blind Method, Humans, Hyperammonemia chemically induced, Hyperammonemia physiopathology, Hyponatremia metabolism, Hyponatremia physiopathology, Imidazoles pharmacology, Isoproterenol pharmacology, Liver Cirrhosis metabolism, Liver Cirrhosis physiopathology, Liver Diseases physiopathology, Male, Middle Aged, Neutrophils drug effects, Phagocytosis drug effects, Pyridines pharmacology, Rats, Rats, Sprague-Dawley, Respiratory Burst drug effects, Respiratory Burst physiology, Signal Transduction drug effects, Signal Transduction physiology, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors, p38 Mitogen-Activated Protein Kinases drug effects, p38 Mitogen-Activated Protein Kinases metabolism, Ammonia metabolism, Hyperammonemia metabolism, Liver Diseases metabolism, Neutrophils physiology, Phagocytosis physiology
- Abstract
Unlabelled: Hyperammonemia is a feature of liver failure, which is associated with increased risk of infection. The aims of the present study were to determine in vitro, in rats fed an ammoniagenic diet and in patients with cirrhosis, whether induction of hyperammonemia results in neutrophil dysfunction. As hyperammonemia produces cell swelling, we explored the role of the osmoregulating, p38 mitogen-activated protein kinase (p38(MAPK)) pathway in mediating this neutrophil dysfunction. Neutrophils were isolated from blood of healthy volunteers and incubated with either 75 microM ammonia or phosphate-buffered saline. Both groups were studied under hyponatremic conditions and/or with the addition of p38(MAPK) modulators. Neutrophil phagocytosis was measured in naive rats and rats fed an ammoniagenic diet and in patients with stable cirrhosis given placebo (n = 8) or an amino acid solution inducing hyperammonemia (n = 8). Cell volume and phagocytosis was analyzed by fluorescent-activated cell sorting using fluorescein isothiocyanate-labeled E. coli. p38(MAPK) phosphorylation was measured by western blotting. In healthy neutrophils incubated with ammonia and in rats fed an ammoniagenic diet, neutrophils showed evidence of swelling, impaired phagocytosis, and increased spontaneous oxidative burst compared to controls. Phagocytosis was significantly impaired in patients with induced hyperammonemia compared to placebo. The effects of hyperammonemia and hyponatremia were synergistic. The p38(MAPK) intracellular signaling pathways were activated in healthy neutrophils exposed to ammonia in association with increased burst activity. Neutrophil phagocytic dysfunction was abrogated by the addition of a p38(MAPK) agonist., Conclusion: Ammonia produces neutrophil swelling and impairs neutrophil phagocytosis. The p38(MAPK) intracellular signaling pathway has been shown to be important in mediating the ammonia-induced neutrophil dysfunction.
- Published
- 2008
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29. Lack of renal improvement with nonselective endothelin antagonism with tezosentan in type 2 hepatorenal syndrome.
- Author
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Wong F, Moore K, Dingemanse J, and Jalan R
- Subjects
- Endothelin-1 blood, Hemodynamics drug effects, Hepatorenal Syndrome physiopathology, Humans, Kidney metabolism, Kidney Function Tests, Liver Cirrhosis physiopathology, Male, Middle Aged, Pilot Projects, Pyridines pharmacology, Sodium metabolism, Tetrazoles pharmacology, Treatment Failure, Water metabolism, Endothelin-1 antagonists & inhibitors, Hepatorenal Syndrome drug therapy, Kidney drug effects, Liver Cirrhosis drug therapy, Pyridines therapeutic use, Tetrazoles therapeutic use
- Abstract
Unlabelled: Renal vasoconstriction is a key factor in the development of hepatorenal syndrome (HRS) and may be secondary to increased activities of endothelin-1, a potent renal vasoconstrictor. To assess the effects of tezosentan, a nonselective endothelin receptor antagonist, on renal function in patients with type 2 HRS, six male patients, 56.3 +/- 2.5 years old, with cirrhosis and type 2 HRS were treated with tezosentan; ascending doses of 0.3, 1.0, and 3.0 mg/hour, each for 24 hours, were used for the initial 2 patients, but a constant dose of 0.3 mg/hour for up to 7 days was used for the remaining 4 patients. The glomerular filtration rate, renal plasma flow, 24-hour urinary volume, mean arterial pressure (MAP), heart rate, tezosentan levels, and vasoactive hormones were measured daily. Albumin was given as required. The study was stopped early because of concerns about the safety of tezosentan in type 2 HRS. Five patients discontinued the study early; one stopped within 4 hours because of systemic hypotension (MAP < 70 mm Hg), and 4 patients stopped at approximately 4 days because of concerns about worsening renal function (serum creatinine increased from 180 +/- 21 to 222 +/- 58 micromol/L, P > 0.05) and decreasing urine volume (P = 0.03) but without a significant change in MAP. The plasma tezosentan concentrations were 79 +/- 34 ng/mL at a steady state during infusion at 0.3 mg/hour. The plasma endothelin-1 concentrations increased from 2.7 +/- 0.3 pg/mL at the baseline to 19.1 +/- 7.3 pg/mL (P < 0.05)., Conclusion: An endothelin receptor blockade potentially can cause a deterioration in renal function in patients with cirrhosis and type 2 HRS. Caution should be taken in future studies using endothelin receptor antagonists in these patients.
- Published
- 2008
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30. Association of reduced extracellular brain ammonia, lactate, and intracranial pressure in pigs with acute liver failure.
- Author
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Rose C, Ytrebø LM, Davies NA, Sen S, Nedredal GI, Belanger M, Revhaug A, and Jalan R
- Subjects
- Animals, Disease Models, Animal, Extracellular Space, Female, Glutamic Acid analysis, Glutamine analysis, Swine, Ammonia analysis, Brain Chemistry, Intracranial Pressure, Lactic Acid analysis, Liver Failure, Acute therapy, Sorption Detoxification
- Abstract
Unlabelled: We previously demonstrated in pigs with acute liver failure (ALF) that albumin dialysis using the molecular adsorbents recirculating system (MARS) attenuated a rise in intracranial pressure (ICP). This was independent of changes in arterial ammonia, cerebral blood flow and inflammation, allowing alternative hypotheses to be tested. The aims of the present study were to determine whether changes in cerebral extracellular ammonia, lactate, glutamine, glutamate, and energy metabolites were associated with the beneficial effects of MARS on ICP. Three randomized groups [sham, ALF (induced by portacaval anastomosis and hepatic artery ligation), and ALF+MARS] were studied over a 6-hour period with a 4-hour MARS treatment given beginning 2 hours after devascularization. Using cerebral microdialysis, the ALF-induced increase in extracellular brain ammonia, lactate, and glutamate was significantly attenuated in the ALF+MARS group as well as the increases in extracellular lactate/pyruvate and lactate/glucose ratios. The percent change in extracellular brain ammonia correlated with the percent change in ICP (r(2) = 0.511). Increases in brain lactate dehydrogenase activity and mitochondrial complex activity for complex IV were found in ALF compared with those in the sham, which was unaffected by MARS treatment. Brain oxygen consumption did not differ among the study groups., Conclusion: The observation that brain oxygen consumption and mitochondrial complex enzyme activity changed in parallel in both ALF- and MARS-treated animals indicates that the attenuation of increased extracellular brain ammonia (and extracellular brain glutamate) in the MARS-treated animals reduces energy demand and increases supply, resulting in attenuation of increased extracellular brain lactate. The mechanism of how MARS reduces extracellular brain ammonia requires further investigation.
- Published
- 2007
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31. The puzzle of endothelial nitric oxide synthase dysfunction in portal hypertension: The missing piece?
- Author
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Mookerjee RP, Vairappan B, and Jalan R
- Published
- 2007
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32. Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome.
- Author
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Mookerjee RP, Stadlbauer V, Lidder S, Wright GA, Hodges SJ, Davies NA, and Jalan R
- Subjects
- Adult, Aged, Antibodies immunology, Endotoxins blood, Endotoxins isolation & purification, Female, Hepatitis, Alcoholic complications, Humans, Immunosuppression Therapy, Infections immunology, Lipopolysaccharide Receptors immunology, Lipopolysaccharides immunology, Liver Cirrhosis, Alcoholic etiology, Male, Middle Aged, Phagocytosis, Prognosis, Respiratory Burst, Serum immunology, Hepatitis, Alcoholic immunology, Hepatitis, Alcoholic mortality, Liver Cirrhosis, Alcoholic immunology, Liver Cirrhosis, Alcoholic mortality, Neutrophils immunology
- Abstract
Unlabelled: Mortality in patients with alcoholic hepatitis (AH) remains high, and although corticosteroids are widely used for treatment, the results vary considerably. In AH, neutrophils are primed and infiltrate the liver to produce injury, but paradoxically, the main cause of death in such patients is infection. Our prospective study addressed this paradox of primed neutrophils on the one hand and increased risk of infection on the other. We hypothesized that the full activation of neutrophils by a humoral factor such as endotoxin renders them unable to respond to further bacterial challenge. We analyzed neutrophil oxidative burst and phagocytosis in whole blood by fluorescence-activated cell sorting analysis in 63 alcoholic patients with cirrhosis and patients with cirrhosis with superimposed AH (cirrhosis+AH). In 16 patients, ex vivo studies determined whether the removal of endotoxin restored neutrophil function. A resting burst greater than or equal to 55[corrected]%, indicating neutrophil activation and a reduced phagocytic capacity lower than 42%, was associated with significantly greater risk of infection, organ failure, and mortality. This defective neutrophil function was transmissible through patients' plasma to normal neutrophils, and patients' neutrophil function could be restored by normal plasma. The ex vivo removal of endotoxin from patients' plasma decreased the resting burst and increased the phagocytic function., Conclusions: Our study provides the rationale for a goal-directed approach to the management of patients with cirrhosis and AH, in which the assessment of neutrophil function may be an important biomarker to select patients for immunosuppressive therapy. The neutrophil dysfunction in cirrhosis and AH is reversible, with endotoxin-removal strategies providing new targets for intervention.
- Published
- 2007
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33. Ammonia and inflammation in the pathogenesis of hepatic encephalopathy: Pandora's box?
- Author
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Wright G and Jalan R
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Cyclic GMP physiology, Cytokines physiology, Hepatic Encephalopathy drug therapy, Nitric Oxide physiology, Nitric Oxide Synthase physiology, Prostaglandin-Endoperoxide Synthases physiology, Rats, Ammonia toxicity, Hepatic Encephalopathy etiology, Inflammation complications
- Published
- 2007
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34. Endotoxemia produces coma and brain swelling in bile duct ligated rats.
- Author
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Wright G, Davies NA, Shawcross DL, Hodges SJ, Zwingmann C, Brooks HF, Mani AR, Harry D, Stadlbauer V, Zou Z, Williams R, Davies C, Moore KP, and Jalan R
- Subjects
- Ammonia blood, Animals, Brain blood supply, Brain metabolism, Brain pathology, Brain Edema pathology, Capillaries pathology, Capillaries ultrastructure, Cholestasis, Extrahepatic pathology, Coma pathology, Consciousness, Cytokines blood, Disease Models, Animal, Endotoxemia chemically induced, Hyperammonemia complications, Ligation, Lipopolysaccharides pharmacology, Liver Cirrhosis, Experimental pathology, Magnetic Resonance Spectroscopy, Male, Microscopy, Electron, Transmission, Nitrates blood, Nitrites blood, Rats, Rats, Sprague-Dawley, Tyrosine analogs & derivatives, Tyrosine metabolism, Brain Edema etiology, Cholestasis, Extrahepatic complications, Coma etiology, Endotoxemia complications, Liver Cirrhosis, Experimental complications
- Abstract
Unlabelled: This study explores the hypothesis that the inflammatory response induced by administration of lipopolysaccharide (LPS) exacerbates brain edema in cirrhotic rats; and if so whether this is associated with altered brain metabolism of ammonia or anatomical disturbance of the blood-brain barrier. Adult Sprague-Dawley rats 4 weeks after bile duct ligation (BDL)/Sham-operation, or naïve rats fed a hyperammonemic diet (HD), were injected with LPS (0.5 mg/kg, intraperitoneally) or saline, and killed 3 hours later. LPS administration increased brain water in HD, BDL, and sham-operated groups significantly (P < 0.05), but this was associated with progression to pre-coma stages only in BDL rats. LPS induced cytotoxic brain swelling and maintained anatomical integrity of the blood-brain barrier. Plasma/brain ammonia levels were higher in HD and BDL rats than in sham-operated controls and did not change with LPS administration. Brain glutamine/myoinositol ratio was increased in the HD group but reduced in the BDL animals. There was a background pro-inflammatory cytokine response in the brains of cirrhotic rats, and plasma/brain tumor necrosis factor alpha (TNF-alpha) and IL-6 significantly increased in LPS-treated animals. Plasma nitrite/nitrate levels increased significantly in LPS groups compared with non-LPS controls; however, frontal cortex nitrotyrosine levels only increased in the BDL + LPS rats (P < 0.005 versus BDL controls)., Conclusion: Injection of LPS into cirrhotic rats induces pre-coma and exacerbates cytotoxic edema because of the synergistic effect of hyperammonemia and the induced inflammatory response. Although the exact mechanism of how hyperammonemia and LPS facilitate cytotoxic edema and pre-coma in cirrhosis is not clear, our data support an important role for the nitrosation of brain proteins.
- Published
- 2007
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35. Isoleucine infusion during "simulated" upper gastrointestinal bleeding improves liver and muscle protein synthesis in cirrhotic patients.
- Author
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Olde Damink SW, Jalan R, Deutz NE, Dejong CH, Redhead DN, Hynd P, Hayes PC, and Soeters PB
- Subjects
- Adult, Amino Acids administration & dosage, Amino Acids metabolism, Female, Gastrointestinal Hemorrhage etiology, Humans, Infusions, Intravenous, Isoleucine administration & dosage, Kidney metabolism, Liver Cirrhosis complications, Male, Middle Aged, Proteins metabolism, Gastrointestinal Hemorrhage metabolism, Isoleucine pharmacology, Liver metabolism, Liver Cirrhosis metabolism, Muscle Proteins metabolism
- Abstract
Unlabelled: Upper gastrointestinal (GI) bleeding in cirrhotic patients has a high incidence of mortality and morbidity. Postbleeding catabolism has been hypothesized to be partly due to the low biological value of hemoglobin, which lacks the essential amino acid isoleucine. The aims were to study the metabolic consequences of a "simulated" upper GI bleed in patients with cirrhosis of the liver and the effects of intravenous infusion of isoleucine. Portal drained viscera, liver, muscle, and kidney protein kinetics were quantified using a multicatheterization technique during routine portography. Sixteen overnight-fasted, metabolically stable patients who received an intragastric infusion of an amino acid solution mimicking hemoglobin every 4 hours were randomized to saline or isoleucine infusion and received a mixture of stable isotopes (L-[ring-2H5]phenylalanine, L-[ring-2H4]tyrosine, and L-[ring-2H2]tyrosine) to determine organ protein kinetics. This simulated bleed resulted in hypoisoleucinemia that was attenuated by isoleucine infusion. Isoleucine infusion during the bleed resulted in a positive net balance of phenylalanine across liver and muscle, whereas renal and portal drained viscera protein kinetics were unaffected. In the control group, no significant effect was shown., Conclusion: The present study investigated hepatic and portal drained viscera protein metabolism selectively in humans. The data show that hepatic and muscle protein synthesis is stimulated by improving the amino acid composition of the upper GI bleed by simultaneous intravenous isoleucine administration.
- Published
- 2007
- Full Text
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36. Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis.
- Author
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Mookerjee RP, Malaki M, Davies NA, Hodges SJ, Dalton RN, Turner C, Sen S, Williams R, Leiper J, Vallance P, and Jalan R
- Subjects
- Adult, Aged, Amidohydrolases genetics, Amidohydrolases metabolism, Arginine blood, Biomarkers blood, Case-Control Studies, Female, Gene Expression Regulation, Hepatitis, Alcoholic complications, Hepatitis, Alcoholic mortality, Humans, Hypertension, Portal blood, Hypertension, Portal etiology, Liver Cirrhosis, Alcoholic blood, Male, Middle Aged, Predictive Value of Tests, Prognosis, Protein-Arginine N-Methyltransferases genetics, Protein-Arginine N-Methyltransferases metabolism, Repressor Proteins genetics, Repressor Proteins metabolism, Sensitivity and Specificity, Survival Rate, Arginine analogs & derivatives, Hepatitis, Alcoholic blood
- Abstract
Unlabelled: Previous studies suggest reduced hepatic endothelial nitric oxide synthase activity contributes to increased intrahepatic resistance. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, undergoes hepatic metabolism via dimethylarginine-dimethylamino-hydrolase, and is derived by the action of protein-arginine-methyltransferases. Our study assessed whether ADMA, and its stereo-isomer symmetric dimethylarginine (SDMA), are increased in alcoholic hepatitis patients, and determined any relationship with severity of portal hypertension (hepatic venous pressure gradient measurement) and outcome. Fifty-two patients with decompensated alcoholic cirrhosis were studied, 27 with acute alcoholic hepatitis and cirrhosis, in whom hepatic venous pressure gradient was higher (P = 0.001) than cirrhosis alone, and correlated with ADMA measurement. Plasma ADMA and SDMA were significantly higher in alcoholic hepatitis patients and in nonsurvivors. Dimethylarginine-dimethylamino-hydrolase protein expression was reduced and protein-arginine-methyltransferase-1 increased in alcoholic hepatitis livers. ADMA, SDMA and their combined sum, which we termed a dimethylarginine score, were better predictors of outcome compared with Pugh score, MELD and Maddrey's discriminant-function., Conclusion: Alcoholic hepatitis patients have higher portal pressures associated with increased ADMA, which may result from both decreased breakdown (decreased hepatic dimethylarginine-dimethylamino-hydrolase) and/or increased production. Elevated dimethylarginines may serve as important biological markers of deleterious outcome in alcoholic hepatitis.
- Published
- 2007
- Full Text
- View/download PDF
37. Infliximab and alcoholic hepatitis.
- Author
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Mookerjee RP, Tilg H, Williams R, and Jalan R
- Subjects
- Anti-Inflammatory Agents therapeutic use, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal adverse effects, Dose-Response Relationship, Drug, Drug Therapy, Combination, Humans, Infliximab, Prednisolone therapeutic use, Antibodies, Monoclonal therapeutic use, Hepatitis, Alcoholic drug therapy
- Published
- 2004
- Full Text
- View/download PDF
38. Worsening of cerebral hyperemia by the administration of terlipressin in acute liver failure with severe encephalopathy.
- Author
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Shawcross DL, Davies NA, Mookerjee RP, Hayes PC, Williams R, Lee A, and Jalan R
- Subjects
- Adult, Blood Pressure drug effects, Cardiac Output drug effects, Cerebrovascular Circulation drug effects, Female, Heart Rate drug effects, Humans, Intracranial Pressure drug effects, Male, Middle Aged, Terlipressin, Vascular Resistance drug effects, Vasodilation drug effects, Antihypertensive Agents adverse effects, Hepatic Encephalopathy drug therapy, Hyperemia drug therapy, Liver Failure, Acute complications, Lypressin adverse effects, Lypressin analogs & derivatives
- Abstract
There is increasing evidence that terlipressin is useful in patients with cirrhosis and hepatorenal syndrome, but there are no data of its use in patients with acute liver failure (ALF) in whom hepatorenal syndrome is common. Although terlipressin produces systemic vasoconstriction, it produces cerebral vasodilatation and may increase cerebral blood flow (CBF). Increased CBF contributes to intracranial hypertension in patients with ALF. The aim of this study was to evaluate the safety of terlipressin in patients with ALF with respect to cerebral hemodynamics. Six successive patients with ALF were ventilated electively for grade IV hepatic encephalopathy. Patients were monitored invasively and CBF was measured (Kety-Schmidt technique). Measurements were made before and at 1, 3, and 5 hours after intravenous (single bolus) administration of terlipressin (0.005 mg/kg), median, 0.25 mg (range, 0.2-0.3 mg). There was no significant change in heart rate, mean arterial pressure, or cardiac output. CBF and jugular venous oxygen saturation both increased significantly at 1 hour (P = 0.016). Intracranial pressure increased significantly at 1 hour (P = 0.031), returning back to baseline values at 2 hours. In conclusion, administration of terlipressin, at a dose that did not alter systemic hemodynamics, resulted in worsening of cerebral hyperemia and intracranial hypertension in patients with ALF and severe hepatic encephalopathy. These data suggest the need to exercise extreme caution in the use of terlipressin in these patients in view of its potentially deleterious consequences on cerebral hemodynamics.
- Published
- 2004
- Full Text
- View/download PDF
39. The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis.
- Author
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Olde Damink SW, Jalan R, Deutz NE, Redhead DN, Dejong CH, Hynd P, Jalan RA, Hayes PC, and Soeters PB
- Subjects
- Adult, Ammonia metabolism, Blood Circulation, Female, Gastrointestinal Hemorrhage metabolism, Gastrointestinal Hemorrhage physiopathology, Humans, Male, Middle Aged, Varicose Veins complications, Gastrointestinal Hemorrhage etiology, Hyperammonemia etiology, Hyperammonemia physiopathology, Kidney physiopathology, Liver Cirrhosis complications
- Abstract
Upper gastrointestinal (UGI) bleeding in cirrhosis is associated with enhanced ammoniagenesis, the site of which is thought to be the colon. The aims of this study were to evaluate interorgan metabolism of ammonia following an UGI bleed in patients with cirrhosis. Study 1: UGI bleed was simulated in 8 patients with cirrhosis and a transjugular intrahepatic portasystemic stent-shunt (TIPSS) by intragastric infusion of an amino acid solution that mimics the hemoglobin molecule. We sampled blood from the femoral artery and a femoral, renal, portal, and hepatic vein for 4 hours during the simulated bleed and measured plasma flows across these organs. Study 2: In 9 cirrhotic patients with an acute UGI bleed that underwent TIPSS insertion, blood was sampled from an artery and a hepatic, renal, and portal vein, and plasma flows were measured. Study 1: During the simulated bleed, arterial concentrations of ammonia increased significantly (P =.002). There was no change in ammonia production from the portal drained viscera, but renal ammonia production increased 6-fold (P =.008). In contrast to an unchanged ammonia removal by the liver, a significant increase in muscle ammonia removal was observed. Study 2: In patients with an acute UGI bleed, ammonia was only produced by the kidneys (572 [184] nmol/kg bw/min) and not by the splanchnic area (-121 [87] nmol/kg bw/min). In conclusion, enhanced renal ammonia release has an important role in the hyperammonemia that follows an UGI bleed in patients with cirrhosis. During this hyperammonemic state, muscle is the major site of ammonia removal.
- Published
- 2003
- Full Text
- View/download PDF
40. Induced hyperammonemia alters neuropsychology, brain MR spectroscopy and magnetization transfer in cirrhosis.
- Author
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Balata S, Olde Damink SW, Ferguson K, Marshall I, Hayes PC, Deutz NE, Williams R, Wardlaw J, and Jalan R
- Subjects
- Amino Acids blood, Ammonia blood, Body Water metabolism, Female, Glutamine metabolism, Hemoglobins chemistry, Humans, Hyperammonemia chemically induced, Male, Middle Aged, Neuropsychological Tests, Protons, Solutions, Brain metabolism, Hyperammonemia diagnosis, Hyperammonemia psychology, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy
- Abstract
Hyperammonemia is a universal finding after gastrointestinal hemorrhage in cirrhosis. We administered an oral amino acid solution mimicking the hemoglobin molecule to examine neuropsychological changes, brain glutamine levels, and brain magnetization transfer ratio (MTR). Forty-eight metabolically stable patients with cirrhosis and no evidence of "overt" hepatic encephalopathy (HE) were randomized to receive 75 g of amino acid solution or placebo; measurements were performed before and 4 hours after administration. Neuropsychological tests included the Trails B Test, Digit Symbol Substitution Test, memory subtest of the Randt battery, and reaction time. Plasma was collected for ammonia and amino acid measurements, and brain metabolism was studied using proton magnetic resonance (MR) spectroscopy in the first 16 randomized patients. In 7 other patients, MTR was measured. A significant increase in ammonia levels was observed in the amino acid group (amino acid group, 76 +/- 7.3 to 121 +/- 6.4 micromol/L; placebo, 83 +/- 3.3 to 78 +/- 2.9 micromol/L; P <.001). Neuropsychological function improved significantly in the placebo group, but no significant change in neuropsychological function was observed in the amino acid group. Brain glutamate/glutamine (Glx)/creatine (Cr) ratio increased significantly in the amino acid group. MTR decreased significantly from 30 +/-2.9 to 23 +/- 4 (P <.01) after administration of the amino acid solution. In conclusion, an improvement in neuropsychological test results followed placebo, which was not observed in patients administered the amino acid solution. Induced hyperammonemia resulted in an increase in brain Glx/Cr ratio and a decrease in MTR, which may indicate an increase in brain water as the operative mechanism.
- Published
- 2003
- Full Text
- View/download PDF
41. Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS.
- Author
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Olde Damink SW, Jalan R, Redhead DN, Hayes PC, Deutz NE, and Soeters PB
- Subjects
- Female, Humans, Hypertension, Portal metabolism, Hypertension, Portal surgery, Kidney metabolism, Liver metabolism, Male, Middle Aged, Muscle, Skeletal metabolism, Splanchnic Circulation physiology, Amino Acids metabolism, Ammonia metabolism, Liver Cirrhosis metabolism, Liver Cirrhosis surgery, Portasystemic Shunt, Transjugular Intrahepatic
- Abstract
Ammonia is central to the pathogenesis of hepatic encephalopathy. This study was designed to determine the quantitative dynamics of ammonia metabolism in patients with cirrhosis and previous treatment with a transjugular intrahepatic portosystemic stent shunt (TIPSS). We studied 24 patients with cirrhosis who underwent TIPSS portography. Blood was sampled and blood flows were measured across portal drained viscera, leg, kidney, and liver, and arteriovenous differences across the spleen and the inferior and superior mesenteric veins. The highest amount of ammonia was produced by the portal drained viscera. The kidneys also produced ammonia in amounts that equaled total hepatosplanchnic area production. Skeletal muscle removed more ammonia than the cirrhotic liver. The amount of nitrogen that was taken up by muscle in the form of ammonia was less than the glutamine that was released. The portal drained viscera consumed glutamine and produced ammonia, alanine, and citrulline. Urea was released in the splenic and superior mesenteric vein, contributing to whole-body ureagenesis in these cirrhotic patients. In conclusion, hyperammonemia in metabolically stable, overnight-fasted patients with cirrhosis of the liver and a TIPSS results from portosystemic shunting and renal ammonia production. Skeletal muscle removes more ammonia from the circulation than the cirrhotic liver. Muscle releases excessive amounts of the nontoxic nitrogen carrier glutamine, which can lead to ammonia production in the portal drained viscera (PDV) and kidneys. Urinary ammonia excretion and urea synthesis appear to be the only way to remove ammonia from the body.
- Published
- 2002
- Full Text
- View/download PDF
42. Extracorporeal albumin dialysis in acute-on-chronic liver failure: will it stand the test of time?
- Author
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Sen S, Jalan R, and Williams R
- Subjects
- Chronic Disease, Humans, Liver Failure, Acute therapy, Renal Dialysis methods, Serum Albumin metabolism
- Published
- 2002
- Full Text
- View/download PDF
43. Is "Gilbert's" the culprit in indinavir-induced hyperbilirubinemia?
- Author
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Sen S and Jalan R
- Published
- 2002
- Full Text
- View/download PDF
44. Restoration of cerebral blood flow autoregulation and reactivity to carbon dioxide in acute liver failure by moderate hypothermia.
- Author
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Jalan R, Olde Damink SW, Deutz NE, Hayes PC, and Lee A
- Subjects
- Adult, Blood Flow Velocity, Blood Pressure, Female, Humans, Intracranial Hypertension etiology, Intracranial Hypertension therapy, Intracranial Pressure, Liver Failure, Acute complications, Liver Failure, Acute therapy, Male, Middle Aged, Norepinephrine administration & dosage, Vascular Resistance, Brain blood supply, Carbon Dioxide blood, Homeostasis, Hypothermia, Induced, Liver Failure, Acute physiopathology
- Abstract
In patients with acute liver failure (ALF) and uncontrolled intracranial hypertension, moderate hypothermia (32 degrees C) reduces intracranial pressure (ICP) and cerebral blood flow (CBF), and can be used as a bridge to liver transplantation. The purpose of this study was to test the hypothesis that moderate hypothermia reduced ICP by restoring CBF autoregulation. Nine patients with uncontrolled intracranial hypertension and ALF who fulfilled the criteria for poor prognosis were studied. CBF autoregulation and reactivity to carbon dioxide were evaluated before and 4 hours after cooling (32 degrees C). Significant reductions were observed in the ICP (median, 46 [range, 27-54] mm Hg to 19 [15-22] mm Hg; P <.01) and CBF (median, 111 [69-134] to 56 [38-67] mL/100 g/min; P <.05). The defective CBF autoregulation and the absence of reactivity to carbon dioxide that was observed in all patients was restored with cooling. The results of our study suggest that the improvement in ICP observed with hypothermia may be the result of its effects on CBF autoregulation and provides a tool to explore the mechanisms associated with the deranged CBF autoregulation in ALF.
- Published
- 2001
- Full Text
- View/download PDF
45. Altered peripheral vascular responses to exogenous and endogenous endothelin-1 in patients with well-compensated cirrhosis.
- Author
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Helmy A, Jalan R, Newby DE, Johnston NR, Hayes PC, and Webb DJ
- Subjects
- Antihypertensive Agents pharmacology, Endothelin Receptor Antagonists, Endothelin-1 blood, Endothelins blood, Female, Hemodynamics, Humans, Male, Middle Aged, Oligopeptides pharmacology, Peptides, Cyclic pharmacology, Piperidines pharmacology, Protein Precursors blood, Receptor, Endothelin A, Receptor, Endothelin B, Reference Values, Endothelin-1 pharmacology, Endothelin-1 physiology, Forearm blood supply, Liver Cirrhosis physiopathology, Vascular Resistance drug effects, Vascular Resistance physiology
- Abstract
Plasma endothelin concentrations are elevated in cirrhosis and correlate with disease severity. This study assessed forearm vascular responses to exogenous endothelin-1 (ET-1), and evaluated the contribution of endogenous ET-1 to the maintenance of basal peripheral vascular tone in patients with well-compensated cirrhosis (n = 11) and matched healthy controls (n = 8). Bilateral forearm blood flow (FBF) was measured at baseline and following unilateral, subsystemic, intrabrachial artery infusions of ET-1 (2 and 6 pmol/min); BQ-123, a selective ET(A) receptor antagonist (3 and 10 nmol/min); and BQ-788, a selective ET(B) receptor antagonist (0.3 and 1 nmol/min) using venous occlusion plethysmography. Baseline systemic hemodynamics and plasma ET-1 and big ET-1 concentrations were measured using electrical bioimpedance and radioimmunoassay, respectively. Patients and controls had similar baseline FBF, systemic hemodynamics, and plasma ET-1 and big ET-1 concentrations. In both groups, ET-1 and BQ-788 caused significant vasoconstriction (P < .001) and BQ-123 caused significant vasodilatation (P < .001). Compared with controls, cirrhotic patients had attenuated ET-1 responses (P < .001), augmented BQ-123 responses (P < .001), and similar BQ-788 responses (P = .62). Despite normal systemic hemodynamics and plasma ET-1 concentrations, forearm vascular responses to exogenous ET-1 are reduced in cirrhotic patients. The augmented vasodilatation to BQ-123 in cirrhotic patients is consistent with a compensated vasodilated state, and a greater contribution of ET-1 to the maintenance of basal vascular tone acting through the ET(A) receptor.
- Published
- 2001
- Full Text
- View/download PDF
46. UROTENSIN II: BETTER THAN SOMATOSTATIN FOR PORTAL HYPERTENSION?
- Author
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Newby DE and Jalan R
- Published
- 2000
- Full Text
- View/download PDF
47. Diagnosis of hepatic encephalopathy: will in vivo proton MRS play a role?
- Author
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Jalan R, Olde Damink SW, Hayes PC, and Wardlaw JM
- Subjects
- Administration, Oral, Brain metabolism, Brain pathology, Hepatic Encephalopathy drug therapy, Hepatic Encephalopathy metabolism, Humans, Lactulose therapeutic use, Hepatic Encephalopathy diagnosis, Magnetic Resonance Imaging
- Published
- 1999
- Full Text
- View/download PDF
48. TIPSS trials: design determines outcome.
- Author
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Jalan R, Finlayson ND, and Hayes PC
- Subjects
- Clinical Trials as Topic, Endoscopy, Esophageal Diseases prevention & control, Hemorrhage prevention & control, Humans, Propranolol therapeutic use, Randomized Controlled Trials as Topic, Recurrence, Research Design, Sclerotherapy, Treatment Outcome, Esophageal Diseases therapy, Esophageal and Gastric Varices therapy, Hemorrhage therapy, Portasystemic Shunt, Transjugular Intrahepatic
- Published
- 1997
- Full Text
- View/download PDF
49. A randomized trial comparing transjugular intrahepatic portosystemic stent-shunt with variceal band ligation in the prevention of rebleeding from esophageal varices.
- Author
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Jalan R, Forrest EH, Stanley AJ, Redhead DN, Forbes J, Dillon JF, MacGilchrist AJ, Finlayson ND, and Hayes PC
- Subjects
- Adolescent, Adult, Aged, Brain Diseases complications, Esophageal and Gastric Varices complications, Esophageal and Gastric Varices mortality, Female, Health Care Costs, Humans, Infections etiology, Length of Stay, Male, Middle Aged, Postoperative Complications, Recurrence, Esophageal Diseases prevention & control, Esophageal and Gastric Varices surgery, Hemorrhage prevention & control, Ligation economics, Portasystemic Shunt, Transjugular Intrahepatic adverse effects, Portasystemic Shunt, Transjugular Intrahepatic economics
- Abstract
The aim of this study was to compare transjugular intrahepatic portosystemic stent-shunt (TIPSS) with variceal band ligation (VBL) in the secondary prophylaxis of esophageal variceal hemorrhage in patients with cirrhosis. Fifty-eight patients with cirrhosis who presented with the first episode of esophageal variceal hemorrhage were randomized to TIPSS (31) or VBL (27), 24 hours after control of bleeding. Shunt function was assessed after 1 month and then at 6 monthly intervals thereafter. VBL was performed weekly until variceal eradication, and then at 3 months, 6 months, and yearly thereafter. Mean follow-up in the TIPSS group was 15.7 (+/-10.2) months; in the VBL group, it was 16.8 (+/-10.9) months. Results for rebleeding and mortality were analyzed on an intention-to-treat basis and using the Kaplan-Meier method. The frequency and the severity of variceal rebleeding was significantly lower in the TIPSS group (9.8%), compared with the VBL group (51.9%) (P < .0006). Although mortality rates were not significantly different, 8 of the patients who rebled in the VBL group required TIPSS therapy for uncontrolled bleeding. No significant differences were found in the frequency of other complications such as encephalopathy and sepsis. Patients in the VBL group required significantly greater time in the intensive care unit during the period of this study (<0.03). The total direct cost of treatment incurred was pound sterling 1,373 ($2,200) per patient, the cost being less in the patients treated with TIPSS compared with VBL. The results of this study show that TIPSS is superior to VBL for the secondary prophylaxis of variceal hemorrhage in patients with cirrhosis.
- Published
- 1997
- Full Text
- View/download PDF
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