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Lim HJ, Kwak HJ. Selective PPARδ Agonist GW501516 Protects Against LPS-Induced Macrophage Inflammation and Acute Liver Failure in Mice via Suppressing Inflammatory Mediators. Molecules 2024; 29:5189. [PMID: 39519830 PMCID: PMC11547330 DOI: 10.3390/molecules29215189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/29/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
Inflammation is critical in the development of acute liver failure (ALF). Peroxisome proliferator-activated receptor delta (PPARδ) regulates anti-inflammatory responses and is protective in several diseases such as obesity and cancer. However, the beneficial effects and underlying mechanisms of PPARδ agonist GW501516 in ALF remain unclear. This study investigated the molecular mechanisms underlying the anti-inflammatory effects of GW501516 in macrophages and assessed its protective potential against lipopolysaccharide (LPS)/galactosamine (GalN)-induced ALF. In vivo administration of GW501516 significantly reduced LPS/GalN-induced hepatotoxicity, as evidenced by lower mortality, decreased liver damage, and attenuated secretion of IL-1β, IL-6, and TNF-α. GW501516 treatment also decreased LPS-induced nitric oxide synthase 2 (NOS2) expression and nitric oxide (NO) production in RAW264.7 cells, an effect reversed by PPARδ siRNA. Additionally, GW501516 inhibited LPS-induced phosphorylation of p38 and c-Jun N-terminal kinase (JNK), suggesting that inactivation of these MAPKs contributes to its effects. The secretion of IL-6, TNF-α, and NF-κB DNA-binding activity were also suppressed by GW501516, while the nuclear translocation of the NF-κB p65 subunit was unaffected. In conclusion, our findings suggest that GW501516 exerts protective effects in ALF by inhibiting the production of inflammatory mediators. Therefore, GW501516 may act as a potential agent for developing anti-inflammatory therapies for ALF.
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Affiliation(s)
- Hyun-Joung Lim
- Division of Cardiovascular Diseases Research, Department of Chronic Diseases Convergence, National Institute of Health, Cheongju 28159, Republic of Korea;
| | - Hyun Jeong Kwak
- Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 02707, Republic of Korea
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2
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Wolpert BM, Rothgerber DJ, Rosner AK, Brunier M, Kuchen R, Schramm P, Griemert EV. Evaluation of dynamic cerebrovascular autoregulation during liver transplantation. PLoS One 2024; 19:e0305658. [PMID: 39058695 PMCID: PMC11280153 DOI: 10.1371/journal.pone.0305658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 06/03/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND Cerebrovascular autoregulation in patients with acute and chronic liver failure is often impaired, yet an intact autoregulation is essential for the demand-driven supply of oxygenated blood to the brain. It is unclear, whether there is a connection between cerebrovascular autoregulation during liver transplantation (LTX) and the underlying disease, and if perioperative anesthesiologic consequences can result from this. METHODS In this prospective observational pilot study, data of twenty patients (35% female) undergoing LTX were analyzed. Cerebral blood velocity was measured using transcranial doppler sonography and was correlated with arterial blood pressure. The integrity of dynamic cerebrovascular autoregulation (dCA) was evaluated in the frequency domain through transfer function analysis (TFA). Standard clinical parameters were recorded. Mixed one-way ANOVA and generalized estimating equations were fitted to data involving repeated measurements on the same patient. For all other correlation analyses, Spearman's rank correlation coefficient (Spearman's-Rho) was used. RESULTS Indications of impaired dCA are seen in frequency domain during different phases of LTX. No correlation was found between various parameter of dCA and primary disease, delirium, laboratory values, length of ICU or hospital stay, mortality or surgical technique. CONCLUSIONS Although in most cases the dCA has been impaired during LTX, the heterogeneity of the underlying diseases seems to be too diverse to draw valid conclusions from this observational pilot study.
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Affiliation(s)
- Bente Marei Wolpert
- Department of Anesthesiology, University Medical Centre of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - David Jonas Rothgerber
- Department of Anesthesiology, University Medical Centre of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Ann Kristin Rosner
- Department of Anesthesiology, University Medical Centre of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Malte Brunier
- Department of Anesthesiology, University Medical Centre of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Robert Kuchen
- Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Centre of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Patrick Schramm
- Department of Neurology, University Hospital of the Justus-Liebig-University Giessen, Giessen, Germany
| | - Eva-Verena Griemert
- Department of Anesthesiology, University Medical Centre of the Johannes-Gutenberg University Mainz, Mainz, Germany
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3
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L'Écuyer S, Charbonney E, Carrier FM, Rose CF. Implication of Hypotension in the Pathogenesis of Cognitive Impairment and Brain Injury in Chronic Liver Disease. Neurochem Res 2024; 49:1437-1449. [PMID: 36635437 DOI: 10.1007/s11064-022-03854-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/23/2022] [Accepted: 12/26/2022] [Indexed: 01/14/2023]
Abstract
The incidence of chronic liver disease is on the rise. One of the primary causes of hospital admissions for patients with cirrhosis is hepatic encephalopathy (HE), a debilitating neurological complication. HE is defined as a reversible syndrome, yet there is growing evidence stating that, under certain conditions, HE is associated with permanent neuronal injury and irreversibility. The pathophysiology of HE primarily implicates a strong role for hyperammonemia, but it is believed other pathogenic factors are involved. The fibrotic scarring of the liver during the progression of chronic liver disease (cirrhosis) consequently leads to increased hepatic resistance and circulatory anomalies characterized by portal hypertension, hyperdynamic circulatory state and systemic hypotension. The possible repercussions of these circulatory anomalies on brain perfusion, including impaired cerebral blood flow (CBF) autoregulation, could be implicated in the development of HE and/or permanent brain injury. Furthermore, hypotensive insults incurring during gastrointestinal bleed, infection, or liver transplantation may also trigger or exacerbate brain dysfunction and cell damage. This review will focus on the role of hypotension in the onset of HE as well as in the occurrence of neuronal cell loss in cirrhosis.
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Affiliation(s)
- Sydnée L'Écuyer
- Hepato-Neuro Laboratory, Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), 900, rue Saint-Denis - Pavillon R, R08.422 Montréal (Québec), Québec, H2X 0A9, Canada
| | - Emmanuel Charbonney
- Department of Medicine, Critical Care Division, Centre Hospitalier de l'Université de Montréal, Montréal, Canada
| | - François Martin Carrier
- Department of Medicine, Critical Care Division, Centre Hospitalier de l'Université de Montréal, Montréal, Canada
- Department of Anesthesiology, Centre Hospitalier de l'Université de Montréal, Montréal, Canada
- Carrefour de l'innovation et santé des populations , Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada
| | - Christopher F Rose
- Hepato-Neuro Laboratory, Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), 900, rue Saint-Denis - Pavillon R, R08.422 Montréal (Québec), Québec, H2X 0A9, Canada.
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Sepehrinezhad A, Stolze Larsen F, Ashayeri Ahmadabad R, Shahbazi A, Sahab Negah S. The Glymphatic System May Play a Vital Role in the Pathogenesis of Hepatic Encephalopathy: A Narrative Review. Cells 2023; 12:cells12070979. [PMID: 37048052 PMCID: PMC10093707 DOI: 10.3390/cells12070979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 02/20/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
Hepatic encephalopathy (HE) is a neurological complication of liver disease resulting in cognitive, psychiatric, and motor symptoms. Although hyperammonemia is a key factor in the pathogenesis of HE, several other factors have recently been discovered. Among these, the impairment of a highly organized perivascular network known as the glymphatic pathway seems to be involved in the progression of some neurological complications due to the accumulation of misfolded proteins and waste substances in the brain interstitial fluids (ISF). The glymphatic system plays an important role in the clearance of brain metabolic derivatives and prevents aggregation of neurotoxic agents in the brain ISF. Impairment of it will result in aggravated accumulation of neurotoxic agents in the brain ISF. This could also be the case in patients with liver failure complicated by HE. Indeed, accumulation of some metabolic by-products and agents such as ammonia, glutamine, glutamate, and aromatic amino acids has been reported in the human brain ISF using microdialysis technique is attributed to worsening of HE and correlates with brain edema. Furthermore, it has been reported that the glymphatic system is impaired in the olfactory bulb, prefrontal cortex, and hippocampus in an experimental model of HE. In this review, we discuss different factors that may affect the function of the glymphatic pathways and how these changes may be involved in HE.
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Affiliation(s)
- Ali Sepehrinezhad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
| | - Fin Stolze Larsen
- Department of Gastroenterology and Hepatology, Rigshospitalet, Copenhagen University Hospital, 999017 Copenhagen, Denmark
| | | | - Ali Shahbazi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Sajad Sahab Negah
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran 1449614535, Iran
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Kang MW, Kim S, Kim YC, Kim DK, Oh KH, Joo KW, Kim YS, Han SS. Machine learning model to predict hypotension after starting continuous renal replacement therapy. Sci Rep 2021; 11:17169. [PMID: 34433892 PMCID: PMC8387375 DOI: 10.1038/s41598-021-96727-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 08/13/2021] [Indexed: 12/20/2022] Open
Abstract
Hypotension after starting continuous renal replacement therapy (CRRT) is associated with worse outcomes compared with normotension, but it is difficult to predict because several factors have interactive and complex effects on the risk. The present study applied machine learning algorithms to develop models to predict hypotension after initiating CRRT. Among 2349 adult patients who started CRRT due to acute kidney injury, 70% and 30% were randomly assigned into the training and testing sets, respectively. Hypotension was defined as a reduction in mean arterial pressure (MAP) ≥ 20 mmHg from the initial value within 6 h. The area under the receiver operating characteristic curves (AUROCs) in machine learning models, such as support vector machine (SVM), deep neural network (DNN), light gradient boosting machine (LGBM), and extreme gradient boosting machine (XGB) were compared with those in disease-severity scores such as the Sequential Organ Failure Assessment and Acute Physiology and Chronic Health Evaluation II. The XGB model showed the highest AUROC (0.828 [0.796-0.861]), and the DNN and LGBM models followed with AUROCs of 0.822 (0.789-0.856) and 0.813 (0.780-0.847), respectively; all machine learning AUROC values were higher than those obtained from disease-severity scores (AUROCs < 0.6). Although other definitions of hypotension were used such as a reduction of MAP ≥ 30 mmHg or a reduction occurring within 1 h, the AUROCs of machine learning models were higher than those of disease-severity scores. Machine learning models successfully predict hypotension after starting CRRT and can serve as the basis of systems to predict hypotension before starting CRRT.
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Affiliation(s)
- Min Woo Kang
- Department of Internal Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Seonmi Kim
- Department of Internal Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Yong Chul Kim
- Department of Internal Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Dong Ki Kim
- Department of Internal Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Kook-Hwan Oh
- Department of Internal Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Kwon Wook Joo
- Department of Internal Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Yon Su Kim
- Department of Internal Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Seung Seok Han
- Department of Internal Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.
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Xu Y, Testro A, Wong A. Analysis of the Australia and New Zealand referral criteria for transfer to a liver unit for paracetamol overdose. Emerg Med Australas 2021; 33:1021-1026. [PMID: 33946130 DOI: 10.1111/1742-6723.13795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 03/11/2021] [Accepted: 04/17/2021] [Indexed: 11/30/2022]
Abstract
OBJECTIVES Paracetamol overdose is common and can lead to fulminant hepatic failure. In cases that are not improving with standard medical therapy with N-acetylcysteine, some patients may require liver transplant. The Australia and New Zealand (ANZ) referral criteria for transfer to a liver unit have not been extensively studied for its predictive value. The aim of this study was to evaluate the ANZ referral criteria for predicting mortality in paracetamol overdose. METHODS This study involves a retrospective analysis of patients who developed hepatotoxicity post-paracetamol overdose presenting to an Australian health service with a liver transplant unit between 2010 and 2019 and were treated with N-acetylcysteine. The primary outcome was death or transplant. RESULTS Out of 983 paracetamol overdose presentations, 81 (8.2%) cases developed hepatotoxicity. Of these, 17 cases (21%) met the composite endpoint of death or transplant. The ANZ referral criteria is highly sensitive at predicting the primary endpoint of death or transplant at time of referral 100% (95% confidence interval 81-100) but had low specificity at 30% (95% confidence interval 19-42). CONCLUSIONS The ANZ referral criteria were highly sensitive for predicting the outcome of mortality and transplant. This is important for screening patients who may become unstable and difficult to transfer at a later stage of their admission.
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Affiliation(s)
- Yifan Xu
- Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia
| | - Adam Testro
- Liver Transplant Unit, Austin Health, Melbourne, Victoria, Australia
| | - Anselm Wong
- Department of Critical Care, The University of Melbourne, Melbourne, Victoria, Australia.,Emergency Department, Austin Health, Melbourne, Victoria, Australia.,Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria, Australia
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Abstract
This article introduces the basic concepts of intracranial physiology and pressure dynamics. It also includes discussion of signs and symptoms and examination and radiographic findings of patients with acute cerebral herniation as a result of increased as well as decreased intracranial pressure. Current best practices regarding medical and surgical treatments and approaches to management of intracranial hypertension as well as future directions are reviewed. Lastly, there is discussion of some of the implications of critical medical illness (sepsis, liver failure, and renal failure) and treatments thereof on causation or worsening of cerebral edema, intracranial hypertension, and cerebral herniation.
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Affiliation(s)
- Aleksey Tadevosyan
- Department of Neurology, Tufts University School of Medicine, Beth Israel Lahey Hospital and Medical Center, 41 Mall Road, Burlington, MA 01805, USA.
| | - Joshua Kornbluth
- Department of Neurology, Tufts University School of Medicine, Tufts Medical Center, 800 Washington Street, Box#314, Boston, MA 02111, USA
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8
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Huang YQ, Tremblay JA, Chapdelaine H, Luong ML, Carrier FM. Pulmonary mucormycosis in a patient with acute liver failure: A case report and systematic review of the literature. J Crit Care 2019; 56:89-93. [PMID: 31881411 DOI: 10.1016/j.jcrc.2019.12.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 12/05/2019] [Accepted: 12/11/2019] [Indexed: 12/14/2022]
Abstract
PURPOSE Pulmonary mucormycosis is a highly lethal invasive fungal infection usually found in immunocompromised patients. We report herein the case of an adult woman who developed pulmonary mucormycosis with possible systemic dissemination after recovering from acute liver failure secondary to acetaminophen overdose. RESULTS Our case developed an invasive pulmonary mucormycosis with probable systemic dissemination. She did not suffer from any immunocompromising disease other than severe acute liver failure. She did not survive the disease, although she received appropriate antifungal treatment. We also performed a systematic review of the literature on pulmonary mucormycosis, with or without dissemination, in immunocompetent patients. We found 16 cases of pulmonary or disseminated mucormycosis in immunocompetent patients. Fifty-seven percent of them died and none occurred after an acute liver failure episode. CONCLUSION This case report is the first one to present an invasive pulmonary mucormycosis infection after acute liver failure in an adult patient. The clinical course of this disease is highly lethal, even in immunocompetent adults.
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Affiliation(s)
- Yu Qing Huang
- Department of Medicine, University of Montreal, Canada
| | | | - Hugo Chapdelaine
- Department of Medicine, Division of Immunology, University of Montreal Hospital Centre, Canada; University of Montreal Hospital Research Center, Canada; Montreal Clinical Research Institute, Canada
| | - Me-Linh Luong
- University of Montreal Hospital Research Center, Canada; Department of Medicine, Division of Infectious diseases, University of Montreal Hospital Centre, Canada
| | - François Martin Carrier
- University of Montreal Hospital Research Center, Canada; Department of Anesthesiology and Department of Medicine, Division of Critical Care, University of Montreal Hospital Centre, Canada.
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Bjerring PN, Bjerrum EJ, Larsen FS. Impaired cerebral microcirculation induced by ammonium chloride in rats is due to cortical adenosine release. J Hepatol 2018; 68:1137-1143. [PMID: 29452205 DOI: 10.1016/j.jhep.2018.01.034] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 01/28/2018] [Accepted: 01/30/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Liver failure results in hyperammonaemia, impaired regulation of cerebral microcirculation, encephalopathy, and death. However, the key mediator that alters cerebral microcirculation remains unidentified. In this study we show that topically applied ammonium significantly increases periarteriolar adenosine tone on the brain surface of healthy rats and is associated with a disturbed microcirculation. METHODS Cranial windows were prepared in anaesthetized Wistar rats. The flow velocities were measured by speckle contrast imaging and compared before and after 30 min of exposure to 10 mM ammonium chloride applied on the brain surface. These flow velocities were compared with those for control groups exposed to artificial cerebrospinal fluid or ammonium plus an adenosine receptor antagonist. A flow preservation curve was obtained by analysis of flow responses to a haemorrhagic hypotensive challenge and during stepwise exsanguination. The periarteriolar adenosine concentration was measured with enzymatic biosensors inserted in the cortex. RESULTS After ammonium exposure the arteriolar flow velocity increased by a median (interquartile range) of 21.7% (23.4%) vs. 7.2% (10.2%) in controls (n = 10 and n = 6, respectively, p <0.05), and the arteriolar surface area increased. There was a profound rise in the periarteriolar adenosine concentration. During the hypotensive challenge the flow decreased by 27.8% (14.9%) vs. 9.2% (14.9%) in controls (p <0.05). The lower limit of flow preservation remained unaffected, 27.7 (3.9) mmHg vs. 27.6 (6.4) mmHg, whereas the autoregulatory index increased, 0.29 (0.33) flow units per millimetre of mercury vs. 0.03 (0.21) flow units per millimetre of mercury (p <0.05). When ammonium exposure was combined with topical application of an adenosine receptor antagonist, the autoregulatory index was normalized. CONCLUSIONS Vasodilation of the cerebral microcirculation during exposure to ammonium chloride is associated with an increase in the adenosine tone. Application of a specific adenosine receptor antagonist restores the regulation of the microcirculation. This indicates that adenosine could be a key mediator of the brain dysfunction seen during hyperammonaemia and is a potential therapeutic target. LAY SUMMARY In patients with liver failure, disturbances in brain function are caused in part by ammonium toxicity. In our project we studied how ammonia, through adenosine release, affects the blood flow in the brain of rats. In our experimental model we demonstrated that the detrimental effect of ammonia on blood flow regulation was counteracted by blocking the adenosine receptors in the brain. With this observation we identified a novel potential treatment target. If we can confirm our findings in a future clinical study, this might help patients with liver failure and the severe condition called hepatic encephalopathy.
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Affiliation(s)
- Peter Nissen Bjerring
- Department of Hepatology, Rigshospitalet, Copenhagen, Denmark; The Gastro Unit, Medical Section, Hvidovre Hospital, Hvidovre, Denmark.
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Thiel K, Klingert W, Klingert K, Morgalla MH, Schuhmann MU, Leckie P, Sharifi Y, Davies NA, Jalan R, Peter A, Grasshoff C, Königsrainer A, Schenk M, Thiel C. Porcine model characterizing various parameters assessing the outcome after acetaminophen intoxication induced acute liver failure. World J Gastroenterol 2017; 23:1576-1585. [PMID: 28321158 PMCID: PMC5340809 DOI: 10.3748/wjg.v23.i9.1576] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 01/24/2017] [Accepted: 02/17/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the changes of hemodynamic and laboratory parameters during the course of acute liver failure following acetaminophen overdose.
METHODS Eight pigs underwent a midline laparotomy following jejunal catheter placement for further acetaminophen intoxication and positioning of a portal vein Doppler flow-probe. Acute liver failure was realized by intrajejunal acetaminophen administration in six animals, two animals were sham operated. All animals were invasively monitored and received standardized intensive care support throughout the study. Portal blood flow, hemodynamic and ventilation parameters were continuously recorded. Laboratory parameters were analysed every eight hours. Liver biopsies were sampled every 24 h following intoxication and upon autopsy.
RESULTS Acute liver failure (ALF) occurred after 28 ± 5 h resulted in multiple organ failure and death despite maximal support after further 21 ± 1 h (study end). Portal blood flow (baseline 1100 ± 156 mL/min) increased to a maximum flow of 1873 ± 175 mL/min at manifestation of ALF, which was significantly elevated (P < 0.01). Immediately after peaking, portal flow declined rapidly to 283 ± 135 mL/min at study end. Thrombocyte values (baseline 307 × 103/µL ± 34 × 103/µL) of intoxicated animals declined slowly to values of 145 × 103/µL ± 46 × 103/µL when liver failure occurred. Subsequent appearance of severe thrombocytopenia in liver failure resulted in values of 11 × 103/µL ± 3 × 103/µL preceding fatality within few hours which was significant (P > 0.01).
CONCLUSION Declining portal blood flow and subsequent severe thrombocytopenia after acetaminophen intoxication precede fatality in a porcine acute liver failure model.
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Brent J, Burkhart K, Dargan P, Hatten B, Megarbane B, Palmer R, White J. Toxicant-Induced Hepatic Injury. CRITICAL CARE TOXICOLOGY 2017. [PMCID: PMC7123957 DOI: 10.1007/978-3-319-17900-1_75] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The sudden failure of a previously healthy and functioning liver is a dramatic and devastating event. Acute liver failure is the common final pathway of a multitude of conditions and insults, all of which result in massive hepatic necrosis or loss of normal hepatic function. The ensuing multiorgan system failure frequently has a fatal outcome, with mortality rates in most series ranging from approximately 55% to 95% [1]. Acute liver failure (ALF, previously often referred to as fulminant hepatic failure (FHF)) knows no age boundaries, with many cases occurring in those younger than 30 years. Short of excellent intensive care unit (ICU) support and liver transplantation in selected cases, few viable treatment options are available. Over the past few decades, however, survival has been improved by anticipation, recognition, and early treatment of associated complications, as well as the application of prognostic criteria for early identification of patients requiring liver transplantation (along with improvement in the techniques and science of transplantation itself). The etiology of ALF varies from country to country and the incidence change over time. Paracetamol (acetaminophen) has now replaced viral hepatitis as the leading cause of ALF [2]. In a study from London including 310 patients with ALF in the period 1994–2004, 42% of the cases were caused by paracetamol [3], whereas this was only the cause in 2% of 267 patients in Spain from 1992 to 2000 [4]. However, less than 10% of all liver transplants are performed in patients with ALF [5, 6].
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Affiliation(s)
- Jeffrey Brent
- Department of Medicine, Division of Clinical Pharmacology and Toxicology, University of Colorado, School of Medicine, Aurora, Colorado USA
| | - Keith Burkhart
- FDA, Office of New Drugs/Immediate Office, Center for Drug Evaluation and Research, Silver Spring, Maryland USA
| | - Paul Dargan
- Clinical Toxicology, St Thomas’ Hospital, Silver Spring, Maryland USA
| | - Benjamin Hatten
- Toxicology Associates, University of Colorado, School of Medicine, Denver, Colorado USA
| | - Bruno Megarbane
- Medical Toxicological Intensive Care Unit, Lariboisiere Hospital, Paris-Diderot University, Paris, France
| | - Robert Palmer
- Toxicology Associates, University of Colorado, School of Medicine, Denver, Colorado USA
| | - Julian White
- Toxinology Department, Women’s and Children’s Hospital, North Adelaide, South Australia Australia
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MRI-based assessment of liver perfusion and hepatocyte injury in the murine model of acute hepatitis. MAGNETIC RESONANCE MATERIALS IN PHYSICS BIOLOGY AND MEDICINE 2016; 29:789-798. [PMID: 27160299 PMCID: PMC5124046 DOI: 10.1007/s10334-016-0563-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2016] [Revised: 04/09/2016] [Accepted: 04/20/2016] [Indexed: 01/23/2023]
Abstract
OBJECTIVE To assess alterations in perfusion and liver function in the concanavalin A (ConA)-induced mouse model of acute liver failure (ALF) using two magnetic resonance imaging (MRI)-based methods: dynamic contrast-enhanced MRI (DCE-MRI) with Gd-EOB-DTPA contrast agent and arterial spin labelling (ASL). MATERIALS AND METHODS BALB/c mice were studied using a 9.4 T MRI system. The IntraGateFLASHTM and FAIR-EPI pulse sequences were used for optimum mouse abdomen imaging. RESULTS The average perfusion values for the liver of the control and ConA group were equal to 245 ± 20 and 200 ± 32 ml/min/100 g (p = 0.008, respectively). DCE-MRI showed that the time to the peak of the image enhancement was 6.14 ± 1.07 min and 9.72 ± 1.69 min in the control and ConA group (p < 0.001, respectively), while the rate of the contrast wash-out in the control and ConA group was 0.037 ± 0.008 and 0.021 ± 0.008 min-1 (p = 0.004, respectively). These results were consistent with hepatocyte injury in the ConA-treated mice as confirmed by histopathological staining. CONCLUSIONS Both the ASL and DCE-MRI techniques represent a reliable methodology to assess alterations in liver perfusion and hepatocyte integrity in murine hepatitis.
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Bernal W, Lee WM, Wendon J, Larsen FS, Williams R. Acute liver failure: A curable disease by 2024? J Hepatol 2015; 62:S112-20. [PMID: 25920080 DOI: 10.1016/j.jhep.2014.12.016] [Citation(s) in RCA: 180] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Revised: 12/04/2014] [Accepted: 12/10/2014] [Indexed: 12/12/2022]
Abstract
Over the last three decades acute liver failure (ALF) has been transformed from a rare and poorly understood condition with a near universally fatal outcome, to one with a well characterized phenotype and disease course. Complex critical care protocols are now applied and emergency liver transplantation (ELT) is an established treatment option. These improvements in care are such that the majority of patients may now be expected to survive (Fig. 1). Key features of the condition have changed dramatically over time, with a remarkable fall in the incidence of cerebral edema and intracranial hypertension, a much feared complication. In this review, we summarize the current understanding of key aspects of the classification, pathophysiology and management of ALF, and discuss the foreseeable challenges that will need to be addressed for further improvements to be achieved.
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Affiliation(s)
- William Bernal
- Liver Intensive Therapy Unit, Institute of Liver Studies, Kings College Hospital, Denmark Hill, London SE5 9RS, United Kingdom.
| | - William M Lee
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8887, USA
| | - Julia Wendon
- Liver Intensive Therapy Unit, Institute of Liver Studies, Kings College Hospital, Denmark Hill, London SE5 9RS, United Kingdom
| | | | - Roger Williams
- Institute of Hepatology London, Foundation for Liver Research, 69-75 Chenies Mews, London WC1 6HX, United Kingdom
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Karvellas CJ, Cavazos J, Battenhouse H, Durkalski V, Balko J, Sanders C, Lee WM. Effects of antimicrobial prophylaxis and blood stream infections in patients with acute liver failure: a retrospective cohort study. Clin Gastroenterol Hepatol 2014. [PMID: 24674942 DOI: 10.106/j.cgh.2014.03.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND & AIMS We investigated whether antimicrobial prophylaxis alters the incidence of bloodstream infection in patients with acute liver failure (ALF), and whether bloodstream infections affect overall mortality within 21 days after development of ALF. METHODS We performed a retrospective cohort analysis of 1551 patients with ALF enrolled by the US Acute Liver Failure Study Group from January 1998 through November 2009. We analyzed data on infections in the first 7 days after admission and the effects of prophylaxis with antimicrobial drugs on the development of bloodstream infections and 21-day mortality. RESULTS In our study population, 600 patients (39%) received antimicrobial prophylaxis and 226 patients (14.6%) developed at least 1 bloodstream infection. Exposure to antimicrobial drugs did not affect the proportion of patients who developed bloodstream infections (12.8% in patients with prophylaxis vs 15.7% in nonprophylaxed patients; P = .12), but a greater percentage of patients who received prophylaxis received liver transplants (28% vs 22%; P = .01). After adjusting for confounding factors, overall mortality within 21 days was associated independently with age (odds ratio [OR], 1.014), Model for End-stage Liver Disease score at admission (OR, 1.078), and vasopressor administration at admission (OR, 2.499). Low grade of coma (OR, 0.47) and liver transplantation (OR, 0.101) reduced mortality. Although bloodstream infection was associated significantly with 21-day mortality (P = .004), an interaction between bloodstream infection and etiology was detected: blood stream infection affected mortality to a greater extent in nonacetaminophen ALF patients (OR, 2.03) than in acetaminophen ALF patients (OR, 1.14). CONCLUSIONS Based on a large, observational study, antimicrobial prophylaxis does not reduce the incidence of bloodstream infection or mortality within 21 days of ALF. However, bloodstream infections were associated with increased 21-day mortality in patients with ALF-to a greater extent in patients without than with acetaminophen-associated ALF. Our findings do not support the routine use of antimicrobial prophylaxis in patients with ALF.
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Affiliation(s)
| | - Jorge Cavazos
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Holly Battenhouse
- Faculty of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Valerie Durkalski
- Faculty of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Jody Balko
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Corron Sanders
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas
| | - William M Lee
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas.
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Effects of antimicrobial prophylaxis and blood stream infections in patients with acute liver failure: a retrospective cohort study. Clin Gastroenterol Hepatol 2014; 12:1942-9.e1. [PMID: 24674942 PMCID: PMC4205208 DOI: 10.1016/j.cgh.2014.03.011] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Revised: 03/11/2014] [Accepted: 03/12/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We investigated whether antimicrobial prophylaxis alters the incidence of bloodstream infection in patients with acute liver failure (ALF), and whether bloodstream infections affect overall mortality within 21 days after development of ALF. METHODS We performed a retrospective cohort analysis of 1551 patients with ALF enrolled by the US Acute Liver Failure Study Group from January 1998 through November 2009. We analyzed data on infections in the first 7 days after admission and the effects of prophylaxis with antimicrobial drugs on the development of bloodstream infections and 21-day mortality. RESULTS In our study population, 600 patients (39%) received antimicrobial prophylaxis and 226 patients (14.6%) developed at least 1 bloodstream infection. Exposure to antimicrobial drugs did not affect the proportion of patients who developed bloodstream infections (12.8% in patients with prophylaxis vs 15.7% in nonprophylaxed patients; P = .12), but a greater percentage of patients who received prophylaxis received liver transplants (28% vs 22%; P = .01). After adjusting for confounding factors, overall mortality within 21 days was associated independently with age (odds ratio [OR], 1.014), Model for End-stage Liver Disease score at admission (OR, 1.078), and vasopressor administration at admission (OR, 2.499). Low grade of coma (OR, 0.47) and liver transplantation (OR, 0.101) reduced mortality. Although bloodstream infection was associated significantly with 21-day mortality (P = .004), an interaction between bloodstream infection and etiology was detected: blood stream infection affected mortality to a greater extent in nonacetaminophen ALF patients (OR, 2.03) than in acetaminophen ALF patients (OR, 1.14). CONCLUSIONS Based on a large, observational study, antimicrobial prophylaxis does not reduce the incidence of bloodstream infection or mortality within 21 days of ALF. However, bloodstream infections were associated with increased 21-day mortality in patients with ALF-to a greater extent in patients without than with acetaminophen-associated ALF. Our findings do not support the routine use of antimicrobial prophylaxis in patients with ALF.
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Kularatne SAM, Imbulpitiya IVB, Abeysekera RA, Waduge RN, Rajapakse RPVJ, Weerakoon KGAD. Extensive haemorrhagic necrosis of liver is an unpredictable fatal complication in dengue infection: a postmortem study. BMC Infect Dis 2014; 14:141. [PMID: 24628767 PMCID: PMC4008311 DOI: 10.1186/1471-2334-14-141] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Accepted: 03/10/2014] [Indexed: 12/31/2022] Open
Abstract
Background Dengue infection carries a potential risk of death despite stringent management of plasma leak and haemorrhage. It appears that the extent of liver dysfunction determines the outcome. Methods We present a postmortem study of five patients, died of dengue shock syndrome who had markedly elevated liver enzymes and irreparable circulatory failure. Results All were females with a median age of 46 years (range 20–50 years). All had positive NS1 and IgM. Clinically, one patient developed severe degree of hepatic encephalopathy whilst three patients developed uncontrollable bleeding manifestations. Dengue virus was detected in three liver specimens by reverse transcription PCR. Histology of the liver revealed massive necrosis with haemorrhages in these patients with evidence of micro and macrovesicular steatosis with significant periportal inflammatory infiltrate. No significant ischaemic changes or necrosis was observed in the other organs. Conclusions Severe haemorrhagic necrosis of the liver was the cause of death in these patients probably due to direct viral infection. Predilection for severe liver disease remains unknown. Therefore, it is prudent to think beyond plasma leak as the main pathology of dengue infection and attempts should be made to develop other treatment modalities to prevent and manage unforeseen fatal complications of dengue infection.
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Audimooolam VK, McPhail MJW, Sherwood R, Willars C, Bernal W, Wendon JA, Auzinger G. Elevated troponin I and its prognostic significance in acute liver failure. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2012. [PMID: 23190744 PMCID: PMC3672613 DOI: 10.1186/cc11883] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Introduction Acute liver failure (ALF) is a life-threatening multisystem illness complicated by multiple organ failure (MOF) and haemodynamic disturbances. Morbidity and mortality remains high and various prognostic and scoring models are in use to predict outcome. A recent observation in a large cohort of ALF patients suggested a prognostic value of troponin I (cTnI) and its role as a marker of subclinical myocardial injury and outcome. Methods Data from consecutive ALF patients over a four-year period from January 2007 to March 2011 were included. The aim of this study was to correlate any relationship that may exist between cTnI, mortality, severity of illness and non-hepatic organ failure. Results A total of 218 subjects (age 36 (16 to 90) years, M:F 103:115) were studied, of which 136 had an elevated cTnI > 0.05 μg/L. Higher organ failure scores were found with positive cTnI: APACHE II (19.5 (3 to 51) vs 14 (2 to 51), P = 0.001), APACHE III (81 (15 to 148) vs 59 (8 to 172), P = < 0.001) SOFA (15 (4 to 20) vs 13 (2 to 21), P = 0.027) and SAPS (48 (12 to 96) vs 34 (12 to 97), P = 0.001). Patients with positive cTnI had higher serum creatinine (192 μmol/l (38 to 550) vs 117 μmol/l (46 to 929), P < 0.001), arterial lactate (0.25, P < 0.001) and a lower pH (-0.21, P = 0.002). Also a higher proportion required renal replacement therapy (78% vs 60%, P = 0.006). Patients with elevated cTnI more frequently required vasopressors-norepinephrine (73% vs 50%, P = 0.008). Elevated cTnI did not predict outcome as effectively as other models (AUROC 0.61 (95% CI 0.52 to 0.68)). Conclusions More than 60% of ALF patients in this study demonstrated elevated cTnI. Despite a close correlation with organ failure severity, cTnI was a poor independent predictor of outcome. cTnI may not represent true myocardial injury and may be better viewed as a marker of metabolic stress.
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Sharma V, Ten Have GAM, Ytrebo L, Sen S, Rose CF, Dalton RN, Turner C, Revhaug A, van-Eijk HMH, Deutz NEP, Jalan R, Mookerjee RP, Davies NA. Nitric oxide and L-arginine metabolism in a devascularized porcine model of acute liver failure. Am J Physiol Gastrointest Liver Physiol 2012; 303:G435-41. [PMID: 22421619 PMCID: PMC3774247 DOI: 10.1152/ajpgi.00268.2011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
In acute liver failure (ALF), the hyperdynamic circulation is believed to be the result of overproduction of nitric oxide (NO) in the splanchnic circulation. However, it has been suggested that arginine concentrations (the substrate for NO) are believed to be decreased, limiting substrate availability for NO production. To characterize the metabolic fate of arginine in early-phase ALF, we systematically assessed its interorgan transport and metabolism and measured the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) in a porcine model of ALF. Female adult pigs (23-30 kg) were randomized to sham (N = 8) or hepatic devascularization ALF (N = 8) procedure for 6 h. We measured plasma arginine, citrulline, ornithine levels; arginase activity, NO, and ADMA. Whole body metabolic rates and interorgan flux measurements were calculated using stable isotope-labeled amino acids. Plasma arginine decreased >85% of the basal level at t = 6 h (P < 0.001), whereas citrulline and ornithine progressively increased in ALF (P < 0.001 and P < 0.001, vs. sham respectively). No difference was found between the groups in the whole body rate of appearance of arginine or NO. However, ALF showed a significant increase in de novo arginine synthesis (P < 0.05). Interorgan data showed citrulline net intestinal production and renal consumption that was related to net renal production of arginine and ornithine. Both plasma arginase activity and plasma ADMA levels significantly increased in ALF (P < 0.001). In this model of early-phase ALF, arginine deficiency or higher ADMA levels do not limit whole body NO production. Arginine deficiency is caused by arginase-related arginine clearance in which arginine production is stimulated de novo.
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Affiliation(s)
- Vikram Sharma
- 1UCL Institute of Hepatology, Royal Free Campus, University College London;
| | - Gabriella A. M. Ten Have
- 2Center for Translational Research in Aging & Longevity, Donald W. Reynolds Institute on Aging, University of Arkansas Medical Sciences, Little Rock, Arkansas; ,3Department of Surgery, University Maastricht, Maastricht, The Netherlands;
| | - Lars Ytrebo
- 5Department of Anesthesiology, University Hospital of North Norway and University of Tromsø, Norway;
| | - Sambit Sen
- 1UCL Institute of Hepatology, Royal Free Campus, University College London;
| | - Christopher F. Rose
- 6Neuroscience Research Unit, Ho^pital Saint-Luc (CRCHUM), Universite' de Montre'al, Que'bec, Canada
| | - R. Neil Dalton
- 4WellChild Laboratory, Evelina Children's Hospital, London, United Kingdom;
| | - Charles Turner
- 4WellChild Laboratory, Evelina Children's Hospital, London, United Kingdom;
| | - Arthur Revhaug
- 5Department of Anesthesiology, University Hospital of North Norway and University of Tromsø, Norway;
| | | | - Nicolaas E. P. Deutz
- 2Center for Translational Research in Aging & Longevity, Donald W. Reynolds Institute on Aging, University of Arkansas Medical Sciences, Little Rock, Arkansas; ,3Department of Surgery, University Maastricht, Maastricht, The Netherlands;
| | - Rajiv Jalan
- 1UCL Institute of Hepatology, Royal Free Campus, University College London;
| | | | - Nathan A. Davies
- 1UCL Institute of Hepatology, Royal Free Campus, University College London;
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Adeva MM, Souto G, Donapetry C, Portals M, Rodriguez A, Lamas D. Brain edema in diseases of different etiology. Neurochem Int 2012; 61:166-74. [PMID: 22579570 DOI: 10.1016/j.neuint.2012.05.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Revised: 04/23/2012] [Accepted: 05/01/2012] [Indexed: 02/06/2023]
Abstract
Cerebral edema is a potentially life-threatening complication shared by diseases of different etiology, such as diabetic ketoacidosis, acute liver failure, high altitude exposure, dialysis disequilibrium syndrome, and salicylate intoxication. Pulmonary edema is also habitually present in these disorders, indicating that the microcirculatory disturbance causing edema is not confined to the brain. Both cerebral and pulmonary subclinical edema may be detected before it becomes clinically evident. Available evidence suggests that tissue hypoxia or intracellular acidosis is a commonality occurring in all of these disorders. Tissue ischemia induces physiological compensatory mechanisms to ensure cell oxygenation and carbon dioxide removal from tissues, including hyperventilation, elevation of red blood cell 2,3-bisphosphoglycerate content, and capillary vasodilatation. Clinical, laboratory, and necropsy findings in these diseases confirm the occurrence of low plasma carbon dioxide partial pressure, increased erythrocyte 2,3-bisphosphoglycerate concentration, and capillary vasodilatation with increased vascular permeability in all of them. Baseline tissue hypoxia or intracellular acidosis induced by the disease may further deteriorate when tissue oxygen requirement is no longer matched to oxygen delivery resulting in massive capillary vasodilatation with increased vascular permeability and plasma fluid leakage into the interstitial compartment leading to edema affecting the brain, lung, and other organs. Causative factors involved in the progression from physiological adaptation to devastating clinical edema are not well known and may include uncontrolled disease, malfunctioning adaptive responses, or unknown factors. The role of carbon monoxide and local nitric oxide production influencing tissue oxygenation is unclear.
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Affiliation(s)
- María M Adeva
- Department of Nephrology, Hospital General Juan Cardona, Ferrol, Spain.
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21
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Laleman W. Hemodynamic effects of albumin dialysis in patients with liver failure: for better or for worse? Ther Apher Dial 2009; 13:384-92. [PMID: 19788454 DOI: 10.1111/j.1744-9987.2009.00756.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Liver failure, irrespective of is cause, is frequently associated with multi-organ dysfunction, including hemodynamic instability, and renal and cerebral insufficiency. As a result of the combined impact of these complications, liver failure carries an exceptionally high risk of mortality. A central role in the etiopathogenesis of different end-organ manifestations, as well as in the aggravation of the underlying liver failure, has been attributed to the hyperdynamic (hypotensive) state, which is characterized by a reduced systemic vascular resistance and mean arterial pressure, as well as an increased cardiac index, heart rate, and total plasma volume. Since the accumulation of toxins due to the decreased detoxification capacity by the failing liver is considered vital herein, the emergence of extracorporeal liver support has provided a rational basis for the potential reversal of these phenomena. The present article critically reviews data with regard to the hemodynamic effects of artificial liver support in the context of liver failure. Although these are scarce for acute liver failure, several uncontrolled series and small randomized trials have clearly documented that artificial liver support is able to improve both portal hypertension and the associated systemic circulatory dysfunction in patients with acute-on-chronic liver failure. The molecular basis for these effects have been related to temporary changes and/or elimination in endogenous vasoactive substances, improved albumin binding capacity, or restoration of oxidative stress-mediated damage to albumin.
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Affiliation(s)
- Wim Laleman
- Department of Hepatology, University Hospital Gasthuisberg, Catholic University Leuven, Leuven, Belgium.
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22
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Karvellas CJ, Pink F, McPhail M, Cross T, Auzinger G, Bernal W, Sizer E, Kutsogiannis DJ, Eltringham I, Wendon JA. Predictors of bacteraemia and mortality in patients with acute liver failure. Intensive Care Med 2009; 35:1390-6. [PMID: 19343322 DOI: 10.1007/s00134-009-1472-x] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2008] [Accepted: 03/05/2009] [Indexed: 12/11/2022]
Abstract
PURPOSE To determine what physiological and biochemical factors predict development of bacteraemia and mortality in patients with acute liver failure (ALF). METHODS Retrospective analysis of 206 ALF patients admitted to a specialist liver intensive therapy unit (LITU) from January 2003 to July 2005 (data collected prospectively). RESULTS A total of 206 patients were defined with ALF: 72 (35%) suffered bacteraemia (BAClf) and 134 (65%) did not (NBAClf). Gram positive organisms were observed in 44% of isolates, gram negatives in 52% and fungaemia in 4%. Median time to first bacteraemia was 10 (7-16) days. On admission, BAClf patients had higher SIRS scores and degrees of hepatic encephalopathy (HE). During their LITU course, BAClf patients had significantly increased requirements for renal replacement therapy (RRT), mechanical ventilation, and longer median LITU stay. Multivariate analysis (logistical regression) demonstrated significant predictors of bacteraemia on admission were HE grade >2 (Odds Ratio 1.6) and SIRS score >1 (OR 2.7). In all patients, independent predictors of mortality (logistical) were age (OR 1.41), maximum HE grade pre-intubation (1.76), Lactate (1.14) and Acute Physiology and Chronic Health Evaluation II score (APACHEII) (1.09), but not bacteraemia. Transplantation was protective (OR 0.20). CONCLUSION In this study, severity of hepatic encephalopathy and SIRS score >1 were predictive of bacteraemia. APACHEII was independently predictive of mortality in all ALF patients but not bacteraemia.
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Affiliation(s)
- Constantine J Karvellas
- Division of Critical Care Medicine, University of Alberta, 3C1.16 Walter C. Mackenzie Centre, 8440-112th Street, Edmonton, AB T6G 2B7, Canada.
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Antoniades CG, Berry PA, Wendon JA, Vergani D. The importance of immune dysfunction in determining outcome in acute liver failure. J Hepatol 2008; 49:845-61. [PMID: 18801592 DOI: 10.1016/j.jhep.2008.08.009] [Citation(s) in RCA: 266] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Acute liver failure (ALF) shares striking similarities with septic shock with regard to the features of systemic inflammation, progression to multiple organ dysfunction and functional immunoparesis. While the existence of opposing systemic pro- and anti-inflammatory profiles resulting in organ failure and immune dysfunction are well recognised in septic shock, characterization of these processes in ALF has only recently been described. This review explores the evolution of the systemic inflammation in acute liver failure, its relation to disease progression, exacerbation of liver injury and development of innate immune dysfunction and extra-hepatic organ failure as sequelae. Defects in innate immunity are described in hepatic and extra-hepatic compartments. Clinical studies measuring levels of pro- and anti-inflammatory cytokines and expression of the antigen presentation molecule HLA-DR on monocytes, in combination with ex-vivo experiments, demonstrate that the persistence of a compensatory anti-inflammatory response syndrome, leading to functional monocyte deactivation, is a central event in the evolution of systemic immune dysfunction. Accurate immune profiling in ALF may permit the development of immunomodulatory strategies in order to improve outcome in this condition.
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Gerlach JC, Zeilinger K, Patzer II JF. Bioartificial liver systems: why, what, whither? Regen Med 2008; 3:575-95. [DOI: 10.2217/17460751.3.4.575] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Acute liver disease is a life-threatening condition for which liver transplantation is the only recognized effective therapy. While etiology varies considerably, the clinical course of acute liver failure is common among the etiologies: encephalopathy progressing toward coma and multiple organ failure. Detoxification processes, such as molecular adsorbent recirculating system (MARS®) and Prometheus, have had limited success in altering blood chemistries positively in clinical evaluations, but have not been shown to be clinically effective with regard to patient survival or other clinical outcomes in any Phase III prospective, randomized trial. Bioartificial liver systems, which use liver cells (hepatocytes) to provide metabolic support as well as detoxification, have shown promising results in early clinical evaluations, but again have not demonstrated clinical significance in any Phase III prospective, randomized trial. Cell transplantation therapy has had limited success but is not practicable for wide use owing to a lack of cells (whole-organ transplantation has priority). New approaches in regenerative medicine for treatment of liver disease need to be directed toward providing a functional cell source, expandable in large quantities, for use in various applications. To this end, a novel bioreactor design is described that closely mimics the native liver cell environment and is easily scaled from microscopic (<1 ml cells) to clinical (∼600 ml cells) size, while maintaining the same local cell environment throughout the bioreactor. The bioreactor is used for study of primary liver cell isolates, liver-derived cell lines and stem/progenitor cells.
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Affiliation(s)
- Jörg C Gerlach
- Departments of Surgery & Bioengineering, McGowan Institute for Regenerative Medicine, Bridgeside Point Bldg., 100 Technology Drive, Suite 225, Pittsburgh, PA 15219-3130, USA
- Charite - Campus Virchow, Humboldt University Berlin, Germany
| | | | - John F Patzer II
- Departments of Bioengineering, Chemical Engineering & Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, PA, USA
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Ekse S, Clapp LH, Revhaug A, Ytrebø LM. Endothelium-derived hyperpolarization factor (EDHF) is up-regulated in a pig model of acute liver failure. Scand J Gastroenterol 2007; 42:356-65. [PMID: 17354116 DOI: 10.1080/00365520600930636] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Acute liver failure (ALF) is hemodynamically characterized by hyperdynamic circulation, but the pathophysiologic mechanisms underlying these disturbances are not known. The purposes of the present experiments were: to study systemic and peripheral hemodynamics in vivo, to measure changes in vascular reactivity in vitro, and to determine the role of endothelium-dependent vasodilator pathways in a well-validated porcine model of ALF. METHODS Landrace pigs (24-29 kg) were allocated to sham operation (n=8) or ALF induced by hepatic devascularization (n=9). Systemic and regional hemodynamics were monitored. Femoral artery rings were prepared for isometric tension recordings 8 h after ALF induction. Contractile responses to phenylephrine were assessed in ring segments of endothelium-intact femoral arteries in the absence or presence of inhibitors of endothelium-derived hyperpolarizing factor, nitric oxide synthase, cyclooxygenase and heme oxygenase pathways. RESULTS Pigs with ALF developed a hyperdynamic circulation. Cardiac index increased (PGT<0.001), while mean arterial pressure (PGT=0.012) and systemic vascular resistance decreased (PGT<0.001) in this group. Femoral artery blood flow decreased in controls, while it remained unchanged in ALF (PGT=0.010). Accordingly, vascular resistance across the hind leg was significantly decreased (PGT<0.001) in ALF. The combination of Ca2+-activated potassium channel inhibitors charybdotoxin and apamin, which block the release of endothelium-derived hyperpolarizing factor, increased the contraction force (ANOVA, PGT=0.05) and Emax (P=0.01) to phenylephrine in ALF. In contrast, inhibitors of nitric oxide synthase, cyclooxygenase and heme oxygenase pathways did not increase isometric contraction force. CONCLUSIONS Endothelium dependent hyperpolarization of vascular smooth muscle contributes to the development of hyperdynamic circulation in ALF.
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MESH Headings
- Analysis of Variance
- Animals
- Apamin/pharmacology
- Biological Factors/metabolism
- Blood Pressure/drug effects
- Cardiac Output/drug effects
- Charybdotoxin/pharmacology
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/physiopathology
- Enzyme Inhibitors/pharmacology
- Female
- Femoral Artery/drug effects
- Femoral Artery/metabolism
- Femoral Artery/physiopathology
- Heme Oxygenase (Decyclizing)/drug effects
- Heme Oxygenase (Decyclizing)/metabolism
- Isometric Contraction/drug effects
- Liver Circulation/drug effects
- Liver Failure, Acute/metabolism
- Liver Failure, Acute/physiopathology
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/physiopathology
- Nitric Oxide Synthase/drug effects
- Nitric Oxide Synthase/metabolism
- Phenylephrine/pharmacology
- Potassium Channel Blockers/pharmacology
- Potassium Channels, Calcium-Activated/drug effects
- Potassium Channels, Calcium-Activated/metabolism
- Prostaglandin-Endoperoxide Synthases/drug effects
- Prostaglandin-Endoperoxide Synthases/metabolism
- Swine
- Up-Regulation/drug effects
- Vascular Resistance/drug effects
- Vasoconstriction/drug effects
- Vasoconstrictor Agents/pharmacology
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Affiliation(s)
- Sveinung Ekse
- Department of Anesthesiology and Intensive Care, University of Tromsø, University Hospital Northern Norway, Tromsø, Norway
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Ytrebø LM, Sen S, Rose C, Davies NA, Nedredal GI, Fuskevaag OM, Ten Have GAM, Prinzen FW, Williams R, Deutz NEP, Jalan R, Revhaug A. Systemic and regional hemodynamics in pigs with acute liver failure and the effect of albumin dialysis. Scand J Gastroenterol 2006; 41:1350-60. [PMID: 17060130 DOI: 10.1080/00365520600714527] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Acute liver failure (ALF) is haemodynamically characterized by a hyperdynamic circulation. The aims of this study were to investigate the systemic and regional haemodynamics in ALF, to measure changes in nitric oxide metabolites (NOx) and to evaluate whether these haemodynamic disturbances could be attenuated with albumin dialysis. MATERIAL AND METHODS Norwegian Landrace pigs (23-30 kg) were randomly allocated to groups as controls (sham-operation, n = 8), ALF (hepatic devascularization, n = 8) and ALF + albumin dialysis (n = 8). Albumin dialysis was started 2 h after ALF induction and continued for 4 h. Systemic and regional haemodynamics were monitored. Creatinine clearance, nitrite/nitrate and catecholamines were measured. A repeated measures ANOVA was used to analyse the data. RESULTS In the ALF group, the cardiac index increased (PGT < 0.0001), while mean arterial pressure (PG = 0.02) and systemic vascular resistance decreased (PGT < 0.0001). Renal resistance (PG = 0.04) and hind-leg resistance (PGT = 0.003) decreased in ALF. There was no difference in jejunal blood flow between the groups. ALF pigs developed renal dysfunction with increased serum creatinine (PGT = 0.002) and decreased creatinine clearance (P = 0.02). Catecholamines were significantly higher in ALF, but NOx levels were not different. Albumin dialysis did not attenuate these haemodynamic or renal disturbances. CONCLUSIONS The haemodynamic disturbances during the early phase of ALF are characterized by progressive systemic vasodilatation with no associated changes in metabolites of NO. Renal vascular resistance decreased and renal dysfunction developed independently of changes in renal blood flow. After 4 h of albumin dialysis there was no attenuation of the haemodynamic or renal disturbances.
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Affiliation(s)
- Lars M Ytrebø
- Department of Digestive Surgery, University Hospital Northern Norway, Tromsø, Norway
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Antoniades CG, Berry PA, Davies ET, Hussain M, Bernal W, Vergani D, Wendon J. Reduced monocyte HLA-DR expression: a novel biomarker of disease severity and outcome in acetaminophen-induced acute liver failure. Hepatology 2006; 44:34-43. [PMID: 16799971 DOI: 10.1002/hep.21240] [Citation(s) in RCA: 121] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Acute liver failure (ALF) shares striking similarities with septic shock where a decrease in HLA-DR expression on monocytes is associated with disease severity and predicts outcome. We investigated monocyte HLA-DR expression in ALF in relation to inflammatory mediator levels and clinical outcome. Monocyte HLA-DR expression was determined in 50 patients with acetaminophen-induced ALF (AALF) and 20 non-acetaminophen-induced ALF (NAALF). AALF patients were divided into dead/transplanted (AALF-NS, n = 26) and spontaneous survivors (AALF-S, n = 24). Fifty patients with chronic liver disease (CLD) and 50 healthy volunteers served as controls. Monocyte HLA-DR expression was determined by double-color flow-cytometry with monoclonal antibodies detecting HLA-DR and monocyte specific CD14. Serum levels of interleukin (IL) -4, -6, -10, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma were concomitantly measured by ELISA. Compared to healthy volunteers (75%) and CLD (67%) monocyte HLA-DR percentage expression was lower in AALF (15%, P < .001) and NAALF (22 %, P < .001). Compared to AALF-S, AALF-NS had lower monocyte HLA-DR % (11% vs. 36%, P < .001) and higher levels of IL-4, IL-6, IL-10 and TNF-alpha (P < .001). HLA-DR percentage negatively correlated with INR, blood lactate, pH and levels of encephalopathy (r = -0.8 to -0.5, P < .01), IL-10 (r = -0.8, P < .0001), TNF-alpha (r = -0.4, P = .02). HLA-DR percentage level <or=15% has a 96% sensitivity and 100% specificity and 98% accuracy in predicting poor prognosis. In conclusion, the strong relationship of monocyte HLA-DR expression with indices of disease severity, mediators of inflammation and outcome indicates a key role for this molecule as a biomarker of disease severity and prognosis.
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Aggarwal S, Obrist W, Yonas H, Kramer D, Kang Y, Scott V, Planinsic R. Cerebral hemodynamic and metabolic profiles in fulminant hepatic failure: relationship to outcome. Liver Transpl 2005; 11:1353-60. [PMID: 16237715 DOI: 10.1002/lt.20479] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The purpose of this retrospective study was to examine the potential role of cerebral hemodynamic and metabolic factors in the outcome of patients with fulminant hepatic failure (FHF). Based on the literature, a hypothetical model was proposed in which physiologic changes progress sequentially in five phases, as defined by intracranial pressure (ICP) and cerebral blood flow (CBF) measurements. Seventy-six cerebral physiologic profiles were obtained in 26 patients (2 to 5 studies each) within 6 days of FHF diagnosis. ICP was continuously measured by an extradural fiber optic monitor. Global CBF estimates were obtained by xenon clearance techniques. Jugular venous and peripheral artery catheters permitted calculation of cerebral arteriovenous oxygen differences (AVDO2), from which cerebral metabolic rate for oxygen (CMRO2) was derived. A depressed CMRO2 was found in all patients. There was no evidence of cerebral ischemia as indicated by elevated AVDO2s. Instead, over 65% of the patients revealed cerebral hyperemia. Eight of the 26 patients underwent orthotopic liver transplantation-all recovered neurologically, including 6 with elevated ICPs. Of the 18 patients receiving medical treatment only, all 7 with increased ICP died in contrast to 9 survivors whose ICP remained normal (P < 0.004). Hyperemia, per se, was not related to outcome, although it occurred more frequently at the time of ICP elevations. Six patients were studied during brain death. All 6 revealed malignant intracranial hypertension, preceded by hyperemia. In conclusion, the above findings are consistent with the hypothetical model proposed. Prospective longitudinal studies are recommended to determine the precise evolution of the pathophysiologic changes.
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Affiliation(s)
- Shushma Aggarwal
- Department of Anesthesiology/Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
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Affiliation(s)
- Rajiv Jalan
- Liver Failure Group, Institute of Hepatology, University College London Medical School, London WC1E 6HX, UK.
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Yoneyama K, Taniguchi H, Kiuchi Y, Shibata M, Mitamura K. Prognostic index of liver cirrhosis with ascites with and without hepatocellular carcinoma. Scand J Gastroenterol 2004; 39:1272-9. [PMID: 15743006 DOI: 10.1080/00365520410008042] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND In Japan, the incidence of liver cirrhosis caused by hepatitis viruses is higher, and cirrhosis is more likely to be complicated by hepatocellular carcinoma, than in Western countries. The aim of this study was to predict the outcome in liver cirrhosis with ascites with and without hepatocellular carcinoma. METHODS The subjects were 146 patients with liver cirrhosis complicated by ascites. Forty-six factors were evaluated concerning clinical laboratory parameters and extracted prognostic factors using the Cox proportional hazards model. RESULTS The mean duration of the follow-up period was 634.9 days, during which 89 (61%) of the patients died, 27 (18.5%) survived, and 30 (20.6%) were lost to follow-up. The cumulative survival rate after the onset of ascites was 59.7% after 1 year, 44.5% after 2 years, and 29.5% after 5 years. Multivariate analysis indicated 9 factors, i.e. age, total bilirubin (T-Bil), alkaline phosphatase (ALP), blood urea nitrogen (BUN), alpha-fetoprotein (AFP), mean arterial pressure (MAP), gastrointestinal bleeding, infection, and portal vein tumor thrombosis (PVTT), as independent prognostic factors. The prognostic index (PI) was calculated by the following formula using these 9 factors. PI = 0.045 x age + 0.180 x T-Bil + 0.088 x ALP + 0.020 x BUN + 0.467 x AFP + (-0.022 x MAP) + 0.662 x gastrointestinal bleeding + 0.521 x infections + 0.882 x PVTT. CONCLUSION Prediction of the outcome using PI based on the 9 factors provides additional information for the determination of the therapeutic approach in cirrhotic patients with ascites with and without hepatocellular carcinoma.
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Affiliation(s)
- K Yoneyama
- Health Service Center, Showa University, Tokyo, Japan.
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Ytrebø LM, Ekse S, Sen S, Rose C, Nedredal GI, Fuskevåg OM, Jalan R, Revhaug A. Contractile response of femoral arteries in pigs with acute liver failure. Scand J Gastroenterol 2004; 39:1000-4. [PMID: 15513341 DOI: 10.1080/00365520410003254] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Acute liver failure (ALF) is characterized haemodynamically by a progressive hyperdynamic circulation. The pathophysiological mechanism is unknown, but impaired contractility of vascular smooth muscle may play an important role. The aim of this study was to evaluate the vascular response to stimulation with norepinephrine and angiotensin II in endothelium-denuded femoral artery rings. METHODS Norwegian Landrace pigs weighing 27.1 +/- 0.5 kg (mean +/- sx (standard error of the mean)) were used. ALF was induced by performing a portacaval shunt followed by ligation of the hepatic arteries (n = 6). Sham-operated animals served as controls (n = 5). Cumulative isometric concentration contraction curves were obtained after in vitro stimulation of the femoral artery rings with either angiotensin II (10(-13) - 10(-5) mol/L) or norepinephrine (10(-13) - 10(-3) mol/L). RESULTS Pigs suffering from ALF developed a hyperdynamic circulation with an increased cardiac index (P = 0.017) and decreased systemic vascular resistance index (P = 0.015). Studies of the hind leg revealed a decreased vascular resistance index and increased blood flow compared to sham-operated controls (P = 0.003 and P = 0.01, respectively). Angiotensin II caused a concentration-dependent contraction of the arterial segments, with no significant differences in vascular responses between the two groups. Maximum force generated did not differ (55 +/- 7 versus 56 +/- 7 mN, P = 0.95). Furthermore, there were no differences for norepinephrine in the cumulative concentration-response curves and the maximum contractile force was not significantly different (87 +/- 8 versus 93 +/- 16 mN, P = 0.55). CONCLUSIONS This study documents for the first time that there are no signs of endothelium-independent peripheral vascular hyporesponsiveness to angiotensin II and norepinephrine in pigs with ALF.
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Affiliation(s)
- L M Ytrebø
- Department of Digestive Surgery, University Hospital Northern Norway, Tromsø.
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Guirl MJ, Weinstein JS, Goldstein RM, Levy MF, Klintmalm GB. Two-stage total hepatectomy and liver transplantation for acute deterioration of chronic liver disease: a new bridge to transplantation. Liver Transpl 2004; 10:564-70. [PMID: 15048803 DOI: 10.1002/lt.20134] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Two-stage total hepatectomy and liver transplantation has been reported for acute liver disease such as fulminant hepatic failure, primary graft failure, severe hepatic trauma, and spontaneous hepatic rupture secondary to hemolysis, elevated liver function tests, low platelets syndrome, and preeclampsia. This is the first report of patients with cirrhosis to undergo a 2-stage total hepatectomy and liver transplantation. From 1984 to 2002, our institution performed 2008 orthotopic liver transplantations. We identified 4 patients with chronic liver disease who underwent a 2-stage hepatectomy and liver transplantation. This is a retrospective review of these 4 patients and a review of the literature on this procedure. All 4 patients were young men with an age range of 29-31 years and had underlying cirrhosis as well as a previous transjugular intrahepatic portosystemic shunt (TIPS)procedure. Acute decompensation fulfilling Ringes' criteria for toxic liver syndrome secondary to an upper gastrointestinal bleed occurred in all patients. The approximate average time between hepatectomy and liver transplantation was 20 hours (range: 8-42 hours). In all cases, the explanted liver showed histological changes of acute hepatic necrosis within the background of cirrhosis. After hepatectomy, vasopressor requirements were well documented in 2 patients. For 1 patient, there was a clear improvement in their hemodynamic status. The mean hospital stay of the 4 patients was 63 days. All patients were discharged from the hospital and are alive and well with adequate liver function at 6 to 37 months follow-up. Two-stage total hepatectomy and liver transplantation may be a life-saving procedure in highly selected cirrhotic patients with acute hepatic decompensation and multiorgan dysfunction.
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Affiliation(s)
- Michael J Guirl
- Department of Internal Medicine, Division of Gastroenterology, Baylor University Medical Center, Dallas, TX 75246, USA.
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Tabernero A, Schneider F, Potenza MA, Randriamboavonjy V, Chasserot S, Wolf P, Mitolo-Chieppa D, Stoclet JC, Andriantsitohaina R. Cyclooxygenase-2 and inducible nitric oxide synthase in omental arteries harvested from patients with severe liver diseases: immuno-localization and influence on vascular tone. Intensive Care Med 2003; 29:262-70. [PMID: 12594587 DOI: 10.1007/s00134-002-1617-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2002] [Accepted: 11/21/2002] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To investigate the expression of inducible cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) and the role of vasodilatory prostanoids and endogenous nitric oxide (NO) in small omental arteries harvested from patients with severe liver diseases. DESIGN Ex vivo study of resistance arteries. SETTING. Intensive care unit. PATIENTS Twenty patients undergoing liver transplantation for fulminant hepatic failure (FHF, n=6), cirrhogenous viral hepatitis (CH, n=6) and limited hepatocarcinoma (controls, n=8). INTERVENTIONS Western blot and immunohistochemical labeling for assessment of COX-2 and iNOS expression and localization and ex vivo vascular reactivity studies. MEASUREMENTS AND RESULTS Significant upregulation of COX-2 and iNOS expressions were detected in arteries from FHF and CH patients with a greater increase in the former than in the latter. Ex vivo contractile responses to norepinephrine and the thromboxane A(2) analog, U46619, were not significantly different between patients with severe liver dysfunction and controls. Exposure to either the NO-synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), the cyclooxygenase inhibitor, indomethacin, or their combination did not significantly modify contractions of agonists in controls and CH patients. In FHF, the specific COX-2 inhibitor, N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide (1 micro m/l), but not L-NAME, significantly enhanced the maximal effect ( p<0.01) and the sensitivity ( p<0.01) to norepinephrine. CONCLUSIONS COX-2 and iNOS are upregulated in omental arteries from patients with cirrhogenous hepatitis and fulminant hepatic failure. Whereas neither NO nor vasodilatory prostaglandins seem to play a major role in counteracting arterial contractility of arteries from control patients, COX-2 derivatives are involved in lowering the arterial contractility of vessels harvested from FHF patients.
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MESH Headings
- Adult
- Arteries/enzymology
- Arteries/physiopathology
- Blotting, Western
- Carcinoma, Hepatocellular/enzymology
- Carcinoma, Hepatocellular/physiopathology
- Carcinoma, Hepatocellular/surgery
- Case-Control Studies
- Cyclooxygenase 2
- Dilatation, Pathologic
- Female
- Hepatitis, Viral, Human/enzymology
- Hepatitis, Viral, Human/physiopathology
- Hepatitis, Viral, Human/surgery
- Humans
- Immunohistochemistry
- Indomethacin/pharmacology
- Isoenzymes/analysis
- Isoenzymes/antagonists & inhibitors
- Isoenzymes/physiology
- Liver Failure/enzymology
- Liver Failure/physiopathology
- Liver Failure/surgery
- Liver Neoplasms/enzymology
- Liver Neoplasms/physiopathology
- Liver Neoplasms/surgery
- Liver Transplantation
- Male
- Membrane Proteins
- Middle Aged
- NG-Nitroarginine Methyl Ester/pharmacology
- Nitric Oxide Synthase/analysis
- Nitric Oxide Synthase/antagonists & inhibitors
- Nitric Oxide Synthase/physiology
- Nitric Oxide Synthase Type II
- Nitrobenzenes/pharmacology
- Norepinephrine/pharmacology
- Omentum/blood supply
- Prostaglandin-Endoperoxide Synthases/analysis
- Prostaglandin-Endoperoxide Synthases/physiology
- Severity of Illness Index
- Sulfonamides/pharmacology
- Up-Regulation
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Affiliation(s)
- Antonia Tabernero
- Laboratoire de Pharmacologie et Physicochimie des Interactions Cellulaires et Moléculaires, CNRS (UMR 7034), Illkirch, France
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Pere P, Höckerstedt K, Isoniemi H, Lindgren L. Cerebral blood flow and oxygenation in liver transplantation for acute or chronic hepatic disease without venovenous bypass. Liver Transpl 2000; 6:471-9. [PMID: 10915171 DOI: 10.1053/jlts.2000.8186] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The autoregulation of cerebral blood flow (CBF) is impaired in patients with end-stage liver disease and encephalopathy. These patients are vulnerable to sudden deterioration of cerebral perfusion and oxygenation during liver transplantation. We compared CBF and metabolism during liver transplantation without venovenous bypass and 24 hours postoperatively in 9 patients with acute liver failure (ALF) and 16 patients with chronic liver disease. A fiberoptic catheter was inserted cranially through the left internal jugular vein for determination of jugular venous oxygen saturation, cerebral oxygen extraction ratio (COER), lactate level, and neuron-specific enolase (NSE) level. Arterial concentrations of lactate were also measured. Flow velocity in the middle cerebral arteries was monitored bilaterally using transcranial Doppler sonography. Mean flow velocity and pulsatility index (PI) were regarded as indicators of intracranial pressure. Core body temperatures were recorded. Mild hyperventilation, perioperative hemofiltration, and N-acetylcysteine infusion were used according to our clinical practice. NSE level was greater in acute patients at the end of surgery (P <.05), but not 24 hours later. Lactate concentrations were greater in patients with ALF (P <.001) preoperatively and intraoperatively but were similar in both groups 24 hours postoperatively. There was no difference between arterial and jugular venous concentrations of lactate. Changes in blood flow velocity, PI, and COER were parallel and without statistical significance between the groups. The patients' core temperature did not correlate with CBF, NSE level, or clinical outcome. Caval clamping was well tolerated in both patient groups.
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Affiliation(s)
- P Pere
- Departments of Anesthesia and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland.
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Deasy NP, Wendon J, Meire HB, Sidhu PS. The value of serial Doppler ultrasound as a predictor of clinical outcome and the need for transplantation in fulminant and severe acute liver failure. Br J Radiol 1999; 72:134-43. [PMID: 10365062 DOI: 10.1259/bjr.72.854.10365062] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
The aim of this study was to document the changes in Doppler ultrasound variables of the hepatic artery and portal vein in fulminant and severe acute liver failure, and to assess their prognostic significance. 18 adult patients with fulminant and severe acute liver failure underwent serial Doppler sonography, in the early stages after presentation. 12 hourly measurements of hepatic artery resistance index (HARI), spleen length, portal vein cross-sectional area, time average velocity (TAV) and flow volume were performed. Mean HARI (p = 0.03) and mean maximum HARI (p = 0.03) were significantly higher in those who fulfilled criteria for liver transplantation. Increased portal vein flow was demonstrated, although the difference between the groups was not significant. A significant increase in portal vein cross-sectional area (p < 0.02) and spleen length (p < 0.02) was demonstrated. In summary, an increase in portal blood flow to the damaged liver has been demonstrated. The mean HARI is significantly higher in patients who fulfil transplant criteria and may possibly be used as an indicator of poorer prognosis and the need for liver transplantation in acute severe and fulminant liver failure.
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Affiliation(s)
- N P Deasy
- Department of Radiology, King's College Hospital, Denmark Hill, London, UK
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Grose RD, Nolan J, Dillon JF, Errington M, Hannan WJ, Bouchier IA, Hayes PC. Exercise-induced left ventricular dysfunction in alcoholic and non-alcoholic cirrhosis. J Hepatol 1995; 22:326-32. [PMID: 7608484 DOI: 10.1016/0168-8278(95)80286-x] [Citation(s) in RCA: 111] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND/AIMS Autonomic and cardiac dysfunction have been reported in patients with cirrhosis. We studied left ventricular and autonomic function in 20 patients with both alcoholic and non-alcoholic cirrhosis. METHODS Autonomic function was assessed by a standard battery of cardiovascular reflex tests. Supine exercise radionuclide ventriculography was used to assess the cardiac response to exercise. RESULTS Exercise capacity was reduced in all patients in association with marked chronotropic incompetence (peak heart rates 120.5 +/- 6 bpm). Unlike normal subjects there was no increase in left ventricular ejection fraction on exercise. Stroke volume increased by 23 +/- 6%, mediated by an increase in end-diastolic.volume of > 20%. Cardiac output was subnormal at maximal exercise, increasing by only 96 +/- 14% and 97 +/- 11% in alcoholic and non-alcoholic groups respectively. The majority (83%) of our patients had autonomic reflex abnormalities. CONCLUSIONS Patients with cirrhosis of alcohol and non-alcohol related aetiologies have significantly impaired cardiovascular responses to exercise, which are similar to those of a denervated heart. This may have important clinical implications for the ability of these patients to withstand cardiovascular stress.
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Affiliation(s)
- R D Grose
- Department of Medicine, Royal Infirmary of Edinburgh, Scotland, UK
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Larsen FS, Knudsen GM, Paulson OB, Vilstrup H. Cerebral blood flow autoregulation is absent in rats with thioacetamide-induced hepatic failure. J Hepatol 1994; 21:491-5. [PMID: 7814793 DOI: 10.1016/s0168-8278(94)80091-x] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Cerebral blood flow normally remains constant within a wide range of mean arterial blood pressure values. In fulminant hepatic failure, however, it is not known whether autoregulation of cerebral blood flow is maintained. In the present study, cerebral blood flow autoregulation was investigated in rats 3 days after induction of fulminant hepatic failure. Wistar rats were given intraperitoneal thioacetamide or saline injections. The mean arterial blood pressure was varied by means of norepinephrine infusion or venesection, respectively. As mean arterial blood pressure declined, repeated cerebral blood flow measurements were performed by the intracarotid 113Xenon injection method. The relation between mean arterial blood pressure and cerebral blood flow was examined by statistical regression analysis, and the lower limit of autoregulation was determined in each rat. Cerebral blood flow baseline values were unaltered in liver failure compared to the control group (73 (36-92) vs. 79 (57-87) ml.100 g-1.min-1, median and range). Baseline mean arterial blood pressure was also similar in the two groups (90 (75-113) vs. 95 (70-112)). Mean arterial blood pressure varied between 40 (35-50) and 110 (90-135) mmHg in the control rats and between 50 (45-68) and 110 (95-126) mmHg in the rats with liver failure. A lower limit of autoregulation was identified in all control rats at a mean arterial blood pressure of 67 (55-78) mmHg. Below this limit, cerebral blood flow declined in parallel with mean arterial blood pressure. None of the rats with liver failure exhibited autoregulation, and cerebral blood flow changed in parallel with mean arterial blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- F S Larsen
- Department of Medicine A, University Hospital, Rigshospitalet, Copenhagen, Denmark
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Aggarwal S, Kramer D, Yonas H, Obrist W, Kang Y, Martin M, Policare R. Cerebral hemodynamic and metabolic changes in fulminant hepatic failure: a retrospective study. Hepatology 1994. [PMID: 8276371 DOI: 10.1002/hep.1840190114] [Citation(s) in RCA: 110] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The purpose of this retrospective study was to determine cerebral hemodynamic and metabolic changes in comatose patients with fulminant hepatic failure. Computerized tomography of the brain and cerebral blood flow measurements by the xenon-computerized tomography scan or intravenous xenon-133 methods were obtained in 33 patients with fulminant hepatic failure. In a subgroup of 22 patients, arteriojugular venous oxygen content difference and cerebral metabolic rate for oxygen were determined. Carbon dioxide reactivity was tested in 17 patients, and intracranial pressure was recorded by an epidural monitor in 8 patients. Cerebral blood flow and arteriojugular venous oxygen content difference were adjusted to the average arterial carbon dioxide pressure of the sample (32 mm Hg). Adjusted cerebral blood flow varied from 16.5 to 94.7 ml/100 gm/min; 52% of the patients had reduced adjusted cerebral blood flows (less than 33 ml/100 gm/min), whereas 24% had hyperemic values (greater than 50 ml/100 gm/min). Patients with higher adjusted cerebral blood flows showed cerebral swelling on computerized tomography scan (p < 0.002), were in deeper coma (p < 0.05) and had greater mortality (p < 0.002). The adjusted arteriojugular venous oxygen content difference was negatively correlated with adjusted cerebral blood flow (r = -0.61, p < 0.002). The majority of patients with reduced adjusted cerebral blood flows had low adjusted arteriojugular venous oxygen content differences (less than 5 vol%), indicating hyperemia rather than ischemia. The average cerebral metabolic rate for oxygen was 50% of normal (1.6 +/- 0.4 ml/100 gm/min); even patients with low cerebral metabolic rates for oxygen recovered neurologically.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- S Aggarwal
- Department of Anesthesiology/Critical Care Medicine, School of Medicine, University of Pittsburgh, Pennsylvania 15213
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Manthous CA, Hall JB, Samsel RW. Endotoxin in human disease. Part 1: Biochemistry, assay, and possible role in diverse disease states. Chest 1993; 104:1572-81. [PMID: 8222826 DOI: 10.1378/chest.104.5.1572] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
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Ringe B, Lübbe N, Kuse E, Frei U, Pichlmayr R. Total hepatectomy and liver transplantation as two-stage procedure. Ann Surg 1993; 218:3-9. [PMID: 8328827 PMCID: PMC1242893 DOI: 10.1097/00000658-199307000-00002] [Citation(s) in RCA: 113] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
OBJECTIVE This article describes the experience with a bridging procedure for a prolonged anhepatic period during clinical liver transplantation in case of special emergency situations. SUMMARY BACKGROUND DATA Hepatic necrosis due to fulminant hepatitis or acute graft failure, as well as severe liver trauma are well-known and accepted indications for urgent liver transplantation. Prerequisite is the allocation of a suitable donor organ. If no allograft is available in time, patients with "toxic liver syndrome" or exsanguinating hemorrhage have been shown to benefit from advanced total hepatectomy. METHODS As a modification of the standard one-stage procedure, recipient hepatectomy and subsequent liver transplantation are performed in two separate operations. To bridge the prolonged anhepatic period and to allow decompression and return of venous blood, an end-to-side portocaval shunt is constructed temporarily. RESULTS Thirteen of thirty-two patients underwent hepatectomy but not transplantation subsequently, and died within 34 hours after progressive deterioration. In 19 of 32 patients, transplantation was realized 6-41 hours after hepatectomy; 9 of 19 patients died, mostly from sepsis. Ten of nineteen liver recipients survived the procedure including three unrelated late deaths; presently, seven patients are alive with a follow-up of 3 to 46 months. CONCLUSIONS Two-stage total hepatectomy with temporary portocaval shunt, and subsequent liver transplantation can be a life-saving approach in patients most likely to die of the sequelae of advanced liver or graft necrosis or exsanguination that cannot be controlled by conventional treatment or immediate liver transplantation.
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Affiliation(s)
- B Ringe
- Medizinische Hochschule Hannover, Zentrum Chirurgie, Germany
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41
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Keays RT, Alexander GJ, Williams R. The safety and value of extradural intracranial pressure monitors in fulminant hepatic failure. J Hepatol 1993; 18:205-9. [PMID: 8409336 DOI: 10.1016/s0168-8278(05)80247-8] [Citation(s) in RCA: 80] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Thirty-six of 68 consecutive patients with fulminant hepatic failure (FHF) progressing to grade 4 encephalopathy who had extradural ICP monitors inserted were reviewed to determine the safety and the value of ICP monitoring. Only minor complications were encountered. These included local wound bleeding at the burrhole site in four patients and a small cerebral hemorrhage in relation to the monitor in one other patient. No significant long-term sequelae were related to the operative procedure. ICP monitoring identified rises in ICP unaccompanied by clinical signs and as a consequence treatment was given to the monitored patients more often than the non-monitored group (median 6 vs. 2 treatments, P < 0.01). The duration of survival from the onset of grade 4 encephalopathy was significantly greater in the ICP monitored group (median 60 vs. 10 h, P < 0.01) although overall survival was unchanged. Monitoring also provided important prognostic information since the peak ICP was higher in non-survivors than in survivors (median 45 vs. 35 mmHg, P = 0.051). The pattern of clinical signs accompanying episodes of intracranial hypertension differed between survivors and non-survivors. Pupillary abnormalities were detected more often in non-survivors while systolic hypertension occurred more frequently amongst survivors with the peak systolic blood pressure being significantly higher. ICP monitoring proved safe and effective, provided valuable information regarding subclinical intracranial hypertension and prognosis and should be regarded as part of the routine management of intracranial hypertension complicating FHF.
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Affiliation(s)
- R T Keays
- Institute of Liver Studies, King's College School of Medicine and Dentistry, London, UK
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42
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43
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Wang XD, Soltesz V, Andersson R, Bengmark S. Bacterial translocation in acute liver failure induced by 90 per cent hepatectomy in the rat. Br J Surg 1993; 80:66-71. [PMID: 8428299 DOI: 10.1002/bjs.1800800124] [Citation(s) in RCA: 56] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Bacterial infection and bacteraemia have been observed in patients with acute liver failure. The exact source of bacteria and nature of pathophysiological mechanisms explaining the development of infection remain unclear. In the present study, acute liver failure was induced by 90 per cent hepatectomy in the rat. The mesenteric lymph nodes and organs were harvested aseptically for bacteriological culture after sham operation or 90 per cent hepatectomy. Function of the liver and reticuloendothelial system (RES) was assayed; gut oxygen extraction was also measured. Translocation of enteric bacteria occurred 2 h after operation and increased with time following hepatectomy. Overgrowth of Escherichia coli in the distal small intestine started 2 h after operation. RES function decreased immediately after 90 per cent hepatectomy; uptake rates per gram tissue in other organs increased significantly. These results indicate that bacterial translocation occurred early after 90 per cent hepatectomy, associated with a decrease in RES function and gut oxygen extraction, and overgrowth of intestinal bacteria.
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Affiliation(s)
- X D Wang
- Department of Surgery, Lund University, Sweden
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44
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Abstract
The pathogenesis of portal hypertension remains poorly understood. Similarly, pharmacological manipulation for the prevention and treatment of variceal haemorrhage has not fulfilled the promise of the 1980s. This article reviews current concepts in the pathophysiology of portal hypertension and considers pharmacotherapy for the treatment of variceal bleeding.
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Affiliation(s)
- R D Grose
- Department of Medicine, Royal Infirmary, Edinburgh, UK
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45
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Navasa M, Garcia-Pagán JC, Bosch J, Riera JR, Bañares R, Mas A, Bruguera M, Rodés J. Portal hypertension in acute liver failure. Gut 1992; 33:965-8. [PMID: 1644339 PMCID: PMC1379414 DOI: 10.1136/gut.33.7.965] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Twenty five patients with acute liver failure were measured for hepatic venous pressure gradient as an index of portal pressure during the course of a transjugular liver biopsy. Hepatic venous pressure gradient ranged from 4 to 24.5 mm Hg with a mean of 12.8 (5.3) mm Hg (normal values less than 5 mm Hg). All patients but one had increased portal pressure gradient. Portal hypertension correlated with the degree of architectural distortion of the liver, as suggested by a direct correlation between hepatic venous pressure gradient and the area of reticulin collapse, evaluated by means of a morphometric analysis on Sirius red stained liver slides (r = 0.43, p less than 0.05). Hepatic venous pressure gradient was significantly higher in patients with ascites (15.1 (5) mm Hg, n = 15) or renal failure (14.4 (5.3) mm Hg, n = 16) than in those without (9.3 (3.4) mm Hg and 10.1 (4) mm Hg, respectively; p less than 0.05). Portal hypertension was associated with systemic vasodilation and a hyperkinetic circulatory state, with decreased arterial pressure, and peripheral resistance and increased cardiac output.
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Affiliation(s)
- M Navasa
- Liver Unit, Hospital Clinic i Provincial, University of Barcelona, Spain
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46
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Murakami N, Saito K, Kato T, Nakamura T, Moriwaki U, Muto Y. Changes in brain monoamine metabolism in rats with acute ischemic hepatic failure under artificial cardiopulmonary management. GASTROENTEROLOGIA JAPONICA 1992; 27:191-8. [PMID: 1577224 DOI: 10.1007/bf02777722] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
A study was conducted to investigate changes in monoamine metabolism in the brain of rats with acute ischemic hepatic failure (AHF) induced by two-stage hepatic devascularization. Strict artificial cardiopulmonary management was used to exclude possible confounding effects of hypotension, hypothermia and hypoxemia that often appear in AHF. Rats were put in an incubator at 34 degrees C before the ligation of the hepatic artery (second stage operation), tracheotomized and ventilated artificially throughout the remaining experimental periods. No significant difference was observed in physiological parameters, including body temperature, pulse rate and systolic arterial blood pressure or PaO2 between AHF and sham operated rats. Brain levels of norepinephrine (NE) and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA), and serotonin (5-hydroxytryptamine, 5HT) and its metabolite 5-hydroxyindoleacetic acid (5HIAA) were determined by HPLC-voltametry. AHF rats showed significantly higher MHPG, DOPAC, 5HIAA and lower NE levels in the brain compared to controls. In addition, a significant negative correlation between NE and tyrosine (Tyr), a significant positive correlation between MHPG and Tyr or phenylalanine (Phe), and a significant positive correlation between DOPAC and Tyr or Phe were observed. In conclusion, the changes in monoamine metabolism in the brain of AHF rats are clearly induced specifically by hepatic failure itself, possibly through an altered metabolism of amino acids.
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Affiliation(s)
- N Murakami
- First Department of Internal Medicine, Gifu University School of Medicine, Japan
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47
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Affiliation(s)
- S Sherlock
- Department of Surgery, Royal Free Hospital, London
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48
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Abstract
The aetiology of chronic liver disease covers a wide range of congenital or acquired abnormalities of the hepatocellular biochemical network. Although our knowledge has considerably increased in recent years, the aetiology of chronic liver disease often remains obscure. Acquired irreversible disturbances of normal liver function can be mediated by hepatotrophic viruses, chemicals, chronic oxygen depletion, or interference with the immune system. Considerable progress has been made in the detection and characterisation of hepatitis B, C, and D viruses as causative agents of chronic active hepatitis. Alcohol abuse remains the predominant cause of chronic liver disease in the Western world. The targets of autoantibodies used to diagnose autoimmune diseases of the liver and primary biliary cirrhosis continue to be biochemically defined. Their significance for the aetiology of the disease, however, remains to be established. Nonparenchymal cells play an important role in the sequence of events following hepatocellular injury and ultimately leading to liver cirrhosis. They release vasoactive compounds, cytokines, and other important mediators, and participate in the modulation of the extracellular matrix that is characteristic of liver fibrosis and cirrhosis. The biochemical basis of liver cell necrosis remains poorly defined. In spite of recent progress, and the detection of some new pathogenic principles that help in the understanding of the complications of chronic liver disease such as portal hypertension, oesophagogastric variceal bleeding, portosystemic encephalopathy, ascites, and other metabolic disturbances, many questions concerning the aetiology and pathophysiology of chronic liver disease and its complications remain to be answered.
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Affiliation(s)
- J Schölmerich
- Department of Internal Medicine, University of Freiburg, Federal Republic of Germany
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49
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Valla D, Flejou JF, Lebrec D, Bernuau J, Rueff B, Salzmann JL, Benhamou JP. Portal hypertension and ascites in acute hepatitis: clinical, hemodynamic and histological correlations. Hepatology 1989; 10:482-7. [PMID: 2777210 DOI: 10.1002/hep.1840100414] [Citation(s) in RCA: 48] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
We attempted to ascertain the mechanism of portal hypertension and ascites complicating acute hepatitis in 66 patients who underwent transvenous liver biopsy and measurement of hepatic venous pressure gradient. Increase in hepatic venous pressure gradient was related to the severity of acute hepatitis, as indicated by the significant correlation between the values for hepatic venous pressure gradient and serum bilirubin, serum albumin or coagulation factor V, and by its higher value in patients with, than in patients without, encephalopathy. Hepatic venous pressure gradient was higher in patients with, than in patients without, ascites (12.5 +/- 3.4 vs. 8.4 +/- 3.6 mmHg, respectively; p less than 0.001). No ascites was clinically detectable in the patients in whom hepatic venous pressure gradient was below 6 mmHg. We tested the hypothesis that sinusoidal collapse due to liver cell dropout was a major factor in portal hypertension. Semiautomatic determination of the fractional area of sinusoidal collapse on chromotrope-stained sections and automatic measurement of Sirius red-stained collagen fiber density were performed. Hepatic venous pressure gradient significantly correlated with fractional sinusoidal collapse area (r = 0.61, p less than 0.001) and with Sirius red-stained collagen fiber density (r = 0.43, p less than 0.01). We conclude that portal hypertension in the course of acute hepatitis is related to the severity of liver damage and is a major factor in the development of ascites. Portal hypertension is mainly determined by intrahepatic vascular space being reduced by the collapse of sinusoids.
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Affiliation(s)
- D Valla
- Service d'Hépatologie, Unité de Recherches de Physiopathologie Hépatique (INSERM U 24), Clichy, France
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50
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Abstract
Most cases of fulminant hepatic failure (FHF) are related to viral hepatitis or to drugs and toxins. With improvement in supportive intensive care, the overall survival has increased, but specific forms of temporary hepatic support pending hepatic regeneration have been disappointing. With the widespread availability of orthotopic liver transplantation, this has become a viable option for those patients with FHF who are unlikely to survive with conservative treatment, although patient selection and timing of transplantation still presents a clinical dilemma.
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Affiliation(s)
- P H Katelaris
- Department of Medicine, University of Sydney, Concord Hospital, Australia
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